TR2022008255T2 - TREATMENT METHODS OF SMALL CELL LUNG CANCER WITH LURBINECTEDIN FORMULATIONS - Google Patents

Abstract

Methods for treating SCLC patients are provided by administering therapeutic amounts of Lurbinectedin via intravenous infusion. Additionally, methods of treating cancer by administering lurbinectedin in combination with other anticancer drugs, particularly topoisomerase inhibitors, are also provided. The invention also relates to the administration of lurbinectedin in combination with antiemetic agents for the effective control of symptoms related to nausea and vomiting, with reduced lurbinectedin dosages and an increase in the number of treatment cycles to ensure safer administration. Stable lyophilized formulations of Lurbinectedin are also provided.

Description

DESCRIPTION METHODS OF TREATMENT OF SMALL CELL LUNG CANCER WITH LURBINECTEDIN FORMULATIONS FIELD OF THE INVENTION Methods for the treatment of SCLC patients are provided by administering therapeutic amounts of Lurbinectedin via intravenous infusion. There are also methods of treating cancer by administering lurbinectedin in combination with other anticancer drugs, especially topoisomerase inhibitors. The invention also relates to the administration of lurbinectedin in combination with antiemetic agents for the effective control of symptoms related to nausea and vomiting, with reduced lurbinectedin dosages and an increase in the number of treatment cycles to provide safer administration. Stable lyophilized formulations of Lurbinectedin are also provided. BACKGROUND OF THE INVENTION Lung cancer has been diagnosed in both men and women in the United States, with approximately 160,100 deaths from this disease occurring. More women die from lung cancer than from breast, ovarian and uterine cancer combined, and the number of men who die from lung cancer is 4 times higher than from prostate cancer. Lung cancer is a disease in which malignant (cancer) cells form in the lung tissues. The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC accounts for only approximately 13-15% of all lung cancers at diagnosis; However, SCLC is the more aggressive form of lung cancer. With SCLC, cancer cells tend to grow rapidly and move to other parts of the body or metastasize more easily. Its incidence is associated with smoking, almost two-thirds of patients present with advanced disease, and although response rates to chemotherapy are high, the benefit is short-lived. Median regimens for untreated SCLC patients include cisplatin or carboplatin and etoposide. Unfortunately, despite a 40-90% response rate to 9807108-1 M&C P0931420WOA first-line chemotherapy, long-term survival is uncommon as patients develop resistance to chemotherapy and relapse (Sundstrom, 2005; Jackman, 2005). The overall average survival expected after disease relapse without treatment is two to four months (Huisman, 1999). Treatment and survival have not changed significantly over the past two decades. Even limited-stage disease is rarely treated with radical local therapy (surgery or radiotherapy), and systemic chemotherapy (platinum plus etoposide) remains the mainstay of first-line therapy in SCLC. Topotecan is the only drug approved for second-line treatment of patients with a chemotherapy-free interval longer than 60 days. Topotecan monotherapy improves cancer-related symptoms as well as survival and quality of life in the second-line setting. Alternatively, doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control. There is no standard treatment for resistant patients. Amrubicin, a new anthracycline, has shown promising activity in refractory and relapsed patients. Phase III trials are continuing. Other agents with activity include paclitaxel, docetaxel, gemcitabine, bendamustine, and vinorelbine. Over the past several years, several clinical studies have evaluated the effect of adding immunotherapy to conventional chemotherapy in patients with disseminated SCLC. Checkpoint inhibitors are currently under investigation, particularly CTLA-4 and PD-1/PD-L1 inhibitors. Nivolumab and Pembrolizumab were the first immunotherapeutic agents approved by the FDA for patients with metastatic SCLC who had disease progression during or after platinum-based chemotherapy and at least one prior line of chemotherapy. Lurbinectedin (PM01183) is a synthetic tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one alkaloid analogue with antineoplastic activity. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand breakage producing apoptosis, and modulates the tumor microenvironment. For example, by inhibiting active transcription in tumor-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF. 9807108-1 M&C P0931420WOA Lurbinectedin demonstrated highly potent in vitro activity against solid and non-solid tumor cell lines as well as significant in vivo activity against several xenographed human tumor cell lines, such as those for breast, kidney and ovarian cancer in mice. Preliminary clinical results have shown that lurbinectedin has activity as a second-line therapeutic as a single agent in SCLC. Treatment is needed for SCLC and other solid tumors. BRIEF DESCRIPTION OF THE INVENTION Phase 2 clinical trial results show an overall response rate of at least 30% (35.2%) for SCLC patients with lurbinectedin as a second-line agent administered as a single agent. Results from a phase 1b-2 trial in solid tumor patients demonstrated activity of the combination of lurbinectedin and irinotecan, specifically in SCLC, endometrial carcinoma, soft tissue sarcoma, and glioblastoma. Accordingly, here we consider patients whose SCLC has progressed after previous treatment, particularly platinum-containing therapy or immunotherapy, in patients who have responded to previous treatment but have subsequently experienced disease progression, among others, in patients who have not responded or adequately responded to previous treatment. Methods for treating SCLC, including metastatic SCLC, are provided in those who have had such a response and in patients who have subsequently progressed more than once. Additionally, methods are provided for administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan or SN-38, in patients with solid tumors, particularly SCLC, endometrial carcinoma, soft tissue sarcoma, and glioblastoma, who require it. Stable lyophilized formulations are also provided. The methods provided herein include administering an effective amount of lurbinectedin via intravenous infusion to a patient, including an adult patient suffering from SCLC, including metastatic SCLC, particularly a SCLC patient who has progressed after prior platinum-based chemotherapy. In some embodiments, a patient suffering from SCLC, including metastatic SCLC, that has progressed after prior immunotherapy is administered to a patient suffering from SCLC, particularly atezolizumab, e.g., in combination with carboplatin and etoposide, or 9807108-1 M&C P0931420WOA nivolumab, by intravenous infusion of an effective amount of Iurbinectedin. implementation is ensured. Lurbinectedin is preferably administered at a dose of 3.2 mg/m2 every 21 days (or every 3 weeks), typically over a period of several months and in most cases until disease progression and death or until the patient experiences unacceptable toxicity, depending on the patient's response to administration. is applied. In some embodiments, therapeutically effective amounts of lurbinectedin are administered to the patient over a 1-hour period using dose levels of 3.2 mg/m2 to achieve a mean total plasma Cmax of approximately 85.6 µg/L to 133.75 pg/L, preferably 107 µg/L. may be administered as an IV infusion every 21 days or every 3 weeks. Treatment results in survival (range 2.6 months to 4.3 months), median in the resistant patient population and median 4.6 months in the susceptible patient populations (CFT1 greater than or equal to 90 days for prior chemotherapy treatment). A median overall survival of 9.3 months (5.0 months for the resistant patient population and 11.9 months for the susceptible patient population) can be achieved according to the methods described herein. In one embodiment, a method of managing hematological adverse events associated with the lurbinectedin treatment regimen is provided by dose reduction and/or G-CSF administration. The provided method involves administering to a SCLC patient a formulation of lurbinectedin by IV infusion at a dose of 3.2 mg/m2; After administration of lurbinectedin, the patient had 2 Grade 3 (severe) non-hematological toxicities related to the administration of lurbinectedin, Grade 4 thrombocytopenia (platelet count below 25,000 cells/mm3), Grade 3 thrombocytopenia (platelet count below 50,000 cells/mm3), bleeding requiring transfusion. , Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3) or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count It is about evaluating whether an adverse reaction (< LLN) is experienced or not. At the next scheduled dose, preferably 3 weeks after the previous dose and the patient's neutrophil count is more than 1500 cells/mm3; platelet count more than approximately 100,000 mm3; and 9807108-1 M&C P0931420WOA When hemoglobin levels are more than approximately 9 g/d, (i) if the adverse reaction consists of an isolated Grade 4 neutropenia, the patient is then given a dose of G-CSF and a dose identical to the previous dose, e.g. 3.2 mg/m2 of lurbinectedin is administered or (ii) if the adverse reaction is a haematological abnormality without isolated Grade 4 neutropenia only, a reduced dose compared to the previous dose is then administered, e.g., 3 to 85% of the previous dose. If it is 2 mg/m2, 2.6 mg/m2 is applied. Optionally, if the adverse reaction is isolated Grade 4 neutropenia, the dose may be reduced at the next scheduled dose, especially the previous one. After receiving low doses of lurbinectedin, the patient experienced 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (platelet count less than 50,000 cells/mm3 with bleeding requiring transfusion). ) or any degree of neutropenia associated with infection/sepsis or any adverse reaction (Neutrophil count < LLN) (but in some embodiments, non-isolated Grade 4 neutropenia), then at the next scheduled dose, preferably 3 weeks after the previous dose and when the patient has an excess of neutrophils; and when hemoglobin levels are greater than approximately 9 g/d, a second reduced dose (60-65% of the dosage) is administered. Optionally, if the adverse reaction after administration of a reduced dose of lurbinectedin is isolated Grade 4 neutropenia, the dose may be reduced at the next scheduled dose, specifically, to 60 to 65% of the initial unreduced dose, e.g. 2.6 if the initial dose was 3.2 mg/m2. It can be reduced to mg/m2. In another embodiment, a method is provided for managing hematological toxicity, myleosuppressive effects, and/or hepatotoxicity that may be associated with the administration of lurbinectedin in the treatment of SCLC, including metastatic SCLC, in a patient, including an adult patient, by dose reduction and/or dose delay. What is provided is administered to a 9807108-1 M&C P0931420WOA patient in need, with an absolute neutrophil count of at least 1500 cells/mm3 and a platelet count of at least 100,000/mm3, at a dose of 3.2 mg/m2 of Iurbinectedin, preferably with a 60-minute infusion, including metastatic SCLC. They are methods of treating SCLC. In another embodiment, 21 days after the previous dose, the patient's absolute neutrophil count is at least 1500 cells/mm3 and the platelet count is at least infused. In embodiments, the patient is monitored and does not have hepatotoxicity before Iurbinectedin is administered. Subsequent treatments are administered at intervals of 21 days (3 weeks) to the patient who is absolute and preferably free of any Grade 2 or greater adverse reactions. In certain embodiments, for treating SCLC, including metastatic SCLC, in a patient in need thereof at a dose of 3.2 mg/m2, including a 60-minute infusion, by monitoring for hepatic reactions or other adverse reactions of Grade 2 or greater. methods are provided. If a patient administered a 3.2 mg/m2 dose of Iurbinectedin exhibits grade 4 neutropenia (neutrophil count less than 500 cells/mm3) or any febrile neutropenia, the next dose of Iurbinectedin cannot be administered until 21 days after the previous dose or until the patient is grade 1. neutropenia (at least 1500 cells/mm3), where more than 21 days may have elapsed since the previous dose and Iurbinectedin is then administered at a reduced dose of 2.6 mg/m2 every three weeks or Iurbinectedin is administered every three weeks with G-CSF prophylaxis. It is administered at a dose of 3.2 mg/m2 every three weeks. platelets/mm3 at a dose of 3.2 mg/m2, the next dose of Iurbinectedin is not administered until 21 days after the previous dose, or when the patient demonstrates a platelet count greater than or equal to 100,000/mm3, the next dose is administered every three weeks. (21 days) is a reduced dose of 2.6 mg/m2. If a patient administered Iurbinectedin at a dose of 3.2 mg/m2 develops hepatotoxicity or other adverse reaction that is Grade 2 or Grade 3 or 4, the next dose of Iurbinectedin may not be administered until 21 days after the previous dose or the patient is Grade 1 9807108-1 M&C P0931420WOA not administered until the patient exhibits less than or equal to hepatotoxicity (or Grade 1 or less of another adverse reaction), and if the patient exhibits Grade 2 hepatotoxicity (or another adverse reaction), the next dose is 3.2 mg/m2 every three weeks (21 days). and if the Patient exhibits Grade 3 or 4 hepatotoxicity or another adverse reaction, the next dose is a reduced dose of 2.6 mg/m2 every three weeks (21 days). If the patient has Grade 4 neutropenia or any grade of febrile neutropenia, Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, or Grade 3 or 4 hepatotoxicity or any other adverse reaction after dose reduction, the next dose may not be delayed until 21 days later or the patient may be advised as detailed above. not until recovery as indicated and then administer a dose of less than 2 mg/m2 of lurbinectedin every three weeks or, in the case of Grade 4 neutropenia, the same dose of lurbinectedin as the previous dose with G-CSF prophylaxis. If the patient ceases to tolerate the 2 mg/m2 dose of lurbinectedin (i.e., develops Grade 4 neutropenia or any grade febrile neutropenia, Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, or Grade 3 or 4 hepatotoxicity or other adverse reaction after lurbinectedin administration) or If the delay is more than 2 weeks after the scheduled dose (21 days after the previous dose) for the patient to recover and meet the criteria for lurbinectedin administration, then treatment is discontinued. Provided are methods for treating SCLC or solid tumor by administering a dose of 2 to 3.2 mg/m2 of lurbinectedin in a patient in need and avoiding coadministration with a strong or moderate CYP3A inhibitor or a strong or moderate CYP3A inducer. In some embodiments, methods are provided for treating SCLC or solid tumor in a patient in need thereof, wherein the patient is also administered a moderate CYP3A inhibitor, then administered a reduced dose of lurbinectedin every 3 weeks (21 days), e.g. A dose of 6 mg/m2 or a dose of 2 mg/m2 is administered. Arrangements are also provided in which an antiemetic is administered prophylactically prior to the administration of lurbinectedin-associated (acute and delayed phase) nausea and/or vomiting, with the patient being treated on the day of and before administration of a dose of 2 to 3.2 mg/m2 of lurbinectedin 9807108-1 M&C P0931420WOA. It includes administering antiemetic prophylaxis, particularly wherein the antiemetic agents include a corticosteroid and a serotonin antagonist. Treatment may be for SCLC, including metastatic SCLC, or any other solid tumor in a patient requiring such treatment. In some embodiments, the corticosteroid is dexamethasone, preferably an 8 mg dose administered intravenously or a corticosteroid dose equivalent to 8 mg dexamethasone intravenously, where the serotonin antagonist is onasetron, preferably an 8 mg dose administered intravenously or 8 mg administered intravenously. A dose of serotonin antagonist equivalent to onasetron is administered. In some embodiments, antiemetic therapy, preferably comprising the administration of a corticosteroid, a serotonin antagonist, and metoclopramide, is administered after infusion on the same day as lurbinectedin or 2, 3, or 4 days thereafter. In specific embodiments, the corticosteroid is dexamethasone administered orally at a dose of 4 mg or a dose of corticosteroid equivalent to 4 mg of oral dexamethasone; serotonin antagonist is a serotonin antagonist administered orally at a dose of 8 mg or equivalent to 8 mg oral onasetron; and metoclopramide is administered intravenously or orally at a dose of 10 mg or the equivalent dose of 10 mg orally or intravenously metoclopramide, wherein metoclopramide is administered every 8 hours. One aspect of the invention is a method of treating patients with solid tumors by administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan. In certain embodiments, the solid tumor patient is administered a dose of 75 mg/m2 of irinotecan on days 1 and 8 of the treatment cycle, where lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 on day 1, and irinotecan is administered together with G-CSF. It is treated with a treatment regimen. The treatment cycle is usually 21 days, so that in the second treatment cycle a dose of lurbinectedin of 1 to 2.5 mg/m2 is administered, a dose of 75 mg/m2 irinotecan is administered on the 22nd day, and a dose of 75 mg/m2 irinotecan is administered 7 days later, on the 29th day after the first treatment. It is applied daily. Subsequent treatments are usually administered every three weeks with a combination of lurbinectedin 1 to 2.5 mg/m2 and irinotecan 75 mg/m2 administered on day 1 of the cycle with G-CSF and irinotecan 75 mg/m2 administered on day 8. In some 9807108-1 M&C P0931420WOA embodiments, if the patient exhibits hematological toxicity following day 1 combination dosing, the irinotecan dose is not administered on day 8. In some embodiments, the solid cancer is selected from endometrial cancer, SCLC, soft tissue sarcoma (including Ewing and synovial sarcoma), glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, and epithelial ovarian cancer. In preferred embodiments, the definitive tumor is endometrial cancer, SCLC, soft tissue sarcoma (including Ewing or synovial sarcoma), or glioblastoma. In one aspect, there is provided a stable, lyophilized formulation of lurbinectedin comprising lurbinectedin, a buffer derived from an organic acid (e.g., an organic carboxylic acid such as lactate buffer), and a disaccharide, such that the formulation has a pH of 3 when reconstituted with 8 mL of water. It is between .8 and 4.5. Reference to reconstitution of 4 mg of lurbinectedin in 8 mL with a concentration of 0.5 mg/mL may be based on a calculated concentration of 0.47 mg/mL in 8.55 mL. In some embodiments, the lyophilized composition contains or consists of (or contains or consists of) 4 mg lurbinectedin, 22.1 mg lactic acid, 1 mg sodium hydroxide, and 800 mg sucrose. The composition is preferably packaged in a 30 ml vial and can be reconstituted in 8 mL of water to give a solution containing 0.5 mg/ml lurbinectedin. In some embodiments, the lyophilized formulation may be stored at 5°C ± 3°C for 24 months or 36 months or longer, during which time lurbinectedin retains its therapeutic efficacy and exhibits minimal chemical degradation. For example, after 24 months or 36 months of storage, the amount of Impurity D (lurbinectedin degradation product resulting from deacetylation of lurbinectedin) present in the composition is not more than 0.8% w/w of the total weight of lurbinectedin. In certain embodiments, the stored formulation contains not more than 2.0%, 1.5%, or 1.3% (area or w/w) total degradation products. Also provided are methods for storing the lurbinectedin lyophilized formulation and methods for treating SCLC and solid tumors by administering a lurbinectedin infusion solution prepared from a stored, stable lyophilized lurbinectedin formulation. 9807108-1 M&C P0931420WOA The present invention describes methods of treatment using Iurbinectedin alone or in combination with other agents. When referring to a method of treatment, the present invention also includes lurbinectedin and/or other said agents in the manufacture of a medicament for the treatment of cancers as disclosed herein, as well as lurbinectedin and/or other said agents for use in the treatment of cancer. BRIEF DESCRIPTION OF THE FIGURES Figure 1: X-ray powder diffractogram of Form A of Lurbinectedin (Batch R05) Figure 2a: X-ray powder diffractograms of two lots of Form B of Lurbinectedin Figure 2b: -ray powder diffractograms (XRPD) were made by mixing 15 mg of Batch 171 with 1 ml of water. The suspension was stirred at room temperature for 24 hours. The resulting solid was filtered off. Figure 3: TG-FT1R of Form B of Lurbinectedin (Batch 1711182-2). Figure 4: DSC of Form B of Lurbinectedin (Batch 1711182-2). Figure 5: DVS of Form B of Lurbinectedin (Batch P05). Figure 6: Overlaid XRPD patterns of Form B of Lubinectedin in the initial 1:1 mixture of Forms A and B of Lubinectedin, from top to bottom, after 6 h of phase equilibration in water and Form B of Iurbinectedin after 24 h of phase equilibration in water. (Mixtures were prepared by mixing Iurbinectedin Form A (batch P02) and Iurbinectedin Form B (lot 1711182-2). Figure 7a: 1R of Form A of Lurbinectedin (Batch P04). Figure 7b: 1R of Form B of Lurbinectedin (Batch 1711182-2). Figure 8: Diagram of the Faraday cage. 9807108-1 M&C P0931420WOA Figure 9a: Different amounts of electrostatic charge (nC) of Form A of Lurbinectedin (Batch P04) and Form B of Iurbinectedin (Batch 1924129-LT). Figure 9b: Different amounts of electrostatic charge (nC) of Form A of Lurbinectedin (Batch R05) and Form B of Iurbinectedin (Batch 1924128-LT). Figure 10a: Charge density of Form A of Lurbinectedin (Batch P04) and Form B of Iurbinectedin (Batch 1924129-LT). Figure 10b: Charge density of Lurbinectedin (Batch R05) and Form B or Form A of Iurbinectedin (Batch 1924128-LT). DETAILED DESCRIPTION OF THE INVENTION Provided herein are methods for the effective treatment of small cell lung cancer (SCLC) based on the administration of lurbinectedin as monotherapy. Also provided are methods for treating solid tumors by administering a combination of lurbinectedin and irinotecan. Such methods include Lurbinectedin prepared from the stable, lyophilized formulations disclosed herein. Lurbinectedin is a synthetic alkaloid and analogue of an ecteinic acid having the following chemical structure: e.g., U.S. Patent No. 5,500,000,000,000, which is incorporated herein by reference in its entirety. Described in No. 7,763,615. Lurbinectedin may be prepared according to methods known in the art, such as 9807108-1 M&C P0931420WOA, incorporated herein by reference. Any lurbinectedin compound referenced herein is intended to represent hydrates, solvates, amorphous and crystalline or partially crystalline forms, and mixtures thereof when such forms are present in the environment. Additionally, the lurbinectedin compounds referred to herein may exist in isotopically labeled forms. All geometric hydrates, solvates and isotopically labeled forms of the compounds referenced herein and their mixtures are considered within the scope of the formulations and methodologies of this invention. In the present application, "cancer" is meant to include tumors, neoplasias, and any other malignant disease having malignant tissue or cells as the cause. The term "treating" as used herein, unless otherwise specified, means reversing, alleviating, or preventing the progression of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein, unless otherwise specified, includes the act of treating, the methods described immediately above, to relieve one or more symptoms of solid tumors, delay the progression of solid tumors, reduce tumor size in a patient with a solid tumor, inhibit solid tumor growth, prolong overall survival. It may be used to prolong progression-free survival, prevent or delay solid tumor metastasis, reduce (e.g. eliminate) pre-existing solid tumor metastasis, reduce the incidence or burden of pre-existing solid tumor metastasis, or prevent recurrence of solid tumors. The term "immunotherapy" as used herein refers to therapy that modulates the immune response, including stimulating an immune response against cancer cells or blocking the inhibition of an immune response, such as, but not limited to, CTLA-4, PD-1, Contains antibodies, proteins, or other agents that bind to a checkpoint inhibitor such as PD-L1 and others with similar 9807108-1 M&C P0931420WOA activity that promotes the immune response against cancer cells. Examples of immunotherapy include, but are not limited to, atezolizumab, nivolumab, pembrolizumab, ipilimumab, cemiplimab, durvalumab, avelumab, and the like. The ratings of adverse events, such as neutropenia, thrombocytopenia, hepatotoxicity, and other adverse reactions, met the criteria specified in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 (May 28, 2009). In general, the grades are as follows: Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not specified; Grade 2: lport; minimal, local or noninvasive intervention is indicated; meal preparation, etc. It limits lawful instrumental activities of daily life, such as; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or extension of hospital stay; obstructive; dressing, toilet etc. limiting self-care activities in daily life, such as, but not being bedridden; Grade 4: Life-threatening consequences; immediate response is indicated; Grade 5: Treatment of SCLC due to adverse event Embodiments of the present invention treat small cell lung cancer (SCLC), including metastatic SCLC, in a patient suffering therefrom by treating the patient therapeutically according to the dosing regimen of one or more treatment cycles using the pharmaceutical formulations of lurbinectedin disclosed herein. It includes treatment methods by applying an effective amount of lurbinectedin. Lurbinectedin therapy, in certain embodiments, is second-line therapy in which patients have progressed in response to previously administered therapies such as platinum-containing therapy or platinum-based chemotherapy and/or immune-oncology therapy. Such treatment regimens preferably administer to the SCLC patient a dose of 2.0 to 3.2 mg/m2 of lurbinectedin via intravenous infusion, in preferred embodiments, for an initial dose of at least 3.2 mg/m2, preferably every three weeks (or every 21 days). ), preferably within 1 hour, provided that the dose may be reduced and/or postponed depending on the occurrence of adverse events, especially hematological abnormalities and hepatotoxicity, as described herein. In some embodiments, the SCLC patient may be administered every 3 weeks until disease progression or unacceptable 9807108-1 M&C P0931420WOA toxicity (e.g., when a patient has not improved enough to meet dosing criteria 5 weeks after the previous dose or ceases to tolerate a second reduced dose of 2.0 mg/m2). 3.2 mg/m2 is administered via a repeated 60-minute intravenous infusion. In aspects of the invention, treatment includes an overall response rate of greater than 30%, such as greater than 35% or 35.2%; median 3.5 months, i.e. 2.6 to 4.6 months or 2.6 months (in resistant patient populations (chemotherapy-free interval (CTFl) less than 90 days)) to 4.6 months (in susceptible patient populations (CTFl greater than 90 days or equal to)) progression-free survival; and results in an average overall survival of 9.3 months (5.0 months for the resistant patient population (less than 90 days) and 11.9 months for the susceptible patient population (CTF1 greater than or equal to 90 days)). In various embodiments, the invention is used in a patient in need thereof, particularly in those whose SCLC has progressed after prior treatment such as platinum-containing therapy or platinum-based chemotherapy, immunotherapy, or both, inter alia, in patients who have not responded or adequately responded to prior therapy. However, it provides methods to treat SCLC, including metastatic SCLC, in those who have subsequently experienced disease progression and in those who may have experienced such a response but subsequently progressed more than once. In some embodiments, the present disclosure provides methods for treating metastatic SCLC. In some embodiments, the present disclosure provides methods for treating adult patients with metastatic SCLC who have disease progression after platinum-based chemotherapy. SCLC Patients Patients with SCLC, including metastatic SCLC, who fail to respond or progress through first-line platinum-containing chemotherapy and/or immunotherapy are considered “resistant” if they initially respond to chemotherapy and then relapse/progress within 90 days (3 months). Patients who respond to initial therapy after discontinuation of first-line therapy with platinum agents but subsequently relapse or whose tumors progress within approximately 91 to 180 days (3-6 months) are considered susceptible, where "91 to 180 days progressive" is a 9807108-1 M&C P0931420WOA SCLC It is assumed to have . Patients who respond to the first recurrence or whose tumors progress after 180 days are "susceptible." Lurbinectedin treatment may be second-line therapy in which the SCLC patient has previously been treated with one or more other chemotherapeutic agents such as carboplatin or cisplatin (platinum-based chemotherapy) and etoposide. In particular, the treatments are suitable for patients with SCLC that has relapsed or is resistant to previous chemotherapy. In some embodiments, the SCLC patient has ceased to respond or has ceased to respond adequately to prior platinum-containing therapy or has failed to respond to prior platinum-containing therapy. More specifically, lurbinectedin therapy may be used within 0 to 90 days or 91 to 180 days after discontinuation of first-line platinum-containing chemotherapy and optionally radiation therapy, in some embodiments, when a SCLC patient is refractory, refractory, or relapsed/progressive. Patients with SCLC who progressed within 0 to 90 days or within 91 to 180 days after discontinuation of first-line therapy, as well as patients with SCLC refractory to treatment and progression within 90 days, 180 days, or any time thereafter, or whose SCLC responded to initial treatment and followed by 90 days Patients with SCLC who progress within 180 days or at any time of discontinuation of initial therapy may advantageously be treated with lurbinectedin to improve one or more of progression-free survival, overall survival, or duration of response. In some embodiments, the SCLC patient has had a chemotherapy-free interval of at least 90 days, at least 120 days, at least 150 days, or at least 180 days after administration of prior platinum-containing therapy. In specific embodiments, the patient has not received platinum-containing therapy for at least 30 days or at least 60 days or at least 90 days prior to lurbinectedin administration. In some embodiments, the present disclosure provides methods for treating patients with SCLC who have progressed after prior platinum-containing therapy. In some embodiments, the present disclosure provides methods for treating adult patients with metastatic SCLC who have disease progression after platinum-based chemotherapy. Lurbinectedin therapy may also be administered following first-line platinum-based chemotherapy such as carboplatin or cisplatin and etoposide, in combination with checkpoint inhibitors such as atezolizumab, pembrolizumab, ipilimum, durvalumab or a combination thereof, or nivolumab or atezolizumab, 9807108-1 M&C P0931420WOA pembrolizumab, ipilimumab or durvalumab. It can be administered following second-line treatment with other immunotherapy such as In particular, the treatments are suitable for patients with relapsed or refractory SCLC to previous immunotherapy. For example, in some embodiments, lurbinectedin therapy is appropriate for SCLC patients who have relapsed or are refractory to prior first-line carboplatin/etoposide/atezolizumab combination therapy or second-line immunotherapy with nivolumab. In some embodiments, the SCLC patient has ceased to respond or has ceased to respond adequately to prior immunotherapy or has not responded to prior immunotherapy. More specifically, lurbinectedin therapy may be used when an SCLC patient is refractory, refractory, susceptible, or relapsed/progressive within 91 to 180 days after discontinuation of first-line platinum-containing chemotherapy in combination with immunotherapy or second-line nivolumab, and in certain embodiments the patient has received radiation therapy. Patients with SCLC who have progressed at any time after treatment (including within 90 days or 180 days after treatment in certain embodiments) after discontinuation of first-line immunotherapy (including in combination with platinum-containing therapy) or second-line immunotherapy, as well as those with treatment-resistant SCLC ( patients whose SCLC responds to initial treatment and progresses within 180 days after discontinuation of initial therapy may benefit from an advantageous treatment to increase one or more of progression-free survival, overall survival, or duration of response. It can be treated with lurbinectedin. In some embodiments, the SCLC patient has a chemotherapy-free interval of less than 90 days based on prior treatment, including immunotherapy, and in other embodiments, the SCLC has a chemotherapy-free interval of at least 90 days, at least 120 days, at least 150 days, or no more. In specific embodiments, the patient has not received first-line immunotherapy (in combination with platinum-containing therapy) or second-line immunotherapy for at least 30 days, or at least 60 days, or at least 90 days prior to lurbinectedin administration. When a treatment described herein is administered to a SCLC patient, including a metastatic SCLC patient in need of such treatment, 9807108-1 M&C P0931420WOA may be affected by the extent of anticancer effect, (overall) response rate, time to disease progression or survival rate. will produce an effect as measured. In one embodiment, the overall response rate is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 60%. In some embodiments, the overall response rate for patients with a chemotherapy-free interval of less than 90 days is at least months (range 2.6 months to 5.6 months), wherein the overall response rate is months (2.6 months to 5.6 months) for patients with a chemotherapy-free interval of at least 90 days, or where the duration of response is at least 90 days. For the susceptible patient with a chemotherapy-free interval of at least 6.2 months (3.5 months to 7.3 months). In some embodiments, the SCLC patient treated with lurbinectedin as described herein is at least 3.5 months (2.6 months to 4.3 months). It has a progression-free survival of 2.6 months for resistant patients (range 1.3 months to 3.9 months) and 4.6 months progression-free survival for susceptible patients (range 2.8 months to 6.5 months). In embodiments, SCLC patients treated with lurbinectedin as described herein have an overall survival of 9.3 months (range 6.3 to 11.8 months) and overall survival for refractory patients is 5.0 months (range 4.1 months to 6.3 months). months) and overall survival for susceptible patients was 11.9 months (range 9.7 months to 16.2 months). Alternatively, treatment may be continued for patients refractory to initial chemotherapy or less than 90 days (3 months) after completion of first-line platinum-containing therapy. It may be a second-line treatment for SCLC with advanced or limited disease. Patients with SCLC who progressed after discontinuation of first-line therapy (which may occur at any time, including but not limited to 30 to 90 days of treatment) and patients whose SCLC is refractory to treatment and progresses or responds to