WO2022101255A1

WO2022101255A1 - Lurbinectedin and irinotecan combinations

Info

Publication number: WO2022101255A1
Application number: PCT/EP2021/081218
Authority: WO
Inventors: José María FERNÁNDEZ SOUSA FARO; Salvador FUDIO MUÑOZ
Original assignee: Pharma Mar, S.A.
Priority date: 2020-11-10
Filing date: 2021-11-10
Publication date: 2022-05-19

Abstract

Described are combination therapies for the treatment of solid tumours, said therapies comprising lurbinectedin and irinotecan.

Description

Lurbinectedin and Irinotecan Combinations

FIELD OF THE INVENTION

The present invention relates to therapeutic treatment of cancers, particularly solid tumours, with combination therapy using lurbinectedin and irinotecan.

BACKGROUND TO THE INVENTION

Irinotecan (CPT-1 1 , Campto®, Camptosar®) is a prodrug that converts to a biologically active metabolite SN-38 and inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA, inhibiting DNA replication and triggering apoptotic cell death.

Lurbinectedin, also known as PM01 183 and initially called tryptamicidin, is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1 H)-one alkaloid analogue with antineoplastic activity, and the subject of WO 03/014127. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand break generating apoptosis, and modulates the tumour microenvironment. For example, by inhibiting active transcription in tumour-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF.

The chemical structure of lurbinectedin is represented as follows:

Lurbinectedin has demonstrated highly potent in vitro activity against solid and non-solid tumour cell lines as well as significant in vivo activity in several xenografted human tumour cell lines in mice, such as those for breast, kidney and ovarian cancer. It is a selective inhibitor of the oncogenic transcription programs on which many tumours are particularly dependent. Together with its effect on cancer cells, lurbinectedin inhibits oncogenic transcription in tumour-associated macrophages, downregulating the production of cytokines that are essential for the growth of the tumour. Transcriptional addiction is an acknowledged target in those diseases, many of them lacking other actionable targets.

Lurbinectedin is being investigated in combination with irinotecan in patients with advanced solid tumours.

There is a need for further effective cancer therapies.

SUMMARY OF THE INVENTION

The present inventors have surprisingly determined dosing regimens of lurbinectedin and irinotecan effective in the treatment of certain cancer types.

Accordingly, in an aspect of the present invention there is provided a method of treatment of a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient, preferably a human patient, in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby treating the solid tumour. In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided the use of irinotecan in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided the use of lurbinectedin and irinotecan in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided lurbinectedin for use in a method of treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided irinotecan for use in a method of treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF. In a further aspect there is provided lurbinectedin and irinotecan for use in a method of treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided lurbinectedin for use in a method of treatment of a solid tumour, wherein in said treatment lurbinectedin is administered in combination with irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

In a further aspect there is provided irinotecan for use in a method of treatment of a solid tumour, wherein in said treatment irinotecan is administered in combination with lurbinectedin to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m². In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered. In a particular embodiment the schedule is q3 weeks lurbinectedin 3 mg/m² day 1 and irinotecan 40 mg/m² days 1 & 8 plus G-CSF.

Dosage forms, pharmaceutical packages and preparations, and kits of parts are also provided by the invention. These may comprise lurbinectedin and/or irinotecan packaged for use in a method of treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof according to the present invention. The dosage forms, packages, preparations and kits may further comprise instructions for providing treatment to a patient according to the present invention.

The following embodiments apply to all aspects of the present invention. Lurbinectedin and irinotecan may be administered concurrently, separately or sequentially. Multiple administrations of either the lurbinectedin, or irinotecan, or both, may be given.

Lurbinectedin and irinotecan may be administered in cycles once every one to four weeks, preferably once every three weeks. A particular administration cycle is once every 21 days. Day 1 q3wk.

Any suitable administration route may be used, for example, subcutaneous, intravenous, intraperitoneal. Different administration routes may be used for the lurbinectedin and irinotecan.

Lurbinectedin may be administered by intravenous infusion. Lurbinectedin may be administered after irinotecan.

Lurbinectedin may be administered as an infusion, preferably with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours and most preferably 1 hour. In embodiments, dosing may be - 5 minutes to +20 minutes of the stated infusion time.

Lurbinectedin may be administered on day 1 . Lurbinectedin may be administered on day 1 of a 21 -day cycle. A window of +/- 2 days may be allowed for administration on day 1 of the cycle. A window may not be allowed in cycle 1 .

Lurbinectedin may be administered in the form of a pharmaceutically acceptable salt selected from the hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate p-toluenesulfonate, sodium, potassium, calcium and ammonium salts, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic amino acids salts.

Irinotecan may be administered at a dose of between 15 to 60 mg/m². Irinotecan may be administered at a dose of 15 mg/m², 30 mg/m², 40 mg/m², 50 mg/m², or 60 mg/m². Preferably, irinotecan is administered at a dose of 40 mg/m². Irinotecan may be administered by intravenous infusion. Irinotecan may be administered before lurbinectedin. Irinotecan may be administered as an infusion, preferably with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours and most preferably 90 minutes. In embodiments, dosing may be - 5 minutes to +30 minutes of the stated infusion time.

Irinotecan may be administered on day 1. Irinotecan may be administered on day 8. Irinotecan may be administered on day 1 and day 8. Irinotecan may be administered on day 1 and day 8 of a 21 -day cycle. A window of +/- 2 days may be allowed for administration on day 1 of the cycle. A window of +/- 3 days may be allowed for administration on day 8 of the cycle. A window may not be allowed in cycle 1 .

Any number of cycles may be used in accordance with the present invention. In an embodiment, the treatment comprises 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more cycles.

Preferably, the patient is also administered granulocyte-colony stimulating factor G-CSF. In embodiments, In Cycle 1 , patients may receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days. Said another way, the patients may receive G-CSF daily for five days with the first dose starting 24-72 hours after Day 1 . In a further embodiment, primary G-CSF prophylaxis for further cycles is administered at the same regimen.

In embodiments according to the present invention, the regimen comprises lurbinectedin administered at a dose of 3 mg/m², irinotecan administered at a dose of between 15 to 60 mg/m², and G-CSF. In further embodiments according to the present invention, the regimen comprises lurbinectedin administered at a dose of 3 mg/m², irinotecan administered at a dose of 40 mg/m², and G-CSF.

The present invention has identified advantageous dosage regimens useful in the treatment of solid tumours.

In embodiments, the solid tumour is an advanced tumour.

In embodiments, the solid tumour is malignant.

In embodiments, the solid tumour is a sarcoma. In embodiments, the solid tumour is a carcinoma.

In embodiments, the solid tumour is a soft tissue sarcoma. Exemplary soft tissue sarcomas include synovial sarcoma, Ewing sarcoma, leiomyosarcoma, liposarcoma, chordoma, extraskeletal myxoid chondrosarcoma, carcinosarcoma and myoepithelial carcinoma.

In embodiments, the solid tumour is lung cancer. The lung cancer may be small cell lung cancer (SCLC).

In embodiments, the solid tumour is gastric cancer.

In embodiments, the solid tumour is glioblastoma

In embodiments, the solid tumour is malignant mesothelioma.

In embodiments, the solid tumour is endometrial carcinoma, ovarian cancer, epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity, GEP-NET, pancreatic adenocarcinoma, or colorectal carcinoma (CRC).

In embodiments, the patient has been pre-treated. In embodiments, the patient has been heavily pre-treated. In embodiments, the patient is progressive.

The treatment may result in one or more of the following outcomes: reduction in tumour size; delay in growth of tumour; prolongation of life of the patient; remission. These outcomes may be in comparison to a control subject (or hypothetical control subject) not given the treatment, or given an alternative treatment.

The above features also apply to the following aspects of the invention, unless otherwise noted.

A further aspect of the present invention provides a method of prolonging survival of a patient having a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby prolonging survival of the patient. In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered.

Also provided is a method of delaying disease progression of a solid tumour in a patient, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby delaying disease progression of the solid tumour. In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered.

Yet further provided is a method of reducing or delaying growth of a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby reducing or delaying growth of the solid tumour. In a preferred embodiment, lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². In a further preferred embodiment, G-CSF is also administered.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows Progression Free Survival (PFS) results in STS;

Figure 2 shows changes in tumour size in all STS patients;

Figure 3 shows the number of cycles in all STS patients.

DETAILED DESCRIPTION OF THE INVENTION

In the present application, a number of general terms and phrases are used, which should be interpreted as follows.

The term “treating”, as used herein, unless otherwise indicated, means reversing, attenuating, alleviating or inhibiting the progress 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 indicated, refers to the act of treating as “treating” is defined immediately above.

"Patient" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).

“Lurbinectedin” (PM01 183) is a new synthetic tetrahydroisoquinoline alkaloid that which binds the DNA minor groove, causing spatial distortion of DNA and protein complexes and leading to the formation of DNA double-strand breaks (DSBs), thus inducing apoptosis and delaying progression through the cell cycle S/G2 phase. Lurbinectedin has the following structure:

Lurbinectedin has a negative COMPARE analysis when compared against other 98 standard anticancer agents in the standard National Cancer Institute (NCI) panel of 36 cell lines. Thus, its mechanism of action is likely to differ significantly from the other drugs. It only showed a positive correlation (S-rank > 0.8) with trabectedin.

In vitro, lurbinectedin demonstrated cytotoxic effects against a broad selection of tumour- derived cell lines with half maximal inhibitory concentration (IC50) values in the low to very low nanomolar range (approximately median IC50 of T¹⁰ M). Lurbinectedin also exhibits in vivo antitumour activity against different murine models of xenografted human- derived tumour types.

The antineoplastic in vitro activity of lurbinectedin was evaluated in a panel of solid tumour cell lines (some of which are shown in Table 1 ), which were exposed to a range of lurbinectedin concentrations for 72 hours and then assayed for viability by a MTT short-term assay.

Table 1. Selected in vitro activity of PM01183.

IG₅O, concentration that results in 50% of cell growth inhibition.

The antineoplastic in vivo activity of lurbinectedin was demonstrated in a panel of several different human-derived tumour types, i.e., breast, colon, lung, ovarian and prostate (Table 2). The resulting tumour susceptibility was analyzed in xenografts grown in athymic mice, when unformulated lurbinectedin was administered at the rodent maximum tolerated dose [0.3 mg/kg (0.9 mg/m²)] as single bolus intravenous (i.v.) injection. Lurbinectedin demonstrated statistically significant antitumour activity (p<0.05) against breast, lung and ovarian xenografts at different time points during the experiment, but had a more moderate antitumour profile against bladder, pancreas and prostate.

Table 2. Selected in vivo activity of PM01183.

D, day; Qdx5x2, two cycles of five daily doses; Q7dx3, three consecutive weekly doses (D-0, 7, 14); T/C, treatment/control.