SCLC within 90 days of initial therapy and subsequently after discontinuation of initial therapy Progression within 90 days may advantageously be treated with lurbinectedin to improve one or more of progression-free survival, overall survival, or duration of response. In some embodiments, the SCLC patient had a chemotherapy-free interval of less than 90 days, such as less than 30 days, less than 60 days, or less than 90 days for the previous 9807108-1 M&C P0931420WOA treatment. In various embodiments, the SCLC patient is first treated with platinum-based chemotherapy treatment and immunotherapy, wherein the platinum-based chemotherapy and immunotherapy are given simultaneously or sequentially, followed by the patient being administered an effective amount of lurbinectedin or cycles of lurbinectedin treatment as described herein, 3 every three weeks. It includes administration of .2 mg/m2 (or delayed or reduced in patients exhibiting hematological toxicity). For example, in some embodiments, a SCLC patient has received prior immunotherapy comprising the administration of antibodies targeting PD-L1, CTLA-4, or PD-1, wherein the antibodies are selected from atezolizumab, nivolumab, pembrolizumab, ipilimum, durvalumab, or a combination thereof. In some embodiments, the patient has previously been administered atezolizumab in combination with platinum-containing therapy and etoposide. In some embodiments, the patient was administered nivolumab. Therefore, methods are provided for treating a patient with progressive SCLC with lurbinectedin at 3.2 mg/m2 every three weeks on atezolizumab (including combination with carboplatin and etoposide) or nivolumab (or delayed or reduced in patients exhibiting hematological toxicity). . In some embodiments, the patient to whom lurbinectedin is administered is an adult. Treatment Cycles Administration of pharmaceutical compositions containing Lurbinectedin is preferably by intravenous infusion. Infusion times of up to 72 hours can be used, but are preferably between 1 and 24 hours and usually approximately 1 hour. Short infusion times that allow treatment to be carried out without hospitalization are particularly desirable. In a preferred embodiment, lurbinectedin is administered by infusion over 1 hour (60 minutes). Preferably, lurbinectedin application is carried out in cycles. In a preferred administration schedule, the patient is given an intravenous infusion of lurbinectedin on the first day of each cycle and the patient is allowed to recover for the remainder of the cycle. The preferred duration of each cycle is 3 weeks or 21 days. However, the treatment cycle may be reduced, for example, from 1 to 6 days, one week or two weeks, or longer than 3 9807108-1 M&C P0931420WOA weeks, such as 22, depending on the patient's response to treatment. In some embodiments, treatment with lurbinectedin may be discontinued if the treatment cycle is delayed for more than 2 weeks because the patient has not recovered from an adverse event and does not meet hematologic criteria for lurbinectedin treatment. Administration of Lurbinectedin via intravenous infusion over approximately 1 hour every 3 weeks is the most preferred administration schedule, although other protocols can be designed as variations. More than one cycle can be given when necessary. During SCLC treatment, 1 to 24 doses of lurbinectedin may be administered, typically 4 to 8 doses, approximately 21 days (three weeks) apart. For example, if it is necessary to change the treatment program to reduce or manage side effects (as discussed in detail below), intervals of up to six weeks, for example 3 to 4 weeks, may be used. During cancer treatment, 1 to 24 lurbinectedin treatments may be administered, typically 4 to 8 treatments administered at intervals of approximately 21 days (three weeks). In some embodiments, one dose per treatment cycle. In embodiments, lurbinectedin is administered in 3-week treatment cycles or delayed to allow the patient to recover from an adverse event until disease progression or unacceptable toxicity. The bioavailability of a drug is defined as the rate of a drug or other substance that, upon entering the body, enters the circulation and is thus able to have an active effect. Bioavailability measures well known in the art include the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax). Cmax is the maximum plasma concentration achieved after drug administration. Provided herein are methods for dosing lurbinectedin by one or more pharmacokinetic parameters, wherein administration of said dosage is effective for treating resistant, refractory or progressive SCLC. In exemplary embodiments, the one or more pharmacokinetic parameters are peak concentration (Cmax) or area under the curve (AUC). In one embodiment, 3.2 mg/m2 lurbinectedin is administered as a 1-hour 9807108-1 M&C P093142OWOA infusion to a SCLC patient in need thereof, resulting in mean total plasma Cmax within 80% to 125% of approximately 107 ug/L and 80% to lurbinectedin of approximately 551 µg*h/L is administered to a SCLC patient in a 1 day on and 20 day off cycle (1/20 cycle). In one embodiment, the administration cycle is 1/20 cycle and the target average AUC°0 is approximately 551 µg*hr/L. In one embodiment, the administration cycle is 1/20 cycle and the target average AUC°0 is about 551 µg*hr/L±5%, µg*hr/L±25%. In a preferred embodiment, the administration cycle is 1/20 cycle and the target average AUC is between 80% and 125% of approximately 551 µg*h/L. In one embodiment, the administration cycle is 1/20 cycle and the average target Cmax is approximately 107 ug/L. In one embodiment, the administration cycle is 1/20 cycle and the average target Cmax is about 107 µg/L ± 5% of about 107 µg/L. to 125%. Before administering lurbinectedin to a patient suffering from SCLC, renal, hepatic and hematological impairment must be excluded. In one embodiment, an initial dose of approximately 3.2 mg/m2 of lurbinectedin is administered to a patient suffering from SCLC who is determined to have an absolute neutrophil-dependent hemoglobin level of at least 9 g/dL (by transfusion, if necessary). In another embodiment, a patient suffering from SCLC determined to have a calculated hepatic clearance greater than mL/min and an AST or ALT of less than 3 1.5XULN and a calculated creatinine clearance greater than 30 mL/min is treated for approximately 3, It is administered as an initial dose of 2 mg/m2 lurbinectedin. Approximately 21 days after the first dose, a second dose of 3.2 mg/m2 lurbinectedin is administered to the patient and dosing is continued at this level if hematological, renal and hepatic parameters remain stable. In a particular embodiment, the patient is administered a dose of lurbinectedin at 3.2 mg/m2, particularly an initial dose or scheduled dose, 3 weeks after a previous dose, or the patient's absolute neutrophil count 9807108-1 M&C P0931420WOA dose is administered. To achieve the preferred dose, preferably approximately 3.2 mg/m2 of lurbinectedin is administered per dose, eg, per intravenous infusion. A dose of lurbinectedin may contain approximately 3.2 mg/m2 of lurbinectedin per dose, e.g., per intravenous infusion or a reduced dose thereof as discussed below. Antiemetic Therapy Optimal supportive care and definitive tumor treatment for SCLC, including metastatic SCLC and adult patients, includes a range of palliative therapies. For example, in one embodiment of the invention, optimal supportive care includes one or more, and preferably all, analgesics to control pain, management of constipation and treatment of shortness of breath, and treatment of anemia, e.g., through transfusions to maintain hemoglobin levels (i.e., 9 g/dL). In other embodiments, therapies to specifically prevent and treat or manage nausea and/or vomiting associated with lurbinectedin administration are set forth below. Chemotherapeutics vary in their emetogenicity. In the absence of antiemetic prophylaxis, agents associated with a 90% risk of vomiting are classified as highly emetogenic chemotherapy, and agents associated with a 30-90% risk of vomiting are classified as moderately emetogenic chemotherapy. The aspects include methods of preventing and treating lurbinectedin-induced (acute and delayed phase) nausea and/or vomiting, wherein an effective antiemetic amount of a serotonin antagonist or corticosteroid, or a combination thereof, is accompanied by the administration of lurbinectedin by administering it to the patient, particularly immediately before the administration of lurbinectedin. Side effects of nausea and vomiting are reduced. A preferred embodiment is the treatment of SCLC, including metastatic SCLC, in a patient in need thereof or to otherwise reduce the side effects of administering lurbinectedin to a patient, comprising: (1) an effective or administration of more antiemetic agents on and before the day when lurbinectedin is administered to the patient; and (2) administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m2. In some embodiments, lurbinectedin is administered as a 9807108-1 M&C P0931420WOA single agent chemotherapeutic agent and/or is not administered in combination with doxorubicin. In other embodiments, the patient may receive anti-emetic treatment prior to and on the same day as lurbinectedin 2 mg/m2 in combination with irinotecan 75 mg/m2 and, in certain embodiments, on day 8 of a treatment cycle with a dose of irinotecan 75 mg/m2. In some embodiments, antiemetic agents are administered intravenously or orally. If one or more antiemetic agents are given intravenously, one or more agents should be administered 30 to 90 minutes before or approximately 30 minutes, approximately 45 minutes, approximately 60 minutes, approximately 75 minutes, or approximately 90 minutes before lurbinectedin administration. It is applied 60 minutes before. If one or more antiemetic agents are given orally, one or more agents may be administered 30 to 60 minutes before the administration of lurbinectedin, approximately 3 hours and 9 hours before the administration of lurbinectedin, or approximately 4 hours, approximately 5 hours, approximately 6 hours, before the administration of lurbinectedin. It is applied approximately 7 hours, approximately 8 hours or approximately 9 hours before. In some embodiments, the antiemetic agents consist of a corticosteroid and a serotonin antagonists, wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, or methylprednisolone, and the serotonin antagonist is selected from the group consisting of onasetron, granisetron, and palonosetron. The dose of corticosteroid is or equivalent to approximately 4 mg to 20 mg of dexamethasone given intravenously, preferably 8 mg given intravenously. The dose of serotonin antagonist is or equivalent to approximately 8 mg to 16 mg of onasetron given intravenously, preferably 8 mg given intravenously. If given orally, the dose may be increased to a dose equivalent to 24 mg of onasetron. In preferred embodiments, prophylactic antiemetic agents include dexamethasone administered intravenously at 8 mg, onasetron administered intravenously at 8 mg, or a combination thereof. In some embodiments, the method also includes administering one or more antiemetic agents to the patient within 2, 3, or 4 days of administering lurbinectedin, e.g. 9807108-1 M&C P0931420WOA on the same day after lurbinectedin administration, e.g., 2, 3, 4, 5, 6, 7 or 8 hours after lurbinectedin administration and/or on days 1, 2, 3 or 4 after Iurbinectedin administration. The one or more antiemetic agents administered after Lurbinectedin administration are selected from the group consisting of a corticosteroid, wherein the corticosteroid is selected from dexamethasone, hydrocortisone, and methylprednisolone, a serotonin antagonist, wherein the serotonin antagonist is selected from onasetron, granisetron, and palonosetron, and metoclopramide. In preferred embodiments, the post-infusion antiemetic treatment is 4 mg dexamethasone (oral), 8 mg onasetron (oral), or 10 mg metoclopramide (oral or infusion), or a combination thereof. Metoclopramide can be administered at 8-hour intervals. In some embodiments, antiemetic agents are administered intravenously after infusion. In some embodiments, the first dose of post-infusion antiemetic agents is administered during the evening of Iurbinectedin administration or 1, 2, 3, 4, 5, 6, 7, or 8 hours after Iurbinectedin administration and is continued for up to 1, 2, 3, or 4 days after infusion. In some embodiments, a corticosteroid, e.g. Dexamethasone is given at a dose equivalent to 4 mg dexamethasone in the evening or 1, 2, 3, 4, 5, 6, 7, or 8 hours after chemotherapy and then given twice daily for up to 1, 2, 3, or 4 days. In some embodiments, metoclopramide is administered orally at a dose of 10 to 20 mg every 8 hours for up to 1, 2, 3, or 4 days after chemotherapy. In other embodiments, a serotonin antagonist, e.g. Ondansetron is administered orally at a dose equivalent to 8 mg or 16 mg of onasetron every 12 hours or every 24 hours, respectively, for up to 1, 2, or 3 days after Iurbinectedin administration. In some embodiments, antiemetic prophylaxis and optional post-infusion antiemetic therapy is administered to a SCLC patient receiving approximately 2.0 mg/m2, approximately 2.6 mg/m2, or approximately 3.2 mg/m2 Iurbinectedin via intravenous infusion. Antiemetic prophylaxis and optional post-infusion antiemetic therapy in combination with irinotecan, 1.0 to 2.0 mg/m2 Dosage and Dosage Reduction Additional embodiments of the invention provide a Grade 2 adverse event in an SCLC patient, particularly a metastatic SCLC adult patient ( 9807108-1 M&C P0931420WOA 9807108-1 M&C P0931420WOA includes a dose modification in the form of dose deferrals beyond the 21-day treatment cycle for Iurbinectedin dosing on day 1, if AE) is determined. In some embodiments, a lower amount of Iurbinectedin is used compared to the amount generally used for individual therapy. In some embodiments, the same or greater therapeutic benefit is achieved by using a smaller amount of Iurbinectedin (e.g., a lower dose or a less frequent dosing schedule) than that typically used for individual therapy. For example, a smaller amount may cause a decrease in the number, severity, frequency or duration of effects. For example, in preferred embodiments, the first dose modification is a dose reduction of lurbinectedin from about 3.2 mg/m2 to about 2.6 mg/m2 (or 80 to 85% of the starting dose) and the second dose modification is dose reduction of lurbinectedin from approximately 2.6 mg/m2 to approximately 2.0 mg/m2 (or 60 to 65% of the initial dose). If, after the second dose reduction, the patient experiences an adverse event that requires a further dose reduction, treatment can be stopped. Adverse events requiring frequent or prolonged (2 weeks) dosing delay include, but are not limited to: any Grade 3 or Grade 4 hematologic toxicity, or any Grade 2, Grade 3, or Grade 4 nonhematologic toxicity or adverse reaction such as hepatotoxicity. In case of non-hematological toxicities of Grade 2, Grade 3 or Grade 4, the next cycle is postponed until non-hematological parameters improve to Grade 1 or 0. Two doses of Iurbinectedin are always administered at least 21 days apart. Until hematological parameters such as neutrophil count, platelet count and optionally hemoglobin level improve, absolute neutrophil count is equal to or greater than 1500 cells/mm3 and platelet counts are greater than 100,000/mm3 and optionally hemoglobin levels are 9 in some embodiments. A treatment cycle is not initiated until greater than or equal to g/dL (with transfusion if necessary). For example, greater than Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (platelet count less than 25,000 cells/mm3). , Grade 3 thrombocytopenia (platelet count less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia 9807108-1 M&C P0931420WOA (neutrophil count less than 500 cells/mm3) or infection/sepsis, or frequent or prolonged ( Any degree of neutropenia (neutrophil count decreased) associated with any adverse reaction requiring dose delay (more than 2 weeks) < LLN), the lurbinectedin dose is reduced from 3.2 mg/m2 to 2.6 mg/m2 (or 80 to 85% of the initial dose) and the patient's neutrophil count is below 1500 cells/mm3 in the next cycle. to the one who stands on it; until the platelet count is more than approximately 100,000/mm3; and delayed until hemoglobin levels are greater than approximately 9 g/dL. In a particular embodiment, if the identified adverse event consists of isolated Grade 4 neutropenia, the method for administering isolated Grade 4 neutropenia followed by a dose of lurbinectedin equal to the previous dose, rather than reducing the dose of lurbinectedin, is to administer the patient a dose of G-CSF as prophylaxis ("secondary G-CSF prophylaxis"). Contains. After the initial dose reduction, the patient may experience Grade 4 thrombocytopenia (platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (platelet count less than 50,000 cells/mm3) requiring dose reduction (severe non-hematological toxicity greater than Grade 3). (below 100%), bleeding requiring transfusion, Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), or any grade of neutropenia associated with infection/sepsis or any adverse reaction requiring frequent or prolonged (more than 2 weeks) dose delay. (neutrophil count < LLN), the patient has recovered with neutrophils greater than or equal to 1500 cells/mm3, platelet count greater than or equal to 100,000 cells/mm3, and hemoglobin levels greater than or equal to 9 g/dL (if necessary by transfusion), after 3 weeks the subsequent dose is reduced to 2.0 mg/m2 (60-65% of the initial dose). After the second dose reduction, the patient experiences a side effect that requires another dose reduction and the treatment is discontinued. If the dose will be delayed for more than 2 weeks because the patient has not improved to an absolute neutrophil count equal to or greater than 1500 cells/mm3 and a platelet count greater than or equal to 100,000 cells/mm2, treatment may be discontinued. If the identified adverse reaction is not merely isolated Grade 4 neutropenia, the method involves administering a reduced dose of lurbinectedin to the patient. Two doses of lurbinectedin should be administered at least 21 days apart, regardless of the lurbinectedin dose. 9807108-1 M&C P0931420WOA A preferred embodiment is the treatment of small cell lung cancer (SCLC), including metastatic SCLC, in a patient in need thereof, comprising: (1) first administering to the patient 3.2 mg/m2 of lurbinectedin by intravenous infusion. administering the dose; (2) identification of an adverse reaction in the patient, where the adverse reaction is selected from the group consisting of: 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia with bleeding requiring transfusion ( Platelet count less than 50,000 cells/mm3), Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count less than 500 cells/mm3). <LLN); and (3) after the adverse reaction is identified and the patient's neutrophil count is greater than 1500 cells/mm3; platelet count greater than approximately 100,000/mm3; and after hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), the patient is given a dose of G-CSF equal to the previous dose and a dose of lurbinectedin giving; or (ii) if the adverse reaction identified is not merely isolated Grade 4 neutropenia, administer the patient a reduced dose of lurbinectedin, where two doses of lurbinectedin are administered 21 . In some embodiments, the initial dose reduction after the first occurrence of a Grade 4 non-neutropenic adverse reaction only is 80 to 85% of the initial dose, or herein, the first reduced dose after the first occurrence of an isolated Grade 4 non-neutropenic adverse reaction only is 2.6 mg/m2 is. In some embodiments, a second reduced dose is 60-65% of the initial dose only after the second occurrence of an isolated Grade 4 non-neutropenia adverse reaction, or wherein a second reduced dose is 2 times only after the second occurrence of an isolated Grade 4 non-neutropenia adverse reaction. up to 0 mg/m2, where the second reduced dose is administered to the patient. The administration of lurbinectedin is stopped after the identification of an adverse reaction after the administration of the second reduced dose. 9807108-1 M&C P0931420WOA Before administration of the initial or subsequent dose of Lubinectedin, the patient suffering from SCLC, especially metastatic SCLC, including an adult patient, must have an absolute neutrophil count of at least 1,500 cells/mm3 and a platelet count of at least 100,000/mm3. mm3. Accordingly, a method is provided for the treatment of a patient with an absolute neutrophil count of at least 1,500 cells/mm3 and a platelet count of at least 100,000 mm3 for SCLC, including metastatic SCLC, by administering lurbinectedin at a dose of 3.2 mg/m2 every 3 weeks. includes dose delays or dose reductions if the patient experiences an adverse event. Methods are provided to manage hematological toxicity, myleosuppressive effects, and/or hepatotoxicity that may be associated with the administration of lurbinectedin in the treatment of SCLC, including metastatic SCLC, by dose reduction and/or dose delay. Adverse events that may trigger dose delay or reduction include Grade 4 or any degree febrile neutropenia (Grade 4 neutropenia is a neutrophil count less than 500 cells/mm3), Grade 3 thrombocytopenia with bleeding, or Grade 4 thrombocytopenia (Grade 3,000 platelets/mm3). Grade 2 or greater hepatotoxicity or other adverse reaction is present. In the event of all these adverse reactions, the next dose may be delayed until the patient recovers, for example, until the patient has a Grade 1 count or hepatotoxicity or other adverse reaction of Grade 1 or less. Patients exhibiting Grade 4 neutropenia or any grade febrile neutropenia, Grade 3 or Grade 4 thrombocytopenia with bleeding, or Grade 3 or higher hepatotoxicity, or another adverse reaction receive, after recovery, a reduced dose for subsequent treatment cycles. If the previous dose was 3.2 mg/m2, the reduced dose is 2.6 mg/m2, and if the previous dose was 2.6 mg/m2, the reduced dose is 2.0 mg/m2 every three weeks. If the patient experiences an adverse event after a dose of 2.0 mg/m2 that would indicate a dose reduction, treatment can be discontinued. For patients exhibiting grade 4 neutropenia, the subsequent dose may not be reduced after the patient recovers, i.e. the same dose as the previous dose every three weeks if the patient is receiving G-CSF prophylaxis. 9807108-1 M&C P0931420WOA For patients exhibiting Grade 2 hepatotoxicity or another adverse reaction, the dose after the patient achieves Grade 1 or less toxicity is the same as the previous dose every three weeks. Accordingly, provided are methods of treating SCLC, including metastatic SCLC, with an absolute neutrophil count of at least 1500 cells/mm 3 and a dose of lurbinectedin, preferably administered by a 60-minute infusion. In another embodiment, 21 days after the previous dose, the patient's absolute neutrophil count is administered at the highest dose of lurbinectedin, preferably by a 60-minute infusion. In embodiments, the patient is monitored and does not have hepatotoxicity prior to administration of lurbinectedin. Subsequent treatments are administered at intervals of at least a week until the absolute neutrophil count is determined. In certain embodiments, methods are provided for treating SCLC, including metastatic SCLC, by administering lurbinectedin at a dose of 3.2 mg/m2, including a 60-minute infusion, to a patient in need thereof, and then monitoring the patient for adverse hematological or hepatic reactions. . If a patient administered a dose of 3.2 mg/m2 of lurbinectedin exhibits grade 4 neutropenia (neutrophil count less than 500 cells/mm3) or any febrile neutropenia, the next dose of lurbinectedin will not be delayed until 21 days after the previous dose or until the patient is grade 1. neutropenia (at least 1500 cells/mm3), where more than 21 days may have elapsed since the previous dose and lurbinectedin is then administered at a reduced dose of 2.6 mg/m2 every three weeks or lurbinectedin is administered every three weeks with G-CSF prophylaxis. It is administered at a dose of 3.2 mg/m2 every three weeks. When Grade 3 thrombocytopenia with bleeding (less than 25,000 platelets/mm3) occurs in a patient administered lurbinectedin at a dose of 3.2 mg/m2, the next dose of lurbinectedin is not administered until 21 days after the previous dose or the patient is treated with a blood pressure greater than or equal to 100,000 platelets/mm3. When the platelet count shows, the next dose is a reduced dose of 2.6 mg/m2 every three weeks (21 days). If a patient administered lurbinectedin 9807108-1 M&C P0931420WOA at a dose of 3.2 mg/m2 develops hepatotoxicity or other adverse reaction that is Grade 2 or Grade 3 or 4, the next dose of lurbinectedin should not be repeated until 21 days after the previous dose or until the patient is Grade 1 If the patient exhibits Grade 2 hepatotoxicity (or another Grade 2 adverse reaction), the next dose is 3.2 mg/m2 every three weeks and the patient is Grade 3 or If 4 patients have experienced hepatotoxicity or another adverse reaction, the next dose is a reduced dose of 2.6 mg/m2 every three weeks (21 days). If, after dose reduction, the patient exhibits Grade 4 neutropenia or any grade febrile neutropenia, Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, or Grade 3 or 4 hepatotoxicity or other adverse reaction, then the next dose is not administered until 21 days later or the patient is treated as detailed above. Once recovered as described and thereafter a lower dose of 2 mg/m2 of Lurbinectedin is administered every three weeks or, in the case of Grade 4 neutropenia, the same dose as the previous dose or Iurbinectedin is administered with G-CSF prophylaxis. If the patient develops Grade 4 neutropenia or any grade febrile neutropenia, Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, or Grade 3 or 4 hepatotoxicity or other adverse reaction after administration of 2 mg/m2) or delay in administration, the planned dose (21 days after the previous dose) If more than 2 weeks have passed, then the treatment is discontinued. Co-administration with a strong or moderate CYP3A inhibitor, patients either discontinue taking the CYP3A inhibitor or are advised to discontinue taking the CYP3A inhibitor or, alternatively, increase the Iurbinectedin dose, e.g. from a dose of 3.2 mg/m2 or to 2.6 mg /m2 or 2.0 mg/m2. Examples of CYP3A inhibitors include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit. Accordingly, 3.2 mg/m2 of Iurbinectedin every 3 weeks unless the patient is taking a CYP3A inhibitor (and the CYP3A inhibitor may have been taken before the Iurbinectedin dose to avoid drug interactions) or 2 if the patient is also taking a CYP3A 9807108-1 M&C P0931420WOA inhibitor. Methods are provided for treating patients for SCLC, particularly metastatic SCLC, or solid tumors by administering a dose of Iurbinectedin, including a dose of less than 3.2 mg/m2, including 6 mg/m2 or 2.0 mg/m2. Coadministration with a strong CYP3A inducer may reduce efficacy, including phenobarbital, phenytoin, rifampicin, St. John's wort, and glucocorticoids. Accordingly, methods are provided for treating patients for solid tumors, including Iurbinectedin at 3.2 mg/m2 every 3 weeks where the patient is not receiving a strong or moderate CYP3A inducer. Combination Therapy for Solid Tumors In further embodiments, the invention is directed to the combination of lurbinectedin with a topoisomerase I and/or II inhibitor in the treatment of cancer, particularly for the treatment of solid tumors, particularly endometrial cancer, SCLC, soft tissue sarcoma (including Ewing and synovial sarcoma), glioblastoma (including Ewing and synovial sarcoma). supratentorial or intratentorial tumors), pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma and epithelial ovarian cancer. In preferred embodiments, the definitive tumor is endometrial cancer, SCLC, soft tissue sarcoma (including Ewing and synovial sarcoma), or glioblastoma. In some embodiments, the method of treating patients with solid tumors includes administering lurbinectedin at a dose of 1 to 2.5 mg/m2 in combination with other anticancer agents such as irinotecan or a topoisomerase inhibitor selected from SN-38, wherein Iurbinectedin is 1 to It is administered at a dose of 2.5 mg/m2, in particular 2.0 mg/m2, where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. The chemotherapeutic group of topoisomerase I and/or II inhibitors includes, but is not limited to, topotecan, SN-38, irinotecan, camptothecin, rubitecan, etoposide, amsacrine, and teniposide. Particularly preferred is Iurbinectedin in the treatment of cancer, in particular solid tumors, and more particularly in the treatment of endometrial cancer, SCLC, soft tissue sarcoma (including Ewing and synovial sarcoma), glioblastoma, pancreatic adenocarcinoma, 9807108-1 M&C P0931420WOA mesothelioma, colorectal carcinoma and epithelial ovarian cancer. It is a combination of with irinotecan. In some embodiments, lurbinectedin is administered at a dose of 1, 1.5, 2, or 2.4 mg/m2 and the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg/m2 irinotecan. In preferred embodiments, lurbinectedin is administered at a dose of 2 mg/m2 and irinotecan is administered at a dose of 75 mg/m2. The patient is given G-CSF along with the combination. In some embodiments, lurbinectedin and the topoisomerase inhibitor are administered on day one of a treatment cycle. In some embodiments, the method further includes administering G-CSF to the patient to manage the myelosuppressive effects of the therapy. In another embodiment, the topoisomerase inhibitor is also administered to the patient on day 7, 8, 9, or 10 of the treatment cycle. In some embodiments, the treatment is administered to a patient in need thereof by administering a dose on day 1 of a treatment cycle, specifically, a dose of lurbinectedin at 2.0 mg/m2 and irinotecan at a dose of 75 mg/m2, followed by a dose of irinotecan at day 1 of the treatment cycle. Administering an irinotecan dose of 75 mg/m2 on day 1 provides methods for treating solid tumors along with G-CSF administration to manage the myelosuppressive effects of treatment. The treatment cycle may be a 3-week (21-day) cycle, with a subsequent treatment cycle starting on day 22. In some embodiments, patients who exhibit hematologic toxicity (including grade 3-4 adverse events) after the combination dose administered on day 1 of the treatment cycle cannot be dosed with irinotecan on day 8 (or at any time during that treatment cycle) or on day 8 of the treatment cycle or during the treatment cycle. A reduced dose of irinotecan may be administered at any time. Treatment may involve multiple treatment cycles until disease progression or unacceptable toxicity. In particular, the patient may receive 1, 2, 3, 4, 5 or more cycles in combination. In certain embodiments, the combination treatment method results in a reduction in tumor size of at least 7.1 months (particularly for endometrial cancer), at least 2.6 months (particularly for soft tissue sarcoma), or at least 1 month. It results in a median progression-free survival of 4 months (especially for glioblastoma). In one embodiment, the method further includes administering a treatment cycle (above of SCLC or more antiemetic agents and post-infusion antiemetic therapy as described herein for the treatment of SCLC. Pharmaceutical Compositions and Methods of Preparation Pharmaceutical compositions of lurbinectedin that may be used include excipients suitable for intravenous administration. and solutions, lyophilized compositions, etc. In one aspect, Iurbinectedin includes Iurbinectedin, a buffer derived from an organic acid (e.g., an organic carboxylic acid buffer), a disaccharide, and a pH sufficient to provide a pH suitable for injection when the composition is reconstituted in a suitable solvent. It is supplied and stored as a stable and sterile lyophilized product containing base.In some embodiments, organic carboxylic acid buffer, lactic acid, butyric acid, propionic acid, acetic acid, succinic acid, citric acid, ascorbic acid, tartaric acid, malic acid, maleic acid. It is derived from an organic acid selected from the group consisting of fumaric acid, glutamic acid, aspartic acid, gluconic acid, and oi-ketoglutaric. In some embodiments, the organic carboxylic acid buffer is derived from an organic acid selected from lactic acid or succinic acid. In some embodiments, the organic carboxylic acid buffer is derived from lactic acid. In some embodiments, the buffer is not a phosphate buffer. In some embodiments, the disaccharide is selected from the group consisting of sucrose, trehalose or lactose, or a combination thereof. In some embodiments, the disaccharide is sucrose. In some embodiments, the base is selected from the group consisting of carbonates, hydroxides, hydrogen carbonates, and ammonium salts. Particularly preferred bases are sodium carbonate, potassium carbonate, calcium carbonate, NH 4 OH, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate and calcium hydrogen carbonate. In some embodiments, the base is sodium hydroxide. 