Toxicology studies in rats and dogs showed that the main target organs were the bone marrow and the liver. The effect of a single bolus injection of PM01183 on cardiovascular parameters [arterial blood pressure (ABP), heart rate (HR) and lead II electrocardiogram (ECG)] was evaluated in dogs for six hours. This study showed no effects on heart, ABP, lead II ECG variables (PR, QT, QTcF and QTcV intervals, and QRS duration), ECG gross morphology or rhythm in dogs treated with PM01 183 at doses up to 0.01 mg/kg (0.2 mg/m²). Additionally, two different toxicity studies found no electrophysiological alterations in the HR and the ECGs of dogs following single or repeated lurbinectedin administration at doses up to 0.05 mg/kg (1 mg/m²).

Part of the in vivo antitumour activity of lurbinectedin could be related to host-mediated effects that occur in vivo but not in vitro.

“G-CSF” or granulocyte-colony stimulating factor is a growth factor which encourages production of neutrophils.

Clinical Data

Based on the positive preclinical results described above, the clinical development program of lurbinectedin was started in March 2009. Currently, this program comprises four phase I single-agent studies (three in solid tumours and one in acute leukemia); six phase lb combination studies (with gemcitabine, capecitabine, doxorubicin, cisplatin, irinotecan, or paclitaxel with or without bevacizumab in selected advanced solid tumours); five phase II studies (four with lurbinectedin as single agent in second-line pancreatic cancer, in BRCA-mutated or in BRCA-unselected metastatic breast cancer patients and in platinum-resistant/refractory ovarian cancer, and also selected advanced solid tumours; and one in combination with gemcitabine as second-line therapy in advanced non-small cell lung cancer [NSCLC]); two phase III studies (one comparing single-agent lurbinectedin vs. pegylated liposomal doxorubicin [PLD] or topotecan in platinum-resistant ovarian cancer, and one comparing lurbinectedin in combination with doxorubicin vs. cyclophosphamide, doxorubicin and vincristine [CAV] or topotecan in small cell lung cancer [SCLC]); one QT evaluation study in patients with normal cardiac conduction and function, systolic blood pressure of 90-150 mmHg and normal serum electrolyte levels already participating in the phase II trial PM1 183-B-005-14; and two investigator-sponsored studies (ISTs: one with PM01 183 in combination with olaparib in advanced solid tumours; and one with lurbinectedin alone or in combination with doxorubicin or gemcitabine in soft tissue sarcoma). As of 15 January 2017 (cutoff date for IB version 9.0), 1515 patients have been enrolled in lurbinectedin clinical studies and 1204 have been treated with lurbinectedin-containing therapy: 460 in phase I trials, 448 in phase II trials, 234 in phase III trials and 62 in ISTs.

The completed PM1183-A-001 -08 phase I trial evaluated i.v. lurbinectedin in human patients for the first time, when infused over one hour (h) every three weeks (q3wk) in 31 patients with advanced and refractory solid tumours. Among these, 15 (48.4%) patients were treated at the defined recommended dose (RD). The RD for phase II studies was defined at a PM01183 dose of 4.0 mg/m² q3wk — equivalent to a 7.0 mg flat dose (FD) q3wk. Treatment at the RD was generally well tolerated with standard antiemetic prophylaxis. The most relevant toxicity at the RD was reversible, short-lasting myelosuppression. One patient had a grade 4 thrombocytopenia, the only dose-limiting toxicity (DLT) at the RD. No signs of cumulative toxicity were observed. Antitumour activity was observed at the RD. The pharmacokinetic (PK) analysis showed high interpatient variability (> 50.0% in the area under the curve [AUC]), and linearity across all explored doses. Linear regression analysis showed correlation between neutropenia and AUC (r²=0.452).

Two other phase I trials have been completed: one with single-agent lurbinectedin with a Day-1 and -8 q3wk schedule in solid tumours (PM1183-A-005-1 1 ) and one with lurbinectedin in combination with gemcitabine in selected advanced solid tumours (PM1183-A-004-10). Antitumour activity has been observed in both studies.

In addition, recruitment has been closed in five phase I trials: one with single-agent lurbinectedin in acute relapsed/refractory adult leukemia and myelodysplastic syndrome (PM1183-A-002-10), and four with lurbinectedin in combination with doxorubicin (PM1183-A-003-10), capecitabine (PM1183-A-006-12), paclitaxel with or without bevacizumab (PM1 183-A-007-13), and cisplatin (PM1 183-A-008-13) in selected solid tumours. Recruitment is currently ongoing in two phase I trials: one with single-agent lurbinectedin in Japanese patients with unresectable/advanced solid tumours (PM1183- A-013-15) and the present study with lurbinectedin in combination with irinotecan in selected advanced solid tumours (PM1 183-A-014-15).

Of the five phase II trials, two that evaluated lurbinectedin as second-line treatment in advanced pancreatic cancer (PM1183-B-001 -10) and in platinum-resistant and platinum- refractory ovarian cancer (PM1183-B-002-1 1 ) have been completed. The other three phase II trials are ongoing (although recruitment is closed in one) and are evaluating lurbinectedin as second-line treatment in BRCA 1 /2-associated or unselected breast cancer (PM1183-B-003-11 ), in NSCLC, either alone or in combination with gemcitabine (PM1183-B-004-13), and in several selected advanced solid tumours: SCLC, head and neck carcinoma (H&N), neuroendocrine tumours (NETs), biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-associated metastatic breast carcinoma, carcinoma of unknown primary site, germ cell tumours (GCTs), and Ewing’s family of tumours (EFTs) (PM1183-B-005-14).

Both phase III studies are ongoing. Recruitment has been closed in the one comparing single-agent lurbinectedin vs. PLD or topotecan in platinum-resistant ovarian cancer (PM1183-C-004-14 [CORAIL]), and is ongoing in the one comparing lurbinectedin in combination with doxorubicin vs. CAV or topotecan in SCLC (PM1 183-C-003-14 [ATLANTIS]).

Recruitment has also been closed in the QT evaluation study (PM1 183-B-005-14-QT) and is ongoing in both ISTs (1ST POLA/ACOG1401 in advanced solid tumours, and 1ST 15-083 in soft tissue sarcoma.

A pooled data logistic regression analysis of phase II data suggested that grade 3/4 neutropenia and thrombocytopenia could be related to body surface area (BSA). Owing to these findings, all actively recruiting and planned studies now use BSA-based dosing to limit severe myelosuppression. The original RD of 4.0 mg/m² q3wk has been reviewed and reduced to 3.2 mg/m² q3wk for the same reason.

Further information regarding its mechanism of action and in vivo efficacy can be found in 100th AACR Annual Meeting, April 18-22, 2009, Denver, CO, Abstract Nr. 2679 and Abstract Nr. 4525; Leal JFM et. al. Br. J. Pharmacol. 2010, 161 , 1099-1 110; and Belgiovine, C et al. Br. J. Cancer, 2017; 1 17(5): 628-638;

Further information regarding the clinical development of PM01183 (lurbinectedin) can be found in:

- Elez, ME. et. al. Clin. Cancer Res. 2014, 20(8), 2205-2214;

- 50th ASCO Annual Meeting, May 30 - June 3, 2014, Chicago, IL, Abstract 5505;

- 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 18-21 , 2014, Barcelona, Spain, published in Eur. J. Cancer 2014, 50 (Suppl. 6), pages 13-14, Abs. No. 23. - 51th ASCO Annual Meeting, May 29 - June 2, 2015, Chicago, IL, Abstract No. TPS2604 and Abstract Nr. 7509, published in J. Clin. Oncol. 33, 2015 (suppl);

- 54th ASCO Annual Meeting, June 1 -5, 2018, Chicago, IL, Abstract No. 1 1519, published in J. Clin. Oncol. 36, 2018 (suppl);

- Cruz, C. et al. J. Clin. Oncol. 2018; in press 1 -21 ;

- 54th ASCO Annual Meeting, June 1 -5, 2018, Chicago, IL, Abstract No. 8570, published in J. Clin. Oncol. 36, 2018 (suppl).

The term “lurbinectedin” is intended here to cover any pharmaceutically acceptable salt, ester, solvate, hydrate, prodrug, or any other compound which, upon administration to the patient is capable of providing (directly or indirectly) the compound as described herein. However, it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts can be carried out by methods known in the art.

For instance, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compounds, which contain a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. Generally, nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic amino acids salts.

Any compound that is a prodrug of lurbinectedin is within the scope and spirit of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to PM01 183. The prodrug can hydrolyze, oxidize, or otherwise react under biological conditions to provide PM01183. Examples of prodrugs include, but are not limited to, derivatives and metabolites of PM01 183 that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Prodrugs can typically be prepared using well-known methods, such as those described by Burger in “Medicinal Chemistry and Drug Discovery” 6th ed. (Donald J. Abraham ed., 2001 , Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985, Harwood Academic Publishers).

In addition, any drug referred to herein may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known within the art.

Moreover, lurbinectedin for use in accordance with the present invention may be prepared following the synthetic process such as the one disclosed in WO 03/014127, which is incorporated herein by reference.

Irinotecan is used alone or in combination to treat colorectal cancer (CRC). It is first-line therapy in combination with 5-fluorouracil and leucovorin (FOLFIRI) for patients with metastatic carcinoma of the colon or rectum and patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. As part of standard chemotherapy regimens in mCRC over the last decades, it has response rates (RR) of 40-50% and recent combinations with oxaliplatin or cetuximab have found RRs of up to 75% (irrespective of k-ras status).

Irinotecan is usually tolerable with relatively common toxicities being diarrhoea, cholinergic reactions, and myelosuppression. Common adverse reactions (> 30%) observed in combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, anorexia, mucositis, neutropenia, leukopenia (including lymphocytopenia), anemia, thrombocytopenia, fatigue, pain, fever, infection, abnormal bilirubin, alopecia which can all usually be controlled satisfactorily with standard prophylaxis and/or treatment. Lurbinectedin and irinotecan have not previously been used in combination therapy. Both drugs have preclinical data suggesting single-agent activity in breast, colorectal and pancreatic cancer models. Preclinical data have also shown synergy or additivity in vitro and in vivo, suggesting a potential clinical relevance in colon, NSCLC or pancreas tumour cell lines. In vivo, a synergistic antitumour effect (Cl<1 .0) was seen after the treatment with lurbinectedin and irinotecan in the HT29 (CI=0.93) and H460 (CI=0.30) experimental models. In SW1990 tumour bearing animals, the lurbinectedin/irinotecan combination produced more antitumour effect (P<0.05) than the more active single agent in this experiment (irinotecan at MTD level). Lurbinectedin and irinotecan lack completely overlapping toxicity profiles.

Irinotecan is indicated as monotherapy and in combination for the treatment of patients with CRC at various doses and in various schedules as a 30- to 90-min i.v. infusion. When used as a single agent, the RD range is 125-350 mg/m². In combination with 5- fluorouracil and leucovorin, the dose range is 125-180 mg/m².

The dosing regimens of the present invention have been found to be useful in the treatment of solid tumours.

Sarcomas are rare cancers that develop in the muscle, bone, nerves, cartilage, tendons, blood vessels and the fatty and fibrous tissues. They can affect almost any part of the body, on the inside or the outside. Sarcomas commonly affect the arms, legs and trunk. They also appear in the stomach and intestines as well as behind the abdomen (retroperitoneal sarcomas) and the female reproductive system (gynaecological sarcomas).

Bone sarcomas affect less than 500 people in the UK each year, making it a very rare form of cancer. Not all bone cancers will be sarcomas.

“Soft-tissue sarcoma” can affect any part of the body. They develop in supporting or connective tissue such as the muscle, nerves, fatty tissue, and blood vessels. Soft tissue sarcomas include: GIST which is a common type of sarcoma which develops in the gastrointestinal (Gl) tract; gynaecological sarcomas which occur in the female reproductive system: the uterus (womb), ovaries, vagina, vulva and fallopian tubes; and retroperitoneal sarcomas which occur in the retroperitoneum.

Unless detected at an early stage when the tumour can be removed by surgery there is currently no cure for soft tissue sarcoma. Approximately 16% of patients with soft tissue sarcoma have advanced stage (metastatic) disease. For these patients, the relative 5 year survival rate is 16% (American Cancer Society).

There are more than 50 different types of soft tissue sarcomas, including:

Leiomyosarcoma is a type of cancer that starts in smooth muscle tissue. These tumours often start in the abdomen, but they can also start in other parts of the body, such as the arms or legs, or in the uterus.

Liposarcomas are malignant tumours of fat tissue. They can start anywhere in the body, but they most often start in the thigh, behind the knee, and inside the back of the abdomen. They occur mostly in adults between 50 and 65 years old.

Synovial sarcoma is a malignant tumour of the tissue around joints. The most common locations are the hip, knee, ankle, and shoulder. This tumour is more common in children and young adults, but it can occur in older people.

The “Ewing family of tumours” is a group of cancers that start in the bones or nearby soft tissues that share some common features. These tumours can develop at any age, but they are most common in the early teen years. The main types of Ewing tumours are:

Ewing sarcoma of bone: Ewing sarcoma that starts in a bone is the most common tumour in this family. This type of tumour was first described by Dr. James Ewing in 1921 , who found it was different from the more common bone tumour, osteosarcoma. Seen under a microscope, its cells looked different from osteosarcoma cells. It was also more likely to respond to radiation therapy.

Extraosseous Ewing tumour (EOE): Extraosseous Ewing tumours start in soft tissues around bones, but they look and act very much like Ewing sarcomas in bones. They are also known as extraskeletal Ewing sarcomas.

Primitive neuroectodermal tumour (PNET): This rare childhood cancer also starts in bone or soft tissue and shares many features with Ewing sarcoma of bone and EOE. PNETs that start in the chest wall are known as Askin tumours. PNETs that start in the bone are known as peripheral neuroectodermal sarcoma of bone.

The cells that make up Ewing sarcoma, EOE, and PNET are very similar. They tend to have the same DNA (gene) abnormalities and share similar proteins, which are rarely found in other types of cancers. The three cancers are thought to develop from the same type of cells and while there are differences among these tumours, they are all currently treated in the same way.

Most Ewing tumours occur in the bones. The most common sites are: the pelvis (hip bones), the chest wall (such as the ribs or shoulder blades), or the legs, mainly in the middle of the long bones. Extraosseous Ewing tumours can occur almost anywhere.

Most Ewing tumours occur in children and teens, but they can also occur in adults.

“Chordoma” is a rare tumour that develops from cells of the notochord, a structure that is present in the developing embryo and is important for the development of the spine. The notochord usually disappears before birth, though a few cells may remain embedded in the bones of the spine or at the base of the skull.

Chordomas typically present in adults between the ages of 40 and 70 and can occur anywhere along the spine. About half of all chordomas occur at the bottom of the spine (sacrum); about one third occur at the base of the skull. The remaining cases of chordomas form in the spine at the level of the neck, chest, or other parts of the lower back. Chordomas grow slowly, extending gradually into the surrounding bone and soft tissue. The actual symptoms depend on the location of the chordoma. A chordoma that occurs at the base of the spine may cause problems with bladder and bowel function. A chordoma at the base of the skull may lead to double vision and headaches.

“Chondrosarcoma” is a malignant bone tumour arising from cartilaginous tissue, most frequently occurring at the ends of the femur and tibia, the proximal end of the humerus and the pelvis; and presenting with a palpable mass and progressive pain. Chondrosarcoma is usually slow growing at low histological grades. “Extraskeletal myxoid chondrosarcoma (ECM)” is distinguished by a biology that is distinct from the genetic heterogeneity observed in other forms of chondrosarcoma (see Kawaguchi S, Wada T, Nagoya S, et al. Extraskeletal myxoid chondrosarcoma: a multi-institutional study of 42 cases in Japan. Cancer. 2003;97:1285-1292). The majority of patients are characterized by translocations that lead to abnormal gene products.

“Carcinosarcoma” is a malignant tumour that is a mixture of carcinoma (cancer of epithelial tissue, which is skin and tissue that lines or covers the internal organs) and sarcoma (cancer of connective tissue, such as bone, cartilage, and fat). “Myoepithelial carcinoma” is a rare malignant (cancerous) tumour that usually occurs in the salivary glands in the mouth, but can also occur in skin and soft tissues. Approximately 66% of these tumours occur in a part of the salivary gland, known as the parotid gland. The average age of diagnosis is 55 years.

Adult fibrosarcoma usually affects fibrous tissue in the legs, arms, or trunk. It's most common in people between the ages of 20 and 60, but can occur in people of any age, even in infants.

Alveolar soft-part sarcoma is a rare cancer that mostly affects young adults. These tumours most commonly start in legs.

Angiosarcoma can start in blood vessels (hemangiosarcomas) or in lymph vessels (lymphangiosarcomas). These tumours sometimes start in a part of the body that has been treated with radiation

Angiosarcomas are sometimes seen in the breast after radiation therapy and in limbs with lymphedema.

Clear cell sarcoma is a rare cancer that often starts in tendons of the arms or legs. Under the microscope, it has some features of malignant melanoma, a type of cancer that starts in pigment-producing skin cells. How cancers with these features start in parts of the body other than the skin is not known.

Desmoplastic small round cell tumour is a rare sarcoma of teens and young adults. It's found most often in the abdomen.

Epithelioid sarcoma most often starts in tissues under the skin of the hands, forearms, feet, or lower legs. Teens and young adults are often affected.

Fibromyxoid sarcoma, low-grade is a slow-growing cancer that most often starts as a painless growth in the trunk or arms and legs (particularly the thigh). It is more common in young to middle aged adults. It is sometimes called an Evans’ tumour.

Gastrointestinal stromal tumour (GIST) is a type of sarcoma that starts in the digestive tract.

Kaposi sarcoma is a type of sarcoma that starts in the cells lining lymph or blood vessels. Malignant mesenchymoma is a rare type of sarcoma that shows features of fibrosarcoma and features of at least 2 other types of sarcoma.

Malignant peripheral nerve sheath tumours include neurofibrosarcomas, malignant schwannomas, and neurogenic sarcomas. These are sarcomas that start in the cells that surround a nerve.

Myxofibrosarcomas, low-grade are most often found in the arms and legs of elderly patients. They are most common in or just under the skin and there might be more than one tumour.

Rhabdomyosarcoma is the most common type of soft tissue sarcoma seen in children.

Undifferentiated pleomorphic sarcoma (UPS) was once called malignant fibrous histiocytoma (MFH). It's most often found in the arms or legs. Less often, it can start inside at the back of the abdomen (the retroperitoneum). This sarcoma is most common in older adults. It mostly tends to grow into other tissues around the place it started, but it can spread to distant parts of the body.

Intermediate soft tissue tumours may grow and invade nearby tissues and organs, but they tend to not spread to other parts of the body.

Dermatofibrosarcoma protuberans is a slow-growing cancer of the fibrous tissue beneath the skin, usually in the trunk or limbs. It grows into nearby tissues but rarely spreads to distant sites.

Fibromatosis is the name given to fibrous tissue tumour with features in between fibrosarcoma and benign tumours such as fibromas and superficial fibromatosis. They tend to grow slowly but, often, steadily. They are also called desmoid tumours, musculoaponeurotic fibromatosis or aggressive fibromatosis. They rarely, if ever, spread to distant sites, but they do cause problems by growing into nearby tissues.

Hemangioendothelioma is a blood vessel tumour that is considered a low-grade cancer. It does grow into nearby tissues and sometimes can spread to distant parts of the body. It may start in soft tissues or in internal organs, such as the liver or lungs.

Infantile fibrosarcoma is the most common soft tissue sarcoma in children under one year of age. It tends to be slow-growing and is less likely to spread to other organs than adult fibrosarcomas. Solitary fibrous tumours are most often not cancer (benign) but can be cancer (malignant). Some start in the thigh, underarm, and pelvis. They can also start in the tissue surrounding the lung (called the pleura). Many tumours that were once called hemangiopericytomas are now considered solitary fibrous tumours.

“Endometrial carcinoma” is a cancer that forms in the tissue lining the uterus. Most endometrial cancers are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids). There are various types of endometrial carcinomas including adenocarcinoma (particularly endometrioid cancer), uterine carcinosarcoma, squamous cell carcinoma, small cell carcinoma, transitional carcinoma or serous carcinoma. Clear-cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common types of endometrial adenocarcinomas. They tend to grow and spread faster than most types of endometrial cancer.

Most endometrial cancers are adenocarcinomas, and endometrioid cancer is the most common type of adenocarcinoma. Endometrioid cancers start in gland cells. Some of these cancers have squamous cells (squamous cells are flat, thin cells), as well as glandular cells. There are many sub-types of endometrioid cancers including: adenocarcinoma, (with squamous differentiation), adenoacanthoma, adenosquamous (or mixed cell), secretory carcinoma, ciliated carcinoma, and villoglandular adenocarcinoma.

“Ovarian cancer” includes epithelial ovarian carcinoma, primary peritoneal disease, fallopian tube carcinomas, or ovarian germ cell tumors.

“Epithelial ovarian tumors” start in the outer surface of the ovaries. These tumors can be benign, borderline, or malignant. Epithelial ovarian tumors that are benign don’t spread and usually don’t lead to serious illness. There are several types of benign epithelial tumors including serous cystadenomas, mucinous cystadenomas, and Brenner tumors. When looked at in the lab, some ovarian epithelial tumors don’t clearly appear to be cancerous and are known as borderline epithelial ovarian cancer. The two most common types are atypical proliferative serous carcinoma and atypical proliferative mucinous carcinoma. They do not grow into the supporting tissue of the ovary (called the ovarian stroma). If they do spread outside the ovary, for example, into the abdominal cavity (belly), they might grow on the lining of the abdomen but not into it. Borderline tumors tend to affect younger women than the typical ovarian cancers. These tumors grow slowly and are less life-threatening than most ovarian cancers. Cancerous epithelial tumors are called carcinomas. About 85% to 90% of malignant ovarian cancers are epithelial ovarian carcinomas. These tumor cells have several features (when looked at in the lab) that can be used to classify epithelial ovarian carcinomas into different types. The serous type is by far the most common, and can include high grade and low grade tumors. The other main types include mucinous, endometrioid, and clear cell.