9807108-1 M&C P0931420WOA In some embodiments, the reconstituted lyophilized composition has a pH of about 4. In some embodiments, the reconstituted lyophilized composition has a pH between about 3 and about 5. In some embodiments, the pH of the reconstituted lyophilized composition is between about 3.5 and about 4.5. In some embodiments, the reconstituted lyophilized composition has a pH of 3.8 to 4.1. In some embodiments, the stable lyophilized product is lurbinectedin; lactic acid; It contains sodium hydroxide and sucrose and the reconstituted lyophilized composition has a pH of 3.8 to 4.1. In some embodiments, the stable lyophilized product is 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or approximately 0.25 mmol lactate included); and contains 800 mg sucrose. In some embodiments, the stable lyophilized product is substantially 4 mg of lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or approximately 0.25 mmol lactate included); and 800 mg sucrose. Formulations of the present invention containing lurbinectedin can be made by freeze-drying a composition of the present invention in the form of a buffered bulk solution comprising the lurbinectedin, a buffer derived from an organic acid such as a lactate buffer or a succinate buffer, and a disaccharide. The disaccharide is preferably sucrose. Generally, the bulk solution will be buffered to a pH of, for example, about 3 to 5, preferably about 3.5 to 4.5, more preferably pH 3.8 to 4.1. The preferred buffering agent is a sodium lactate buffer. In preferred embodiments, the lactate buffer contains lactic acid and a base, preferably an inorganic, pharmaceutically acceptable base such as sodium hydroxide. Thus, in embodiments of the present invention, a buffered lyophilized composition is provided including lurbinectedin, a buffer derived from an organic acid such as a lactate buffer or a succinate buffer, and a disaccharide; wherein the buffer is reconstituted so that the lyophilized composition is reconstituted after reconstitution. The present invention describes methodologies that allow lurbinectedin to be completely dissolved in desired buffers while minimizing impurity formation. In embodiments, the use of an organic acid buffer allows direct dissolution of lurbinectedin in the organic acid buffer (preferably at a pH of about 1 to 5, about 2 to 9807108-1 M&C P0931420WOA 4.5, about 3 to 4.5, or about 4) followed by disaccharide , preferably allowing the addition of a bulking agent such as sucrose. Such a formulation strategy enables direct dissolution in the batch formulation and eliminates the need for a pre-dissolution step. In one embodiment, direct solubilization of lurbinectedin is achieved by dissolving lurbinectedin in an organic acid buffer (preferably at a pH of about 1 to 5, about 2 to 4.5, about 3 to 4.5, or about 4), followed by a It involves adding a bulking agent such as a disaccharide, preferably sucrose, to form a bulk solution. The bulk solution may be subjected to sterilizing filtration. The bulk solution can then be filled into vials according to the desired dosage. The bulk solution in vials can then be lyophilized to create a lyophilized buffered lurbinectedin formulation. The lyophilized formulation can then be reconstituted to form a reconstituted solution. The reconstituted solution can be diluted to form an injection solution. Preferably, by direct dissolution the lurbinectedin is amorphous or substantially amorphous. As described here, lurbinectedin has limited water solubility. The solubility of lurbinectedin in bulk solution was found to be improved by first forming a concentrated pre-solution of lurbinectedin in a buffer derived from an organic acid, e.g. lactic acid, succinic acid, citric acid or acetic acid further diluted with water for injection. A disaccharide is then dissolved in an aqueous solution containing a basic component, such as an aqueous solution of sodium hydroxide, and after adjusting the pH to a setting value, the pre-solution of lurbinectedin and the buffer solution containing a disaccharide are mixed to form a solution containing a disaccharide (e.g. sucrose). A bulk solution of lurbinectedin is obtained in an organic buffer of pH=4. Following this process, the vial filling volume can be reduced by increasing the lurbinectedin concentration in the bulk solution. In these embodiments of the present invention, the fill volume is generally reduced by about 80% relative to the conventional fill volume. By way of example, but not limitation, embodiments of the present invention include 1 mg lurbinectedin in 2 ml of solution in a 10 ml vial; or provides a fill volume of 4 mg lurbinectedin in 8 ml solution in a 30 ml vial. The fill volume may be further reduced by increasing the concentration of Iurbinectedin in other embodiments of the present invention, optionally 9807108-1 M&C P0931420WOA. Provided are processes useful for improving the solubility of Iurbinectedin in bulking solution, which include dissolving Iurbinectedin in lactic acid, e.g. 0.31M lactic acid (25 mg/mL) and concentrating Iurbinectedin in 0.1M lactic acid. It involves subsequent dilution of the solution with water for injection to obtain a solution, mixing with previously dissolved buffer saline and optionally adjusting the pH. In some illustrative but not limiting embodiments of the present invention, pH adjustment is accomplished with a lactate buffer. Illustrative embodiments of the bulk solution for freeze drying according to the present invention are provided with a solution of Iurbinectedin buffered at pH 4 with sodium hydroxide and Iactic acid as bulking agents. An illustrative embodiment of the methodology according to the present invention provides the following: diluting with water to yield a concentrated solution of 8.3 mg/mL Iurbinectedin in 0.1M Iactic acid, pH ~3. Sodium lactate buffer salt solution is prepared by mixing 0.31M Ilactic acid solution with 0.01M sodium hydroxide solution to obtain a 0.05M lactate buffer salt solution. Sucrose is then added to the sodium lactate buffer salt solution. Dilute 0.05M lactate buffer saline containing sucrose with water for injection to obtain 0.04M sodium lactate buffer containing 17% sucrose, pH~4.2. Both solutions, 8.3 mg/mL Iurbinectedin in 0.1M Iactic acid, pH ~3, and 17% sucrose in 0.04M sodium lactate buffer, pH ~4.2, are then mixed. Dissolution is visually checked at all steps before proceeding and dissolution is considered complete when visually appreciated. The pH of the solution is controlled and, by slow addition of a suitable acid or base, a value in the range of about 1 to about 5, more preferably in the range of about 2 to about 4.5, more preferably in the range of about 3 to about 4.5, and most preferably in the range of about The pH is adjusted to 4.0. A preferred embodiment of this acid is lactic acid, in which case the preferred concentration is about 0.1 M. For pH control, a suitable base is added upon request. A preferred embodiment of this base is sodium hydroxide, preferably in solution, in which case the preferred concentration is about 0.1 M. The volume is finally adjusted by adding a suitable, biocompatible fluid, preferably water for injection. The resulting bulk solution preferably contains 0.5 mg lurbinectedin with 0.03M sodium lactate buffer, pH=4, 10% (w/v) sucrose. The bulk solution is then distributed into vials according to the desired dosage. In embodiments, the lurbinectedin to be dissolved is at least partially crystalline. The lurbinectedin to be dissolved may be in the solid state form(s) described herein. Crystalline lurbinectedin (including partially crystalline) lurbinectedin has been found to be less soluble than amorphous lurbinectedin. For example, direct dissolution of amorphous lurbinectedin at 0.5 mg/mL in 0.03 M sodium lactate buffer pH 4 was completed in approximately 30 min, whereas partially crystalline lurbinectedin reached only 60–70% of the target concentration within 2 h, This meant that it had much slower dissolution kinetics. It was found that lowering the pH accelerated the dissolution kinetics of partially crystalline lurbinectedin. Thus, in embodiments, a concentrated solution of lurbinectedin is prepared in organic acid before adding other excipients. In preferred embodiments, the organic acid has a pH of less than 4, preferably less than 3.5, more preferably less than 3 or around 3. The maximum solubility of Lurbinectedin was investigated in different molarity of the organic acid lactic acid. The solubility was high and increased linearly from 7.2mg/ml for 0.05M lactic acid to 90.4mg/ml for 0.5M lactic acid. In a preferred embodiment, lurbinectedin is dissolved in an organic acid having a molarity of about 0.1M to 0.5M, preferably about 0.2M to 0.4M, more preferably about 0.3M organic acid. An example molarity is 0.31M organic acid. Lurbinectedin can be pre-dissolved in high concentration organic acid. In a preferred embodiment, the pre-dissolution step is at least 30 minutes, at least 60 minutes and about 60 minutes. Following dissolution, the predissolution solution can be diluted to create the required concentration of, for example, 8.3mg/ml. The dilution may include X1, X2, X3 or more 9807108-1 M&C P0931420WOA dilution with WFl to obtain the target concentration. In embodiments, dilutions are made to obtain the desired concentration at the appropriate molarity. As an example, X3 dilutions to add 2 times the initial volume of organic acid can reach 8.3mg/mL at 0.1M organic acid (e.g. lactic acid). During manufacture, there may be limited volume capacity for the dissolution step and therefore dissolution of lurbinectedin with limited organic acid is advantageously achieved. Therefore, by using high molarity organic acid, a high concentration of lurbinectedin can be achieved in a limited volume of organic acid. In embodiments, a multistep compounding strategy is used to prepare lurbinectedin. Step 1 is the predissolution step described above, i.e.: predissolving partially crystalline lurbinectedin in 0.31M lactic acid at 25 mg/mL and diluting 3x with WFl to 8.3 mg/mL in 0.1 M lactic acid. concentrated solution is obtained. To prevent precipitation of Lurbinectedin, remaining excipients must have acid pH when added to the compound formulation. It has been found that a highly concentrated lurbinectedin solution can be mixed with a buffer solution of pH 5.6 or lower, e.g. 4 to 5.6 or 4.2 to 5.6, without precipitating the lurbinectedin. As such, in Step 2, an organic buffer solution containing bulking agent (e.g. disaccharide) at the appropriate pH can be prepared. As an example, this may involve preparing a 0.04 M sodium lactate buffer at a pH of approximately 4.2 containing sucrose. In step 3, the solutions from step 1 and step 2 are combined to form the final bulk solution. The final bulk solution can be adjusted with WFl to achieve the final target weight. For example, in step 3, a concentrated solution of 8.3 mg/mL lurbinectedin in 0.1M lactic acid, pH~3, is diluted with 0.04M sodium lactate buffer sz4.2 containing sucrose. After adjustment of WFl to final weight, the final bulk solution composition may be, for example, 0.5 mg/mL lurbinectedin in 0.03M sodium lactate buffer pH=4 + 10% (w/v) sucrose. Thus, the present invention describes a compounding strategy for formulating partially crystalline lurbinectedin. In one embodiment, the lyophilized composition contains or consists of 4 mg lurbinectedin, 800 mg sucrose, 22.1 mg lactic acid, and 5.1 mg sodium hydroxide. In some embodiments, the weight fraction in the lyophilized composition is between 0.4% and 0.6% (w/w) active compound, 96% to 98% (w/w) sucrose, 2% to 3% (w). /a) Iactic acid and 0.5% to 0.5% by weight in lyophilized composition, 0.5% (w/w) active compound, 96.2% (w/w) sucrose, containing approximately 0.25 mmol of lactate ion per mg lurbinectedin . When reconstituted to 8 ml in the vial, the resulting solution is 0.5 mg/ml lurbinectedin, 0.03M to 10% w/v sucrose. The lyophilized material is usually contained in a vial containing a certain amount of lurbinectedin. Preferably, the lyophilized composition of lurbinectedin is provided in a 30 mL vial. The amount of lurbinectedin indicated in a lyophilized composition may be from 0.2 to 5 mg, or about 1 mg, about 2 mg, about 3 mg, or about 4 mg. The stated amount of lurbinectedin in a lyophilized composition is preferably 4 mg. In lyophilized embodiments, the composition contains between 0.4% and 0.6% by weight lurbinectedin, preferably 0.5%. It is necessary to ensure that Lurbinectedin is sterile and filled into vials aseptically. This is critical for parenteral drugs. According to embodiments of the present invention, terminal sterilization by heat or gamma radiation is not used to prevent degradation of lurbinectedin. Instead, according to embodiments of the present invention, a sterilization filtration of the bulk lurbinectedin solution is performed prior to aseptic vial filling. In embodiments, the filter may be filters such as PVDF or PES. In embodiments, the filter may be a 0.2 µm filter. Storage of Pharmaceutical Lurbinectedin Formulations Embodiments of the present invention also provide a method for storing a lyophilized lurbinectedin composition. It is necessary to ensure that Lurbinectedin is stable for at least 24 months. Lurbinectedin lyophilized formulations are storage stable and after long-term storage at 5°C ± 30°C, lurbinectedin retains its therapeutic efficacy and exhibits minimal chemical degradation (i.e., degradation is minimized and within acceptable tolerance; i.e., impurity and degradation of lurbinectedin products profile, the amount of each impurity and 9807108-1 M&C P0931420WOA degradation product, Iurbinectedin content, are substantially the same before and after long-term storage, as determined by HPLC analysis). In one aspect, the lyophilized Iurbinectedin compositions of the present disclosure minimize the amount of a Iurbinectedin degradation product resulting from deacetylation of Lurbinectedin ("Impurity D") when the composition is stored for extended periods (e.g., at least 24 months) (from 0.87 to 0.87 by commercial HPLC assay). It has a relative retention time of 0.88). In some embodiments, the amount of impurity D present, the total Iurbinectedin and G in the formulation after long-term storage at 5°C ± 3°C have the following structures: In a preferred embodiment, a method of storing a lyophilized Iurbinectedin composition, 4 mg Iurbinectedin; lactate buffer; and storing a lyophilized composition containing the disaccharide at 5°C ± 3°C for at least 24 months, wherein the lyophilized composition is reconstituted with 8 mL of water at a pH of 3.5 to 4.5 and 0.5 mg/ml. It is formulated to yield a solution with an Iurbinectedin concentration of 100% and wherein, after storage for at least 24 months, the amount of Impurity D present in the composition is not more than 0.8% w/w based on the total weight of Iurbinectedin. In some embodiments, after lyophilized or 60 months of storage, the amount of an Iurbinectedin degradation product Impurity D present in the composition is not more than 0.8% w/w, based on the total weight of Iurbinectedin. In some embodiments, the amount of Impurity 9807108-1 M&C P0931420WOA D present in the composition after storage at approximately 5°C ± 3°C for 60 months is not more than 0.8% w/w or w/w, based on the total weight of Iurbinectedin less than 0.7% w/w, less than 0.6% w/w, less than 0.5% w/w or less than 0.4% w/w. In one embodiment, the amount of Iurbinectedin degradation product Impurity D present in the composition is not more than 0.8% w/w based on the total weight of Iurbinectedin after at least 36 months of storage. In some embodiments, percentage of total impurities and degradation products (% by area) after storage at approximately 5°C ± 3°C for 24 months, months, or 36 months 0.6%, 0.7%, 0.8% 0% Not more than .9 or 1.0% (% area). In some embodiments, the initial amount of Impurity D present in the composition (i.e., one day's lyophilization) is less than 0.4% w/w based on the total weight of Iurbinectedin. In some embodiments, the initial amount of Impurity D present in the composition is at least 0.8% w/w based on the total Iurbinectedin weight and not more than 0.5% w/w based on the total Iurbinectedin weight. not more than 0.1% w/w. After storage at °C ± 3°C, the stable, lyophilized, Iurbinectedin formulation shows a reduction in the amount of Iurbinectedin to within 1.0%, 0.5% or 0.2% of the total amount of Iurbinectedin. Accordingly, when reconstituted in water containing a buffer derived from an organic acid (e.g., an organic carboxylic acid buffer such as succinate, citrate, acetate, or lactate buffer) and at a molar ratio of buffer to lurbinectedin of approximately 48, e.g., 52 to 46, 54 to Stable, lyophilized Iurbinectedin formulations are provided containing sucrose as a bulking agent with a pH of approximately 4.0, including pH 3.5-4.5 or pH 3.8-4.1, 0% by total weight of lurbinectedin. .8% w/w or less, or 0.7% w/w or less, or 0.6% w/w or less, or 0.5% w/w or less, or 0.4% w/w /a Contains impurity D and without storage at ± 3°C; or without storage at 9807108-1 M&C P0931420WOA °C/60% relative humidity for 3 months, 6 months, 9 months, 12 months or 18 months; or increases to not more than 0.8% w/w of the total weight of Iurbinectedin after storage at 40°C/60% relative humidity for 1 month, 3 months, 6 months or 12 months. In these embodiments, it is the amount of lurbinectedin assayed per day. Also provided are methods of reducing degradation of lurbinectedin in a lyophilized formulation by including in the lyophilized formulation a buffer derived from an organic acid, preferably a lactate or succinate buffer, specifically, the amount of lurbinectedin is 95 to 105% of 4 mg of lurbinectedin or, with lurbinectedin, Impurity D in the formulation, storage at 5°C ± 3° for 12 months, 24 months, 30 °C/60% relative humidity; or Total weight of lurbinectedin after storage at 40°C/60% relative humidity for 1 month, 3 months, 6 months or 12 months. Other impurities or degradation products that may be minimized in the storage of the stable, lyophilized lurbinectedin formulation. Degradation products with the following relative retention time in the commercial HPLC method can be: rrt 0.68, rrt 0.80, rrt and rrt 1.12. In other embodiments, the total residual water content for the lyophilized lurbinectedin formulation is not more than 3% (w/w), preferably not more than 1.5% (w/w), preferably Embodiments of the present invention also include a vial containing the lyophilized lurbinectedin composition. Provides a pharmaceutical product containing In a preferred embodiment, the pharmaceutical product includes 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or approximately 0.25 mmol lactate); and a lyophilized composition comprising 800 mg sucrose; and a label affixed to the vial containing an expiration date of at least 48 months from the date of manufacture. In some embodiments, the label affixed to the vial includes an expiration date of at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months from the date of manufacture. Some have a size between 50 mL. In a preferred embodiment, the vial is a 30 9807108-1 M&C P0931420WOA mL vial. A 30 mL vial size was optimized to overcome the limitations of larger vial sizes leading to reduced production capacity due to reduced freeze-drying capacity as well as adequate extractable volumes due to size. A 30 mL vial size overcomes both of these limitations. Solid state forms and uses of lurbinectedin In embodiments according to the present invention, pre-lyophilized lurbinectedin contains at least some crystalline material. Previously lyophilized lurbinectedin may be partially crystalline. The use of partially crystalline pre-lyophilized lurbinectedin leads to advantages including better control of impurities and/or degradation products. The present invention describes a new solid state form of lurbinectedin, hereinafter referred to as Form A, that is easier to process than the known amorphous form under typical pharmaceutical processing conditions. Amorphous Form A can be obtained by the process described in WO 03/014127. Form A becomes electrostatically charged during manipulation, causing production problems. Therefore, there is a need to obtain a form of lurbinectedin that is easier to process under typical pharmaceutical processing conditions. In embodiments according to the present invention, a new solid state form of lurbinectedin is provided, hereinafter referred to as Form B of lurbinectedin. Form B shows advantageous physical properties compared to the known Form A. For example, Form B shows improved triboelectric properties over currently known forms of lurbinectedin. Triboelectric charging is the process by which certain materials become electrically charged after coming into contact with a different material through friction. In many pharmaceutical operations, uncontrolled static electricity can cause serious production problems. These problems may include product contamination, product loss, cleanliness, and safety, and the problems may be exacerbated by a nanomolar cytotoxic drug such as lurbinectedin. Even in the strictest cleanrooms, static charge attracts particles from people, processes and equipment, so it is important to take appropriate measures to ensure it is kept to a minimum. 9807108-1 M&C P0931420WOA Form B shows a lower average charge density than the known Iurbinectedin form. Form B also shows a narrower charge density distribution than the known Iurbinectedin form. Form B of Lurbinectedin has a simplified impurity profile compared to the also known form of Lurbinectedin. These properties make it particularly suitable for the preparation of a medicine. Prior to lyophilization, Iurbinectedin may contain Form B. The amount of Form B may vary and can be considered a crystalline mixture (partially crystalline). In other embodiments, the crystalline mixture may contain other crystalline Iurbinectedin (e.g., non-form-B crystalline Iurbinectedin). In other embodiments, the present invention relates to a process for preparing Form B of lurbinectedin comprising: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or a basic buffer to precipitate Form B of lurbinectedin. Lurbinectedin's Form B can then be converted into a different physical form, preferably an amorphous form. Form B can be used in the manufacturing process to prepare lyophilized bulk product. In other embodiments, the present invention relates to pharmaceutical compositions comprising Form B of lurbinectedin and a pharmaceutically acceptable carrier. Such compositions may be pre-lyophilization compositions. In further embodiments, the present invention relates to a pharmaceutical composition comprising Iurbinectedin produced using Form B of Lurbinectedin and a pharmaceutically acceptable carrier. The pharmaceutical composition now uses at least one Form B in any Form B step. In other embodiments, the present invention relates to Form B of lurbinectedin for use in the manufacture of a pharmaceutical composition containing Iurbinectedin. In still other embodiments, the present invention relates to the use of Form B of lurbinectedin in the manufacture of a pharmaceutical composition containing lurbinectedin. In still other embodiments, the present invention relates to Form B of lurbinectedin for use as a medicine. Again, Form B may no longer be present in the final composition but may be used during manufacturing. 9807108-1 M&C P0931420WOA In other embodiments, the present invention relates to compositions comprising Form B of Iurbinectedin and a pharmaceutically acceptable carrier for use as a medicament. In other embodiments, the present invention relates to Form B of Iurbinectedin for use as a drug for the treatment of cancer. In further embodiments, the present invention relates to processes for the production of Form B of Iurbinectedin and a pharmaceutically acceptable carrier for use as a drug for the treatment of cancer. In other embodiments, the present invention is also directed to the use of Form B of Iurbinectedin or to the use of a pharmaceutical composition comprising Form B of Iurbinectedin and a pharmaceutically acceptable carrier in the treatment of cancer. In other embodiments, the present invention is also directed to the use of Form B of Iurbinectedin or a pharmaceutical composition comprising it in the preparation of a medicament for the treatment of cancer. Other embodiments of the invention provide methods of treatment and a method for treating any affected mammal, especially a human, for use therein, comprising administering to the affected individual Form B of Iurbinectedin or a pharmaceutical composition comprising; or administering a therapeutically effective amount of a pharmaceutical composition made from a process utilizing Form B of Iurbinectedin. The present invention also provides a method of treating any mammal, especially a human, affected by cancer, comprising administering to the affected individual a therapeutically effective amount of Iurbinectedin produced via Form B of Iurbinectedin. The present invention also provides a method of treating any mammal, especially a human, affected by cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising lurbinectedin produced via lurbinectedin Form B and a pharmaceutically acceptable carrier. It involves administration to the affected individual. In another embodiment, the present invention relates to lurbinectedin having not more than 1% but not more than 0.5%. In another embodiment, the present invention relates to lurbinectedin having a water content above 1.6% w/w or 1.7-5% w/w. In another embodiment, the present invention has a water content of 5%, 4%, or solid state forms of Lubinectedin by weight. The alkanes of the present invention may be branched or unbranched and have from about 5 to about 10 carbon atoms. A more preferred class of alkanes has 5 to 9 carbon atoms. Alkanes having 5, 6 or 7 carbon atoms are even more preferred. Particularly preferred alkanes of this invention are n-pentane, n-hexane, n-heptane, cyclohexane and methylcyclohexane. The term alkane, as used herein, refers to both cyclic and non-cyclic alkanes unless otherwise stated. Pharmaceutically acceptable solvents in the context of solid-state forms of lubinectedin are those classified under classes 2 and 3 of the International Conference on Harmonization of Technical Requirements for the Registration of Medicines for Human Use, "lmpurities: Guideline for residual solvents Q3C(R6)". In one embodiment, the present invention relates to Form B of lurbinectedin. It can be characterized by the demonstration of an X-ray powder diffractogram pattern containing four or more characteristic peaks at 2-theta angles selected between 0.2° and 15.3 ± 0.2°. Form B may alternatively be characterized by showing an X-ray powder diffractogram pattern containing five or more of said characteristic peaks. Alternatively, Form B can be characterized by displaying an X-ray powder diffraction diagram pattern containing all six characteristic peaks mentioned. In particular, Form B of lurbinectedin can be characterized by an Other peaks may be found at angles .6 ± 0.2 ° 100± 3 9.0 ± 0.2 ° 63 ± 3 14.9±0.20 76±3 .3±0.20 75±3. In particular, Form B of Iurbinectedin can be characterized by an X-ray powder diffractogram pattern containing characteristic peaks and intensities as shown in the table below: Angle[2-theta] Relative intensity Angle Relative intensity 12.4±0.20 40 Other peaks may be found at ±3 2-theta angles. In particular, Form B of Iurbinectedin can be characterized by an It can be characterized as showing an 1R spectrum with Form B of Iurbinectedin exhibiting an X-ray powder diffraction pattern substantially identical to either of the X-ray powder diffraction patterns shown in 2a or 2b. An illustrative 1R spectrum is shown in Figure 7b. Additionally, Form B of Iurbinectedin can be characterized by the degradation of TG-FT1R above 150°C. Alternatively or additionally, Form B of Iurbinectedin can be characterized by a TG-FT1R mass shift due to water loss to 150°C. Loss due to water may be less than about 5%, less than about 4%, or less than about 3%. Alternatively or additionally, Form B of Iurbinectedin may be characterized by TG-FT1R indicating a loss of water, preferably about 2-3% by weight, more preferably 2.6% by weight. An illustrative TG-FT1R is shown in Figure 3. Additionally, Form B of Iurbinectedin can be characterized by DSC, where degradation begins above 130°C. An illustrative DSC thermogram is shown in Figure 4. In one embodiment, Form B of Iurbinectedin, not more than about 30 nC/g, not more than about 20 nC/g, not more than about 10 nC/g, not more than about 6 nC/g , more than about 5 nC/g 9807108-1 M&C P0931420non-WOA, about 5 ± 2 nC/g, about 4 ± 2 nC/g, about 4-5 nC/g, about 5 nC/g, or about 4 nC/ It has an average charge density of g. In one embodiment, Form B of lurbinectedin has a concentration of less than 4.8 nC/g, approximately 0.7 nC/g to less than 4.8 nC/g, or 2.4 ± 2 nC/g. It has load density distribution. In one embodiment, Form B of lurbinectedin has a water content of greater than 1.6% w/w or 1.7-5% w/w. In one embodiment, Form B of lurbinectedin has undetectable residual solvents. The present invention includes lurbinectedin containing at least a detectable amount of Form B, up to 1% w/w Form B, or which may be substantially pure Form B. In one embodiment, partially crystalline lurbinectedin as described herein contains at least a detectable amount of Form B, up to 1% w/w Form B, up to 5% w/w Form B, up to 95% w/w Form B may contain up to 98% w/w Form B or substantially pure Form B. a/a is intended to express the amount of lurbinectedin in Form B state. Thus, by way of example only, 50% w/w means that lurbinectedin AP1 contains 50% by weight Form B and 50% by weight of another form, such as amorphous Form A. In one embodiment, the invention relates to a process for preparing Form B of lurbinectedin comprising: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or a buffer to precipitate Form B of lurbinectedin. In step a), a solution of lurbinectedin in acidic water is provided. Examples of methods for preparing such a solution include, but are not limited to: 9807108-1 M&C P0931420WOA extracting Iurbinectedin from a solution containing Iurbinectedin in an immiscible organic phase into acidic water. In a preferred embodiment, it is obtained by dissolving. Any form of Iurbinectedin, e.g., amorphous Iurbinectedin, can be used to generate crystalline Iurbinectedin. The concentration of Iurbinectedin in acidic water can vary from approximately 10 to approximately 50 g/L. Concentrations between about 15 and about 40 g/L are particularly preferred, with more preferred concentrations being between about 20 and about 30 g/L. The most preferred Iurbinectedin concentration in acid water is approximately 26 g/L. The preferred pH of acidic water is about 1 to about 4, more preferably about 1 to about 3, even more preferably about 1 to about 2, and most preferably about 1. The acid state can be maintained with an acid or a buffer. Suitable pharmaceutically acceptable acids include carboxylic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, aliphatic and aromatic carboxylic acids. More preferred acids include hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, nitrobenzoic acid and citric acid. Suitable acid buffering agents provide a pH of about 1 to about 4. Examples of suitable acid buffering agents include, but are not limited to, phosphate buffer, citrate buffer, lactate buffer, ascorbate buffer, tartaric/citrate buffer, bicarbonate/hydrochloric acid buffer, acetate buffer, succinate buffer and glycine/hydrochloric acid buffer. More preferably the acid state is provided by an acid, and most preferably the acid is hydrochloric acid. In acidic water it can range from about 3 to about 3 or about 2 to about 3. In step b), the resulting acidic aqueous solution is treated with an excess of base or buffer to basify and precipitate Form B of Iurbinectedin. Basification can be accomplished with a base or a buffer. The preferred pH of the resulting basic solution may be between about 8 and about 11, most preferably between about 9 and about 11. Suitable pharmaceutically acceptable bases include carbonates, hydroxides, hydrogen carbonates and ammonium salts. Particularly preferred bases are sodium carbonate, potassium carbonate, NH 4 OH, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate and potassium hydrogen carbonate. Suitable basic buffers provide a pH of about 8 to about 11. Examples of suitable basic buffers include KH2PO4 buffer, Na2HPO4/citric acid, and ammonium and phosphate buffers such as NH4Cl - NH4OH. In a preferred embodiment, basification is accomplished with a buffer, and in a most preferred embodiment, basification is accomplished with a NH4Cl -NH4OH buffer. The resulting Form B of Lurbinectedin can be separated by isolation processes such as filtration or centrifugation, preferably by filtration. Furthermore, after separation, the separated solid may be subjected to a drying process by any known method. The precipitate is preferably left under vacuum, preferably at a temperature ranging from about 15 to 35 °C, more preferably at about 20 to 30 °C and most preferably at about 25 °C, preferably for about 10 to 24 hours, more preferably for about 16 to 20 hours and It can be dried at varying temperatures, most preferably approximately 18 hours. In a preferred embodiment, the acidic aqueous solution obtained after step a) is washed one or more times with a pharmaceutically acceptable, water-immiscible, polar solvent and treated with an excess of a pharmaceutically acceptable base or buffer in step b). is washed one or more times with a water-immiscible, non-polar solvent. Examples of pharmaceutically acceptable, water-immiscible, polar solvents suitable for this wash include chloroform, 1-butanol, 2-butanol, butyl acetate, ethyl acetate, methyl acetate, 1-pentanol, propyl acetate and dichloromethane. More preferred pharmaceutically acceptable, water-immiscible polar solvents for this wash are chloroform, ethyl acetate and dichloromethane, most preferred being dichloromethane. Preferred pharmaceutically acceptable, water-immiscible, non-polar solvents suitable for this wash include C5-C7 alkanes such as n-heptane, n-hexane, n-pentane, cyclohexane and methylcyclohexane; n-pentane is most preferred. In one embodiment, the present invention relates to pharmaceutical compositions comprising Form B of lurbinectedin and a pharmaceutically acceptable carrier, or produced from lurbinectedin 9807108-1 M&C P0931420WOA containing Form B. The lurbinectedin used in the compositions or used during the manufacture of the compositions may contain at least a detectable amount of Form lurbinectedin. Partially crystalline lurbinectedin as described herein contains at least a detectable amount of Form B in embodiments, up to 1% w/w Form B, up to 5% w/w Form B, up to 95% w/w Form B, May contain up to 98 w/w Form B or substantially pure Form B. In alternative embodiments, other non-Form B crystalline lurbinectedin may form partially crystalline lurbinectedin in the same w/w amounts. The partially crystalline lurbinectedin disclosed herein can be used to form pharmaceutical compositions according to the present invention. Accordingly, in embodiments, partially crystalline lurbinectedin is used in the manufacture of a bulk lurbinectedin solution and is then lyophilized to form the lyophilized lurbinectedin formulation. Partially crystalline lurbinectedin may include Form B as described herein. Although partially crystalline lurbinectedin is not present in the final dosage form (due to dissolution and subsequent lyophilization steps), it can still affect the properties of the final dosage form. As an example, the use of partially crystalline lurbinectedin can reduce and/or simplify the total impurities, including degradation products. Characteristic impurity profiles may indicate the use of partially crystalline lurbinectedin during manufacturing. According to one embodiment, the total in the final lyophilized product may not be excess. In a preferred embodiment, the total degradation products contain 0.8% NMT of impurity D. According to another embodiment, the final lyophilized product contains 0.3% NMT of any unspecified impurities. 