Primary peritoneal carcinoma (PPC) is a rare cancer closely related to epithelial ovarian cancer. At surgery, it looks the same as an epithelial ovarian cancer that has spread through the abdomen. In the lab, PPC also looks just like epithelial ovarian cancer. Other names for this cancer include extra-ovarian (meaning outside the ovary) primary peritoneal carcinoma (EOPPC) and serous surface papillary carcinoma. PPC appears to start in the cells lining the inside of the fallopian tubes. Like ovarian cancer, PPC tends to spread along the surfaces of the pelvis and abdomen, so it is often difficult to tell exactly where the cancer first started. This type of cancer can occur in women who still have their ovaries, but it is of more concern for women who have had their ovaries removed to prevent ovarian cancer. This cancer does rarely occur in men.

Fallopian tube cancer is another rare cancer that is similar to epithelial ovarian cancer but begins in the fallopian tube. Like PPC, fallopian tube cancer and ovarian cancer have similar symptoms.

Most ovarian germ cell tumors are benign, but <2% of ovarian cancers are germ cell tumors. There are several subtypes of germ cell tumors. The most common germ cell tumors are teratomas, dysgerminomas, endodermal sinus tumors, and choriocarcinomas. Germ cell tumors can also be a mix of more than a single subtype. Teratomas are germ cell tumors with areas that, when seen under the microscope, look like each of the 3 layers of a developing embryo: the endoderm (innermost layer), mesoderm (middle layer), and ectoderm (outer layer). This germ cell tumor has a benign form called mature teratoma and a cancerous form called immature teratoma. Immature teratomas occur in girls and young women, usually younger than 18. These are rare cancers that contain cells that look like those from embryonic or fetal tissues such as connective tissue, respiratory passages, and brain. Dysgerminoma is rare, but it is the most common ovarian germ cell cancer. It usually affects women in their teens and twenties. Endodermal sinus tumor (yolk sac tumor) and choriocarcinoma are very rare tumors which typically affect girls and young women. They tend to grow and spread rapidly but are usually very sensitive to chemotherapy. About 1% of ovarian cancers are ovarian stromal cell tumors. More than half of stromal tumors are found in women older than 50, but about 5% of stromal tumors occur in young girls.

The ovarian cancers according to embodiments of the present invention may be selected regardless of platinum sensitivity.

“Small cell lung cancer (SCLC)” is a fast growing form of lung cancer. It is sometimes called oat cell cancer. Lung cancer is the leading cause of cancer death in both men and women in the United States. In 1998, an estimated 171 ,500 new cases were diagnosed, and about 160,100 deaths resulted from this disease. More women die from lung cancer than breast, ovarian, and uterine cancer combined, and 4 times as many men die from lung cancer than from prostate cancer.

Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. The two major types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC comprises only about 13-15% of all lung cancers at diagnosis; however, SCLC is the more aggressive form of lung cancer. With SCLC, the cancer cells tend to grow quickly and travel 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. The median survival of patients with untreated SCLC is two to four months. The most common regimens include cisplatin or carboplatin and etoposide. Unfortunately, despite the 40-90% response rate to first-line chemotherapy, long-term survival is unusual because patients develop resistance to chemotherapy and relapse. The overall expected mean survival after disease relapse without treatment was typically two to four months.

However, in June 2020, the FDA approved lurbinectedin for the treatment adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity. The main efficacy outcome measures were confirmed overall response rate (ORR) determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was 35% (95% Cl: 26%, 45%), with a median response duration of 5.3 months (95% Cl: 4.1 , 6.4). The ORR as per independent review committee was 30% (95% Cl: 22%, 40%) with a median response duration of 5.1 months (95% Cl: 4.9, 6.4). The recommended lurbinectedin dose is 3.2 mg/m2 every 21 days.

“Glioblastoma” is a fast-growing type of central nervous system tumour that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Also called GBM, glioblastoma multiforme, and grade IV astrocytoma.

“Pancreatic adenocarcinoma” is a disease in which malignant (cancer) cells are found in the tissues of the pancreas. Pancreatic cancer can develop from two kinds of cells in the pancreas: exocrine cells and neuroendocrine cells, such as islet cells. The exocrine type is more common and is usually found at an advanced stage. Pancreatic neuroendocrine tumours (islet cell tumours) are less common but have a better prognosis (discussed separately below).

The most common type of pancreatic cancer, adenocarcinoma of the pancreas, starts when exocrine cells in the pancreas start to grow out of control. Most of the pancreas is made up of exocrine cells which form the exocrine glands and ducts. The exocrine glands make pancreatic enzymes that are released into the intestines to help you digest foods (especially fats). The enzymes are released into tiny tubes called ducts which eventually empty into the pancreatic duct. The pancreatic duct merges with the common bile duct (the duct that carries bile from the liver), and empties into the duodenum (the first part of the small intestine) at the ampulla of Vater.

Exocrine cancers are by far the most common type of pancreas cancer. About 95% of cancers of the exocrine pancreas are adenocarcinomas. These cancers usually start in the ducts of the pancreas. Less often, they develop from the cells that make the pancreatic enzymes, in which case they are called acinar cell carcinomas.

Other, less common exocrine cancers include adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with giant cells.

Ampullary cancer (carcinoma of the ampulla of Vater) is a cancer which starts in the ampulla of Vater. Ampullary cancers often block the bile duct while they are still small and have not spread far. This blockage causes bile to build up in the body, which leads to yellowing of the skin and eyes (jaundice). Because of this, these cancers are usually found earlier than most pancreatic cancers, and they usually have a better prognosis.

“GEP-NET” is a rare type of tumour that can form in the pancreas or in other parts of the gastrointestinal tract, including the stomach, small intestine, colon, rectum, and appendix. GEP-NETs usually form in cells that secrete hormones. Some of these tumours make extra amounts of hormones and other substances that may cause signs and symptoms of disease, including a condition called carcinoid syndrome. GEP-NETs may be benign or malignant. They are sometimes called carcinoid tumours or islet cell tumours. Also called gastroenteropancreatic neuroendocrine tumour.

Pancreatic NETs are classified based on whether they are functioning (making hormones that cause symptoms) or non-functioning (not making hormones).

Functioning NETs: About half of pancreatic NETs make hormones that are released into the blood and cause symptoms. These are called functioning NETs. Each one is named for the type of hormone the tumour cells make. Insulinomas come from cells that make insulin; glucagonomas come from cells that make glucagon; gastrinomas come from cells that make gastrin; somatostatinomas come from cells that make somatostatin; VIPomas come from cells that make vasoactive intestinal peptide (VIP); ACTH-secreting tumours come from cells that make adrenocorticotropic hormone (ACTH). Most (up to 70%) functioning NETs are insulinomas. The other types are much less common.

Non-functioning NETs: These tumours don’t make enough excess hormones to cause symptoms. Because they don’t make excess hormones that cause symptoms, they can often grow quite large before they're found. Symptoms that may occur when they grow to a large size include abdominal (belly) pain, lack of appetite, and weight loss.

Carcinoid tumours: These NETs are much more common in other parts of the digestive system, although rarely they can start in the pancreas. These tumours often make serotonin.

“Gastric carcinoma” is a cancer that forms in tissues lining the stomach. Risk factors include smoking, infection with H. pylori bacteria, and certain inherited conditions.

“Malignant mesothelioma” is a disease in which malignant (cancer) cells are found in the pleura (the thin layer of tissue that lines the chest cavity and covers the lungs) or the peritoneum (the thin layer of tissue that lines the abdomen and covers most of the organs in the abdomen). Malignant mesothelioma may also form in the heart or testicles, but this is rare. The four types of mesothelioma are therefore pleural (lung lining), peritoneal (abdominal lining), pericardial (heart sac) and testicular.

Mesothelioma can also be identified by three cancer cell types: epithelioid, sarcomatoid and biphasic, and can therefore be defined as epithelioid mesothelioma (epithelioid cells), sarcomatoid mesothelioma (sarcomatoid cells) or biphasic mesothelioma (epithelioid and sarcomatoid cells).

Pleural is the most common mesothelioma. Approximately 70% to 75% of cases occur in the pleura. Peritoneal disease accounts for 10% to 20% of mesothelioma cases. There is less research available on peritoneal compared to pleural; however, the prognosis for this tumour type is better. Pericardial Mesothelioma is extremely rare. Around 200 cases are reported in medical literature. Testicular mesothelioma develops in the lining of the testes. This form of mesothelioma is the most rare. Less than 100 cases are reported in the medical literature.

The three mesothelioma cell varieties are epithelial, sarcomatoid and biphasic. Biphasic is a mix of the first two cell types. Different mesothelioma tumours respond differently to treatment. Epithelial or epithelioid cells typically respond the best to treatment, and sarcomatoid cells are typically more resistant to treatment.

Epithelioid mesothelioma makes up approximately 70% to 75% of all cases of asbestos- related mesothelioma cancers. Epithelioid cell typically has the best prognosis. It tends to be less aggressive and doesn’t spread as quickly as sarcomatoid and biphasic cell disease. About 50% of pleural disease is epithelioid. Around 75% of peritoneal tumours are made up of epithelioid cells.

Sarcomatoid is the least common mesothelioma cell category. It is typically the most aggressive and difficult to treat. It accounts for around 10% to 20% of all mesothelioma diagnoses. About 20% of pleural tumours are sarcomatoid, while only 1 % of peritoneal mesothelioma are sarcomatous.

Biphasic mesothelioma refers to tumours that contain epithelial and sarcomatoid cells. Life expectancy after diagnosis with biphasic mesothelioma depends upon which cell predominates in the tumour. More epithelioid cells generally mean a better prognosis. If the tumour is mostly sarcomatous, it is harder to treat and life expectancy is shorter. Around 30% of pleural and 25% of peritoneal tumours are biphasic cell.

Prevalence of Mesothelioma Tumours by Cell Type

Based on the limited number of cases reported in the medical literature, pericardial mesothelioma exhibits roughly equal distribution of the three mesothelioma cell types. Approximately two-thirds of testicular mesothelioma cases are epithelioid cell. The rest of testicular cases are biphasic. Only one case of purely sarcomatoid cell disease is reported for testicular mesothelioma.

“Colorectal carcinoma (CRC)” is a cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus). Colorectal cancer often begins as a growth called a polyp inside the colon or rectum.

Most colorectal cancers are adenocarcinomas. These cancers start in cells that make mucus to lubricate the inside of the colon and rectum. Some sub-types of adenocarcinoma, such as signet ring and mucinous, may have a worse prognosis than other subtypes of adenocarcinoma.

In embodiments, the present invention provides dosing schedules to treat the cancer defined herein.

The patient may also receive prophylactic medication whilst getting treatment as described in the present invention. Prophylactic medication includes corticosteroids and 5-HT₃ receptor antagonists. Particular corticosteroids include dexamethasone. Particular 5-HT₃ receptor antagonists include ondansetron. Particular dosages include dexamethasone 8 mg i.v. (or an equivalent dose of another i.v. corticosteroid) and ondansetron 8 mg i.v. (or an equivalent dose of another i.v. 5-HT3 receptor antagonist). Prophylactic medication may be administered on Day 1 and Day 8 of each cycle. In addition, further prophylactic medication may be administered as needed. An example includes metoclopramide or equivalent, which in embodiments may be administered every eight hours. After Day 1 and Day 8 of each cycle extended oral corticosteroids (for example dexamethasone not exceeding 20 mg/days) and/or 5-HT₃ receptor antagonists (for example oral (or i.v.) ondansetron 4-8 mg (or equivalent)) may be administered. The patient may also be administered granulocyte-colony stimulating factor G-CSF. In embodiments, In Cycle 1 , patients may receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days. Primary G-CSF prophylaxis for further cycles may be administered at the same regimen, but could also be administered according to physician discretion.

Pharmaceutical compositions comprising lurbinectedin or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier may be formulated according to the chosen route of administration. Examples of the administration form include without limitation oral, topical, parenteral, sublingual, rectal, vaginal, ocular and intranasal. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Preferably the compositions are administered parenterally. Pharmaceutical compositions can be formulated so as to allow a compound to be bioavailable upon administration of the composition to an animal, preferably human. Compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a compound may contain the compound in liquid or in aerosol form and may hold a single or a plurality of dosage units.

The pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) can be gaseous, or liquid so as to provide an aerosol composition useful in, for example inhalatory administration. Powders may also be used for inhalation dosage forms. The term “carrier” refers to a diluent, adjuvant or excipient, with which the compound according to the present invention is administered. Such pharmaceutical carriers can be liquids, such as water and oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. In one embodiment, when administered to an animal, the compounds and compositions and pharmaceutically acceptable carriers are sterile. Water is a preferred carrier when the compounds are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition typically contains one or more inert diluents. In addition, one or more for the following can be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agent such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.

When the composition is in the form of a capsule (e.g. a gelatin capsule), it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrins or a fatty oil.

The composition can be in the form of a liquid, e.g. an elixir, syrup, solution, emulsion or suspension. The liquid can be useful for oral administration or for delivery by injection. When intended for oral administration, a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavour enhancer. In a composition for administration by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.

The preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal or transdermal. The preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition. In a more preferred embodiment, the compound(s) according to the present invention are administered intravenously. Infusion times of up to 24 hours are preferred to be used, more preferably 1 to 12 hours, with 1 to 6 hours being most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in a hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks, preferably once every three weeks.

Liquid compositions, whether they are solutions, suspensions or other like form, can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides, polyethylene glycols, glycerin, or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in an ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material. Physiological saline is a preferred adjuvant.

The compositions comprise an effective amount of a lurbinectedin and/or irinotecan such that a suitable dosage will be obtained. Administration can be carried out continuously or periodically within the maximum tolerated dose.

In specific embodiments, it can be desirable to administer lurbinectedin or irinotecan locally to the area in need of treatment. In one embodiment, administration can be by direct injection at the site (or former site) of a cancer, tumour or neoplastic or pre- neoplastic tissue.

Pulmonary administration can also be employed, e.g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, lurbinectedin can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

The present compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin.

The pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical art. For example, a composition intended to be administered by injection can be prepared by combining lurbinectedin with water, or other physiologically suitable diluent, such as phosphate buffered saline, so as to form a solution. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension.

Preferred compositions comprising lurbinectedin may invention include:

• Pharmaceutical compositions comprising lurbinectedin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.

• Lyophilised pharmaceutical compositions comprising lurbinectedin and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.

The ratio of lurbinectedin to the disaccharide in embodiments of the present invention is determined according to the solubility of the disaccharide and, when the formulation is freeze dried, also according to the freeze-dryability of the disaccharide. It is envisaged that this lurbinectedimdisaccharide ratio (w/w) can be about 1 :10 in some embodiments, about 1 :20 in other embodiments, about 1 :50 in still other embodiments. It is envisaged that other embodiments have such ratios in the range from about 1 :5 to about 1 :500, and still further embodiments have such ratios in the range from about 1 :10 to about 1 :500.

The composition comprising lurbinectedin may be lyophilized. The composition comprising lurbinectedin is usually presented in a vial which contains a specified amount of such compound.

Lurbinectedin may be a lyophilized powder for concentrate for solution for infusion, as 4 mg/vial. Before use, the 4-mg vial may be reconstituted with 8 mL of sterile water for injection, to give a solution containing 0.5 mg/mL of lurbinectedin. For administration to patients as i.v. infusion, reconstituted vials may be diluted with glucose 50 mg/mL (5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.

The full composition of the PM01183 4-mg vials and the reconstituted solution per mL may be as follows:

T o provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value.

The invention will now be described further with reference to the following example.

EXAMPLE

Phase l/ll, Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination with Irinotecan in Pretreated Patients with Selected Advanced Solid Tumours

STUDY OBJECTIVES

Primary:

• Phase I escalation stage: To determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with irinotecan in patients with selected advanced solid tumours.

• Phase II expansion stage: To obtain information on the clinical antitumour activity of this combination in patients with selected advanced solid tumours.

Secondary:

• To determine the MTD and the RD of PM01183 in combination with irinotecan with or without primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) in patients with selected advanced solid tumours (if dose-limiting toxicities [DLTs] of the combination without G-CSF prophylaxis are exclusively related to neutropenia).

To characterize the safety profile and feasibility of this combination in patients with selected advanced solid tumours.

• To characterize the pharmacokinetics (PK) of this combination and to detect potential major drug-drug PK interactions.

• In the Phase I escalation stage: To obtain preliminary information on the clinical antitumour activity of this combination in non-heavily pretreated selected solid tumour patients.

• To evaluate pharmacogenomics (PGx) in tumour samples of patients exposed to PM01 183 and irinotecan in order to assess potential markers of response and/or resistance.

To evaluate pharmacogenetics (PGt) in germline DNA by the presence or absence of mutations or polymorphisms that may explain individual variability in main PK parameters.

STUDY DESIGN

Prospective, open-label, dose-ranging, uncontrolled phase l/ll study with PM01183 in combination with irinotecan. The study will be divided into two stages: a Phase I dose escalation stage and a Phase II expansion stage.

During the Phase I escalation stage, patients with selected advanced solid tumours will be divided into a PM01183 Escalation Group and an Irinotecan Escalation Group. Each group will have a different dose escalation scheme.

On Day 1 , patients will receive both drugs of the study combination at the appropriate dose level, regardless of the group they have been assigned to. The starting dose level (DL1 ) will be as follows:

• PM01183 Escalation Group: Irinotecan 75 mg/m² as a 90-min (-5-min/+30- min) intravenous (i.v.) infusion, followed by PM01 183 1.0 mg/m² as a 60-min (-5-min/+20-min) i.v. infusion followed by irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion).

• Irinotecan Escalation Group: Irinotecan 15 mg/m² as a 90-min (-5-min/+30- min) i.v. infusion, followed by PM01183 3.0 mg/m² as a 60-min (-5-min/+20- min) i.v. infusion followed by irinotecan alone on Day 8 (at the same dose as Day 1 and as a 90-min [-5-min/+30-min] i.v. infusion).

Only at Cycle 1 , irinotecan will be administered by i.v. infusion lasting 90-min followed by that of PM01183 lasting 60-min within a permitted window of +6-min between both treatments.

In all groups, administration of irinotecan and PM01 183 as described in the bullet points above will be repeated every three weeks (q3wk). A treatment cycle is defined as an interval of three weeks.

Three to six patients will be included at each dose level. If dose-limiting toxicity (DLT) occurs in less than one third of evaluable patients in each cohort, escalation can proceed to the next dose level within each group.

The MTD in each group will be the lowest dose level explored during dose escalation in which one third or more of evaluable patients develops a DLT in Cycle 1 . At any dose level, if one among the first three evaluable patients has a DLT, the dose level should be expanded up to six patients. Dose escalation will be terminated once the MTD or the last dose level is reached, whichever occurs first, except if all DLTs occurring at a given dose level are related to neutropenia (i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis) in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis.

Once the MTD has been reached, a minimum of nine evaluable patients will be recruited at the immediately lower dose level (or at the last dose level if the MTD is not defined yet): this level will be confirmed as the RD if less than one third of the first nine evaluable patients develop DLT during Cycle 1 .

In the PM01183 Escalation Group (Cohort A), in the event of DLT occurring in the first patient at the first dose level, the second and third patients will nevertheless be included but three weeks apart. In case another DLT occurs in these two new patients, DL1 will be closed and DL-1 initiated. Otherwise (at DL1 or at subsequent dose levels), all patients within a dose level may be treated simultaneously. All evaluable patients within a dose level will be followed for at least one cycle (i.e., three weeks) before dose escalation may proceed.

In the Irinotecan Escalation Group (Cohort B), once the first patient has been included and treated at the first dose level, the second and third patients at this dose level will be included three weeks later. At subsequent dose levels, all patients may be treated simultaneously. All evaluable patients within a dose level will be followed for at least one cycle (i.e., three weeks) before dose escalation may proceed.

Other dose levels and schedules of both drugs may be tested in any group on agreement between the Investigator and the Sponsor if deemed appropriate.

If signs of activity are observed in one or more tumour type, there will be a phase II type expansion stage after the RD is defined for each group. A tumour-specific expansion cohort (or cohorts if signs of activity are observed in more than one of the permitted 10 tumour types) at each of these RDs will include approximately 20 patients per tumour type other than small cell lung cancer (SCLC), and approximately 47 patients with SCLC.

The tumour type(s) to be included in the tumour-specific expansion cohort(s) at the RD for each group will be chosen according to preliminary efficacy observed among those treated during the dose escalation phase, and will be agreed between the Investigators and the Sponsor. If no indication of efficacy is observed in the dose escalation phase, then the trial may be terminated.

Pharmacogenomic/ Pharmacogenetic substudy

The aim of the pharmacogenomic (PGx) component of this study is to identify and validate putative molecular markers associated with the clinical outcome of patients treated with PM01183 combined with irinotecan. These molecular markers would help to select future patients who might preferentially benefit from the PM01 183 and irinotecan combination, thus contributing to a more individualized medicine.

If there is evidence of clinical benefit, patients consenting specifically to the substudy and with available tumour samples obtained at diagnosis or relapse, will be analyzed for molecular markers of response to treatment and other markers related to the mechanism of action of PM01 183 or irinotecan, or to the pathogenesis of the disease.

The aim of the pharmacogenetic (PGt) component of this study is to explore genetic factors that may help explain individual variability in main PK parameters.

STUDY POPULATION Inclusion criteria

1 ) Voluntarily signed and dated written informed consent prior to any specific-study procedure.

2) Age > 18 years.

3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 1.

4) Life expectancy > 3 months.

5) No more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease [excluding gastroenteropancreatic neuroendocrine tumours (GEP-NET)]. No more than three prior lines of cytotoxic-containing chemotherapy regimens for GEP-NET.

There is no limit for prior targeted therapy, hormonal therapy and immunotherapy (such as nivolumab).