9807108-1 M&C P0931420WOA The use of partially crystalline Iurbinectedin can also advantageously control residual solvents. In one embodiment, Iurbinectedin contains not more than 0.2% residual solvents, preferably not more than 0.1% residual solvents, preferably the residual solvents are substantially undetectable. In one embodiment, the partially crystalline Iurbinectedin used in the manufacture of the compositions disclosed herein may have an assay (%) in the range of 94.0-102.0% and an impurity level of less than 1.0%. Specified impurities and their limits, impurities of any unspecified impurities, S may have a limit of 0.20%. Use of Pharmaceutical Lurbinectedin Formulations The present invention describes a series of methods of treatment using lurbinectedin alone or in combination with other agents. When referring to a method of treatment, the present invention also includes Iurbinectedin and/or other said agents in the manufacture of a medicament for the treatment of cancer. The following methods may use compositions of the invention as described herein. In some embodiments, the method of treating SCLC in a patient in need thereof thus includes: (1) administering to the patient lurbinectedin at a dose of 3.2 mg/m2 (or 2.6 mg/m2 or 2.0 mg /m2), wherein the Iurbinectedin infusion solution administered to the patient consists of 4 mg Iurbinectedin, a lactate buffer, and a solution reconstituted to form a reconstituted solution at pH 3.8 to 4.5. It is prepared from a lyophilized composition containing disaccharides. In preferred embodiments, the disaccharide is sucrose. In a preferred embodiment, the lyophilized composition includes 4 mg Iurbinectedin, a lactate buffer (preferably resulting from a solution containing 22.1 mg lactic acid and 5.1 mg sodium hydroxide, including approximately 0.25 mmol lactate) and a disaccharide (preferably sucrose, specifically containing 800 mg of sucrose), wherein the lyophilized composition is reconstituted in about 8 mL of an aqueous solution by diluting the reconstituted solution with an isotonic solution of 0.5 mg/mL 9807108-1 M&C P0931420WOA with a pH of about 3.8 to about 4.5. Iurbinectedin infusion solution is prepared, where the isotonic solution is 0.9% sodium chloride solution or 5% dextrose solution. In some embodiments, the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare an Iurbinectedin infusion solution. In some embodiments, after reconstitution or dilution, the solution may be stored at room temperature (i.e., approximately 23°C)/bright or refrigerated (5°C ±3°C) conditions for up to 24 hours, including the infusion period following reconstitution. In certain embodiments, w/w% of Impurity D based on lurbinectedin, the reconstituted or diluted solution is incubated at room temperature (i.e., approximately 23°C)/bright or refrigerated (5°C ±3°C) conditions for 24, 48, or 72 hours. weight/weight upon storage Some embodiments provide a method of administering a pharmaceutical composition to a patient in need thereof, such as a patient suffering from SCLC refractory to first-line treatment, which method includes (1) administering the lyophilized pharmaceutical composition to the patient for 30 to 36 or 48 months. wherein the lyophilized pharmaceutical composition is prepared by lyophilizing a stock solution containing a ratio of mg lactic acid:5.1 mg sodium hydroxide:800 mg sucrose:8 mL water; and (2) administering the reconstituted solution to a patient, wherein the reconstituted solution may be diluted with a volume of 100 ml to 250 ml of solution for administration to the patient as an infusion solution. In another aspect, the use of lurbinectedin is provided in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises (1) administering to the patient a prophylactic dose of an effective corticosteroid and a serotonin antagonist to reduce nausea associated with the administration of lurbinectedin; administered to the patient on and before the day of administration of lurbinectedin; 9807108-1 M&C P0931420WOA (2) Iurbinectedin administered by intravenous infusion to the patient at a dose of 2 to 3.2 mg/m2. In another aspect, the use of corticosteroids is provided in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: (1) administering to the patient a prophylactic dose of said corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of Iurbinectedin. , administered to the patient on and before the day of administration of Iurbinectedin; and (2) administering Iurbinectedin via intravenous infusion to the patient at a dose of 2 to 3.2 mg/m2. In another aspect, there is provided the use of a serotonin antagonist in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: (1) prophylactic use of said corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of Iurbinectedin to the patient. administering a dose before and on the day of administration of Iurbinectedin to the patient; and (2) administering Iurbinectedin via intravenous infusion to the patient at a dose of 2 to 3.2 mg/m2. In another aspect, the use of Iurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC) is provided. The method includes: (1) administering to the patient an initial dose of 3.2 mg/m2 Iurbinectedin via intravenous infusion; and (2) identification of an adverse reaction in the patient, where the adverse reaction is selected from the group consisting of: 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 25,000 cells/mm3). Less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count <LLN); 9807108-1 M&C P0931420WOA (3) after the adverse reaction is detected and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), administer to the patient a dose of G-CSF and a dose of lurbinectedin equal to the initial dose; or (ii) if the identified adverse reaction is not solely Grade 4 neutropenia, administering to the patient a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. In another aspect, there is provided the use of G-CSF in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said method comprises: (1) administering to the patient an initial dose of 3.2 mg/m 2 of lurbinectedin by intravenous infusion. ; and (2) identification of an adverse reaction in the patient, where the adverse reaction is selected from the group consisting of: 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 25,000 cells/mm3). Less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count <LLN); (3) after the adverse reaction is detected and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), administer to the patient a dose of G-CSF and a dose of lurbinectedin equal to the initial dose; or (ii) if the identified adverse reaction is not solely Grade 4 neutropenia, administering to the patient a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. 9807108-1 M&C P0931420WOA In another aspect, there is provided the use of Iurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said method comprises administering to the patient Iurbinectedin by intravenous infusion of a lurbinectedin infusion solution. m2, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition containing 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide reconstituted to form a reconstituted solution at pH 3.5 to 4.5 . In another aspect, the use of lurbinectedin is provided in the manufacture of a medicament for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma or epithelial ovarian cancer, wherein said treatment offers the patient a combination of lurbinectedin and SN-38 and irinotecan. administering a selected topoisomerase inhibitor on day one of a treatment cycle; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. In another aspect, there is provided the use of a topoisomerase inhibitor selected from SN-38 and irinotecan in the manufacture of a medicament for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma or epithelial ovarian cancer, wherein said treatment offers comprising: administering to the patient on the first day of a treatment cycle lurbinectedin and said topoisomerase inhibitor selected from SN-38 and irinotecan; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. In another aspect, there is provided the use of Iurbinectedin in the manufacture of a medicament for the treatment of cancer, the treatment comprising: 9807108-1 M&C P0931420WOA reconstitution of a lyophilized pharmaceutical composition in a vial, wherein the lyophilized pharmaceutical composition, 4 mg lurbinectedin, after the composition has been stored for 30 to 60 months. Prepared by lyophilizing a stock solution containing sucrose and a buffer derived from an organic carboxylic acid, wherein the composition contains lurbinectedin and the disaccharide in a ratio of 1 mol lurbinectedin:455 to 465 mol sucrose, wherein the lyophilized composition reconstitutes with 8 mL of water has a pH of 3. It is formulated to give a solution of .5 to 4.5; and administering the diluted solution to a patient. In another aspect, there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m 2 ; wherein the patient is administered an immunotherapeutic antibody to treat SCLC prior to initiating the treatment cycle, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months, or wherein the overall response rate is at least 40%. In another aspect, the use of lurbinectedin is provided in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises administering lurbinectedin to a patient at a dose of 2 to 3.2 mg/m 2 by intravenous infusion every 3 weeks. , wherein lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, a buffer derived from lactic acid, and sucrose, wherein the lurbinectedin:lactic acid:sucrose ratio is between 1 mol:46 mol:455 mol and 1 mol:50 mol:465 mol, wherein the formulation is 5 degrees It is stable at C ± 3, so that the lurbinectedin degradation product resulting from deacetylation does not exceed 0.8% w/w of the total lurbinectedin weight. 9807108-1 M&C P0931420WOA In another aspect, there is provided the use of Iurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment delivers 1) lurbinectedin in a packaged, lyophilized package containing 4 mg of lurbinectedin, a buffer derived from an organic acid and a disaccharide. dissolving the composition in about 8 mL of water and providing a solution of lurbinectedin with a pH of about 3.5 to about 4.1, 2) administering to a patient with progressive SCLC by intravenous infusion every 3 weeks after prior platinum-containing therapy about 2 to Administration of 3.2 mg/m2 of lurbinectedin wherein the lyophilized composition contains less than approximately 0.3% Impurity D (w/w based on lurbinectedin) when the composition is packaged and wherein upon storage at approximately 5 degrees Celsius for approximately 24, 36 or 48 months In another aspect, there is provided lurbinectedin for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: (1) administering to the patient a prophylactic dose of an effective corticosteroid and a serotonin antagonist to reduce nausea associated with the administration of lurbinectedin. , administered to the patient on and before the day of administration of Iurbinectedin; (2) Administering Iurbinectedin to the patient via intravenous infusion at a dose of 2 to 3.2 mg/m2. In another aspect, a corticosteroid is provided for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: (1) administering to the patient a prophylactic dose of said corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of Iurbinectedin. Application before and on the day of application of Iurbinectedin; and (2) administering Iurbinectedin via intravenous infusion to the patient at a dose of 2 to 3.2 mg/m2. In another aspect, a serotonin antagonist is provided for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: 9807108-1 M&C P0931420WOA (1) said corticosteroid and a serotonin effective to reduce nausea associated with the administration of Iurbinectedin to the patient. administering a prophylactic dose of the antagonist before and on the day of administration of Iurbinectedin to the patient; and (2) administering Iurbinectedin via intravenous infusion to the patient at a dose of 2 to 3.2 mg/m2. In another aspect, lurbinectedin is provided for use in the treatment of small cell lung cancer (SCLC), wherein said method includes: (1) administering to the patient a first dose of 3.2 mg/m 2 of Iurbinectedin by intravenous infusion; and (2) identification of an adverse reaction in the patient, where the adverse reaction is selected from the group consisting of: 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 25,000 cells/mm3). Less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count <LLN); (3) after the adverse reaction is detected and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), administer to the patient a dose of G-CSF and a dose of lurbinectedin equal to the initial dose; or (ii) if the identified adverse reaction is not solely Grade 4 neutropenia, administering to the patient a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. In another aspect, G-CSF is provided for use in the treatment of small cell lung cancer (SCLC), wherein said method includes: (1) administering to the patient a first dose of 3.2 mg/m 2 Iurbinectedin by intravenous infusion; and (2) identification of an adverse reaction in the patient, where the adverse reaction is selected from the group consisting of: Grade 2 Grade 3 (severe) hematological 9807108-1 M&C P0931420 Non-WOA toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia (Neutrophil count less than 500 cells/mm3) associated with infection/sepsis or any other adverse reaction <LLN); (3) after the adverse reaction is detected and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), administer to the patient a dose of G-CSF and a dose of lurbinectedin equal to the initial dose; or (ii) if the identified adverse reaction is not solely Grade 4 neutropenia, administering to the patient a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. In another aspect, lurbinectedin is provided for use in the treatment of small cell lung cancer (SCLC), wherein said method comprises: administering to the patient a dose of 3.2 mg/m 2 of lurbinectedin by intravenous infusion of a lurbinectedin infusion solution, wherein administered to the patient lurbinectedin infusion solution is prepared from a lyophilized composition containing 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide reconstituted to form a reconstituted solution at pH 3.5 to 4.5. In another aspect, lurbinectedin is provided for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, or epithelial ovarian cancer, wherein said treatment comprises: lurbinectedin to the patient and a combination selected from SN-38 and irinotecan. administering the topoisomerase inhibitor on day one of a treatment cycle; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. 9807108-1 M&C P0931420WOA In another aspect, there is provided a topoisomerase inhibitor selected from SN-38 and irinotecan for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, or epithelial ovarian cancer, wherein said treatment offers comprising: administering to the patient on the first day of a treatment cycle lurbinectedin and said topoisomerase inhibitor selected from SN-38 and irinotecan; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. In another aspect, lurbinectedin is provided for use in the treatment of cancer, the treatment comprising: reconstitution of a lyophilized pharmaceutical composition in a vial, wherein the lyophilized pharmaceutical composition includes 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid, and sucrose, after the composition has been stored for 30 to 60 months. prepared by lyophilizing a stock solution of It is formulated as follows; and administering the diluted solution to a patient. In another aspect, lurbinectedin is provided for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: administering lurbinectedin via intravenous infusion to the patient at a dose of 2 to 3.2 mg/m 2 ; wherein the patient is administered an immunotherapeutic antibody to treat SCLC prior to initiating the treatment cycle, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months, or wherein the overall response rate is at least 40%. In another aspect, lurbinectedin is provided for use in the treatment of small cell lung cancer (SCLC), wherein said treatment includes: 9807108-1 M&C P0931420WOA Iurbinectedin at a dose of 2 to 3.2 mg/m 2 by intravenous infusion to a patient every 3 weeks. The administration of lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid and sucrose, wherein the lurbinectedin:lactic acid:sucrose ratio is between 1 mol:46 mol:455 mol and 1 mol:50 mol:465 mol, wherein the formulation is 5 degrees Stable for at least 24 months or at least 36 months or at least 48 months or at least 60 months at ± 3 degrees C so that the lurbinectedin degradation product resulting from deacetylation does not exceed 0.8% of the total lurbinectedin weight, w/w . In another aspect, lurbinectedin is provided for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: 1) dissolving in about 8 mL of water a packaged, lyophilized composition comprising 4 mg of lurbinectedin, an organic acid, and a buffer derived from the disaccharide. and providing a solution of lurbinectedin with a pH of about 3.5 to about 4.1, 2) administering to a patient with progressive SCLC about 2 to 3.2 mg/m 2 of lurbinectedin by intravenous infusion every 3 weeks after previous platinum-containing therapy. administration and wherein the lyophilized composition contains less than about 0.3% Impurity D (w/w based on lurbinectedin) when the composition is packaged and wherein upon storage at about 5 degrees Celsius for about 24, 36 or 48 months, the composition contains about. In the manufacture of a medicament for the treatment of solid tumors, including SCLC, endometrial carcinoma, soft tissue sarcoma or glioblastoma, (1) a prophylactic dose of an effective corticosteroid and a serotonin antagonist is administered to the patient on the day of administration of Iurbinectedin to reduce nausea associated with the administration of Iurbinectedin. and its implementation beforehand; (2) Administering Iurbinectedin to the patient via intravenous infusion at doses of 2 mg/m2 and 75 mg/m2 irinotecan. In another aspect, the use of corticosteroids is provided in the manufacture of a medicament for the treatment of solid tumor, wherein said treatment includes: 9807108-1 M&C P0931420WOA (1) administering to the patient a prophylactic dose of said corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of Iurbinectedin. , administered to the patient on and before the day of administration of Iurbinectedin; and (2) giving the patient lurbinectedin at a dose of 2 mg/m2 and irinotecanine at a dose of 75 mg/m2 via intravenous infusion. In another aspect, there is provided the use of a serotonin antagonist in the manufacture of a medicament for the treatment of solid tumors, including SCLC, endometrial carcinoma, soft tissue sarcoma or glioblastoma, wherein said treatment is (1) effective for reducing nausea associated with the administration of Iurbinectedin to the patient. administering a prophylactic dose of the corticosteroid and a serotonin antagonist to the patient on and before the day of administration of Iurbinectedin; and (2) giving the patient lurbinectedin at a dose of 2 mg/m2 and irinotecanine at a dose of 75 mg/m2 via intravenous infusion. In another aspect, in the manufacture of a medicament for the treatment of solid tumors, including SCLC, endometrial carcinoma, soft tissue sarcoma or glioblastoma, by (1) administering to the patient by intravenous infusion lurbinectedin at a dose of 2 mg/m2 and irinotecan at a dose of 75 mg/m2; (2) After 7 days, administer irinotecan to the patient at a dose of 75 mg/m2 irinotecan via intravenous infusion; and (3) administering G-CSF to the patient to manage the myelosuppressive effect of the administration. In another aspect, in the manufacture of a medicament for the treatment of solid tumors including SCLC, endometrial carcinoma, soft tissue sarcoma or glioblastoma, (1) lurbinectedin at a dose of 2 mg/m2 and irinotecan at a dose of 75 mg/m2 by intravenous infusion to the patient. implementation; and (2) determining whether the patient exhibits Grade 3 or 4 hematologic toxicity after such administration; 9807108-1 M&C P0931420WOA (3) If the patient does not have Grade 3 or 4 hematological toxicity, give the patient a dose of 75 mg/m2 irinotecan via intravenous infusion 7 days after step 1. In another aspect, lurbinectedin is used in the manufacture of a drug for the treatment of solid tumor. is provided, wherein said method comprises: administering to the patient a dose of 2.0 mg/m2 of lurbinectedin by intravenous infusion of a lurbinectedin infusion solution and administering to the patient a dose of 75 mg/m2 of irinotecan by intravenous infusion, wherein the lurbinectedin infusion solution administered to the patient is administered to the patient by 4 mg of lurbinectedin, It is prepared from a lyophilized composition comprising a buffer derived from an organic carboxylic acid and a disaccharide reconstituted to form a reconstituted solution at pH 3.5 to 4.5. Examples Example 1: Preparation of Lurbinectedin in Different Buffers Bulk lurbinectedin solution containing 0.5 mg/mL (calculated reconstituted concentration in an acetate buffered to pH 3, 4, and 5 with sodium hydroxide with buffer concentrations of 0.02 to 0.05 M , citrate, lactate and succinate were prepared in buffered solution. An example of a lurbinectedin formulation with lactate buffered to pH=4 is given in Table 1 below. Table 1: Composition of Lurbinectedin 4 mg reconstituted solution Concentration Lurbinectedin 0.5 Active ingredient Sucrose 100 Volume enhancer Lactic acid 2.76 Buffering Sodium hydroxide 0.64 Buffering Example 2: Solubility of Lurbinectedin in Different Buffers To determine the maximum solubility of lubinectedin, bulk solutions of phosphate, acetate, citrate, lactate and succinate buffers were prepared. Table 2, 9807108 at pH=4 It indicates a solubility of -1 M&C P0931420WOA. The results show that Iurbinectedin is poorly soluble in a phosphate buffer. The results also show that the molarity of the buffer does not have a significant effect on the solubility. Table 2: Maximum solubility of Lurbinectedin in various buffers pH=4. Effect of buffer molarity Lurbinectedin maximum solubility Buffer pH=4 (mglmL) Monopotassium phosphate 0.21 0.32 Sodium acetate 0.94 0.86 Sodium citrate 0.93 0.93 Sodium Iactate 0.90 0.92 Sodium succinate 0.97r 0.95 Example 3: Stability of Lurbinectedin Formulations with Different Organic Carboxylic Buffers at Different pH Values Stability and solubility studies were performed to determine a pH at which Lurbinectedin exhibited good stability. Table 3 shows the solubility and impurities and degradation products profile of Iurbinectedin in alternative 0.02M–0.05 M buffers at pH 3, pH 4, and pH 5. The solubility was similar for pH 3 and pH 4 and decreased greatly at pH 5. This decrease in solubility is accompanied by an increase in degradation products as buffer pH increases. 9807108-1 M&C P0931420WOA Table 3: Sodium acetate Sodium citrate Sodium in different organic carboxylic buffers in the pH range of 3 to 5 Sodium Degradation Products1 rrt: Relative Retention Time. 1HPLC Development method: lANA-072 Ed02. 2 Main decomposition products. Area 2 0.10% 3 Total % degradation products, 100% - calculated as % area affected in the main peak The stability of Iurbinectedin in different buffers is important in the assay and purity at 14 pH = 5 with conditions of 25 °C / 60% RH A decrease is observed (Table 4). 9807108-1 was evaluated separately in a day. While Lurbinectedin is relatively stable at pH 3 and 4, M&C P0931420WOA Table 4: Solubility and stability of Lurbinectedin in different 0.02M-0.05M organic carboxylic buffers in the pH range of 3 to 5 (25°C / 60% RH 14 day) Concentration1 (mg/mL) Concentration Purity1 (%) Buffer pH Degradation (%) Sodium Sodium Sodium Succinate 1 HPLC Development method: lANA-072 Ed02. These results showed that an organic carboxylic buffer with pH not more than 4.5 was most sufficient to increase the concentration of lurbinectedin in solution and maintain an adequate stability. Sodium lactate and sodium citrate buffers were considered most suitable. Example 4: Stability of Lyophilized Vials Formulated in Sodium Lactate and Sodium Citrate Buffers with pH = 4.0 under Stress Conditions (50°C) To determine which of the two buffers is optimal for lurbinectedin, batches of lyophilized vials containing 1 mg lurbinectedin/vial were tested at laboratory scale, 0. .03M 9807108-1 M&C P0931420WOA was produced with Iurbinectedin formulated at 0.5 mg/mL in sodium lactate pH = 4 and 0.05M sodium citrate pH = 4. pH 4 was chosen due to its greater physiological compatibility compared to pH 3. Sucrose was included as a bulking agent at 10% (w/v). The stability of the active substance in the lyophilized product under stress conditions of temperature (50°C) was evaluated. Freeze-dried vials formulated in 0.05M monopotassium phosphate buffer pH = 4 were also included in these studies for comparison. Stability results of lyophilized vials after 1 month at 50°C are shown in Table 5. Due to the large number of degradation products occurring under these conditions, only 2 The three formulations showed comparable properties at t = 0. After storage at 50 °C for 1 month, quality characteristics such as the appearance of the lyophilized solid, color and pH of the reconstituted solution, and water content did not change. Lurbinectedin assay decreased significantly (between 11 and 17%) relative to the starting content for the three compounds, with the major differences observed being the % degradation products. Vials formulated in sodium lactate buffer or monopotassium phosphate buffer showed very similar behavior, although sodium citrate buffer promoted greater degradation after 1 month of storage at 50°C. In all cases, the major degradation product was an impurity eluting at rrt 0.49-0.50 (HPLC Development method), which was significantly higher in the lyophilized vial formulated in sodium citrate buffer. In addition, they are impurities with a rrt of 1.09-1.10 that occur in very significant percentages. Based on the solubility and stability results, an optimized lactate buffer pH 4 was concluded. 9807108-1 M&C P0931420WOA Table 5. Formulated with 0.05M monopotassium phosphate buffer pH = 4, 0.05M sodium citrate buffer pH = 4, or 0.03M sodium lactate buffer pH = 4, 10% (w/) bulking agent h) Stability of Lurbinectedin freeze-dried vials containing sucrose under stress conditions (1 month, 50°C) Monopotassium phosphate Sodium citrate Sodium Lactate .. _ Irregular Irregular _ _ _ .. .. .. icy cake with shrunken shape. White White White cake. _ _ _ shrunken cake. Appearance _ __ Sticky _ __ lyophilized lyophilized cake .. .. .. lyophilized cake Sticky Sticky greenish-yellow __ _ greenish-yellow yellowish color Reconstitution particle particle Reconstituted _ particle particle particle _ particle appearance of the solution containing not containing containing not containing _ clear solution clear solutionclear solution _ clear solution solution solution Colorless Yellowish Colorless Yellowish Colorless Slightly yellowish color of solution solution solution solution solution solution 9807108-1 M&C P0931420WOA 4.0 Water of diluted solution d 9 1.7 Impurities and decomposition products1(%) Total2 0 .7 Individual3 (rrt) 0.20-0.21 - 0.23 - 0.24 - 0.25 - 0.25-0.26 - 0.28 - 0.29-0.30 - 037-0, 38 - 0.49-0.50 - 0.63 - 0.73- 1.09-1.10 - 1.28-1.29 - nominal) initial) 102.0 1 HPLC Development method: lANA-090 Ed05 2 % Total impurities and degradation products calculated as 100% - % area affected in the main peak 3 Reported impurities and degradation products: Area 2 0.20% 9807108-1 M&C P0931420WOA NA: Not applicable Example 5: Bulk Solution pH Effect on Lyophilized Product Stability The stability of 4 mg of lyophilized product produced from various 0.03M sodium lactate buffer Iurbinectedin bulk solutions was examined. Bulk solutions had a concentration of 0.5 mg Iurbinectedin/mL at pH 3.6, pH 4.0, and pH 4.5 using 10% sucrose (w/v) as bulking agent (8 mL filling in 30 mL glass vials) . The stability of these batches was evaluated under °C / 60% RH to determine whether small changes in pH would have a significant impact on the stability of the product. The stability results of the lyophilized vials after 6 months at °C are shown in Table 6. All parties showed similar behavior. Quality characteristics such as the appearance of the lyophilized solution, the appearance, color and pH of the reconstituted solution, water content (%) and assay were kept constant. Total decomposition products did not undergo significant changes. As a result, and based on the solubility and stability data, Iurbinectedin solution, and freeze-dried presentation, 0.03M sodium lactate buffer pH 4.0 was selected as the optimal dissolution medium for Iurbinectedin presentations. 9807108-1 M&C P0931420WOA Table 6. Stability property of Iurbinectedin 4 mg vial 30 mL at 25°C / 60% RH at different pH 3 months 6 months O 3 months 6 months O 3 months 6 months Appearance lyophilized lyophilized lyophilized lyophilized lyophilized lyophilized lyophilized lyophilized li lyophilized lyophilized HPLC (RT ) Standard Standard Standard Standard Standard Standard Standard Standard Dilution in water Dilute Visible Visible Visible Visible Visible Visible Visible Visible Visible visible solution clear clear clear clear clear clear clear clear clear view" solution solution solution solution solution solution solution solution solution Dilute mis Colorless Colorless Colorless Colorless Colorless Colorless Colorless Colorless Colorless Impurities decomposition products of diluted solution (% 9807108-1 M&C P0931420WOA Individual3 0.87-0.88 nominal) rrt: relative retention time 2 Total Impurities and decomposition products, sum of individual impurities 0.05 (%a/ a) Calculated as 3 Impurities and degradation products: 2% w/w 2 0.20% Example 6: Bulking Concentration The stability of 4 mg of lyophilized product produced from various 0.03M sodium lactate buffer Iurbinectedin bulk solutions was examined. Bulk solutions had a concentration of 0.5 mg Iurbinectedin/mL at pH 3.6, pH 4.0, and pH 4.5 using 10% sucrose (w/v) as bulking agent (8 mL filling in 30 mL glass vials) . The stability of these batches was evaluated under °C / 60% RH to determine whether small changes in pH would have a significant impact on the stability of the product. Once the dissolution medium was selected, different bulking agents were screened at different concentrations: sucrose (5%, 7.5%, and 10%), mannitol (5%), and the combination of sucrose and mannitol (5% sucrose + 2.5% mannitol). For this purpose, several batches of freeze-dried Iurbinectedin with a strength of 4 mg/vial containing different bulking agents at various concentrations were produced. Lurbinectedin was dissolved 9807108-1 M&C P0931420WOA at 0.5 mg/mL in 0.03M sodium Iactate buffer pH 4. The lot composition is detailed in Table 7. Batches were characterized and their stability under stress conditions was evaluated (40°C/75% RH). Table 7. Composition of 30 mL lurbinectedin 4 mg vial lots produced with different sucrose and mannitol contents Vial composition Lurbinectedin 4 mg 4 mg 4 mg 4 mg 4 mg Sodium hydroxide Mannitol NA NA NA 400 mg 200 mg Water1 8 mL up to 8 mL Up to 8 mL Up to 8 mL Up to 8 mL sufficient sufficient quantity sufficient quantity sufficient quantity sufficient quantity quantity 1 Evaporates during lyophilization N.A.: Not applicable Table 8 below After 3 months stored at 40 °C/75% RH It shows the stability results of the batches lyophilized with different bulking agents. was stable as it did not change in appearance nor in the reconstituted solution, continued the lurbinectedin assay and showed only a slight increase in degradation products, with impurity D being the main degradation product observed (rrt However, batches formulated with mixtures of sucrose and mannitol or with mannitol alone, at 40 °C It degraded significantly during storage at . In both cases the appearance of the freeze-dried cake differed from batches containing only sucrose (5 or 10%). The formulation containing 5% mannitol experienced a very significant decrease in the lurbinectedin test (43% of the nominal target) As Annex 9807108-1 M&C P0931420WOA, the percentage of degradation products increased in both formulations (up to 57% in the formulation containing 5% mannitol).The two main degradation products in the mannitol-containing formulations are rrt 0.67-0.68 and rrt 1, These are the products separated at 06. 9807108-1 M&C P0931420WOA Table 8. Stress stability CQAs of Iurbinectedin series containing different bulking agents 5% Sucrose + 3 at 40°C 3 months at 40°C t=0 t=0 40 3 months at °C t=0 White White White Very slightly yellow, White Slightly yellow, lyophilized lyophilized lyophilized shrunken and lyophilized cracked Appearance cake cake cake shrunken cake cake lyophilized cake Description _ _ Dilution in water NMT 3 min NMT 3 min NMT 3 min NMT 3 min NMT 3 min NMT 3 min _ _ _ _ _ _ appearance of the reconstituted solution clear clear clear clear solution clear clear solution Colorless Colorless Colorless Very light Colorless _ color of the reconstituted solution solution solution yellow solution solution Reconstituted 9807108-1 M&C P0931420WOA Impurities and its degradation products1 (% ala) Individual3 0.29 - - - - - 3.6 0.5 - - - 1.7 - - 0.70-0.71 - - - - - 1.7 0.72 - - - - - 1.5 0.73 - - - - - 1.7 0.77 - - - - - 1.0 0.78 - - - - - 1.0 0.87-0.88 1.06 - - - - - 12.9 1.12 - 0.12 - - - - 1.19-1.20 - - - - - 6.7 2 Total impurities and degradation products as the sum of all individual impurities 3 Reported individual impurities and degradation products: 5% Sucrose: (%w/w) 2 0.10%; 5% 9807108-1 M&C P0931420WOA Table 9 shows the stability results of lyophilized vials formulated in 0.03M sodium lactate buffer pH = 4 with different concentrations of sucrose ranging from 5% to 10% under stress conditions (40°C / 75% RH). Table 9. Stress stability of lurbinectedin freeze-dried vials formulated with different concentrations of sucrose as bulking agent in 0.03M lactate buffer pH 4 CQAs 5% Sucrose 7.5% Sucrose 10% Mannitol Appearance White White lyophilized White White White White lyophilized HPLC (RT) with Standard with Standard Standard with Standard identification compatible with compatible compatible with compatible compatible with compatible Reconstitution in water NMT3min NMT3min NMT3min NMT3deMT3min NMT3min Reconstituted particle particle particle particle particle particle particle particle particle particulate appearance of the solution containing without containing without containing without containing clear clear solution clear clear solution clear clear solution solution solution solution Reconstituted _ _ _ _ _ _ of solution _ _ _ _ _ Reconstituted 9807108-1 M&C P0931420WOA Impurities and decomposition products Individual3 0.24 - 0.10 - - - _ 1.12 - 0 .12 - - - _ (%nominal) 2 Total impurities and degradation products as the sum of all individual impurities 3 Reported individual impurities and degradation products: %w/w 2 0.10% Batches containing 3 different concentrations of sucrose showed similar behavior and were stable remained. The freeze-dried cake and lurbinectedin assay (%) did not undergo significant changes in appearance. A slight increase in % degradation products was observed. In particular, Impurity D (rrt) was the main degradation product. Although 10% sucrose showed the lowest degradation, the percentage of sucrose does not significantly affect the stability of the product. In conclusion, sucrose showed a protective effect to prevent the degradation of lurbinectedin during high temperature storage. Based on these results, sucrose was selected as the most suitable bulking agent at a concentration of 10% (w/v), which is an optimal amount for a suitable and stable delivery of lurbinectedin 9807108-1 M&C P0931420WOA Example 7: Stability of Lurbinectedin under Long-Term Storage Conditions Long-term storage ( The stability of the lyophilized Iurbinectedin composition (4 mg) at recommended conditions (5°C ± 3°C) was evaluated for 36 months. A batch with a high residual water content was selected as this was considered the worst case. The product remained stable throughout the 36 months of the study (Table 10).None of the quality attributes have undergone significant changes.Lurbinectedin content has undergone minor changes during the first 24 months, which are attributed to analytical variability. Total decomposition products did not change during the storage period. The substance of concern observed at reportable levels was Impurity D, which remained constant and was found at levels found in the active ingredient used to manufacture the batch. Table 4 mg Lurbinectedin Stability Study at 10.5°C ± 3°C Acceptance Time (months) Test*i _ _ White and off-white Appearance Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible lyophilized cake HPLC(RT)iIe Identification compatible with Standard in the water <3 <3 <3 <3 <3 <3 <3 <3 <3 generation NMT 3 min extent Diluted particle of visible solution Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Solution without appearance Colorless Diluted _ solution Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible Compatible solution 9807108-1 M&C P0931420WOA pH of diluted solution Visible 3.8 to 4.5 4.1 4.0 particles (per vial) from um to um Decomposition products (% w) Total NMT 1.3 0.4 0.4 Specified Impurity D NMT 0.8 0, 3 03 Not specified, individual 90.0 to 100.0 % of specified) Sterility Sterile Sterile NA 100.0 100.3 100.7 Sterile Sterile Sterile NA: Not applicable Example 8: Clinical Study - Treatment of SCLC Patients with Lurbinectedin As defined herein A clinical study of Iurbinectedin monotherapy was conducted for patients with refractory or resistant disease, collectively suffering from SCLC. This clinic is a single-arm, multicenter, open-label, phase 2 study for patients with measurable disease whose SCLC does not respond to first-line platinum-containing chemotherapy (cisplatin, carboplatin, or oxaliplatin) (refractory) and SCLC within 90 days of discontinuation of first-line therapy. A cohort of 105 patients, including 100,000 relapsed patients (refractory), was treated with Iurbinectedin at a dose of 3.2 mg/m administered intravenously over a 1-hour period every 21 days. Lurbinectedin was supplied as a sterile isotonic aqueous solution for IV infusion as described below. 