6) Histologically or cytolog ically confirmed diagnosis of advanced disease of any of the following tumour types:

For the PM01183 Escalation Group and the Irinotecan Escalation Group: a) Glioblastoma. b) Soft-tissue sarcoma (excluding gastrointestinal stromal tumours [GIST]). c) Endometrial carcinoma. d) Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity. e) Mesothelioma. f) GEP-NET. g) Small cell lung cancer (SCLC). h) Pancreatic adenocarcinoma. i) Gastric carcinoma. j) Colorectal carcinoma (CRC).

7) Phase II expansion stage: Tumour-specific cohort(s) at the RD: a) Measurable disease according to Response Evaluation Criteria in Solid

Tumours (RECIST) v.1.1.

For patients with glioblastoma: Measurable disease according to RECIST v.1 .1 and RANG criteria. b) Documented disease progression per RECIST v.1.1 during or immediately after last therapy according to any of the aforementioned criteria.

For patients with glioblastoma: Documented disease progression per RECIST v.1 .1 and RANG criteria. ) At least three weeks since the last anticancer therapy (excluding immunotherapy that must be at least two weeks, provided that is not combined with chemotherapy), including investigational drugs and radiotherapy, and at least six weeks since nitrosoureas and mitomycin C (systemic).

For biological/in vestigational anticancer therapies given orally, the aforementioned period of at least three weeks could be changed for one of at least five half-lives (whichever occurred first), provided that the therapy is given as single agent and not combined with other drugs. If this is not the case, this exception will not be acceptable.

For patients with glioblastoma: at least 12 weeks since the end of radiotherapy, except if: a) The patient has a new lesion outside of the radiotherapy field, or b)The patient has undergone brain surgery to remove the tumour before study entry, and progressive disease has been confirmed histologically.

Note: washout periods will be referred to the day of first cycle administration (Day 1 ), not to the day of registration (Day 0). ) Adequate bone marrow, renal, hepatic, and metabolic function (assessed < 7 days before inclusion in the trial): a) Platelet count s 100 x 1O⁹/L, hemoglobin > 9.0 g/dL and absolute neutrophil count (ANC) > 2.0 x 1O⁹/L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x the upper limit of normal (ULN), even in the presence of liver metastases. c) Alkaline phosphatase (ALP) < 2.5 x ULN (< 5 x ULN if disease-related/in the case of liver metastases). d)Total bilirubin < 1.5 x ULN or direct bilirubin < ULN. e) International Normalized Ratio (INR) < 1 .5 (except if patient is on oral anticoagulation therapy). f) Calculated creatinine clearance (CrCL) > 30 mL/minute (using Cockcroft-Gault formula). g)Creatine phosphokinase (CPK) < 2.5 x ULN. h)Albumin > 3.0 g/dL.*

10) Recovery to grade < 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade < 2).

* Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden.

Exclusion criteria

1 ) Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart). d) Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease. e) Active uncontrolled infection. f) Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B. g) Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis. h) Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days. i) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this trial. 2) Prior treatment with PM01183, trabectedin (Yondelis®) or topoisomerase I inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g., irinotecan) are only allowed in patients with colorectal carcinoma.

3) Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.

4) Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. Exception: patients with brain metastases are eligible provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of already being tapered within two weeks prior to screening are allowed). Brain CT- scan or MRI results must be provided at baseline.

5) Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception.

6) Limitation of the patient’s ability to comply with the treatment or follow-up protocol.

* Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least three months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.

Pharmacogenomic/ Pharmacogenetic substudy eligibility criteria

Patients who are eligible for the trial will also be eligible for the PGx/PGt substudy with a separate, voluntarily signed and dated informed consent form. Refusal to participate in the PGx/PGt components will not affect patient participation in the clinical trial PM1183-A-014-15.

Expected number of patients

The number of patients will vary depending on tolerability of the PM01183/irinotecan combination and on the number of dose levels required to identify the MTD. It may also vary according to the number of tumour-specific groups in the Phase II expansion stage at the RD for each group. Approximately 200 evaluable patients are expected to participate in this trial.

STUDY DRUG

Formulation

PM01183:

PM01183 drug product will be presented as a lyophilized powder for concentrate for solution for infusion, as 4 mg/vial.

Before use, the 4-mg vial should be reconstituted with 8 mL of sterile water for injection, to give a solution containing 0.5 mg/mL of PM01 183. For administration to patients as i.v. infusion, reconstituted vials will be diluted with glucose 50 mg/mL (5%) or sodium chloride 9 mg/mL (0.9%) solution for infusion.

The full composition of the PM01 183 4-mg vials and the reconstituted solution per mL are as follows:

Irinotecan:

Commercially-available irinotecan (injection) will be provided.

Treatment schedule, administration route and dose

Regardless of group, patients will consecutively receive the following on Day 1 q3wk (every three weeks = one treatment cycle):

• Irinotecan: a total volume of 250 mL to 500 mL dilution on 0.9% sodium chloride or 5% glucose by i.v. infusion lasting 90 minutes (-5-min/+30-min) via a central or peripheral venous catheter (after appropriate visual confirmation of effective venous blood return through the line), followed by: • PM01 183: a minimum of 100 mL dilution (5% glucose or 0.9% sodium chloride) at a fixed rate via a central catheter (or a minimum of 250 mL dilution via a peripheral line) by i.v. infusion lasting 60 minutes (-5-min/+20- min) through a pump device.

Only at Cycle 1 , irinotecan will be administered by i.v. infusion lasting 90-min followed by that of PM01183 lasting 60-min within a permitted window of +6-min between both treatments. No windows are allowed for infusion lengths in Cycle 1 .

Whenever possible, central venous access is preferred over peripheral line infusion to ensure optimal tolerance.

On Day 8 of each cycle in the PM01183 Escalation Group and the Irinotecan Escalation Group, irinotecan alone will be administered at the same dose, schedule and modalities as Day 1 (unless toxicities require dose omission).

The starting dose of the two study drugs in the combination will be as follows:

• PM01183 Escalation Group: Irinotecan 75 mg/m² and PM01 183 1.0 mg/m².

• Irinotecan Escalation Group: Irinotecan 15 mg/m² and PM01 183 3.0 mg/m².

Both irinotecan and PM01 183 doses will be capped at 2.0 m² of BSA for individuals exceeding this BSA value. Doses will have to be recalculated for patients showing a > 10% change in total body weight value compared with baseline.

Doses of both PM01 183 and irinotecan will be rounded to the tenth of one milligram.

A window of 7+ 2 days is allowed for administration of the combination of PM01183 and irinotecan on Day 1 in all groups, and a window of + 3 days is allowed for administration of irinotecan on Day 8 in the PM01183 Escalation Group and the Irinotecan Escalation Group.

DOSE ESCALATION SCHEDULE

The dose escalation scheme in each group will follow pre-defined dose levels, starting at DL1 and including a minimum of three evaluable patients per dose level, as summarized below:

Dose escalation levels in the PM01183 Escalation Group.

D. day; DL, dose level.

Dose escalation levels in the Irinotecan Escalation Group.

D. day; DL, dose level.

Dose escalation in each group will be terminated once the MTD or the last dose level is reached (whichever occurs first) except if all DLTs occurring at a given dose level are related to neutropenia (e.g., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis) in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis.

Dose escalation in the PM01183 Escalation Group and the Irinotecan Escalation Group can also continue in the event of a Day-8 irinotecan dose omission (DLT in

Cycle 1 ) due to specific irinotecan-related toxicity (i.e., gastrointestinal and/or cholinergic syndrome) grade > 2, provided adequate prophylactic and/or curative therapy is administered to the patient. This will be decided individually on a patient-by- patient basis. In the event of antitumour activity in the dose escalation process in any of the subtypes included, tumour-specific expansion cohort(s) treated at the RD will include approximately 20 evaluable patients per disease type in each group.

* Patients not evaluable for DLT during dose escalation must be replaced.

DL, dose level; DLT, dose-limiting toxicity; MTD, maximum tolerated dose.

According to the toxicity observed, other dose levels and/or schedules of both drugs may be explored if considered appropriate by the Investigators and the Sponsor.

Intrapatient dose escalation will not be allowed under any circumstances.

Prophylactic medication

On Day 1 and Day 8 of each cycle in the PM01183 Escalation Group and the Irinotecan Escalation Group, all patients must receive the following prophylactic medication before infusion of study treatment:

• Dexamethasone 8 mg i.v. (or an equivalent dose of another i.v. corticosteroid).

• Ondansetron 8 mg i.v. (or an equivalent dose of another i.v. 5-HT₃ receptor antagonist).

• If necessary and in addition to the above, 10 mg of oral or i.v. metoclopramide or equivalent can be administered every eight hours (according to tolerance and Investigator criteria).

After Day 1 and Day 8 of each cycle in the PM01183 Escalation Group and the Irinotecan Escalation Group, extended oral dexamethasone not exceeding 20 mg/days and/or oral (or i.v.) ondansetron 4-8 mg (or equivalent) is optional and according to Investigator criteria. For the purpose of safety evaluations, an optimal antiemetic prophylaxis is defined as all the medications at their respectively maximum dose of either option described above.

Additional antiemetics might be used if needed although aprepitant and fosaprepitant are not allowed and will not be used under any circumstances during study participation.

Antidiarrheal prophylaxis: in patients experiencing cholinergic syndrome, prophylactic atropine should be considered with 0.25-1 mg of i.v. or subcutaneous atropine (unless clinically contraindicated).

Primary G-CSF prophylaxis will be required in specific cohorts of patients. In Cycle 1 , these patients will receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days. Primary G-CSF prophylaxis for further cycles is suggested to be at the same regimen, but could also be administered according to standard institutional practice, at the investigator’s discretion.

Allowed medications/therapies

• Therapies for preexisting and treatment-emergent medical conditions, including pain management.

• Blood products and transfusions, as clinically indicated.

• Bisphosphonates.

• In case of nausea or vomiting, secondary prophylaxis and/or symptomatic treatment for nausea and/or emesis according to American Society of Clinical Oncology (ASCO) guidelines will be allowed.

• Erythropoietin use according to ASCO guidelines will be allowed.

• Palliative local radiation (excluding thorax and mediastinum) may be applied if needed after the first cycle of study treatment is completed. Any lesion within the irradiated area will then not be considered an area of measurable/evaluable disease. Thorax and mediastinum may be irradiated, if required, after a minimum of three weeks of study treatment discontinuation.

• Megestrol acetate for appetite stimulation.

Prohibited medications/therapies

• Concomitant administration of any other antineoplastic therapy is prohibited.

• Medroxyprogesterone (if given for the treatment of endometrial cancer). • Other investigational agents.

• Aprepitant or directly related substances (e.g., fosaprepitant).

• Immunosuppressive therapies other than corticosteroids given as antiemetic prophylaxis or pain control, or low-dose cortisol replacement. Exceptionally for patients with glioblastoma, corticosteroids should be used at the minimal possible dose to control symptoms of cerebral edema and mass effect, and should be reduced and/or discontinued if possible.

• Primary prophylaxis and/or treatment with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) during Cycle 1 (except if patient(s) is/are treated in a specific cohort with primary G-CSF prophylaxis, in which case use is compulsory). Secondary prophylaxis might be allowed in subsequent cycles (instead of a dose reduction due to exclusively hematological reasons) if previously agreed with the Sponsor.

• Thoracic and/or mediastinal irradiation concomitant with study treatment.

Drug-drug interactions

In vitro studies with human microsomes have shown that CYP3A4 is the major CYP isoform involved in the metabolism of PM01183, followed by CYP2E1 , CYP2D6 and CYP2C9. The estimated contribution of the other CYP isoenzymes to the PM01183 metabolism is considered to be negligible. Therefore, concomitant drugs which induce or inhibit any of these cytochromes, especially CYP3A4, should be carefully monitored or avoided, whenever is possible.

A potentially significant interaction with aprepitant is suggested by available phase II data from ovarian cancer patients and phase I data from the PM1183-A-008-13 study. PM01183 clearance was reduced by 50%, approximately, in the presence of aprepitant. In consequence, the use of aprepitant is currently forbidden in PM01 183 studies.

Criteria for treatment continuation

Patients will be treated with additional cycles of PM01183 combined with irinotecan as long as no unacceptable toxicity and/or progression of the disease and/or withdrawal of consent occurs. Administration should be delayed if the criteria in the tables below are not met on Day 1 of any cycle after Cycle 1 . Parameters will be reevaluated at minimum intervals of 48 hours. The new cycle will be started upon recovery of these parameters.

A maximum delay of 15 days will be allowed for recovery from drug-related adverse events. If recovery has not occurred after a 15-day delay, the patient should discontinue the treatment, except in case of obvious patient benefit at the criteria of the Investigator and upon agreement with the Sponsor.

After a dose delay due to drug-related toxicity (except for neutropenia exclusively) exceeding the 15-day delay, treatment may continue after appropriate dose reduction, or appropriate secondary prophylaxis with G-CSF (when due to neutropenia exclusively), or irinotecan interruption (i.e., due to digestive toxicity [diarrhea, intestinal obstruction, nausea, vomiting, abdominal distension, dehydration grade > 3 or as per Investigator criteria] and/or cholinergic syndrome) but only with Sponsor approval.

Not meeting Day-8 (+ 3 days) criteria for irinotecan retreatment in Cycle 1 of the PM01183 Escalation Group and the Irinotecan Escalation Group is a DLT. If irinotecan treatment continuation criteria are not met on Day 8 (+ 3 days) of any cycle, the scheduled irinotecan infusion will be skipped and the patient reevaluated for Day 1 of the subsequent cycle.

Criteria for treatment continuation in the PM01183 Escalation Group and the Irinotecan Escalation Group.

These criteria do not apply to Day 1 of Cycle 1 .

If a patient does not meet the requirements for treatment continuation on Day 1 of further cycles, both drug infusions (PM01183 and irinotecan) will be withheld until recovery for a maximum of 15 days after the theoretical treatment date. If recovery has not occurred after a delay of > 15 days, discontinue treatment or reduce dose if there is evidence of clinical benefit (up to twice).

If a patient does not meet the requirements for treatment continuation due to digestive toxicity (diarrhea, intestinal obstruction, nausea, vomiting, abdominal distension, dehydration and/or cholinergic syndrome grade > 3 or as per Investigator criteria), irinotecan will be permanently discontinued and treatment may continue with PM01183 alone at its single-agent RD — 3.2 mg/m² q3wk — without any delay (if clinically appropriate). Patients treated with PM01 183 as a single agent can have two additional dose reductions (2.6 and 2.0 mg/m²). Once a patient had permanently discontinued Irinotecan, Day 8 visits will not be required in further cycles. Only if a patient had a toxicity in previous cycle (defined as any grade > 3 AE or grade > 3 laboratory abnormality related to PM01183), then laboratory assessments should be performed at Day 8.

* Albumin transfusion is forbidden.

** Non-symptomatic metabolic abnormalities (e.g., increase/decrease of sodium, potassium, calcium).

AEs, adverse event(s); ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CrCL, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; GGT, gamma-glutamyltransferase; q3wk, every three weeks; ULN, upper limit of normal.

If a patient does not meet the requirements for treatment continuation on Day 1 of any cycle after Cycle 1 , re-assessments should be performed periodically at interval of at least 48 hours, and treatment will be withheld until appropriate recovery, for a maximum of two weeks after the treatment due date. If there is no recovery after a 2- week delay, treatment must be discontinued, except if objective clinical benefit is adequately documented by the Investigator, and upon agreement with the Sponsor. Then, treatment may continue after appropriate dose reduction.

Dose reduction

After a DLT related to the combination, or after an infusion delay greater than 15 days related to the combination, or after toxicity considered as unacceptable by the Investigators, treatment may continue — with appropriate dose reduction (PM01183 or irinotecan, depending on the drug that is being escalated) — only if there is clear evidence of objective patient benefit. This will always be discussed with the Sponsor. Under this circumstance, and following recovery to pre-specified re-treatment criteria, the patient will be retreated at the immediately lower dose level within the dose escalation scheme of the group he/she has been allocated to.

Up to two individual dose reductions will be allowed per patient; any patients requiring more than two dose reductions will be withdrawn from the study. Once the dose has been reduced for an individual patient, it will not be re-escalated again under any circumstances.

If a patient does not meet the requirements for treatment continuation due to digestive toxicity (diarrhea, intestinal obstruction, nausea, vomiting, abdominal distension, dehydration and/or cholinergic syndrome grade > 3 or as per Investigator criteria), irinotecan will be permanently discontinued and treatment may continue with PM01183 alone at its single-agent RD — 3.2 mg/m² q3wk — without any delay (if clinically appropriate). Patients cannot continue treatment with irinotecan alone.

Patients requiring dose reduction exclusively due to grade 4 neutropenia or any grade febrile neutropenia that occurred during the preceding cycle are allowed to receive secondary prophylaxis with G-CSF instead of a dose reduction per Investigator decision. If toxicity re-occurs despite G-CSF use, up to two individual dose reductions should then be implemented.

EVALUABILITY OF PATIENTS

In all groups, an evaluable patient for the primary objective of the Phase I escalation stage (determination of the MTD and RD) should have received at least one complete cycle (defined as three weeks: PM01 183 plus irinotecan on Day 1 [week 1]; irinotecan on Day 8 [week 2]; and rest period [week 3] in the PM01183 Escalation Group and the Irinotecan Escalation Group, except if early discontinuations or missed doses and/or assessments were the consequence of drug-related toxicity (excluding hypersensitivity reactions and/or extravasations).

In the tumour-specific expansion cohort(s) at the RD for each group, a patient evaluable for efficacy should have received at least one dose each of PM01183 and irinotecan and have had one disease evaluation per RECIST v.1.1 (patients with glioblastoma should have had one disease evaluation per RECIST v.1.1 and RANG criteria), except in case of treatment failure such as drug-related toxicity, death or early disease progression (PD after only one cycle).

EVALUATION CRITERIA

Primary endpoint

Phase I escalation stage:

Determination of MTD and RD

• The MTD for each group will be the lowest dose level explored during dose escalation in which one third or more of evaluable patients develops DLT in Cycle 1.

• The RD for each group will be the highest dose level explored during dose escalation in which less than one third of evaluable patients develop DLT during Cycle 1 .

If the DLTs of the irinotecan and PM01183 combination without G-CSF prophylaxis are exclusively related to neutropenia, the MTD and RD with primary G-CSF prophylaxis will also be determined for each group. Phase II expansion stage:

Efficacy

Antitumour activity will be measured according to RECIST v.1.1 at least six weeks after treatment initiation in all patients with measurable disease.

Patients included in the tumour-specific expansion cohort(s) at the RD for each group must be evaluable per RECIST v.1 .1 (including ovarian cancer patients). Specifically, patients with glioblastoma must be evaluated per RECIST v.1.1 and RANG criteria. In the tumour-specific expansion cohort(s) at the RD for each group, a patient evaluable for efficacy should have received at least one dose each of PM01183 and irinotecan and have had one disease evaluation per RECIST v.1.1 (patients with glioblastoma should have had one disease evaluation per RECIST v.1 .1 and RANG criteria), except in case of treatment failure such as drug-related toxicity, death or early disease progression (PD after only one cycle). In the tumour-specific expansion cohort(s), exploratory assessment for duration of response (DoR), progression-free survival (PFS), and overall survival (OS) will be performed.

Dose-limiting toxicities

DLTs are defined as any AE or laboratory abnormalities related to the study treatment in an evaluable patient during the first cycle of treatment and fulfilling at least one of the criteria outlined below.

• Grade 4 neutropenia (ANC < 0.5 x 10⁹/L) lasting > 3 days.

• Febrile neutropenia of any duration or neutropenic sepsis.

• Grade 4 thrombocytopenia (platelet count < 25 x 10⁹/L) or grade 3 thrombocytopenia with clinically significant bleeding requiring a platelet transfusion.

• Grade 4 ALT and/or AST increase (or grade 3 lasting > 14 days).

• Treatment-related grade > 2 increased ALT or AST concomitantly with total bilirubin increase > 2.0 x ULN and normal ALP (i.e. fulfilling Hy’s law criteria).

Grade > 3 diarrhea lasting > 5 days and despite adequate corrective treatment (loperamide, hydration, atropine or as determined by Investigator). Onset can be early (occurring up to 24 hours of the irinotecan administration) or late (occurring > 24 hours after irinotecan administration).

• Grade > 3 CPK increase.

• Any other grade > 3 non-hematological, treatment-related AE, excluding nausea/vomiting (unless the patient is receiving an optimal antiemetic regimen), hypersensitivity reactions, extravasations, grade 3 fatigue lasting less than one week, and non-clinically relevant, isolated biochemical abnormalities (e.g., isolated increased GGT). In any case, the clinical relevance should be discussed between the Investigators and the Sponsor.

• Delay in the administration of Cycle 2 of the combination exceeding 15 days from the theoretical date (Day 22) due to any AEs related to the study drug(s).

• Failure to meet the Day-8 treatment continuation criteria for irinotecan in Cycle 1

DLTs with delayed onset (i.e., those occurring after Cycle 1 ) will be discussed between the Investigator and the Sponsor, and the final consensus will be documented.

Secondary endpoints

• Safety: patients will be evaluable for safety if they have received at least one partial or complete infusion of the study treatment. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- CTCAE) version 4. Additionally, treatment compliance, in particular dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be analyzed.

• Pharmacokinetics: PK analyses will be evaluated in plasma by standard noncompartmental methods (compartmental modeling may be performed if appropriate).

• Efficacy (secondary endpoint in the Phase I escalation stage): antitumour activity will be measured according to RECIST v.1.1 at least six weeks after treatment initiation in all patients with measurable disease, or by evaluation of tumour markers (CA-125 in ovarian cancer patients with non-measurable disease during dose escalation). In patients with glioblastoma, antitumour activity will be measured according to RECIST v.1.1 and RANG criteria.