9807108-1 M&C P0931420WOA Study Population Adult patients at least 18 years of age with a pathologically proven diagnosis of SCLC were included if they had: pretreatment with a prior chemotherapy-only treatment line (immunotherapy with or without chemotherapy was permitted); Measurable response according to Response Criteria for Solid Tumors (REClST version 1.1) and documented progression prior to study entry; and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were required to have adequate bone marrow function (assessed by laboratory tests for absolute neutrophil count, platelet count, and hemoglobin), kidneys (assessed by serum creatinine and creatinine kinase), liver (assessed by total bilirubin, albumin, and aminotransferases). The minimum interval between any previous treatment and the start of the study should be 3 weeks for chemotherapy, 4 weeks for immunotherapy or radiotherapy, and 2 weeks for any investigational or palliative treatment. Only patients with grade 1 or lower toxicity from any of the previous treatments were included, except for cases with alopecia and peripheral sensory neuropathy (both grade 2), which were also permitted. Women of childbearing age had to receive adequate birth control during the study and for at least 3 months after the study ended. Patients were excluded if they: had previously received lurbinectedin or trabectedin; Prior or concurrent malignant disease unless in complete remission for more than 5 years; known CNS involvement (initial screening for CNS metastasis is mandatory); Unstable or serious co-existing medical condition within the past year (history or presence of unstable angina, myocardial infarction, congestive heart failure, valvular heart disease, arrhythmia, severe dyspnea, or active infection such as hepatitis or HIV); impending need for radiotherapy; or inability or limited compliance with the study protocol. More details about the inclusion and exclusion criteria can be found in Table 11. 9807108-1 M&C P0931420WOA Inclusion Age 218 years. Voluntary signals obtain the patient's informed consent prior to any study-specific procedure. Pathologically proven diagnosis of small cell lung cancer. Patients must have previously received a line containing chemotherapy. Measurable disease as defined by REClST v1.1 and documented progression prior to study entry. Eastern Cooperative Oncology group performance status 5 2. Adequate major organ function: . Hemoglobin 2 9 g/dL, cell transfusions are clinically permitted; absolute neutrophil count 2 2.0 < 109/L; and platelet count 2 100 X 109/L. . Alanineaminotransferase and aspartate aminotransferase < 3.0 <ULN. . total bilirubin < 1.5 < ULN or direct bilirubin <ULN. . Albumin 2 3 g/dL. . Serum creatinine 5 1.5 < ULN or creatinine clearance 2 30 mL/min. . Creatine phosphokinase 5 2.5 <ULN. Washout periods before day 1 of Cycle 1: 9807108-1 Exclusion Previous treatment with lurbinectedin or trabectedin. Prior or concurrent malignant disease, treated cervical carcinoma in situ, basal or squamous cell skin carcinoma, and transitional cell carcinoma of the bladder in situ unless in complete remission for more than five years. Known central nervous system involvement. Brain computed tomography scan or magnetic resonance imaging results should be provided at baseline. Relevant diseases or clinical conditions that may increase the patient's risk: . History or presence within the past year of unstable angina, heart failure, or clinically relevant valvular heart disease or symptomatic arrhythmia or any asymptomatic ventricular arrhythmia requiring ongoing treatment. . Grade 2 3 dyspnea or intermittent oxygen requirement from the beginning of study therapy. M&C P0931420WOA . At least three weeks after the last chemotherapy (six if the treatment involved nitrosourea or systemic mitomycin C. At least four weeks after the last monoclonal antibody-containing treatment or radiotherapy. At least two weeks have passed since the last biologic/investigational treatment (excluding monoclonal antibodies), or palliative radiotherapy (s 10 fractions or 5 to 30 Gy total Grade 5 1 toxicity due to any previous cancer treatment according to National Cancer Institute Common Terminology Criteria for Adverse Events, v.4. Grade 2 allowed in case of alopecia and/or peripheral sensory neuropathy Women should have pregnancy excluded by appropriate testing before commencing the study. Fertile women should use a medically acceptable method of birth control throughout the course of treatment and for at least three months after discontinuation of treatment. Fertile men should use birth control during the trial and for four months after the last infusion 9807108-1 . Active infection. . Unhealed wounds or the presence of any external drainage. . Known chronic active hepatitis or known infection by patients. Pregnant or breastfeeding women and fertile patients (men and women) not using an effective method of birth control.* Impending need for radiotherapy (e.g. risk of painful bone metastasis and/or spinal cord compression). or limiting the ability to follow protocol. *Women of childbearing potential must agree to use an effective method of birth control to avoid pregnancy for the duration of the study (and for at least three months after the last infusion). Fertile men must father a child during the trial and agree to refrain from fathering a child or donating sperm for four months after the last infusion M&C P0931420WOA. They had to agree to refrain from doing so or donating sperm. Study Drug Formulation - Preparation and Administration Lurbinectedin was presented as lyophilized powder for solution concentration for infusion in 4 mg vials. Before use, the 4 mg vials were reconstituted with 8 mL of water for injection to yield a solution containing 0.5 mg/mL lurbinectedin. Patients were given i.v. For administration as an infusion, reconstituted vials were diluted with glucose 50 mg/mL (5%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. The exact composition and reconstituted solution per mL were as shown in Table 12. Table 12. Composition of 4 mg lurbinectedin vials After reconstitution Component Concentration/vial concentration/vial PMO1183 4.0 mg 0.5 mg/ml Sucrose 800 mg 100 mg/ml Sodium hydroxide 5.12 mg 0.64 mg/ml Dosage and Application Lurbinectedin was administered via a central catheter over a total volume of infusion solution of at least 100 mL (on 5% glucose or 0.9% sodium chloride) or, if administered through a peripheral line, always a constant infusion with a minimum total volume greater than 250 mL. It was applied in more than an hour at speed. The starting dose was 3.2 mg/m2. The dose is limited to 2.0 mg/m2 body surface area (e.g. the dose is not allowed to exceed 6.4 mg). Patients should receive Iurbinectedin i.v. every three weeks on Day 1 until disease progression or unacceptable toxicity 9807108-1 M&C P0931420WOA. It was taken as a one-hour infusion. Three weeks was defined as one treatment cycle. Premedication All patients received antiemetic prophylaxis before each treatment infusion. These agents are administered i.v. formulations have been used in this setting: corticosteroid (dexamethasone 8 mg or equivalent), serotonin antagonists (ondansetron 8 mg or equivalent), long-term treatment with oral serotonin antagonists, and two consecutive days of oral dexamethasone. If necessary and in addition to the above, 10 mg orally or i.v. every 8 hours. metoclopramide (or equivalent). Aprepitant and equivalent agents are prohibited in patients treated with Lurbinectedin. If the patient met all treatment criteria described in Table 13, subsequent treatment cycles were administered q3wk (±48 hours). 9807108-1 M&C P0931420WOA Variable Retreatment (Day 1) ECOG PS 5 2 Hemoglobin* 2 8.0 g/dl Platelets 2 100 x 109/l AST/ALT 5 3.0 x ULN Total bilirubin or 5 1.5 x ULN or direct bilirubin x ULN Albumin 2 3 g/dl Serum creatinine 1.5 < ULN or creatinine clearance 2 30 mI/min Other non-hematological related AEs increased GGT and/or AP; constipation, peripheral neuropathy to drug (excluding isolated grade 2 asthenia, alopecia, or suboptimally treated nausea and/or vomiting) Active infection (any grade) and/or bleeding AE(s), adverse event(s); ANC, absolute neutrophil count; AP, alkaline phosphatase; AST/ALT, aspartate aminotransferase/alanine aminotransferase; CPK, creatinine phosphokinase; Group; GGT, gamma-glutamyltransferase; PS, performance status; ULN, upper normal nerve. Patients received transfusion of packed red blood cells and/or erythropoietin therapy if clinically indicated to increase/maintain adequate hemoglobin levels. If a patient did not meet the 9807108-1 M&C P0931420WOA treatment requirements again on day 1 of any subsequent cycle, regardless of the cause, reassessments were performed at least every 48-72 hours. Treatment was then stopped until appropriate recovery was achieved, up to a maximum of three weeks after maturity. After a maximum delay of 3 weeks, patients who did not meet the criteria for retreatment had to withdraw from the study. For any delay resulting from treatment-related adverse events lasting more than one week, a dose reduction was applied upon recovery following the guidelines described in the next section. Dose Changes for Adverse Reactions Patients continued treatment if they presented with any of the following: (1) Grade 2 3 treatment-related non-hematological toxicity. Exceptions were: grade 23 nausea and/or vomiting that was not optimally treated, S grade 3 asthenia lasting 3 days, grade 3 diarrhea lasting 2 days or not optimally treated, grade 3 transient ALT that was rapidly reversible and did not lead to subsequent delays. /AST elevations and non-clinically relevant biochemical abnormalities. (2) Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with Grade 2 to 3 bleeding. (3) Grade 4 neutropenia, any grade febrile neutropenia, or infection/sepsis-associated neutropenia. (4) Frequent long-term (1 week) dose delays due to treatment-related adverse events. Study treatment was discontinued in patients who experienced Grade 3 or 4 hypersensitivity reactions. Previous analysis with lurbinectedin administered following a dose based on body surface area has shown that the incidence of febrile neutropenia with lurbinectedin use is less than 10%. Therefore, according to the American Society of Clinical Oncology and European Society of Medical Oncology guidelines, primary prophylaxis with granulocyte colony-stimulating factors (G-CSF) was not allowed (secondary prophylaxis with G-CSF for neutropenia was allowed). Dose reduction levels are shown in Table 14 below: 9807108-1 M&C P0931420WOA Table 14. Dose Modification Dose Reduction Lurbinectedin Dose (mg/m2) 1 (initial dose) 3.2** **Dose, BSA, will be limited by body surface area. Up to 2 dose reductions per patient were allowed. Patients who continued to experience treatment-related toxicity and/or frequent dose delays after permitted dose reductions were withdrawn from the study. If objective clinical benefit is adequately documented, they can continue taking the study drug. After a dose reduction for an individual patient, the dose was not increased again under any circumstances. Efficacy Evaluations The primary objective of this study was to evaluate the antitumor activity of Iurbinectedin in terms of overall response rate (ORR) as the primary endpoint, supported by duration of response (DOR) as the secondary endpoint. ORR was assessed using REClST v1.1 on a series of measurable lesions, initially identified as target lesions or non-target lesions (if present), and followed until disease progression (PD) by an appropriate method. Radiological tumor evaluation (CT scan or MRI) was performed at baseline and every 6 weeks from the start of study treatment until cycle 6 or evidence of PD and every 9 weeks thereafter. According to REClST v1.1, if an objective response was observed, it had to be confirmed by the same method at least four weeks after the date when the response was first documented. ORR was defined as the percentage of evaluable patients with a confirmed response as complete (CR) or partial response (PR) from the start of treatment to the date of progression or the start of a subsequent treatment or the end of patient follow-up according to REClST v1.1. DOR was calculated from the date of first documented PD, recurrence, or death from any cause in responding patients. Date of response, date of radiologic or clinical PD, and date of death were appropriately recorded and documented according to investigator review and independent review by an independent review 9807108-1 M&C P0931420WOA committee (lRC). The lRC determined the patient's best response and assigned the date of first documentation of response and progression/censoring according to REClST v1.1. Numbers and percentages were calculated for binomial endpoints (i.e., ORR, clinical benefit) with their corresponding exact 95% confidence intervals. Time-to-event variables (OS, PFS, and DOR) and their adjusted time estimates (i.e., PFS4/6 and 086/12) were analyzed according to the Kaplan-Meier method. Evaluation of efficacy endpoints assessed by lA and lRC were analyzed and compared. Pharmacokinetic Evaluations Plasma PK of Lurbinectedin was evaluated during Cycles 1 and 2 in all treated patients. The sampling schedule is shown in Table 15 and Table 16 respectively. PK analysis of plasma-concentration-time data of Lurbinectedin was performed using non-linear mixed-effects modeling and/or non-compartmental analysis. Table 15. Blood samples from PK assessments - Cycle 1 Sampling Sample No. Day Sampling time window * Sample #2 should be collected before EOl D, day; EOl, end of infusion. 9807108-1 M&C P0931420WOA Table 16. Blood samples from PK assessments - Cycle 2 Sample No. Day Sampling time Sampling window * Sample #10 should be taken before EOl; D, day; EOl, end of infusion. Safety Assessment Patients were evaluated for safety if they received any partial or full infusion of Lurbinectedin. All adverse events were graded according to the National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCl-CTCAE, v4). Patients' safety profile was monitored throughout treatment and until 30 days after the last Iurbinectedin infusion (end of treatment) or until the patient started a new anti-tumor therapy or until the date of death, whichever occurred first. Treatment delays, dose reduction requirements, transfusions, and reasons for discontinuation were monitored throughout the study. Any treatment-related adverse events were monitored until at least grade 1 improvement or stabilization of symptoms or initiation of a new anti-tumor therapy, whichever occurred first. Study Endpoints Primary Endpoint Overall Response Rate (ORR) ORR is defined as the percentage of patients with a complete (CR) or partial (PR) confirmed response according to REClST (v1.1). Secondary Endpoints Duration of Response (DR) DR, the date at which response criteria (PR or CR, whichever is reached first) is met first, and PD, relapse, or death It is defined as the period between the first date it was documented. Clinical Benefit is defined as ORR lasting more than four months or stable disease (SD 2 to 4 months) PSF is defined as the time from the date of first infusion to the date of PD, death (from any cause), or last tumor evaluation. PFS4/PF86 are defined as Kaplan-Meier estimates of the probability of freedom from progression and death after the first infusion at these time points (4 and 6 months). OS is defined as the time from the date of first infusion to the date of death or last contact if patients were lost to follow-up or survived within the clinical limit established for the cohort. DSG/0812 is defined as Kaplan-Meier estimates of the probability of survival after the first infusion at these time points (6 and 12 months). Non-compartmental (NCA) PK parameters: area under the curve (AUC), Cmax, clearance (CL) and half-life (t1/2). Population PK parameters of the compartment model to be developed (initially based on Volumes and Span) and PK/PD correlation parameters, if any. o Clinical examinations. o Clinical evaluation of AEs and serious adverse events (SAEs). o Changes in laboratory parameters (hematological and biochemical, including liver function tests). o Reasons for discontinuing treatment. M&C P0931420WOA o Reasons for dose reduction and treatment delays. Statistical Methods: This phase II trial was designed to evaluate the antitumor activity of lurbinectedin in terms of ORR according to REClST v1.1 assessed by IA and tumor assessment was also performed by IRC. Up to 100 evaluable patients were recruited to test the null hypothesis that or more patients responded (p 2 0.30). The variance of the standardized test was based on the null hypothesis. The type I error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 0.051 (normal approximation; ~0.05 if exact binomial distribution); therefore, statistical power is 95% (normal approximation; exact binomial distribution is ~95%). With these assumptions, if the number of patients achieving a confirmed response was 2 23, this would allow the null hypothesis to be rejected. For interim analyses, judgment regarding patient evaluability and replacement of unevaluable patients in each cohort was guided by investigator assessment. Duration of Study Period Patients were evaluated at scheduled visits within three study periods: (1) Pretreatment: from signing of the IC to first infusion of study treatment; (2) Treatment: from the first infusion of study treatment to the end of treatment; and (3) Follow-up: after the end of treatment; Patients were followed every 4 weeks until all drug-related adverse events, if any, resolved or stabilized or until new anti-tumor therapy was started. Patients were followed for at least 1 year after the first lurbinectedin infusion. Patients who completed treatment without PD were followed every 2 months for the first six months and then every 3 months until PD, start of a new anti-tumor therapy, death, or end of study. Results 105 SCLC patients were included in the study. All 105 patients were treated and included in the analysis for the primary endpoint. Of the 105 patients treated, 60% were male, 9807108-1 M&C P0931420WOA had previously undergone surgery (curative resection in one patient). 75 patients (71.4%) had previously received radiotherapy. Patients had received a median of one previous line of chemotherapy for advanced disease (range, 1–2 lines). without chemotherapy and was 90 days or longer in 60 (57%) patients. One patient with CNS metastases at baseline was included and another patient rechallenged with carboplatin plus etoposide and atezolizumab as prior line of therapy; these two cases were considered protocol deviations, but they were minor and were included in the primary analysis. A total of 618 treatment cycles were administered, with a median of four cycles per patient, and 46 (44%) patients received six or more cycles. The median relative dose intensity of study drug was 97.4% of the maximum planned dose. Dosing was delayed in 23 (22%) and reduced in 28 (26%) due to treatment-related adverse events. (neutropenia was the most common cause of dose delays in 13 (12%) of patients and 17 (16%) of patients). Efficacy of Lurbinectedin in SCLC Patients At data cutoff, median follow-up time was 17.1 months. According to investigator assessment of all treated patients, 37 (35.2%) showed an overall response as shown in Table 17. Parameter Evaluation Total Resistant Susceptibility (n=105) Disease Disease Overall response rate Investigator 35.2% 22.2% (95% CI) 45.2) 9807108-1 M&C P0931420WOA Parameter Evaluation Total Resistant Susceptibility (n=105) ) Disease Disease 40.2) Response time, Investigator 5.3 months 4.7 months 6.2 months 60 patients with a chemotherapy-free interval of 90 days or longer (i.e., those with chemotherapy-sensitive disease) had a chemotherapy-free interval (290 days - In a preplanned analysis of overall response by <90 days), 27 (45.0%) achieved overall response and median duration of response was 6.2 months, compared with 45 patients with chemotherapy-free duration of less than 90 days (i.e., chemotherapy-refractory disease). ten (22.2%) had overall response, and the median duration of response was 4.7 months. Progression-free survival Investigator-assessed median progression-free survival was 4.6 months in patients with longer overall and 2.6 months in patients with a chemotherapy-free interval of less than 90 days. Eight of 94 patients (9%) who discontinued Lurbinectedin treatment developed new CNS tumors. Therefore, no increase in the incidence of CNS metastases was observed. There was disease progression with lesions. Overall survival was 11.9 months (9.7-16.2) in patients with a chemotherapy-free interval of days or more and 5.0 months (4.1-6.3) in patients with a chemotherapy-free interval of less than 90 days. Specifically, 29 of 60 patients (48%) with a chemotherapy-free interval of 90 days or more and seven of 45 patients (16%) with a 9807108-1 M&C P0931420WOA chemotherapy-free interval of less than 90 days were alive 1 year after the first dose. In a post-hoc analysis, of the 37 patients with an initial objective response, patients with general and susceptible disease (15.8 months, 10.2-not reached) and refractory Safety All 105 treated patients were evaluable for safety (Table 18). The most common Grade 3-4 adverse events and laboratory abnormalities (occurring in 2% of patients) were hematological disorders, anemia (nine [9%] patients), leukopenia (30 [29%]), neutropenia (48 [46%]), thrombocytopenia (seven [7%]) and febrile neutropenia (five [5%]); Of these, only febrile neutropenia was considered to be treatment-related (Table 18). Notably, no cases of drug-induced liver damage have been reported. 23 of 105 patients (22%) received G-CSF secondary prophylaxis or treatment for neutropenia. Treatment-related serious adverse events occurred in 11 of 105 patients (10%); neutropenia and febrile neutropenia were the most common (five [5%] patients each). Grade 3 pneumonia was reported in two (2%) patients; These attacks were associated with grade 3 febrile neutropenia and grade 4 neutropenia, lasted 3 days for one patient and 13 days for the other, and resolved with no clinical consequences. One patient had a grade 3 skin ulcer that did not produce clinical results due to extravasation. Only two (2%) patients discontinued lurbinectedin treatment due to treatment-related adverse events. No treatment-related deaths occurred, but 66 of 105 patients (63%) died from disease progression. Hematological abnormalities (regardless of relationship to study drug)* Thrombocytopenia 39 (37%) 3 (3%) 4 (4%) Biochemical abnormalities (regardless of relationship to study drug)* 9807108-1 M&C P0931420WOA Creatinine 't 86/104 (83%) ) 0 0 Treatment-related adverse events Burnout 54 (51%) 7 (7%) 0 Nausea 34 (32%) 0 0 Decreased appetite 22 (21%) 0 0 Febrile neutropenia 0 2 (2%) 3 (3%) Pneumonia 0 2 (2%) 0 Skin ulcer 0 1 (1%) 0 Data are n (%) patients. NCI-CTCAE=UIusaI Cancer Institute Common Terminology Criteria for Adverse Events version 4-0. *Based on all patients with laboratory data available. rates any creatinine increase as abnormal. Previous Immunotherapy A post-hoc exploratory analysis was performed on response in patients who had previously received immunotherapy (n=8). Data from this group of patients tended to favor single-agent Iurbinectedin in combination with first-line platinum-containing chemotherapy with checkpoint inhibitors or second-line nivqumab (Table 19). This is an important finding in light of the recent approval of atezolizumab in combination with carboplatin/etoposide in first-line SCLC; Therefore, Iurbinectedin may provide a suitable option for patients progressing on immunotherapy. 9807108-1 M&C P0931420WOA Disease Last Lurbinectedin treatment before therapy (resistant __ Best Previous Best or __ I _ Agent or response TTP t PFS DoR OS reim erin immediate sensitive)a J regimen (months) y (months) (months) (all) C/E/Atezolisum Resistant 2 Nivolumab PD 2.5 PR 6.9 5.3 6.9+ CE/Atezolisum Resistant 2 Nivolumab SD 2.2 SD 6.0 - 12.0 Resistant 2 Nivolumab SD 4, 1 PD 1.3 - 4.9 CE/Athezolisum Sensitivity 1 b PR 7.6 PR 7.6 6.4 9.3 Sensitivity 2 Nivolumab PD 1.4 PD 1.3 - 2.3 Summary and Conclusions 105 SCLC patients recorded and treated with Iurbinectedin. Median follow-up time was 17.1 months (lQR 6.5-25.3). Common adverse events (regardless of causation) by investigator assessment included hematological abnormalities—namely, anemia (in nine [9%] patients), leukopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (in seven [7%]). ]) was. Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients each). No treatment-related deaths have been reported. Lurbinectedin was active as a second-line treatment for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin may represent a potential new treatment for SCLC patients, especially those with few options in case of relapse. 9807108-1 M&C P0931420WOA Example 8: Clinical Study - Treatment of Solid Cancer Patients with Lurbinectedin and Irinotecan In combination with irinotecan for patients suffering from solid tumors, increasing doses of Iurbinectedin on day (D) 1 every 3 weeks (q3w) plus D1 and a Phase 1 trial to evaluate fixed-dose doses of 75 mg/m2 irinotecan at D8. Patients were enrolled following a standard 3 + 3 dose escalation design. Phase lb/ll expansion was performed at the recommended dose (RD) to investigate the effectiveness in indications where the antitumor activity signal was observed. 9807108-1 M&C P0931420WOA Study Population Details of inclusion and exclusion criteria can be found in Table 20. Inclusion Voluntary, signed and dated written informed consent prior to any procedure. Age 2 18 years. Eastern Group (ECOG) performance status (PS) 5 1. Life expectancy 2 3 months. Cooperative Oncology Up to two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease. There is no limit to previous targeted therapy, hormonal therapy, and immunotherapy (such as nivolumab). Glioblastoma with histologically or cytologically confirmed advanced stage disease of any of the following tumor types; Except for soft tissue sarcoma (GlST)]; Endometrial carcinoma; Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas), regardless of platinum sensitivity; Mesothelioma; Gastroenteropancreatic neuroendocrine tumors (GEP-NET); 9807108-1 Exclusion Concomitant diseases/conditions: History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year. Symptomatic arrhythmia or any uncontrolled Myopathy or CPK requiring ongoing treatment and any significant clinical condition (on two separate determinations made one week apart). Ongoing chronic alcohol consumption or cirrhosis with a Child-Pugh score of B or C. Known Gilbert's disease. Actively uncontrolled infection. Known human immunodeficiency virus immunodeficiency virus (HIV) or hepatitis C (HCV) infection or active hepatitis B. infection. Known human Any past or present chronic inflammatory colon liver disease, past bowel obstruction, pseudo or subocclusion, or stroke. M&C P0931420WOA Small cell lung cancer (SCLC); cancer; Colorectal carcinoma (CRC); Pancreatic adenocarcinoma; Expansion phase: Tumor-specific cohort(s) in RD: Measurable disease according to Response Evaluation Criteria in Solid Tumors (REClST) v1.1. For patients with glioblastoma: REClST measurable disease REClST disease progression during or immediately following last treatment according to any of the criteria listed above. For patients with glioblastoma: documented disease progression to REClST v1.1 RANO criteria. Documented according to v1.1 At least three weeks since last anticancer treatment, including investigational drugs and radiotherapy (except immunotherapy, which should be at least two weeks but not combined with chemotherapy) and at least three weeks since nitrosoureas and mitomycin C (systemic) For patients with glioblastoma: At least 12 weeks from the end of radiotherapy unless: The patient has a new lesion in the field other than radiotherapy or 9807108-1 Significant symptomatic pulmonary fibrosis or interstitial pneumonia, pleural or cardiac effusion. Any other significant disease that, in the opinion of the investigator, would significantly increase the risk associated with the patient's participation in the study. PM01183, previous treatment with trabectedin (Yondelis®), or topoisomerase l inhibitors (irinotecan, topotecan, etc.). Previous topoisomerase inhibitors (e.g., irinotecan) are allowed only in patients with colorectal carcinoma. Previous bone marrow or stem cell transplant or radiation therapy in more than 35% of the bone marrow. Metastases disease Known brain or leptomeningeal involvement. Glioblastoma lesions (primary or advanced with leptomeningeal disease involvement) are eligible. brain metastases or patients must be radiologically stable, i.e. no evidence of progression by repeat imaging for at least 4 weeks (note that repeat imaging must be performed at the time of the study scan), are clinically stable on steroid therapy, and M&C P0931420WOA The patient must undergo brain surgery to remove the tumor before starting the study. He underwent surgery and progressive disease was confirmed histologically. Adequate bone marrow, kidney, liver and metabolic function (assessed within 5 to 7 days before inclusion in the study): platelet count 2 100 ,0 < 10^9/L. Even in the presence of liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 5 3.0 X upper limit of normal (ULN). Alkaline phosphatase (ALP) 5 2.5 < ULN (in case of disease and metastases, s 5 x ULN). Total bilirubin 5 1.5 < ULN or direct bilirubin s ULN. if relevant/liver International Normalized Ratio (lNR) < 1.5 (patient receiving oral anticoagulation therapy). Calculated creatinine clearance (CrCL) 2 mL/minute (using the Cockcroft-Gault formula). Creatine phosphokinase (CPK) 5 2.5 <ULN. Albumin 2 3.0 g/dL(*). Grade s 1 or improvement to baseline from any adverse event (AE) derived from prior treatment is appropriate provided that it does not require alopecia and/or 9807108-1 (patients already taking steroids in the tapering process within two weeks before screening are allowed) results should be provided at baseline. An effective non-user pregnant or breastfeeding screening or contraceptive women and fertile patients (men and women).(*) Limitation of the patient's ability to comply with the treatment or follow-up protocol. M&C P0931420WOA cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade 5 2 except). Study Drug Formulation - Preparation and Administration Lurbinectedin was presented as lyophilized powder for solution concentration for infusion in 4 mg vials. Before use, the 4 mg vials were reconstituted with 8 mL of water for injection to yield a solution containing 0.5 mg/mL lurbinectedin. Patients were given i.v. For administration as an infusion, reconstituted vials were diluted with glucose 50 mg/mL (5%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. The exact composition and reconstituted solution per mL were as shown in Table 12, above. Irinotecan was offered as lyophilized powder for solution concentration for infusion in vials of 40 mg, 100 mg, or 300 mg. Dosage and Administration Lurbinectedin was administered via a central catheter over a total volume of infusion solution of at least 100 mL (on 5% glucose or 0.9% sodium chloride) or, if administered through a peripheral line, always with a minimum total volume greater than 250 mL. It was administered over one hour at a constant infusion rate. Dose levels in patients in the escalation phase (n=39) are as shown in Table 21. Patients receive lurbinectedin i.v. as a one-hour infusion on Day 1 every three weeks. and irinotecan, i.v., as a 90-minute infusion on days 1 and 8. they took it. Three weeks was defined as one treatment cycle. 9807108-1 M&C P0931420WOA Level Irinotecan D1 and D8, Lurbinectedin Treatment DLTs/ Evaluable patients DLTs G3 removal of D8 due to neutropenia Delay DLT (cycle 3); G3 without GB CSF D8 removal due to neutropenia, G4 D8 removal due to neutropenia, 2 episodes 3* (G- D8 removal due to thrombocytopenia, G3 2 episodes of D8 removal due to neutropenia 4* (G- 9807108-1 M&C P0931420WOA (with CSF thrombocytopenia MTD) removal of D8 due to G4 neutropenia Outcome Measures Primary outcome measures were (1) maximum tolerated dose (MTD) and (2) recommended dose (RD). MTD in one-third of evaluable patients was defined as the lowest dose investigated during dose escalation at which one or more of the evaluable patients developed DLT during Cycle 1. RD was defined as the highest dose level explored during dose escalation at which less than one-third of evaluable patients developed DLT during Cycle 1. Secondary outcome measures included safety assessment, peak plasma concentration (Cmax), area under the plasma concentration versus time curve (AUC), volume of distribution based on terminal half-life (Vz), volume of distribution at steady state (Vss), clearance (CL), half-life (t1/2). , assessment of antitumor response (REClST v1.1, initiation of treatment until PD, other antitumor therapy, death, or 12 months after the last evaluable patient is enrolled in the study (end of study), whichever comes first), progression-free survival (first infusion of study treatment date of progression or death or 12 months after the end of the study, whichever comes first) and overall survival (from the date of the first infusion of the study treatment until the date of death or 12 months after the end of the study, whichever comes first). Pharmacokinetic Evaluations Patients underwent PK sampling to evaluate lurbinectedin, irinotecan, and SN38 (the active metabolite of irinotecan), aiming to exclude major drug-drug interactions. 9807108-1 M&C P0931420WOA Safety Assessment Patients were evaluated for safety if they received any partial or full infusion of Lurbinectedin and irinotecan. All adverse events were graded according to the National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCl-CTCAE, v4). The safety profile of patients was monitored throughout treatment and until 30 days after the last administration of study treatment (end of treatment) or until the patient started a new anti-tumor therapy or until the date of death, whichever occurred first. Treatment delays, dose reduction requirements, transfusions, and reasons for discontinuation were monitored throughout the study. Any treatment-related adverse events were monitored until at least grade 1 improvement or stabilization of symptoms or initiation of a new anti-tumor therapy, whichever occurred first. Results 39 patients initially at 5 dose levels (DL, see Table 21, above); 13 were treated at the recommended dose (RD). 56% were women, defined as median of 2 previous lines of chemotherapy for disease (range, 0 to 4), at D1. In Cycle 1, dose-limiting toxicities were observed in 3/13 evaluable patients at maximum tolerated dose (MTD) and RD. At MTD and RD, DLTs were missing doses of irinotecan D8 due to grade (G) 3-4 neutropenia (n = 3 patients) or G2-4 thrombocytopenia (n = 2). Common G1/2 toxicities in RD were nausea, vomiting, fatigue, diarrhea, anorexia, and neuropathy; G3/4 hematological abnormalities included neutropenia (33%) but no thrombocytopenia. Pharmacokinetic Data: Concentration time data for Lurbinectedin, irinotecan, and SN-38 were available from 39 patients. The mean (±SD) of the main PK parameters, along with those reported on site, are given in the Table below. Based on comparability with reference PK data, these PK results for the three analytes evaluated do not suggest any major type of drug-drug interaction, indicating that the drug combination of Iurbinectedin and irinotecan can be safely administered from a PK perspective. Compound Dose n Cmax CL HL (h) Vz (L) Level (ng/mL) (L/h) (22.4) (345.5) -- (label) 64 NA (11.9) Efficacy Data Some cases Encouraging activity has been observed in patients with SCLC, including as third-line therapy. Activity signals were also observed in endometrial carcinoma and soft tissue sarcoma (STS) and glioblastoma (GBM). Consequently, a Phase II expansion of RD to further investigate efficacy and safety in SCLC, GBM, STS, and endometrial carcinoma. A total of 59 patients were treated at RD, including n=15 SCLC, n=11 endometrial cancer, n=10 STS, and n=20 GBM patients. Efficacy data per tumor type at all doses are shown in the table below. Tumor Type SCLC Endometria STS GBM (Evaluable (n=13) I (n=10) (n=16) number of patients) 9807108-1 M&C P0931420WOA Tumor Type SCLC Endometria STS GBM (Evaluable (n=13) I (n=10) ) (n=16) number of patients) (n=10) Median DoR (months) 4.6 4.6 - - Safety Two patients (3.4%) discontinued treatment due to a treatment-related adverse event (Bilirubin G2, weakness G3). has left. Dose reductions were made in 17 patients (28.8%) (76% of the reductions were not due to irinotecan omissions on day 8 related to adverse events (mostly due to hematological toxicity). Treatment-related death was due). No irinotecan infusions occurred on the 8th day. A detailed description of the adverse events and laboratory abnormalities observed in RD patients is shown in Table 24. Adverse Events and patients in RD Laboratory LUR + IRI (n=59) Abnormalities G1-2 (%) G3-4 (%) Treatment-related Burnout 33 (55.9%) 5 (8.5%) adverse events Nausea 33 (55.9%) 1 (1.7%) Constipation 7 (11.9%) - Abdominal pain 6 (10.2%) - Anorexia 18 (30.5%) - 9807108-1 M&C P0931420WOA Febrile Neutropenia - 3 (5.1%) Laboratory Anemia 46 (78%) 8 (13.6%) Thrombocytopenia 30 (50.8%) 6 (10.1%) ALT increase 23 (39%) 3 (5.1%) AST increase 23 (39%) 2 (3.4%) Summary and Results RD for solid tumors was 2.0 mg/m2 Iurbinectedin on day 1 with GCS-F and 75 mg/m2 irinotecan over 3 weeks on days 1 and 8 . DLTs are removals of irinotecan, most commonly on day 8 of cycle 1, due to hematologic toxicity. The main toxicities observed were myelosuppression, gastrointestinal, and fatigue. Gastrointestinal and myelosuppression were predictable and manageable. Promising activity has been observed in SCLC. Significant activity has been observed in endometrial carcinoma, and hints of activity have been found in STS (especially Ewing and synovial sarcoma). Moderate activity was observed in glioblastoma patients. Expansion cohorts in SCLC, endometrial carcinoma, and STS patients are currently ongoing to enroll a total of 20 patients in each indication. Lurbinectedin Solid State Form Examples Abbreviations: DSC Differential scanning calorimetry DVS Dynamic vapor absorption XRPD X-ray powder diffractograms TG-FTlR Thermogravimetry combined with Fourier transformed infrared spectroscopy r.h. Relative humidity Cie GmbH). The pattern was created by applying a step size of 0.02° 2-theta with 12 seconds per step in the 1.5° to 50.5° 2-theta angle range at a tube voltage of 40 kV, a tube current of 40 mA. was recorded. The detector pitch was 1° 2-theta. Typical precision of 2 theta values is in the range of approximately ± 0.2° 2 theta. Therefore, a diffraction peak appearing at 5.0° 2-theta may appear between 4.8 and 5.2° 2-theta on most X-ray diffractometers under standard conditions. TG-FTlR experiments were performed in N2 with a Thermo-Microbalance TG- equipped with a FT-lR Spectrometer Vector 22 (Bruker) using an Al crucible (open or micro-hole) with a heating range between 25 and 250 °C and a heating rate of 10 oC/min. was carried out under atmospheric conditions. DSC experiments were performed with a Perkin Elmer DSC 7 using sealed Au crucibles with a heating range from −50 to 250 °C and a heating rate of 10 or 20 °C/min. DVS experiments were performed with a Projekt Messtechnik SPS 11-100n multi-sample water vapor absorption analyzer. The sample was allowed to equilibrate at 50% relative humidity before starting a predefined humidity program. The schedule was: - 2 hours at 50% relative humidity - 50% to 0% relative humidity (5%/hour) - 5 hours at 0% relative humidity - 0% to 95% relative humidity (5%/hour) - 95% relative humidity 5 hours - 95% to 50% (5%/hour) - 2 hours at 50% relative humidity It was obtained by following the procedure described in . XRPD pattern of Form A of Lurbinectedin confirmed that this form is amorphous. See Figure 1. Several batches of Lubinectedin Form A were produced by this method. Analytical results for the five are shown in Table 25. Discrete PO1 P02 PO3 PO4 R05 Acetonitrile 0.01 Dichloromethane Residual Solvents Ethyl acetate ND: not detected LOQ: limit of quantification Table 26 shows the impurity profile of several batches of Form A lurbinectedin. 9807108-1 M&C P0931420WOA Impurity 0.66- 0.72- 0.90- 1.10- 1.27- 1.29- 1.30- 1.28- 2.41- RRT - Relative Retention Time Example 10. Production of Lurbinectedin Form B was prepared by dissolving crude lurbinectedin (10 g) obtained as described in Example 1, aqueous HCl (0.1 pentane (1X) and treatment with an aqueous NH4Cl/NH4OH solution. Form B of Lubinectedin was precipitated, which was filtered, washed with water and dried under vacuum to yield 7.5 9, 9.45 mmol. Several batches of Lubinectedin Form B were produced by this method. Analytical results for ten are shown in Table 27. Dashed 1924 1924 Total Impurities nitriI Q Q Q Q Q Q Q Q Q Q 2 Q Q Q Q Q Q Q Q Q Q Q Solvents t NA NA NA NA NA Q NA NA NA Q Hexa LOQ: limit of quantification NA: not analyzed 9807108-1 M&C P0931420WOA Form B of Lurbinectedin relative to Form A of Iurbinectedin As an additional advantage, Table 28 shows the impurity profile (% area) of several batches of Form B of Iurbinectedin. Impurity Form B 2 8 2 6 4 1.10-1.11 - - - - 0.06 - - 1.12 - - - - - - - - - - 1.27-1.34 - - - - - - - - - - 1.29-1.30 - - - - - - - - - - 1.30-1.32 - - - - - - - - - - 1.28-1.37 - - - - - - - - - - 2.41-2.52 - - - - - - - - - - 2.85 - - - - - - - - - - RRT - Relative Retention Time A comparison between the impurity profiles of the A and B forms of Lubinectedin , clearly shows that it offers less impurities. Solid State Characterization - Form B of lubinectedin was characterized by XRPD, 1R, TG-FT1R, DSC and DVS. XRPD patterning of several batches of Lubinectedin Form B confirmed that this form was partially crystalline (broad peaks, amorphous background) and that the process for its production was 9807108-1 M&C P0931420WOA reproducible. See Figures 2a and 2b. XRPD angles 2-theta and Iurbinectedin are shown. The relative intensities of two batches of Form B are in Table 29. Table 29 73 9.0 62 9.0 64 9.8 31 9.6 30 TG-FTlR indicates degradation above 150 0C for Form B of Iurbinectedin. It was not possible to predict amorphous content by DSC. It has been observed that deterioration begins above 130 0C, see. Figure 4. A glass transition temperature or melting point was not detected. DVS shows continuous water uptake and release, stepless and virtually hysteresis-free. This is due to the partially amorphous character of Form B. The sample is not soluble with moisture. Am (50% to 96% r.h.) z A mass change of 4% was observed, indicating 9807108-1 M&C P0931420WOA that lurbinectedin Form B is hygroscopic. By lowering the relative humidity again, the water content decreased and almost returned to the original mass, see fig. Figure 5. Relative Stability of Lurbinectedin Form B - Three 1:1 mixtures of Lurbinectedin forms A and B (15 mg each) were prepared and suspended in water (1 mL). Samples were taken after 6 and 24 hours. Powder patterns after 6 and 24 hours are consistent with those of the Form B starting material. See Figure 6. Both patterns after phase compensation show sharper peaks and higher peak resolution. These are indicators of improved crystallinity. It was not possible to quantify the amorphous content with the available data. 1R spectra were obtained for Form A of lurbinectedin shown in Figure 7a and for Form B of lurbinectedin shown in Figure 7b. The correlation factor between the lR of the three batches of Lurbinectedin Form B and the lR of Lurbinectedin Form A varies between 0.81 and 0.86. On the other hand, the correlation factor of several lR spectra of Iurbinectedin Form A varies between 0.97 and 0.99. Example 11. Electrostatic charge measurements in air were measured using Form A of Lurbinectedin (Batch P04 and R05) and Form lurbinectedin using a Faraday cage made of stainless steel (See Figure 8) with concentric spheres of 20 cm ratio. This technique consists of placing the sample (q) to be measured on the inside of the inner sphere (a) and measuring the induced potential difference between the sphere (a) and another reference conductor, the sphere (b). The outer sphere (c) is grounded to protect the system. Measurements of the potential difference were made with a sensitive electrometer (Keithley 617, resolution 10fC). Measurements were carried out under a controlled dry nitrogen atmosphere to prevent the effect of ambient humidity on the electrostatic charge of the samples. Samples were placed in glass capsules using non-conductive equipment to prevent loss of electrostatic charge. Capsules loaded with samples were placed in a Faraday cage via a grounded conductive tube to avoid parasitic static charges in the glass capsule. The entry and exit of the capsules were performed by a computer-controlled servo motor to ensure a constant entry and exit speed of the capsules in each measurement to minimize the generation of static charges resulting from the friction of the insulating elements 9807108-1 M&C P0931420WOA. Results: Several measurements were made with different amounts of material for each batch of each form of lurbinectedin. The capsules were washed before loading and their remaining static charge was measured to correct levels. Each sample was inserted and removed five times, and several consecutive measurements were taken after each introduction to average out any possible drift effects. Figures 9a and 9b summarize the results of such measurement for each pair of the A and B forms of lurbinectedin. The measured load Q increases with the amount of material analyzed. Both forms of Lurbinectedin have a positive electrostatic charge. Form A of lurbinectedin has a significantly higher total static charge than Form B of lurbinectedin. The data were fitted by linear regression (dashed lines in Figures 9a and 9b) to obtain the charge density (Q/m) as the slope of the line. Extrapolation of the linear regression to a mass of 0 mg represents the residual electrostatic charge of the glass capsules and does not affect the Q/m value. The results of this regression and the distribution of load density are summarized in Table 30. All ranges Form Discrete density (le) distribution of average charge density (le) Figures 10a and 10b show the distribution of charge density for each pair of forms A and B of lurbinectedin. 9807108-1 M&C P0931420WOA Form B of Lurbinectedin has been shown to have an average charge density one order of magnitude lower than Form A of Lurbinectedin. This difference in triboelectrification was demonstrated using two different batches of each form. Example 12. Exemplary process for the production of a pharmaceutical composition using Form B as starting material Lurbinectedin Form B was dissolved in a concentrated lactic acid solution (0.31 M) at a concentration of 25 mg/ml. This solution was then diluted with water for injection (WFl) into a lactic acid solution (0.1 M) containing PM01183 at a concentration of 8.33 mg/ml. This solution was then added to a pre-prepared sucrose/buffer solution (pH) consisting of lactic acid (3.7 mg/ml), sodium hydroxide (1.1 mg/ml) and the bulking agent sucrose (167.7 mg/ml). = 4.2) was added with mixing. If necessary, the mixed solution will be adjusted to pH = 4.0 with lactic acid solution or sodium hydroxide solution. Then, by bringing the batch solution to the final volume or weight (taking into account the density value of 1.04 g/cc), the final bulk solution (0.5 mg/ml lurbinectedin, 2.76 mg/ml lactic acid, 0.64 mg/ml NaOH) , 100 mg/ml sucrose) was created. The bulk solution was then filtered through sterilizing PVDF filters (0.22 μm) and filled into 30 ml glass vials at 8 ml/vial. Vials were lyophilized according to a cycle detailed in Table 31. After lyophilization, the vials were closed with collapsible caps and stored at +5 °C. Step (conditions) Time Freezer, -5 °C 1.5 h Freezer, -40 °C 5.5 h Primary drying (-25 °C, 0.1-0.2 mb) 60 h Secondary drying (+25 °C) C, maximum 30 hrs 9807108-1 M&C P0931420WOA Stopper NA NA: Not Applicable Although the invention has been described in detail with reference to its specific embodiments, it will be understood that functionally equivalent variations are within the scope of this invention. In fact, various modifications of the invention in addition to those shown and described herein, It will be apparent to those skilled in the art from the foregoing description and accompanying drawings that such modifications are intended to fall within the scope of the appended claims (and clauses). Many equivalents to specific embodiments of the invention described herein will be recognized or identified by those skilled in the art without the use of anything more than routine testing. Equivalents are intended to be encompassed by the following claims (and clauses).All publications, patents and patent applications cited in this specification are incorporated herein as if each individual publication, patent or patent application were specifically and individually incorporated herein by reference in their entirety. incorporated by reference into the specification. 9807108-1 M&C P0931420WOA The invention will now be described with reference to: 1. A method for treating small cell lung cancer (SCLC) in a patient, characterized in that; comprising: (1) administering to the patient a prophylactic dose of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of lurbinectedin to the patient on and before the day of administration of lurbinectedin; and (2) administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m2. 2. It is a method according to Article 1 and its feature is; where corticosteroid is an 8 mg dose of dexamethasone administered intravenously or a dose of corticosteroid equivalent to a dose of 8 mg dexamethasone administered intravenously. 3. It is a method according to Article 1 or 2 and its feature is; wherein the serotonin antagonist is a method according to any one of clauses 1 to 3, characterized in that the serotonin antagonist is a dose of 8 mg of onasetron administered intravenously or a dose equivalent to 8 mg of onusetron administered intravenously. It also includes administering one or more antiemetic agents to the patient within 2, 3, or 4 days after administration of lurbinectedin. . It is a method according to Article 4 and its feature is; wherein the one or more antiemetic agents administered after administration of lurbinectedin are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 6. It is a method according to Article 5 and its feature is; wherein one or more antiemetic agents are administered at a dose of 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 9807108-1 M&C P0931420WOA 7. Method according to any one of clauses 1 to 6, characterized in that; wherein the patient is not treated with doxorubicin in combination with Iurbinectedin. 8. Method according to any one of Articles 1 to 7, characterized in that; where the patient has progressed after previous platinum-containing therapy or previous immunotherapy. 9.A method for treating small cell lung cancer (SCLC), including metastatic SCLC, in a patient in need thereof; (1) If the patient's absolute neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000/mm3, the first dose of 3.2 mg/m2 lurbinectedin is administered to the patient via intravenous infusion; and (2) identifying the adverse reaction in the patient after such administration, where the adverse reaction is Grade 2 hepatotoxicity or other adverse reaction, 2 Grade 3 (severe) hepatotoxicity or other adverse reaction, Grade 4 thrombocytopenia (platelet count less than 0.000 cells/mm3). Grade 3 thrombocytopenia with bleeding (platelet count less than 50,000 cells/mm3), Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade febrile neutropenia (Neutrophil count <LLN); (3) after the adverse reaction is identified and 21 days after administration of the first dose or after the patient's neutrophil count exceeds 1500 cells/mm3; platelet count is greater than approximately 100,000 mm3 and optional hemoglobin levels are greater than approximately 9 g/dL and hepatotoxicity or other adverse reaction is Grade 1 or less: (i) the adverse reaction described is greater than isolated Grade 4 neutropenia (neutrophil count less than 500 cells/dl). mm3), give the patient Iurbinectedin at a dose equal to the first dose every three weeks with G-CSF prophylaxis; 9807108-1 M&C P0931420WOA (ii) if the described adverse reaction consists of Grade 2 hepatoxicity or another adverse reaction, administer Iurbinectedin to the patient every three weeks at a dose equal to the initial dose; or (ii) identified adverse reaction 2 Grade 3 (severe) hepatotoxicity or other adverse reaction, Grade 4 thrombocytopenia (platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia with bleeding (platelet count less than 50,000 cells/mm3), or Any degree of febrile neutropenia involves giving the patient a lower dose of Iurbinectedin compared to the initial dose every 3 weeks. . It is a method according to Article 9 and its feature is; where the first reduced dose is 2.6 mg/m2. 11. It is a method according to Article 10 and its feature is; if the patient experiences 2 Grade 3 (severe) hepatotoxicity or other adverse reactions, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia with bleeding (after administration of a reduced dose of 2.6 mg/m2). platelet count less than 50,000 cells/mm3) or if the patient experiences any degree of febrile neutropenia, 21 days after administration of the previous dose, or the patient has neutrophil count greater than mm3 and hemoglobin levels greater than approximately 9 g/dL and may experience hepatotoxicity or other adverse events. The reaction is Grade 1 or less, involves administering the patient a second reduced dose of lurbinectedin 2.0 mg/m2 every three weeks. 12. It is a method according to Article 11 and its feature is; In addition, if the patient does not reach an absolute neutrophil count of at least 1500 cells/mm3 and a platelet count of at least 100,000/mm3 within 2 weeks of the planned dose, after the identification of the adverse reaction after the administration of the second reduced dose 13. It is a method according to any of the previous items, its feature is; wherein Iurbinectedin is prepared by diluting 4 mg of a lyophilized formulation consisting of Iurbinectedin, a buffer derived from an organic carboxylic acid (e.g. lactic acid) and a disaccharide (e.g. sucrose), having a pH value of 3.5 to 4 when reconstituted. It is applied as an infusion formulation between .5 and . 14. A method of treating small cell lung cancer (SCLC) in a patient, characterized in that: comprising: administering lurbinectedin to the patient by intravenous infusion of a lurbinectedin infusion solution at a dose of 3.2 mg/m2, wherein the lurbinectedin infusion solution administered to the patient consists of 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid and a pH of 3.5 to Containing a disaccharide that has been reconstituted to form a solution diluted at 4.5. It is a method according to Article 14 and its feature is; wherein the disaccharide is sucrose and optionally wherein the composition comprises lurbinectedin and sucrose in a ratio of 1 mole of lurbinectedin: 455 to 465 moles of sucrose. 16. It is a method according to Article 14 or 15 and its feature is; wherein the organic carboxylic acid is lactic acid and optionally wherein the composition includes lurbinectedin and lactic acid in a ratio of 1 mole lurbinectedin: 44 to 54 moles lactic acid. 17. Method according to any of Articles 14 to 16, characterized in that; wherein pH is 3.8 to 4.5 18. The method according to any one of clauses 14 to 17, characterized in that; wherein the lyophilized composition was reconstituted in approximately 8 mL of an aqueous solution to obtain the reconstituted solution. 19. It is a method according to Article 18 and its feature is; wherein lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. . It is a method according to any of Articles 14 to 19, and its feature is; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 9807108-1 M&C P0931420WOA 21. It is a method according to Article 20 and its feature is; where isotonic solution 22. It is a method according to any of the previous articles, its feature is; wherein the lyophilized composition contains: 22.1 mg lactic acid; .1 mg sodium hydroxide; and 800 mg sucrose, or wherein the lyophilized composition contains 800 mg sucrose, 0.245 mmol lactate, and 0.128 mmol sodium. 23. It is a method according to any of the previous articles and its feature is; wherein the lyophilized composition is provided in a 30 mL vial. 24. It is a method according to any of the previous articles and its feature is; wherein the lyophilized composition is 0.8%, based on the total weight of lurbinectedin. It is a method according to any of the previous articles and its feature is; wherein the lyophilized composition does not contain a phosphate buffer. 26. It is a method according to any of the previous articles and its feature is; wherein the reconstituted solution or lurbinectedin infusion solution is 0.8%, 0.7%, 0.6%, 0.5% or 27 based on the total weight of lurbinectedin. The method according to any one of clauses 14 to 26, characterized in ; 9807108-1 M&C P0931420WOA 28. It is a method according to Article 27, characterized in that; a prophylactic dose of an effective corticosteroid and a serotonin antagonist is administered to the patient on and before the day of administration of lurbinectedin to reduce the nausea associated with the administration of lurbinectedin to the patient. where corticosteroid is an 8 mg dose of dexamethasone administered intravenously or a dose of corticosteroid equivalent to a dose of 8 mg dexamethasone administered intravenously. 29. It is a method according to Article 27 or 28 and its feature is; wherein the serotonin antagonist is a dose of 8 mg of onusetron administered intravenously or an equivalent dose of 8 mg of onasetron administered intravenously. It is a method according to any of Articles 27 to 29, and its feature is; It also includes administering one or more antiemetic agents to the patient within 2, 3, or 4 days after administration of lurbinectedin. 31. It is a method according to Article 30 and its feature is; wherein the one or more antiemetic agents are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 32. It is a method according to Article 31 and its feature is; wherein the one or more antiemetic agents are 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 33. It is a method according to any of the previous articles and its feature is; It also includes administering G-CSF to a patient whose neutrophil count is determined to be greater than 500/mm3 or any value below the normal range and is associated with infection/sepsis. 34. It is a method according to any of the previous articles and its feature is; where one dose of lurbinectedin is administered per treatment cycle and the patient receives at least 1 treatment cycle. . It is a method according to any of the previous articles and its feature is; where CTFl range The overall response rate for patients with <90 days is at least 11% or at least 20%, or for patients with a CTFl interval of 90 days, the overall response rate is at least 30% or at least 40%. 36. It is a method according to any of the previous articles and its feature is; where CTFl range For a patient with a CTFl interval of <90 days, the response time is at least 2.5 months or at least 4.5 months, or for a patient with a CTFl interval of 90 days, the response time is at least 3.5 months, months, or 6 months. 37. It is a method according to any of the previous articles and its feature is; wherein the patient has not received platinum-containing therapy for at least 30 or at least 60 or at least 90 days prior to lurbinectedin administration. 38. It is a method according to any of the previous articles and its feature is; where the patient had stopped responding to a platinum-containing treatment prior to lurbinectedin administration. 39. It is a method according to any of the previous articles and its feature is; Here, the patient has previously received immunotherapy. 40. It is a method according to Article 39 and its feature is; wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody or an anti-PD-L1 antibody. 41. It is a method according to Article 40 and its feature is; where the immunotherapy is atezolizumab optionally in combination with carboplatin and etoposide or nivolumab. 42. Method according to any of Articles 39 to 41, characterized in that; where the patient progressed after receiving immunotherapy. 43. It is a method according to any of the previous articles and its feature is; where the patient's calculated creatinine clearance is more than 30 mL/min and AST or ALT value is 3 44. It is a method according to any of the previous articles, its feature is; where Lurbinectedin achieves total plasma 9807108-1 M&C P0931420WOA Cmax at 80% to 125% of approximately 107 pg/L and AUC°°° at 80% to 125% of approximately 551 pg*h/L It is administered to a patient as a 1-hour intravenous infusion. 45. It is a method of storing a lyophilized lurbinectedin composition and its feature is; 4 mg lurbinectedin; a buffer derived from an organic carboxylic acid; and storing a lyophilized composition containing the disaccharide at 50°C ± 3°C for at least 48 months, wherein the lyophilized composition is formulated such that reconstitution with 8 mL of water yields a solution having a pH of 3.5 to 4.5; and wherein, after 24 months of storage, the amount of Impurity D present in the composition, weight/weight relative to the total weight of lurbinectedin 46. Method according to Article 45, characterized in that; wherein after 48 months of storage the amount of Impurity D present in the composition is not more than 0.8% w/w based on the total weight of lurbinectedin. 47. It is a method according to Article 45 or 46 and its feature is; wherein the lyophilized composition contains 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide; and 800 mg sucrose, or wherein the lyophilized composition contains 800 mg sucrose, 0.245 mmol lactate and 0.128 mmol sodium. 48. Method according to any of Articles 45 to 47, characterized in that; wherein the lyophilized composition is stored in a 30 mL vial. 49. It is a pharmaceutical product and its feature is; 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide; and a lyophilized composition comprising 800 mg sucrose or a lyophilized composition comprising 800 mg sucrose, 0.245 mmol lactate and 0.128 mmol sodium; It contains a vial with a label affixed to the vial containing an expiration date of at least 24 months from the date of manufacture. 9807108-1 M&C P0931420WOA 50. It is a method according to Article 49 and its feature is; The label affixed to the vial here includes an expiration date of at least 48 months from the date of production. 51. It is a method according to Article 49 or 50 and its feature is; where the vial is a 30 mL vial. 52. Pharmaceutical product according to any of Articles 49 to 51, characterized in that; wherein the lyophilized composition is 0.8%, 0.7% of the total weight of lurbinectedin, 53. The pharmaceutical product according to any of clauses 49 to 52, characterized in that; wherein the lyophilized composition does not contain a phosphate buffer. 54. It is a method for the treatment of solid tumor, endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma or epithelial ovarian cancer in a patient in need, and its feature is; the method comprising: administering to the patient on the first day of a treatment cycle a topoisomerase inhibitor selected from lurbinectedin and SN-38 and irinotecan; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. 55. It is a method according to Article 54 and its feature is; wherein a topoisomerase inhibitor dose equivalent to 50 mg to 75 mg irinotecan/m2 is administered on day 8 of the treatment cycle. 56. It is a method according to Article 54 or 55 and its feature is; wherein the treatment is a method according to any one of Article 57, Articles 54 to 56, characterized in that; where lurbinectedin is administered at a dose of 2 mg/m2. 9807108-1 M&C P0931420WOA 58. Method according to any of Clauses 54 to 57, characterized in that; wherein the topoisomerase inhibitor is irinotecan and is administered at a dose of 75 mg/m2. 59. Method according to any of Articles 54 to 58, characterized in that; here the treatment cycle is 21 days. 60. Method according to any of Articles 54 to 59, characterized in that; wherein the solid tumor is SCLC, endometrial carcinoma, soft tissue sarcoma or glioblastoma. 61. Method according to any of Articles 54 to 60, characterized in that; wherein the patient is administered G-CSF to manage the myelosuppressive effects of said treatment. 62. Method according to any of Articles 54 to 61, characterized in that; wherein if the patient exhibits hematological toxicity after administration on day 1, then administration of the irinotecan dose on day 8 of the treatment cycle is omitted. 63. Method according to any of Articles 54 to 62, characterized in that; It also includes administering one or more antiemetics on the first day of a treatment cycle. 64. Method according to any of Articles 55 to 64, characterized in that; It is administered as an infusion formulation prepared by diluting mg sodium hydroxide or a reconstituted lyophilized formulation consisting of 0.128 mmol sodium and 800 mg sucrose, with a pH value between 3.5 and 4.5 when reconstituted. 65. It is a method according to Article 64 and its feature is; where pH is 3.8 to 4.5. 66. It is a method according to Article 64 or 65 and its feature is; wherein the lyophilized composition was reconstituted in approximately 8 mL of an aqueous solution to obtain the reconstituted solution. 9807108-1 M&C P0931420WOA 67. It is a method according to Article 66 and its feature is; where Iurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 68. Method according to any of Articles 64 to 67, characterized in that; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare Iurbinectedin infusion solution. 69. It is a method according to Article 68 and its feature is; where isotonic solution 70. The method according to any one of Articles 64 to 69, characterized in that; wherein the lyophilized composition is provided in a 30 mL vial. 71. Method according to any of Articles 64 to 70, characterized in that; It contains a non-existent level of Impurity D. 72. Method according to any of Articles 64 to 71, characterized in that; where diluted solution or Iurbinectedin infusion solution, 0.8%, 0.7%, 73. It is a pharmaceutical composition and its feature is; Lyophilizing an aqueous stock solution containing Iurbinectedin, an organic carboxylic acid, sodium hydroxide, and sucrose to produce a lyophilized powder, wherein the concentration of Iurbinectedin in the aqueous stock solution is 0.5 mg/mL, where the ratio of lurbinectedin to sucrose is 1 mol of lurbinectedin. is 455 to 465 moles of sucrose, wherein the lyophilized powder is formulated such that reconstitution with 8 mL of water yields a solution with a pH of 3.5 to 4.1; and to produce the pharmaceutical composition by storing the lyophilized powder at 50 C ± 3° C for 30 months to 60 months, 9807108-1 M&C P0931420WOA wherein, after storage, the amount of Impurity D present in the composition is % w/w based on the weight of the total Iurbinectedin. It is not more than 0.8. 74. A method for administering a pharmaceutical composition, characterized in that; comprising: reconstitution of a lyophilized pharmaceutical composition in a vial after the composition has been stored for 30 to 60 months, wherein the lyophilized pharmaceutical composition is prepared by lyophilizing a stock solution containing 4 mg of Iurbinectedin, a buffer derived from an organic carboxylic acid, and sucrose, wherein the composition is 1 mol Iurbinectedin: at a ratio of 455 to 465 mol sucrose wherein the lyophilized composition is formulated such that reconstitution with 8 mL of water yields a solution having a pH of 3.5 to 4.5; and administering the diluted solution to a patient. 75. It is a method according to Article 74 and its feature is; wherein the pharmaceutical composition is at least 95% of the amount of Iurbinectedin on the first day of storage. 76. The method according to Clause 74 or 75, characterized in that; where the vial is a 30 mL vial. 77. A method of treating SCLC in a patient, characterized in that; comprising: administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m2; wherein the patient has been administered an immunotherapeutic antibody to treat SCLC prior to initiating the treatment cycle and 9807108-1 M&C P0931420WOA wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months or 6 months or wherein the overall response rate is at least 40% 'truck. 78. It is a method according to Article 77 and its feature is; wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 79. It is a method according to Article 78 and its feature is; wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 80. It is a method according to Article 79 and its feature is; wherein the immunotherapeutic antibody was administered to the patient simultaneously with a chemotherapeutic. 81. It is a method according to Article 80 and its feature is; where the chemotherapeutic is carboplatin or etoposide. 82. It is a method according to Article 81 and its feature is; wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic is carboplatin or etoposide. 83. Method according to any of Articles 69 to 74, characterized in that; wherein one dose of lurbinectedin is administered per treatment cycle and treatment cycle 84. The method according to any one of clauses 77 to 83, characterized in that; where one dose of lurbinectedin is administered per treatment cycle and the patient undergoes at least 2 cycles. 85. Method according to any of Articles 77 to 84, characterized by; where the overall response rate is at least 40% or at least 50% or at least 60%. 86. Method according to any of Articles 77 to 85, characterized in that; Here the response time is at least 2 months, 3 months, 4 months, 5 months or 6 months. 87. Method according to any of Articles 77 to 86, characterized by; wherein the patient has not received the immuno-oncogenic therapeutic antibody for at least 30 or at least 60 or at least 90 days prior to lurbinectedin administration. 9807108-1 M&C P0931420WOA 88. Method according to any of Articles 77 to 87, characterized in that; wherein the patient ceased responding to the immuno-oncogenic therapeutic antibody prior to Iurbinectedin administration. 89. It is a method according to any one of Articles 77 to 87, and its feature is; wherein an immuno-oncogenic therapeutic antibody is not administered simultaneously with Iurbinectedin. 90. It is a pharmaceutical composition and its feature is; Containing 4 mg of Iurbinectedin, a lyophilized composition comprising a buffer derived from an organic acid and a disaccharide, wherein Iurbinectedin and the disaccharide are present in the ratio of 1 mole of Iurbinectedin to 455 to 465 moles of disaccharide, wherein the lyophilized composition reconstitutes with 8 mL of water has a pH of 3 It is formulated to give a solution of .5 to 4.5; and wherein the lyophilized composition further comprises a degradation product resulting from deacetylation of lurbinectedin in a value not greater than the total weight of lurbinectedin. 91. It is a pharmaceutical composition according to Article 90 and its feature is; Available at here. 92. It is a pharmaceutical composition according to Article 90 or 91, and its feature is; where the vial is a 30 mL vial. 93. Pharmaceutical composition according to any one of Articles 90 to 92, characterized in that; wherein the lyophilized composition does not contain a phosphate buffer. 94. Pharmaceutical composition according to any one of Articles 90 to 93, characterized in that; wherein an organic acid derived buffer, a lactic acid buffer, a butyric acid buffer, a propionic acid buffer, an acetic acid buffer, a 9807108-1 M&C P0931420WOA succinic acid buffer, a citric acid buffer, an ascorbic acid buffer, a tartaric acid The buffer is selected from a malic acid buffer, a maleic acid buffer, a fumaric acid buffer, a glutamic acid buffer, an aspartic acid buffer, a gluconic acid buffer, and an oi-ketoglutaric buffer. 95. Pharmaceutical composition according to any one of Articles 90 to 94, characterized in that; wherein the buffer derived from an organic acid is lactic acid. 96. The pharmaceutical composition of any one of clauses 90 to 95, wherein the composition contains 22.1 mg lactic acid; 5.1 mg sodium hydroxide; and contains 800 mg sucrose sodium. 97. A method to reduce lurbinectedin degradation in a lyophilized formulation containing lurbinectedin, characterized in that; The method includes adding lactate buffer to a stock solution from which the lyophilized formulation has been prepared, wherein the resulting ratio of lurbinectedin to lactate buffer is between 1 mol:44 mol and 1 mol:54 mol; wherein the degradation product of lurbinectedin from deacetylation is the weight of the total lurbinectedin when stored for at least 24 months or at least 36 months or at least 48 months or at least 60 months at degrees C ± 3 degrees C. 98. It is the method according to Article 97, its feature is; It involves adding sucrose to a stock solution from which the lyophilized formulation is prepared, where the final ratio of lurbinectedin to lactate buffer is between 1 mol:455 mol and 1 mol:465 mol. 99. It is a method according to Article 97 and its feature is; wherein the lyophilized formulation does not contain a phosphate buffer. It is a method to treat, its feature is; It involves administering lurbinectedin to a patient at a dose of 2 to 3.2 mg/m 2 by intravenous infusion every 3 weeks, wherein lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, and sucrose, wherein the lurbinectedin:lactic acid:sucrose ratio is 1 mol:46 9807108-1 M&C P0931420WOA is stable for at least 24 months or at least 36 months or at least 48 months or at least 60 months at ± 3 degrees C, so that the Iurbinectedin degradation product resulting from deacetylation is the total weight/weight It does not exceed 0.8% of the weight of urbinectedin. 101. It is a method according to Article 100 and its feature is; wherein the topoisomerase inhibitor is administered at a dose equivalent to 75 mg irinotecan/m2 and Iurbinectedin is administered at a dose of 2.0 mg/m2. 102. It is a packaged, lyophilized composition and its feature is; It contains: 4 mg Iurbinectedin, a buffer derived from an organic acid and a disaccharide packaged in a vial, wherein dissolving the lyophilized composition in approximately 8 mL of water provides a solution of Iurbinectedin with a pH of about 3.5 to about 4.1 wherein The lyophilized composition contains less than approximately 0.3% Impurity D (w/w based on Iurbinectedin) when the composition is packaged, wherein upon storage at approximately 5 degrees Celsius for approximately 24 months or approximately 36 months or approximately 48 months the composition contains approximately 0%, Contains not more than 8 Impurities D (a/w based on Iurbinectedin). 103. It is a lyophilized composition according to Article 102 and its feature is; wherein the composition contains substantially the same amount of Impurity D (w/w based on Iurbinectedin) when the composition is packaged and after storage of the composition at about 5 degrees Celsius for about 24 months or about 36 months or about 48 months. 104. It is a composition according to any of Articles 102 to 103, and its feature is; wherein buffer is the salt of an organic anion selected from the group consisting of acetate, succinate, citrate and lactate. 105. It is a lyophilized composition according to Article 104, and its feature is; where salt is lactate. 9807108-1 M&C P0931420WOA 106. Composition according to any of Articles 102 to 105, characterized in that; wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and a combination of two or three disaccharides thereof. 107. It is a lyophilized composition according to Article 106 and its feature is; where the disaccharide is sucrose. 108. It is a lyophilized composition according to Article 107 and its feature is; where the w/w ratio of lurbinectedin to sucrose is approximately 1:200. 109. It is a composition according to any of Articles 102 to 108, and its feature is; wherein the composition contains: 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide mmol lactate and 0.128 mmol sodium. 110. It is a composition according to any of Articles 102 to 109, and its feature is; where dissolution in approximately 8 mL of water provides a lurbinectedin solution with a pH of approximately 4.0. 111. It is a packaged, lyophilized composition and its feature is; It contains: 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide packaged in a vial, wherein dissolving the lyophilized composition in approximately 8 mL of water provides a solution of lurbinectedin with a pH of about 3.8 to about 4.1 wherein The lyophilized composition contains less than approximately 0.3% Impurity D (w/w based on lurbinectedin) when the composition is packaged and wherein the packaged composition is stored at approximately 25 degrees C for up to approximately 1, 2, 3, 6, 9 or 12 months and Contains substantially the same amount of Impurity D (w/w based on lurbinectedin) after storage at approximately 60% relative humidity. 112. It is a composition according to Article 111 and its feature is; wherein the composition is: 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide and 800 mg sucrose 9807108-1 M&C P093142OWOA contains mmol sodium. 113. It is a composition according to Article 111 or Article 112, and its feature is; where dissolution in approximately 8 mL of water provides a lurbinectedin solution with a pH of approximately 4.0. 114. It is a composition according to any of Articles 102 to 113, and its feature is; wherein the composition is prepared by a process comprising: (a) providing a solution of lurbinectedin and an organic acid; (b) providing a solution of a base, an organic acid and a disaccharide; (0) Combining the solutions of Step (a) and Step (b); (d) adjusting the pH of the solution in step (c) to about 3.8 to about 4.1; and (e) Lyophilizing the solution in Step (d) to provide the lyophilized composition. 115. It is a lyophilized composition according to Article 114 and its feature is; wherein the organic acid is selected from the group consisting of citric acid, succinic acid, lactic acid and acetic acid. 116. It is a lyophilized composition according to Article 114 and its feature is; where the organic acid is lactic acid. 117. It is a composition according to any of Articles 114 to 116, and its feature is; where the base is sodium hydroxide. 118. It is a composition according to any of Articles 114 to 117, and its feature is; wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and a combination of two or three disaccharides thereof. 119. It is a composition according to any of Articles 14 to 117, and its feature is; where the organic acid is lactic acid, the base is sodium hydroxide, and the disaccharide is sucrose. 9807108-1 M&C P0931420WOA is a method to treat, its feature is; comprising: 1) dissolving a packaged, lyophilized composition containing 4 mg of lurbinectedin, an organic acid, and a buffer derived from the disaccharide in approximately 8 mL of water to provide a lurbinectedin solution having a pH of about 3.5 to about 4.1, 2) Administering approximately 2 to 3.2 mg/m2 of lurbinectedin by intravenous infusion every 3 weeks to a patient with progressive SCLC following prior platinum-containing therapy, wherein the lyophilized composition contains less than approximately 0.3% Impurity D (lurbinectedin) at the time of packaging. on a w/w basis) wherein upon storage at approximately 5 degrees Celsius for approximately 24 months, the composition contains less than approximately 0.8% Impurity D (w/w on a lurbinectedin basis). 121. It is a method according to Article 120 and its feature is; wherein administration is 1) dissolving a packaged, lyophilized composition containing 4 mg of lurbinectedin, an organic acid, and a buffer derived from the disaccharide in approximately 8 mL of water to provide a lurbinectedin solution having a pH of approximately 3.8 to approximately 4.1, 2) Administration of lurbinectedin to the patient in need wherein the lyophilized composition contains less than approximately 0.3% Impurity D (w/w based on lurbinectedin) when the composition is packaged and wherein upon storage at approximately 5 degrees Celsius for approximately 24 months, the composition contains approximately 0% Contains less than .8 Impurity D (w/w based on lurbinectedin). 9807108-1 M&C P0931420WOA 122. It is a method according to Article 120 or 121, and its feature is; Herein, prior to administration, the lyophilized composition is reconstituted in approximately 8 mL of an aqueous solution to obtain a reconstituted lurbinectedin solution. 123. It is a method according to Article 122 and its feature is; wherein before administration, said reconstituted lurbinectin solution is reconstituted and stored at room temperature or 5°C±3°C for up to 24 hours, wherein after storage, said reconstituted lurbinectin solution is 0.8%, 0.7%, 124%. It is a method according to Article 122 or 123 and its feature is; wherein a lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 125. It is a method according to Article 124 and its feature is; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 126. It is a method according to Article 124 or 125 and its feature is; where the isotonic solution is 0.9% sodium chloride solution or 5% dextrose solution. 127. Method according to any of Articles 120 to 126, characterized in that; wherein the infused lurbinectedin solution is stored at room temperature or 5°C±3°C for up to 24 hours following reconstitution of the lyophilized lurbinectedin formulation, wherein after storage, the reconstituted lurbinectin solution is 0.8%, 0%, based on the total weight of lurbinectedin. 7, 0.6%, 0.5% or the use of lurbinectedin in the production of a drug for use in therapeutic therapy, its feature is; The drug herein shall be administered to the patient at a dose of 2 to 3.2 mg/m2 by intravenous infusion in combination with a prophylactic dose of an effective corticosteroid and a serotonin antagonist to reduce nausea associated with the administration of lurbinectedin to the patient, 9807108-1 M&C P0931420WOA herein prophylactically. The dose is administered to the patient on and before the day of administration of Iurbinectedin. 129. It is a use according to Article 128 and its feature is; wherein the corticosteroid is dexamethasone formulated at a dose of 8 mg dexamethasone for intravenous administration or a corticosteroid dose equivalent to 8 mg dexamethasone administered intravenously. 130. It is a use according to Article 128 or 129 and its feature is; wherein the serotonin antagonist is onasetron formulated at a dose of 8 mg of onasetron for intravenous administration or a dose of serotonin antagonist equivalent to 8 mg of onasetron administered intravenously. 131. Use according to any of Articles 128 to 130, characterized by; wherein said drug is administered in combination with one or more antiemetic agents administered to the patient 2, 3 or 4 days after administration of Iurbinectedin. 132. It is a use according to Article 131 and its feature is; wherein the one or more antiemetic agents administered after administration of lurbinectedin are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 133. It is a use according to Article 132 and its feature is; wherein the one or more antiemetic agents are 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 134. Use according to any of Articles 121 to 126, characterized by; wherein the patient is not treated with doxorubicin in combination with lurbinectedin. 135.Use according to any of Articles 128 to 134, its feature is; where the patient has progressed after previous platinum-containing therapy or previous immunotherapy. It is the use of Iurbinectedin's 9807108-1 M&C P0931420WOA in the production of a drug for use in therapy for the treatment of: wherein the drug in question will be administered to the patient by intravenous infusion at an initial dose of 3.2 mg/m2 in a first treatment cycle and the same dose will be administered in a subsequent treatment unless an adverse reaction is detected in the patient, wherein the adverse reaction is selected from the group consisting of: Grade 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells). /mm3) or any degree of neutropenia (Neutrophil count) associated with infection/sepsis or any other adverse reaction <LLN); after the adverse reaction is identified and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), a G-in combination with a dose of lurbinectedin equal to the initial dose in the subsequent treatment cycle CSF dose is administered; or (ii) if the identified adverse reaction is not isolated grade 4 neutropenia, the patient is administered a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. 137. It is a use according to Article 136 and its feature is; where the first reduced dose after the first occurrence of an isolated Grade 4 non-neutropenic adverse reaction is 80 to 85% of the initial dose, or where the first reduced dose is 2.6 mg/m2 after the first occurrence of an isolated Grade 4 non-neutropenic adverse reaction . 138. It is a use according to Article 137 and its feature is; 9807108-1 M&C P0931420WOA a second reduced dose is 60-65% of the first dose following the second occurrence of an isolated Grade 4 non-neutropenic adverse reaction, or wherein a second reduced dose is administered after the second occurrence of an isolated Grade 4 non-neutropenic adverse reaction. then up to 2.0 mg/m2, where the second reduced dose is administered to the patient. 139. It is a use according to Article 138 and its feature is; where the administration of lurbinectedin is stopped after the identification of an adverse reaction after administration of the second reduced dose. 140. It is a use according to any of the previous articles and its feature is; It is administered as an infusion formulation prepared by diluting mg sodium hydroxide or a reconstituted lyophilized formulation consisting of 0.128 mmol sodium and 800 mg sucrose, with a pH value between 3.5 and 4.5 when reconstituted. It is the use of lurbinectedin in the production of a drug for use in therapy for the treatment of: wherein said drug will be administered to the patient at a dose of 3.2 mg/m 2 by intravenous infusion of a lurbinectedin infusion solution, wherein the lurbinectedin infusion solution administered to the patient contains 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid and a pH of 3.5 to 4. It is prepared from a lyophilized composition containing a disaccharide reconstituted to form a solution diluted at .5. 142. It is a use according to Article 141 and its feature is; wherein the disaccharide is sucrose and optionally wherein the composition comprises lurbinectedin and sucrose in a ratio of 1 mole of lurbinectedin: 455 to 465 moles of sucrose. 143. It is a use according to Article 141 or 142 and its feature is; wherein the organic carboxylic acid is lactic acid and optionally wherein the composition is lurbinectedin and lactic acid in the ratio of 1 mol lurbinectedin: 44 to 54 moles lactic acid 9807108-1 M&C P0931420WOA 144. Use according to any one of Clauses 141 to 143, characterized in that; where pH is 3.8 to 4.5. 145. Use according to any of Articles 141 to 144, characterized by; wherein the lyophilized composition was reconstituted in approximately 8 mL of an aqueous solution to obtain the reconstituted solution. 146. It is a use according to Article 145 and its feature is; wherein lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 147. Use according to any of Articles 141 to 146, characterized by; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 148. It is a use according to Article 146 and its feature is; where isotonic solution 149. Use according to any of Articles 141 to 148, characterized in that; wherein the lyophilized composition contains: 22.1 mg lactic acid; .1 mg sodium hydroxide; and 800 mg sucrose, or wherein the lyophilized composition contains 800 mg sucrose, 0.245 mmol lactate, and 0.128 mmol sodium. 150. Use according to any of Articles 141 to 149, characterized by; wherein the lyophilized composition is provided in a 30 mL vial. 151. Use according to any of Articles 141 to 150, characterized by; wherein the lyophilized composition is 0.8% based on the total weight of lurbinectedin, 9807108-1 M&C P0931420WOA 152. Use according to any of Clauses 141 to 151, characterized in that; wherein the lyophilized composition does not contain a phosphate buffer. 153. Use according to any of Articles 141 to 152, characterized by; wherein the reconstituted solution or lurbinectedin infusion solution is 0.8%, 0.7%, 0.6%, 0.5% or 154 based on the total weight of lurbinectedin. Use according to any of Clauses 141 to 153, characterized by ; is administered to the patient in combination with a prophylactic dose of an effective corticosteroid and a serotonin antagonist to reduce nausea associated with the administration of lurbinectedin, wherein the prophylactic dose is administered to the patient on and before the day that lurbinectedin is administered. 155. It is a use according to Article 154 and its feature is; wherein the corticosteroid is dexamethasone formulated at a dose of 8 mg dexamethasone for intravenous administration or a corticosteroid dose equivalent to 8 mg dexamethasone administered intravenously. 156. It is a use according to Article 154 or 155 and its feature is; wherein the serotonin antagonist is onasetron formulated at a dose of 8 mg of onasetron for intravenous administration or a dose of serotonin antagonist equivalent to 8 mg of onasetron administered intravenously. 157. Use according to any of Articles 154 to 156, characterized by; wherein the drug is administered in combination with one or more antiemetic agents, which are administered 2, 3 or 4 days after administration of lurbinectedin to the patient. 158. It is a use according to Article 157 and its feature is; wherein the one or more antiemetic agents are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 9807108-1 M&C P0931420WOA 159. Use according to Article 158, its feature is; wherein the one or more antiemetic agents are 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 160. It is a use according to any of the previous articles and its feature is; wherein the drug is administered in combination with G-CSF to a patient determined to have a neutrophil count of 500/mm3 or any value below the normal range and is associated with infection/sepsis. 161. It is a use according to any of the previous articles and its feature is; where one dose of lurbinectedin is administered per treatment cycle and the patient receives at least 1 treatment cycle. 162. It is a use according to any of the previous articles and its feature is; where CTFl range The overall response rate for patients with <90 days is at least 11% or at least 20%, or where the overall response rate for patients with a CTFl interval of 90 days is at least 30% or at least 40%. 163. It is a use according to any of the previous articles and its feature is; where CTFl range For a patient with a CTFl interval of <90 days, the response time is at least 2.5 months or at least 4.5 months, or for a patient with a CTFl interval of 90 days, the response time is at least 3.5 months, months, or 6 months. 164. It is a use according to any of the previous articles and its feature is; wherein the patient has not received platinum-containing therapy for at least 30 or at least 60 or at least 90 days prior to lurbinectedin administration. 165. It is a use according to any of the previous articles and its feature is; where the patient had stopped responding to a platinum-containing treatment prior to lurbinectedin administration. 166. It is a use according to any of the previous articles and its feature is; Here, the patient has previously received immunotherapy. 9807108-1 M&C P0931420WOA 167. Use according to Article 166, its feature is; wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody or an anti-PD-L1 antibody. 168. It is a use according to Article 167 and its feature is; where the immunotherapy is atezolizumab or nivolumab. 169. Use according to any of Articles 166 to 168, characterized by; where the patient progressed after receiving immunotherapy. 170. It is a use according to any of the previous articles and its feature is; where the patient's calculated creatinine clearance is more than 30 mL/min and AST or ALT value is 3 171. It is used according to any of the previous articles, and its feature is; wherein Lurbinectedin was administered to a patient over 1 hour to achieve total plasma Cmax at 80% to 125% of approximately 107 pg/L and AUC°° at 80% to 125% of approximately 551 pg*h/L. It is administered as an intravenous infusion. 172. The use of lurbinectedin in the manufacture of a medicament for use in therapy for the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma or epithelial ovarian cancer in a patient in need; wherein said drug will be administered to the patient by intravenous infusion at a dose of 1 to 2.5 mg/m2 in combination with a topoisomerase inhibitor selected from SN-38 and irinotecan on the first day of a treatment cycle, wherein the topoisomerase inhibitor is administered at a dose of 50 to 75 mg irinotecan/m2. It is applied at a dose equivalent to m2. 173. It is a use according to Article 172 and its feature is; wherein lurbinectedin is administered at a dose of 2.0 mg/m2 and irinotecan is administered at a dose of 75 mg/m2 via intravenous administration on day 1 of the treatment cycle. A subsequent irinotecan dose of mg/m2 is administered on day 8 of the treatment cycle. 9807108-1 M&C P0931420WOA 175. Use in accordance with any of Articles 172 to 174, characterized in that; The treatment cycle mentioned here is 21 days. 176. Use according to any of Articles 172 to 175, characterized by; wherein the drug is administered in combination with G-CSF during the treatment cycle. 177. Use according to any of Articles 172 to 176, characterized by; wherein if the patient exhibits hematological toxicity after the day 1 dose, no subsequent dose of irinotecan is administered to said patient during the treatment cycle. 178. Use according to any of Articles 172 to 177, characterized by; It also includes administering one or more antiemetics on the first day of a treatment cycle. 179. Use according to any of Articles 172 to 178, characterized by; here, patients are treated for endometrial cancer, SCLC, soft tissue sarcoma, or glioblastoma. 180. A use of a lyophilized pharmaceutical composition to administer a pharmaceutical composition to a patient in need thereof, characterized in that; wherein the lyophilized pharmaceutical composition is reconstituted in a vial and administered to the patient after the composition has been stored for 30 to 60 months, wherein the lyophilized pharmaceutical composition is prepared by lyophilizing a stock solution containing 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid, and sucrose, wherein the composition is contains lurbinectedin and its disaccharide in a ratio of 1 mol lurbinectedin:455 to 465 mol sucrose, wherein the lyophilized composition is formulated such that reconstitution with 8 mL of water yields a solution with a pH of 3.5 to 4.5. 9807108-1 M&C P0931420WOA 181. Use according to Article 180, its feature is; wherein the pharmaceutical composition contains an amount of Iurbinectedin that is at least 95% of the amount of Iurbinectedin on the first day of storage. 182. It is a use according to Article 180 or 181 and its feature is; where vial is a mL vial. 183. A use of lurbinectedin in the production of a drug for the treatment of SCLC in a patient in need; wherein Iurbinectedin is administered to the patient via intravenous infusion for 2 to 3.2 wherein an immunotherapeutic antibody is administered to the patient prior to initiating the treatment cycle wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months or wherein The overall response rate is at least 40%. 184. It is a use according to Article 183 and its feature is; wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 185. It is a use according to Article 184 and its feature is; wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 186. It is a use according to Article 185 and its feature is; wherein the immunotherapeutic antibody was administered to the patient simultaneously with a chemotherapeutic. 187. It is a use according to Article 186 and its feature is; where the chemotherapeutic is carboplatin or etoposide. 188. It is a use according to Article 187 and its feature is; wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic is carboplatin or etoposide. 9807108-1 M&C P0931420WOA 189. Use in accordance with any of Articles 183 to 188, characterized in that; wherein one dose of Iurbinectedin is administered per treatment cycle and treatment cycle 190. Use according to any of Clauses 183 to 189, characterized in that; Here, one dose of Iurbinectedin is administered per treatment cycle and the patient undergoes at least 2 cycles. 191. Use according to any of Articles 183 to 190, characterized by; wherein the patient is administered 5 doses of Iurbinectedin over a period of 17 weeks, or at least 6 doses of Iurbinectedin over a period of 20 weeks, or at least 7 doses of Iurbinectedin over a period of 22 weeks. 192. Use according to any of Articles 183 to 191, characterized by; where the overall response rate is at least 40% or at least 50% or at least 60%. 193. Use according to any of Articles 183 to 192, characterized by; Here the response time is at least 2 months, 3 months, 4 months, 5 months or 6 months. 194. Use according to any of Articles 183 to 193, characterized by; wherein the patient has not received the immuno-oncogenic therapeutic antibody for at least 30 or at least 60 or at least 90 days prior to Iurbinectedin administration. 195. Use according to any of Articles 183 to 194, characterized by; wherein the patient ceased responding to the immuno-oncogenic therapeutic antibody prior to Iurbinectedin administration. 196. Use according to any of Articles 183 to 195, characterized by; wherein an immuno-oncogenic therapeutic antibody is not administered simultaneously with Iurbinectedin. It is a use of lurbinectedin in the production of a drug for use in the treatment of; wherein Iurbinectedin is administered to a patient at a dose of 2 to 3.2 mg/m2 by intravenous infusion every 3 weeks, wherein the drug is 9807108-1 M&C P0931420WOA wherein Iurbinectedin:lactic acid:sucrose ratio is 1 mol:46 mol:455 mol. Between 1 mol:50 mol:465 mol, where the Iurbinectedin degradation product resulting from deacetylation is stable for at least 36 months or at least 48 months or at least 60 months of the total Iurbinectedin weight, w/w. 198. It is a use according to Article 197 and its feature is; wherein the drug is used in combination with a topoisomerase inhibitor, administered at a dose equivalent to 75 mg irinotecan/m2 and Iurbinectedin administered at a dose of 2.0 mg/m2. It is a use of lurbinectedin in the production of a drug for use in the treatment of; wherein the medicament is a packaged lyophilized composition comprising 4 mg of Iurbinectedin, a buffer derived from an organic acid and a disaccharide, with a pH of about 3.5 to about 4.1, administered to a patient with progressive SCLC every 3 days after prior platinum-containing therapy. For the administration of approximately 2 to 3.2 mg/m2 of Iurbinectedin by intravenous infusion weekly, wherein the lyophilized composition contains less than approximately 0.3% Impurity D (w/w based on Iurbinectedin) when the composition is packaged, wherein the lyophilized composition is packaged for approximately 24 months or approximately Upon storage at approximately 5 degrees Celsius for 36 months, the composition contains less than approximately 0.8% Impurity D (w/w based on Iurbinectedin). 200. Use according to any of Articles 128 to 199, characterized in that; wherein the medicament is a packaged, lyophilized composition comprising 4 mg of Iurbinectedin, an organic acid, and a buffer derived from the disaccharide, and a pH of between about 3.8 and about 4.1 for administration to the patient in need thereof. wherein the lyophilized composition, when the composition is packaged, is about Contains less than 0.3% Impurity D (w/w based on Iurbinectedin) where upon storage at approximately 5 degrees Celsius for approximately 24 months or approximately 36 months, the composition contains less than approximately 0.8% Contains impurity D (a/w based on lurbinectedin). 201. It is a use according to any of the previous articles and its feature is; wherein prior to administration, the lyophilized composition is reconstituted in approximately 8 mL of an aqueous solution to obtain a reconstituted lurbinectedin solution. 202. It is a use according to Article 201 and its feature is; wherein prior to administration, said reconstituted lurbinectin solution is reconstituted and stored at room temperature or 5°C±3°C for up to 24 hours, wherein after storage, the reconstituted lurbinectin solution contains not more than w/w Impurity D. 203. It is a use according to Article 201 or 202 and its feature is; wherein a lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 204. It is a use according to Article 203 and its feature is; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 205. It is a use according to Article 203 or 204 and its feature is; where the isotonic solution is 0.9% sodium chloride solution or 5% dextrose solution. 206. Use according to any of Articles 203 to 205, characterized by; wherein the infused lurbinectedin solution is stored at room temperature or 5°C±3°C for up to 24 hours following reconstitution of the lyophilized lurbinectedin formulation, where after storage the reconstituted lurbinectedin solution is 0.8%, 0%, 0.8% based on the total weight of lurbinectedin. 7, 0.6%, 9807108-1 M&C P0931420WOA is a composition for the treatment of patients and its features are; comprising: (1) administering to the patient a prophylactic dose of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with the administration of lurbinectedin to the patient on and before the day of administration of lurbinectedin; and (2) administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m2. 208. It is a lyophilized composition according to Article 207, and its feature is; where corticosteroid is an 8 mg dose of dexamethasone administered intravenously or a dose of corticosteroid equivalent to a dose of 8 mg dexamethasone administered intravenously. 209. It is a lyophilized composition according to Article 207 or 208, and its feature is; wherein serotonin antagonist is a dose of 8 mg of onasetron administered intravenously or a dose of serotonin antagonist equivalent to 8 mg of onasetron administered intravenously. 210. It is a composition according to any of Articles 207 to 209, and its feature is; It also includes administering one or more antiemetic agents to the patient within 2, 3, or 4 days after administration of lurbinectedin. 211. It is a lyophilized composition according to Article 210 and its feature is; wherein the one or more antiemetic agents administered after administration of lurbinectedin are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 212. It is a lyophilized composition according to Article 211 and its feature is; wherein the one or more antiemetic agents are 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 213. It is a composition according to any of Articles 207 to 212, and its feature is; where the patient has progressed after previous platinum-containing therapy or previous immunotherapy. 9807108-1 M&C P0931420WOA is a composition for the treatment of patients and its feature is; It includes: (1) administering to the patient an initial dose of 3.2 mg/m2 lurbinectedin via intravenous infusion; and (2) identification of an adverse reaction in the patient, wherein the adverse reaction is selected from the group consisting of: 2 Grade 3 (severe) non-hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 0.000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 0.000 cells/mm3). (Neutrophil count less than 50,000 cells/mm3), bleeding requiring transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm3), or any grade neutropenia associated with infection/sepsis or any other adverse reaction (Neutrophil count less than 50,000 cells/mm3). <LLN); (3) after the adverse reaction is detected and the patient's neutrophil count is more than 1500 cells/mm3; platelet count is more than approximately 100,000 mm3; and hemoglobin levels are greater than approximately 9 g/dL: (i) if the described adverse reaction consists of Grade 4 neutropenia (neutrophil count less than 500 cells/mm3), administer to the patient a dose of G-CSF and a dose of lurbinectedin equal to the initial dose; or (ii) if the identified adverse reaction is not solely Grade 4 neutropenia, administering to the patient a lower dose of lurbinectedin compared to the initial dose, where two doses of lurbinectedin are administered at least 21 days apart. 215. It is a lyophilized composition according to Article 214, and its feature is; where the first reduced dose only after the first occurrence of a Grade 4 non-neutropenia adverse reaction is 80 to 85% of the initial dose, or where the first reduced dose only after the first occurrence of a Grade 4 non-neutropenic adverse reaction is 2.6 mg/m2 . 9807108-1 M&C P0931420WOA 216. It is a lyophilized composition according to Article 215 and its feature is; wherein a second reduced dose is 60-65% of the initial dose only after the second occurrence of a Grade 4 non-neutropenic adverse reaction, or where a second reduced dose is 2.0 mg/d only after the second occurrence of a Grade 4 non-neutropenic adverse reaction. m2, where the second reduced dose is administered to the patient. 217. It is a lyophilized composition according to Article 216 and its feature is; It also includes discontinuation of lurbinectedin administration upon identification of an adverse reaction after administration of the second reduced dose. 218. It is a composition according to any of the previous articles and its feature is; lurbinectedin is administered as an infusion formulation prepared by diluting a reconstituted lyophilized formulation consisting of 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide and 800 mg sucrose, with a pH value between 3.5 and 4.5 when reconstituted. It is a composition intended for the treatment of patients and its properties are; comprising: administering lurbinectedin to the patient by intravenous infusion of a lurbinectedin infusion solution at a dose of 3.2 mg/m2, wherein the lurbinectedin infusion solution administered to the patient consists of 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid and a pH of 3.5 to It is a lyophilized composition according to Article 220, Article 219, which contains a disaccharide restructured to form a solution diluted at 4.5, and its feature is; wherein the disaccharide is sucrose and optionally wherein the composition comprises lurbinectedin and sucrose in a ratio of 1 mole of lurbinectedin: 455 to 465 moles of sucrose. 221. It is a lyophilized composition according to Article 219 or 220, and its feature is; wherein the organic carboxylic acid is lactic acid and optionally wherein the composition includes lurbinectedin and lactic acid in a ratio of 1 mole lurbinectedin: 44 to 54 moles lactic acid. 9807108-1 M&C P0931420WOA 222. Composition according to any of Articles 219 to 221, characterized by; where pH is 3.8 to 4.5 223. Composition according to any one of Articles 219 to 222, characterized in that; wherein the lyophilized composition was reconstituted in approximately 8 mL of an aqueous solution to obtain the reconstituted solution. 224. It is a lyophilized composition according to Article 223 and its feature is; wherein lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 225. It is a composition according to any of Articles 219 to 224, and its feature is; wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 226. It is a lyophilized composition according to Article 225 and its feature is; where the isotonic solution is 0.9% sodium chloride solution or 5% dextrose solution. 227. It is a composition according to any of Articles 219 to 226, and its feature is; wherein the lyophilized composition contains: 22.1 mg lactic acid; .1 mg sodium hydroxide; and 800 mg sucrose. 228. It is a composition according to any of Articles 219 to 227, and its feature is; wherein the lyophilized composition is provided in a 30 mL vial. 229. It is a composition according to any of Articles 219 to 228, and its feature is; wherein the lyophilized composition is 0.8% based on the total weight of lurbinectedin, 230. The composition according to any one of Clauses 219 to 229, characterized in that; wherein the lyophilized composition does not contain a phosphate buffer. 9807108-1 M&C P0931420WOA 231. Composition according to any of Articles 219 to 231, characterized by; wherein the reconstituted solution or lurbinectedin infusion solution is 0.8%, 0.7%, 0.6%, 0.5% or the composition according to any one of Clauses 219 to 231, based on the total weight of lurbinectedin. ; It is also a prophylactic dose of an effective corticosteroid and a serotonin antagonist to reduce nausea associated with the administration of lurbinectedin to the patient, on the day of and before the administration of lurbinectedin to the patient. 233. It is a lyophilized composition according to Article 232, characterized in that; where corticosteroid is an 8 mg dose of dexamethasone administered intravenously or a dose of corticosteroid equivalent to a dose of 8 mg dexamethasone administered intravenously. 234. It is a lyophilized composition according to Article 232 or 233, and its feature is; wherein the serotonin antagonist is a dose of 8 mg of onasetron administered intravenously or a dose of serotonin antagonist equivalent to 8 mg of onusetron administered intravenously. 235. It is a composition according to any of Articles 232 to 234, and its feature is; It also includes administering one or more antiemetic agents to the patient within 2, 3, or 4 days after administration of lurbinectedin. 236. It is a lyophilized composition according to Article 235 and its feature is; wherein the one or more antiemetic agents are selected from a corticosteroid, a serotonin antagonist, and metoclopramide. 237. It is a lyophilized composition according to Article 236 and its feature is; wherein the one or more antiemetic agents are 4 mg dexamethasone, 8 mg onasetron, or 10 mg metoclopramide, or a combination thereof. 238. It is a composition according to any previous substance and its feature is; It also includes administering G-CSF to a patient determined to have a neutrophil count greater than 500/mm3 or any 9807108-1 M&C P0931420WOA value below the normal range and associated with infection/sepsis. 239. It is a composition according to any previous substance and its feature is; where one dose of lurbinectedin is administered per treatment cycle and the patient receives at least 1, 2, 3, 4 cycles. 240. It is a composition according to any previous substance and its feature is; where CTFl range The overall response rate for patients <90 days is at least 11% or at least 30% or at least 40%. 241. It is a composition according to any previous substance and its feature is; where CTFl range The response time for a patient with <90 days is at least 2.5 months or at least 4.5 months, or where the response time for a patient with a CTFl interval of 90 days is at least 3.5 months, 5 months or 6 months. 242. It is a composition according to any previous substance and its feature is; wherein the patient has not received platinum-containing therapy for at least 30 or at least 60 or at least 90 days prior to lurbinectedin administration. 243. It is a composition according to any previous substance and its feature is; where the patient had stopped responding to a platinum-containing treatment prior to lurbinectedin administration. 244. It is a composition according to any previous substance and its feature is; Here, the patient has previously received immunotherapy. 245. It is a lyophilized composition according to Article 244 and its feature is; wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody or an anti-PD-L1 antibody. 246. It is a lyophilized composition according to Article 245, characterized in that; where the immunotherapy is atezolizumab or nivolumab. 9807108-1 M&C P0931420WOA 247. Composition according to any of Articles 244 to 246, characterized by; where the patient progressed after receiving immunotherapy. 248. It is a composition according to any previous substance and its feature is; where the patient's calculated creatinine clearance is more than 30 mL/min and the AST or ALT value is 3 249. It is a composition according to any previous item, and its feature is; wherein Lurbinectedin was administered to a patient over 1 hour to achieve total plasma Cmax at 80% to 125% of approximately 107 pg/L and AUC°° at 80% to 125% of approximately 551 pg*h/L. It is administered as an intravenous infusion. 250. Composition for the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma or epithelial ovarian cancer in a patient in need, characterized in that; treatment includes: administering to the patient a topoisomerase inhibitor selected from lurbinectedin and SN-38 and irinotecan on the first day of a treatment cycle; wherein lurbinectedin is administered at a dose of 1 to 2.5 mg/m2 and where the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg irinotecan/m2. 251. It is a lyophilized composition according to Article 250 and its feature is; wherein lurbinectedin is administered at a dose of 2.0 mg/m2 and irinotecan is administered at a dose of 75 mg/m2 via intravenous administration on day 1 of the treatment cycle. 252. It is a lyophilized composition according to Article 250 or 251, and its feature is; where a subsequent dose of irinotecan of 75 mg/m2 is administered on day 8 of the treatment cycle. 253. It is a composition according to any of Articles 250 to 252, and its feature is; The treatment cycle mentioned here is 21 days. 9807108-1 M&C P0931420WOA 254. Composition according to any of Articles 250 to 254, characterized by; wherein the drug is administered in combination with G-CSF during the treatment cycle. 255. It is a composition according to any of Articles 250 to 254, and its feature is; wherein if the patient exhibits hematological toxicity after the day 1 dose, a subsequent dose of irinotecan is not administered to said patient during the treatment cycle. 256. It is a composition according to any of Articles 250 to 255, and its feature is; It also includes administering one or more antiemetics on the first day of a treatment cycle. 257. It is a composition according to any of Articles 250 to 256, and its feature is; here, patients are treated for endometrial cancer, SCLC, soft tissue sarcoma, or glioblastoma. 258. A composition for the treatment of SCLC in a patient in need thereof; comprising: administering lurbinectedin to the patient by intravenous infusion at a dose of 2 to 3.2 mg/m2; wherein the patient is administered an immunotherapeutic antibody to treat SCLC prior to initiating the treatment cycle, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months, or wherein the overall response rate is at least 40%. 259. It is a lyophilized composition according to Article 258 and its feature is; wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 260. It is a lyophilized composition according to Article 259 and its feature is; wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 9807108-1 M&C P0931420WOA 261. It is a lyophilized composition according to Article 260 and its feature is; wherein the immunotherapeutic antibody was administered to the patient simultaneously with a chemotherapeutic. 262. It is a lyophilized composition according to Article 261 and its feature is; where the chemotherapeutic is carboplatin or etoposide. 263. It is a lyophilized composition according to Article 262 and its feature is; wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic is carboplatin or etoposide. 264. It is a composition according to any of Articles 258 to 263, and its feature is; wherein one dose of lurbinectedin is administered per treatment cycle and treatment cycle 265. The composition according to any one of clauses 258 to 264, characterized in that; where one dose of lurbinectedin is administered per treatment cycle and the patient undergoes at least 2 cycles. 266. It is a composition according to any of Articles 258 to 264, and its feature is; where the overall response rate is at least 40% or at least 50% or at least 60%. 267. It is a composition according to any of Articles 258 to 264, and its feature is; Here the response time is at least 2 months, 3 months, 4 months, 5 months or 6 months. 268. It is a composition according to any of Articles 258 to 264, and its feature is; wherein the patient has not received the immuno-oncogenic therapeutic antibody for at least 30 or at least 60 or at least 90 days prior to lurbinectedin administration. 269. It is a composition according to any of Articles 258 to 264, and its feature is; wherein the patient ceased responding to the immuno-oncogenic therapeutic antibody prior to lurbinectedin administration. 9807108-1 M&C P0931420WOA 270. Composition according to any of Articles 258 to 269, characterized in that; wherein an immuno-oncogenic therapeutic antibody is not administered simultaneously with lurbinectedin. It is a composition for treatment and its feature is; It involves administering lurbinectedin to a patient at a dose of 2 to 3.2 mg/m 2 by intravenous infusion every 3 weeks, wherein lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, a buffer derived from lactic acid, and sucrose, wherein lurbinectedin:lactic wherein: The formulation should be incubated at 5 degrees C ± 3 degrees C for at least 24 months or at least 36 months or at least 48 months or at least 60 months so that the degradation product of lurbinectedin resulting from deacetylation does not exceed 0.8%, w/w, of the total weight of lurbinectedin. is determined. It is a composition for treatment and its feature is; comprising: 1) dissolving a packaged, lyophilized composition containing 4 mg of lurbinectedin, an organic acid, and a buffer derived from the disaccharide in approximately 8 mL of water to provide a lurbinectedin solution having a pH of about 3.5 to about 4.1, 2) Administering approximately 2 to 3.2 mg/m2 of lurbinectedin by intravenous infusion every 3 weeks to a patient with progressive SCLC following prior platinum-containing therapy, wherein the lyophilized composition contains less than approximately 0.3% Impurity D (lurbinectedin) when the composition is packaged. on a w/w basis) wherein upon storage at approximately 5 degrees Celsius for approximately 24 months, the composition contains less than approximately 0.8% Impurity D (w/w on a lurbinectedin basis). 9807108-1 M&C P0931420Method, composition or use according to any of WOA 120, characterized in that; here the patient is an adult patient. It is a method, composition or use according to one of them and its feature is; where the cancer is metastatic SCLC. It is a method, composition or use according to one of them and its feature is; wherein the cancer is metastatic SCLC with disease progression after platinum-based chemotherapy. 276. It is a method for reducing the side effects associated with the application of lurbinectedin for cancer treatment in a patient in need, and its feature is; This method includes: administering lurbinectedin to the patient by intravenous infusion at a dose of 3.2 mg/m2; determining whether the patient has experienced an adverse event selected from the group consisting of neutropenia, thrombocytopenia and hepatotoxicity; and changing the dose if the patient experiences neutropenia, thrombocytopenia, or hepatotoxicity, where a lurbinectedin dose of 3.2 mg/m2 is administered every 21 days in the absence of dose changes (i.e., normal administration schedule). 277. It is a method according to Article 276 and its feature is; Here, before the application, the patient's absolute neutrophil count (ANC) is at least 1,500 cells/mm3 and the platelet count is at least 100,000/mm3. 278. It is a method according to any of Articles 276 to 277, its feature is; here the dose is modified by delaying the administration of lurbinectedin compared to the normal administration schedule. 9807108-1 M&C P0931420WOA 279. Method according to any of Articles 276 to 278, characterized in that; here the dose is modified by reducing the amount of lurbinectedin administered compared to the normal administration schedule. 280. It is a method according to Article 279 and its feature is; wherein dose modification involves administering lurbinectedin at a dose of 2.6 mg/m2 every 21 days. 281. It is a method according to Article 279 and its feature is; wherein dose modification involves administering lurbinectedin at a dose of 2.0 mg/m2 every 21 days. 282. It is a method according to any of Articles 276 to 277, its feature is; where the patient experiences Grade 4 neutropenia or any degree of febrile neutropenia; The dose is changed by discontinuing lurbinectedin treatment until the patient's neutropenia reaches Grade 51, and when the patient's neutropenia reaches Grade 51, lurbinectedin is administered at a dose of 2.6 mg/m2 every 21 days. 283. It is a method according to any of Articles 276 to 277, its feature is; where the patient experiences isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3); The dose is changed by discontinuing lurbinectedin treatment until the patient's neutropenia reaches Grade 51, and when the patient's neutropenia reaches Grade 51, it includes administering lurbinectedin at a dose of 3.2 mg/m2 every 21 days along with G-CSF prophylaxis. 284. It is a method according to any of Articles 276 to 277, its feature is; where the patient experiences Grade 3 thrombocytopenia or Grade 4 thrombocytopenia with bleeding; The dose is changed by discontinuing lurbinectedin treatment until the patient's platelet count is at least 100,000/mm3 and applying lurbinectedin at a dose of 2.6 mg/m2 every 21 days. 285. It is a method according to any of Articles 276 to 277, its feature is; Here, when Grade 2 hepatotoxicity is observed in the patient, the dose is changed by discontinuing Iurbinectedin treatment until the patient's hepatotoxicity is Grade 51, and when the hepatotoxicity is Grade 51, the dose is changed by applying Iurbinectedin at a dose of 3.2 mg/m2 every 21 days. 286. It is a method according to any of Articles 276 to 277, its feature is; Here, when Grade 2 to 3 hepatotoxicity is observed in the patient, Iurbinectedin treatment is discontinued and the dose is changed until the patient's hepatotoxicity reaches Grade 51, and when the hepatotoxicity reaches Grade 51, the dose is changed by applying Iurbinectedin at a dose of 2.6 mg/m2 every 21 days. 287. It is a method according to any one of Articles 282 to 286, its feature is; It also includes: determining whether the patient experiences an adverse event selected from the group consisting of modified dose neutropenia, thrombocytopenia, and hepatotoxicity; and further modification of the dose if the patient experiences neutropenia, thrombocytopenia, or hepatotoxicity. 288. It is a method according to Article 287 and its feature is; where the patient experiences Grade 4 neutropenia or any grade febrile neutropenia on the modified dose; The dose is also changed by administering Iurbinectedin at a dose of 2.0 mg/m2 every 21 days when the patient's neutropenia reaches Grade 51. 289. It is a method according to Article 287 and its feature is; where the patient experiences Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia on the modified dose; The dose is also increased by discontinuing Iurbinectedin treatment until the patient's platelet count is at the minimum, at a dose of 2.0 mg/m2 every 21 days. It is a method according to Article 290, Article 287, and its feature is; Here, when the patient experiences Grade 2 hepatotoxicity at the modified dose, the dose is changed by discontinuing Iurbinectedin treatment until the patient's 9807108-1 M&C P0931420WOA hepatotoxicity reaches Grade 51, and when the hepatotoxicity reaches Grade 51, the dose is further modified by administering Iurbinectedin at a dose of 3.2 mg/m2 every 21 days. 291. It is a method according to Article 287 and its feature is; Here, when the patient experiences Grade 2 3 hepatotoxicity at the modified dose, the dose is changed by discontinuing Iurbinectedin treatment until the patient's hepatotoxicity reaches Grade 51, and when the hepatotoxicity reaches Grade 51, the dose is further modified by administering Iurbinectedin at a dose of 2.0 mg/m2 every 21 days. 292. It is a method according to any of Articles 277 to 291, its feature is; Here, if the interruption of Iurbinectedin treatment is longer than two weeks, the application is permanently interrupted. where discontinuation of Iurbinectedin therapy exceeds two weeks to achieve Grade 51 neutropenia, administration is permanently discontinued. 292b. It is a method according to any of Articles 284 and 289, and its feature is; Here, when stopping Iurbinectedin treatment exceeds two weeks to achieve a platelet count of at least 100,000/mm3, the application is stopped permanently. and its feature is; where discontinuation of Iurbinectedin treatment exceeds two weeks to achieve Grade 51 hepotoxicity, administration is permanently discontinued. 293. It is a method according to any one of Articles 277 to 291, its feature is; Here, if the patient cannot tolerate a dose of 2 mg/m2, the administration is permanently discontinued. 294. It is a method according to any one of Articles 277 to 293, its feature is; wherein the cancer is metastatic SCLC with disease progression after platinum-based chemotherapy. 9807108-1 M&C P0931420WOA 295. A method of safely administering Iurbinectedin for the treatment of cancer in a patient in need thereof, comprising: determining whether the patient has been administered a CYP3A inhibitor; and a potential drug/drug interaction warning resulting from the combination of the CYP3A inhibitor and lurbinectedin when the patient is administered a moderate or strong CYP3A inhibitor; and When coadministration of a moderate CYP3A inhibitor and Iurbinectedin cannot be avoided, administering Iurbinectedin at a modified dose compared to the usual schedule of administration. 296. It is a method according to Article 295 and its feature is; The caveat here is to avoid coadministration of a strong or moderate CYP3A inhibitor and Iurbinectedin. 297. It is a method according to Article 295 and its feature is; Here, a moderate CYP3A inhibitor and lurbinectedin are administered to the patient together with lurbinectedin at a dose of 2.6 mg/m2 every 21 days. 298. It is a method according to Article 295 and its feature is; wherein the patient is co-administered a moderate CYP3A inhibitor and lurbinectedin at a dose of 2.0 mg/m2 every 21 days. 299. It is a lyophilized composition and its feature is; 4 mg of a buffer derived from lurbinectedin, an organic acid, and a disaccharide wherein the lyophilized composition is approximately Contains less than 0.8 Impurity D (w/w based on lurbinectedin). 300. It is a lyophilized composition according to Article 299, and its feature is; wherein the lyophilized composition contains less than approximately 0.5% Impurity D (lurbinectedin) when stored at approximately 25°C and approximately 60% relative humidity. Includes a/a) on the basis. 301. It is a lyophilized composition according to Article 299 and its feature is; wherein the Lyophilized composition has less than approximately 0.3% Impurity D (w/w based on lurbinectedin) when the composition is stored at approximately 25°C and approximately 60% relative humidity for up to approximately 1, 2, 3, 6, 9, or 12 months. Contains. 302. It is a lyophilized composition according to Article 299 and its feature is; wherein the Lyophilized composition has less than approximately 0.1% Impurity D (w/w based on lurbinectedin) when the composition is stored at approximately 25°C and approximately 60% relative humidity for up to approximately 1, 2, 3, 6, 9, or 12 months. Contains. 303. It is a lyophilized composition according to any of Articles 299-302, and its feature is; wherein the organic acid is selected from the group consisting of citric acid, succinic acid, lactic acid and acetic acid. 304. It is a lyophilized composition according to Article 303 and its feature is; where the organic acid is lactic acid. 305. It is a lyophilized composition according to any of the articles 299-304 and its feature is; wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and a combination of two or three disaccharides thereof. 306. It is a lyophilized composition according to any of the articles 299-305, and its feature is; where the organic acid is lactic acid and the disaccharide is sucrose. 307. It is a lyophilized composition according to any of the articles 299-306 and its feature is; wherein the composition contains: 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide and 800 mg sucrose, or wherein the lyophilized composition contains 800 mg sucrose, 0.245 mmol lactate and 0.128 mmol sodium. 308. It is a lyophilized composition according to any of the articles 299-307, and its feature is; wherein dissolving the lyophilized composition in approximately 8 mL of water provides a lurbinectedin solution with a pH of approximately 3.8 to approximately 4.1. 9807108-1 M&C P0931420WOA 309. It is a lyophilized composition according to any of the articles 299-307, and its feature is; where dissolution in approximately 8 mL of water provides a lurbinectedin solution with a pH of approximately 4.0. 310. It is a lyophilized composition according to any of the articles 299-307, and its feature is; wherein dissolving in about 8 mL of water, a lurbinectedin solution containing 0.47-0.5 mg/mL lurbinectedin and having a pH of about 3.5-4.5 is 311. The lyophilized composition according to any one of Clauses 299 to 310 , feature; wherein the lyophilized composition is packaged in a vial. 311a. It is a lyophilized composition according to any of Articles 299 to 311, and its feature is; wherein the lyophilized composition is packaged in a 30 mL vial. 312. According to Formula (1), Lurbinectedin is Form B and its feature is; It exhibits an X-ray powder diffraction pattern containing four or more peaks at 2-theta angles selected from the group consisting of 0.2°. 313. According to Article 312, it is Lurbinectedin and its feature is; where five or more peaks at 2-theta angles selected from the group consisting of where the X-ray powder contains peaks at 2-theta angles of ± 0.2°. 315. Lurbinectedin according to any of clauses 312 to 314, including dots. 316. Lurbinectedin according to any of clauses 312 to 315, including dots. 317. According to Article 312, it is Lurbinectedin and its feature is; also includes the following peaks and relative intensities: Angle Relative intensity 6.2 ± 0.2 ° 79 ± 6 7.6 ± 0.2 ° 100± 3 9.0 ± 0.2 ° 63 ± 3 .9±0.2 ° 100±3 14.9±0.2° 76±3 .3±0.2° 75±3 318. According to Article 312, it is Lurbinectedin and its feature is; It also includes the following peaks and relative intensities: 9807108-1 M&C P0931420WOA Angle[2-theta] Relative intensity Angle Relative intensity 12.4±0.20 40±3 319. It is Lurbinectedin according to Article 312 and its feature is; It also includes the following peaks and relative intensities: Angle Relative Angle Relative Lurbinectedin according to any of Clauses 312 to 319, characterized by; It exhibits an X-ray powder diffraction pattern substantially identical to either of the X-ray powder diffraction patterns shown in Figures 2a or 2b. Lurbinectedin according to any one of clauses 312 to 320, 9807108-1 M&C P0931420WOA characterized by an 1R spectrum containing peaks at wavelengths (cm'1) 959, 916 and 587. 322. Lurbinectedin according to any of Articles 312 to 321, characterized in that; It is also characterized by a degradation of TG-FT1R above 150°C; and/or a TG-FT1R mass change to 150°C due to water loss; and/or characterized by less than about 5%, less than about 4%, or about; and/or water loss, preferably about 2-3% water loss, more preferably 2.6% water loss. 323. Lurbinectedin according to any of Articles 312 to 322, characterized in that; also characterized by DSC where deterioration begins above 130°C. Lurbinectedin according to any of Articles 312 to 323. also not more than approximately 30 nC/g, not more than approximately 20 nC/g, not more than approximately 10 nC/g, not more than approximately 6 nC/g, not more than approximately 5 nC/g is characterized by an average charge density of about 5 ± 2 nC/g, about 4 ± 2 nC/g, about 4-5 nC/g, about 5 nC/g or about 4 nC/g. 325. Lurbinectedin according to any of Articles 312 to 324, characterized in that; It is also characterized by a charge density distribution of less than 4.8 nC/g, approximately 0.7 nC/g to less than 4.8 nC/g, or 2.4 ± 2 nC/g. 326. Lurbinectedin according to any of Articles 312 to 325, characterized in that; It is characterized by a water content of 1.6% w/w or 1.7-5% w/w. 327. Lurbinectedin according to any of Articles 312 to 326, characterized in that; It is also characterized by residual solvents not exceeding 1%, 0.5%, 0.1% or being largely undetected. 328. Partially crystalline lurbinectedin. 9807108-1 M&C P0931420WOA 329. It is a partially crystalline Iurbinectedin according to Article 328, and its feature is; wherein the partially crystalline Iurbinectedin includes Iurbinectedin Form B as defined in any of items 312 to 327. 330. It is a partially crystalline Iurbinectedin according to Article 328 or 329, and its feature is; contains at least a detectable amount of crystalline Iurbinectedin, up to 1% crystalline partially crystalline Form B according to any of Clauses 328 to 330, or substantially pure Form B. 332. Partially crystalline as amorphous Iurbinectedin, as amorphous Iurbinectedin, as amorphous Iurbinectedin, as amorphous Iurbinectedin, as amorphous Iurbinectedin according to any of clauses 328 to 331, 9807108-1 M&C P0931420WOA 333. A pharmaceutical composition or a pharmaceutical intermediate, feature; containing partially crystalline lurbinectedin according to any one of items 328 to 332. 334. Pharmaceutical compositions made from a process comprising partially crystalline lurbinectedin according to any one of clauses 328 to 332. 335. It is a composition according to Article 333 or Article 334, and its feature is; wherein the total water content of the composition is not more than 3%; and/or residual solvents 1%, and/or impurity D not more than 0.8%; and/or not more than 0.3% of any unspecified impurities; and/or total relevant substances not more than 2.0% and unspecified substances (peak) not more than 0.7%. 336. The pharmaceutical composition of any of the articles 333 to 335, characterized by; wherein the pharmaceutical composition is a lyophilized composition. 337. A process for the preparation of lurbinectedin Form B as defined in any of Articles 312 to 327, characterized in that; comprising the steps of: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or a buffer to precipitate Form B of lurbinectedin. 338. It is a process according to Article 337 and its feature is; wherein an acidic aqueous solution containing lurbinectedin is prepared by dissolving any form of lurbinectedin in acidic water. 339. It is a process according to Article 337 and its feature is; where acidic water is preferably a 0.1 M aqueous solution of HCl. 9807108-1 M&C P0931420WOA 340. Process according to any of Articles 337 to 339, characterized in that; The acidic aqueous solution obtained here is basified with a buffer. 341. It is a process according to Article 340 and its feature is; where the buffer is NH4Cl/NH4OH. 342. It is a process according to any of Articles 337 to 341, its feature is; further includes a washing step between steps a) and b); wherein the aqueous acid solution is washed one or more times with a pharmaceutically acceptable, water-immiscible, polar solvent and one or more times with a pharmaceutically acceptable, water-immiscible, non-polar solvent, preferably a C5-C7 alkane. 343. It is a process according to Article 342 and its feature is; wherein the aqueous acid solution is washed one or more times with dichloromethane and one or more times with n-pentane. 344. It is a process according to any of Articles 337 to 343, its feature is; where lurbinectedin Form B is collected by filtering. 345. It is a process according to any of Articles 337 to 344, its feature is; Here Form B of lurbinectedin is dried under vacuum. 346. It is a process according to any of Articles 337 to 345, its feature is; where Form B of lurbinected is converted to a different physical form. 347. It is a process according to Article 346 and its feature is; where the different physical form is amorphous. 348. It is a pharmaceutical composition and its feature is; lurbinectedin as defined in any one of clauses 312 to 327 and a pharmaceutically acceptable carrier. 349. It is a pharmaceutical composition and its feature is; lurbinectedin and a pharmaceutically acceptable carrier, wherein said pharmaceutical composition is produced by lurbinectedin as defined in any one of clauses 312 to 327 of 9807108-1 M&C P0931420WOA. 350. It is a pharmaceutical composition according to Article 348 or 349, and its feature is; wherein the pharmaceutical composition comprises Iurbinectedin and a disaccharide. 351. A process for the production of an Iurbinectedin compound, characterized by; said process comprising lurbinectedin as defined in any of clauses 312 to 327 or partially crystalline lurbinectedin as defined in any of clauses 328 to 332; preferably use it as a starting material. 352. It is a process according to Article 351 and its feature is; wherein the process includes pre-dissolving lurbinectedin in an organic acid. 353. It is a process according to Article 352 and its feature is; wherein the pH of the organic acid is below 4, preferably below 3.5, more preferably below 3 or about 3. 354. It is a process according to Article 352 or 353 and its feature is; wherein the molarity of the organic acid is about 0.1M to 0.5M, preferably about 0.2M to 0.4M, more preferably about 0.3M or 0.31M. 355. It is a process according to any of Articles 352 to 354, its feature is; wherein the molarity of the organic acid is about 0.1M to 0.5M, preferably about 0.2M to 0.4M, more preferably about 0.3M or 0.31M. 356. It is a process according to any of Articles 352 to 354, its feature is; wherein the pre-dissolution step is at least 30 minutes, at least 60 minutes or at least 90 minutes. 357. It is a process according to any of Articles 352 to 356, characterized in that; wherein the solution is diluted with water for injection (WFl) to create a target concentration; where the target concentration is optionally 8.3 mg/mL in 0.1 M organic acid. 9807108-1 M&C P0931420WOA 358. Process according to any of Articles 352 to 357, characterized in that; wherein the organic acid is a carboxylic acid such as succinic acid, citric acid, acetic acid or lactic acid, preferably lactic acid. 359. It is a process according to any of Articles 351 to 358, its feature is; wherein a solution containing an organic buffer and bulking agent (e.g. disaccharide) is prepared to form a buffer solution. 360. It is a process according to Article 359 and its feature is; wherein the pH of the buffer solution is about 5.6 or less, preferably about 4 to about 5.6 or about 4.2 to about 5.6. 361. It is a process according to Article 359 or 360 and its feature is; wherein the buffer is derived from an organic acid, preferably an organic carboxylic acid, such as an organic acid carboxylic acid buffer, such as a lactic acid buffer, a butyric acid buffer, a propionic acid buffer, an acetic acid buffer, a succinic acid buffer, a citric acid buffer, an ascorbic acid buffer, a tartaric acid buffer, a malic acid buffer, a maleic acid buffer, a fumaric acid buffer, a glutamic acid buffer, an aspartic acid buffer, a gluconic acid buffer and an oi-ketoglutaric buffer. 362. It is a process according to any of Articles 359 to 361, its feature is; wherein the bulking agent is a disaccharide, preferably sucrose. 363. It is a process according to any of Articles 352 to 362, its feature is; wherein the dissolved lurbinectedin solution as defined in any of clauses 352 to 358 is mixed with the buffer solution of any of clauses 359 to 362 to form the final bulk solution. 364. It is a process according to Article 363 and its feature is; where the final bulk solution is adjusted by WFl to reach the final target weight. 365. It is a process according to any of Articles 352 to 364, its feature is; wherein the final target composition contains 0.5 mg/mL lurbinectedin in 0.03M sodium lactate buffer pH=4 + 10% (w/v) sucrose. 9807108-1 M&C P0931420WOA 366. Process according to any of Articles 352 to 365, characterized in that; wherein the bulk solution according to any one of clauses 363 to 365 undergoes sterilization filtration before being filled into vials. 367. It is a process according to any of Articles 351 to 366, its feature is; wherein the composition is subjected to freeze drying to form a lyophilized formulation. 368. It is a process according to Article 367 and its feature is; where the lyophilized composition is the process according to Article 369, Article 367 or 368, and its feature is; wherein the lyophilized composition is reconstituted for use. 370. It is a process according to Article 369 and its feature is; wherein the composition is diluted with 8 mL of water to give a solution with a pH of 3.5 to 4.5 and a lurbinectedin concentration of 0.5 mg/ml. 371. It is a process according to Article 369 or 370 and its feature is; wherein the diluted solution is used to form an infusion solution; Optionally, wherein the reconstituted solution is diluted to at least 100 mL or at least 250 mL to prepare a lurbinectedin infusion solution. 372. A lurbinectedin infusion solution made according to the process of any of clauses 351 to 371. 373. A diluted solution made according to the process of any of Clauses 351 to 370. 374. A lyophilized composition made according to the process of any of Clauses 351 to 368. 375. A bulk composition made according to the process of any of Clauses 351 to 366. 9807108-1 M&C P0931420WOA 376. Partially crystalline Iurbinectedin as defined in any of Clauses 312 to 327, characterized by; It is intended for use as a medicine. 377. Partially crystalline Iurbinectedin as defined in any of Articles 312 to 327, characterized by; It is for use in the production of a drug. 378. Partially crystalline Iurbinectedin as defined in any of Articles 312 to 327, characterized by; For use in the production of a drug for the treatment of cancer. 379. It is a method for treating a person affected by cancer, and its feature is; comprising administering to said affected individual a therapeutically effective amount of lurbinectedin as defined in any of clauses 312 to 327 or partially crystalline lurbinectedin as defined in any of clauses 328 to 332. 380. It is a method for treating a person affected by cancer, and its feature is; 381 administering to said affected individual a therapeutically effective amount of an Iurbinectedin composition produced using Iurbinectedin as defined in any of clauses 312 to 327 or partially crystalline lurbinectedin as defined in any of clauses 328 to 332. It is a composition, method, use or process as defined in one, and its feature is; where reference to diluting 4 mg of lurbinectedin in 8 mL with a concentration of 0.5 mg/mL is reference to a calculated concentration of 0.47 mg/mL in 8.55 mL. 382. Iurbinectedin essentially as described herein before with reference to examples, except for comparative examples. 9807108-1 M&C P0931420WOA 383. Lubinectedin compositions essentially as described herein before with reference to examples, except for comparative examples.TR TR TR