• Pharmacoqenomics: mutations/polymorphisms and/or protein expression levels of factors involved in the development of the disease or in the mechanism of action of PM01183 or irinotecan will be evaluated from prior available tumour tissue samples (formalin-fixed paraffin-embedded [FFPE] tissue). The presence of mutations/polymorphisms that could affect the activity of the drugs will be analyzed through DNA sequencing, while the level of expression of proteins will be determined by immunohistochemistry (IHC). Their correlation with the clinical response and outcome after treatment will be assessed. This exploratory analysis will be performed if there is evidence of clinical benefit in the PGx sample cohort.

• Pharmacogenetics: a blood sample will be collected at any time during the study — but preferably at the same time as the pre-treatment PK sample on Day 1 of Cycle 1 — to evaluate germline DNA for the presence or absence of mutations or polymorphisms that may explain individual variability in main PK parameters.

PHARMACO-KINETICS

All patients included in the study will be sampled for PK analysis. The plasma PK of irinotecan (and its metabolite SN-38) and PM01183 will be evaluated during Cycle 1 with a schedule of 12 samples. The sampling schedule will be as follows:

Draw one blood sample per time-point: after centrifuging, however, separate the plasma in two samples — one for PM01 183 analysis and the other for irinotecan and metabolite analysis — except as indicated below.

Single sample only for analysis of irinotecan and metabolite. ** Single sample only for analysis of PM01183.

PK parameters will be calculated using non-compartmental analysis and population methods if appropriate, after pooling data with other studies to check any PK interaction.

REPLACEMENT OF PATIENTS

In all groups, an evaluable patient for the primary objective of the Phase I escalation stage (determination of the MTD and RD) should have received at least one complete cycle (defined as three weeks: PM01 183 plus irinotecan on Day 1 [week 1]; irinotecan on Day 8 [week 2]; and rest period [week 3] in the PM01183 Escalation Group and the Irinotecan Escalation Group, if early discontinuations or missed doses and/or assessments were the consequence of drug-related toxicity (excluding hypersensitivity reactions and/or extravasations).

Patients must be replaced if they are not evaluable for the assessment of the primary endpoint of the Phase I escalation stage, specifically if:

• The patient discontinues treatment before completing Cycle 1 for any reason other than toxicity (e.g., early disease progression, hypersensitivity reaction to any of the study drugs).

• The patient requires radiotherapy (RT) or other therapeutic procedure within three weeks of the first dose, unless they previously had another treatment-related AE/laboratory abnormality included in the definition of DLT.

• There is a protocol deviation to an extent precluding any conclusion regarding the safety of the study therapy.

Patients enrolled in the tumour-specific expansion cohort(s) at the RD for each group must be replaced if they are not evaluable for efficacy as per RECIST v.1 .1 (including ovarian carcinoma) (in patients with glioblastoma by RECIST v.1 .1 and RANG criteria) for reasons other than treatment failure (drug-related toxicity, death, or early PD — clinical or radiological disease progression, or death due to progressive disease, which occurs before the first radiological assessment planned as per protocol).

All replaced patients will be included in the general safety analysis and in the efficacy analysis (if appropriate).

STATISTICAL METHODS

Sample size:

Approximately 200 evaluable patients are expected to participate in this trial.

T umour-specific expansion cohort(s) at each RD will include approximately 20 patients per tumour type other than SCLC, and approximately 47 patients with SCLC.

In expansion cohorts of patients with tumour types other than SCLC, the maximum half-width of the confidence interval (Cl) would be between 8% (if all 20 included patients showed response to treatment) and 23% (if none of the 20 included patients showed response to treatment).

In the expansion cohort of patients with SCLC, and based on newly available information, additional patients will be recruited to test the null hypothesis that 40% or less patients get a response (p < 0.40) versus the alternative hypothesis that 60% or more patients get a response (p > 0.60). The variance of the standardized test is 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 0.2. With these assumptions, if the number of patients who achieve a confirmed response in this expansion cohort is >26 in a total of 47 patients, then this would allow the rejection of the null hypothesis.

Demographics:

Descriptive statistics (mean, median, standard deviation and 95% confidence interval, range of value, frequencies and percentages) will be used. Tables will be displayed by dose level/escalation group (and by tumour type if appropriate).

Safety:

Descriptive statistics will be used to characterize DLTs, the profiles of drug-related AEs, drug-related deaths, serious adverse events (SAEs), drug-related delays, dose reductions, and/or treatment discontinuations. All AEs will be graded according to the current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4. Tables will be displayed by dose level/escalation group. Efficacy:

Response rates (percentage of patients with any response [partial response (PR) or complete response (CR): overall response rate], percentages for PR and CR separately, as well as percentage of patients with prolonged stable disease (SD) > 4 months) will be characterized using descriptive statistics (95% exact binomial confidence interval). In specific tumour types in the expansion cohort at the RD for each group (and if any type is adequately represented in the escalation phase), time- related parameters (i.e., duration of response [DoR], progression-free survival [PFS], and overall survival [OS]) will be analyzed according to the Kaplan-Meier method as appropriate. Tumour types represented in both the escalation phase and tumourspecific expansion cohort(s) will be grouped if appropriate. The characteristics of the patients achieving an objective response or SD > 4 months by RECIST v.1.1 (in patients with glioblastoma by RECIST v.1.1 and RANG criteria), or a clinically significant improvement as measured by tumour markers, if applicable, will be displayed.

Analysis of data and patient characteristics in the expansion cohort for SCLC will take into account the patient’s chemotherapy-free interval (CTFI), central nervous system (CNS) involvement, and treatment setting (second-line and third-line).

All patients will be followed for up to 12 months after the inclusion of the last evaluable patient.

Pharmacokinetics:

The PK parameters will be tabulated and selected parameters will be graphically displayed per dose level/escalation group. The dose-exposure relationships for maximum plasma concentration (C_max) and area under the curve (AUC) will be evaluated. Any potential PK interaction between PM01183, irinotecan and SN-38 will be also explored. The potential influence on selected PK parameters of selected demographic and clinical dichotomous variables (gender, laboratory test results above/below selected cutoff values, etc.) will be evaluated by Student’s t test or Mann- Whitney’s U test as appropriate. For multinomial variables, analysis of variance will be used. For selected continuous demographic and clinical variables, relationship with selected PK parameters will be graphically explored and assessed using correlation and regression methods. Pharmacoqenomics:

Mutations/polymorphisms and IHC scoring will be performed blind, and clinical data compiled only after all analyses are completed. Fisher’s exact test will be used to test whether a specific protein-expression profile is associated with the clinical outcome after treatment with PM01183 and irinotecan. The prognosis value of markers will be explored for objective clinical response, progression-free survival and overall survival. In each case, if applicable, a multivariate model will be developed by stepwise elimination, starting with all markers with a p-value lower than 0.10 in the univariate analysis. If applicable, hazard ratios will be calculated with the univariate Cox model, and comparison between Kaplan-Meier survival (whenever available) and progression-free survival curves will be performed with the log-rank test. All tests of statistical significance will be exploratory and significance will be set at 0.05 (two- sided).

Pharmacogenetics:

The influence of known polymorphisms on main PK parameters will be assessed by a Student’s test or Mann-Whitney’s U test as appropriate.

DURATION OF STUDY PERIOD (per patient)

Patients will be evaluated at scheduled visits in three study periods:

• Pre-treatment: from signature of informed consent to first infusion of study treatment.

• Treatment: from the first infusion of a study drug to the last study treatment administration plus 30 days (end of treatment).

• Follow-up: after treatment discontinuation, patients with treatment-related toxicities > grade 2 will be followed every four weeks until resolution or stabilization at a level acceptable to the Investigator and the Sponsor or until the start of new therapy. Patients who finish treatment without disease progression will be followed every eight weeks (± two weeks) until disease progression, other antitumour therapy, death or until 12 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first. After disease progression or a new antitumour therapy is started, patients will be followed at least every three months (± two weeks) until death or until 12 months after the inclusion of the last evaluable patient in the study (end of study). Patients will be considered to be on- study from the signature of the informed consent to the end of the follow-up period (or screening failure, if applicable). Patients will be considered to be on-treatment for the duration of their treatment and until the day of end of treatment. Investigators can appraise potential study candidates in a pre-screening period but only perform study-specific screening assessments after the patient formally consents.

End of treatment (EOT) is defined as 30 days after treatment discontinuation unless the patient starts a new antitumour therapy or dies (whichever occurs first). An EOT visit will be performed 30 days (± 7 days) after administration of the last dose of study treatment unless the patient dies or starts any subsequent antitumour therapy, in which case the EOT visit should be performed immediately before the start of the new therapy.

Patients will receive the study medications for as long as it is considered in their best interest. Specifically, treatment will continue until:

• Disease progression. *

• Unacceptable toxicity.

• Intercurrent illness of sufficient magnitude to preclude fulfillment of appropriate retreatment criteria and/or safety continuation of the study.

• Non-compliance with study requirements. *

• Cycle delay > 15 days due to toxicity. *

• Requirement of > 2 dose reductions. *

• Patient refusal.

Patients discontinuing irinotecan only, at any time after Cycle 1 , can continue receiving PM01183 at its single-agent RD (3.2 mg/m²) if appropriate. If PM01 183 treatment needs to be discontinued, the patient will proceed to EOT.

*except if, objective clinical benefit is adequately documented by the Investigator, and upon agreement with the Sponsor. Then, treatment may continue.

Results Recommended Dose (RD) in cohort A: LUR 2 mg/m2 day 1 + IRI 75 mg/m2 day 1 & 8 + G-CSF q3weeks. DLTs were omission of day 8 IRI infusions due to neutropenia grade 3-4 and thrombocytopenia grade 2-3.

Recommended Dose (RD) in cohort B: LUR 3 mg/m2 day 1 + IRI 40 mg/m2 day 1 & 8 + G-CSF q3weeks.

One patient diagnosed with chordoma had not received prior treatment

CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; mets, metastases; NA, not available; PD, progressive disease; PR, partial response; SD, stable disease; STS, soft tissue sarcoma; UK, unknown.

Safety

* 7 (30.5%) grade 4 **4 (50%) grade 4

ALT, alanine aminotransferase; AST, aspartate aminotransferase

Adverse events related (or with unknown relationship) to lurbinectedin + irinotecan in at least 10% of patients or that reached grade 3 or 4 at the RDs with primary G-CSF prophylaxis in the the Irinotecan Escalation Group of study PM1183-A-014-15 (worst grade per patient).

Hematological and biochemical abnormalities with lurbinectedin + irinotecan at the RDs with primary G-CSF prophylaxis in the Irinotecan Escalation Group of study PM1183-A- 014-15 regardless of relationship (worst grade per patient).

a Version 4.0 of the NCI-CTCAE grades creatinine increases from baseline, even if creatinine values remain normal.

In the Irinotecan Escalation Group, 11 patients were treated at DL1 (lurbinectedin 3.0 mg/m2 + irinotecan 15 mg/m2) without primary G-CSF prophylaxis. Nine of these patients were evaluable for DLTs, and two (22.2%) had DLTs (grade 3 neutropenia) that prevented administration of irinotecan on D8. The level of grade 3/4 neutropenia observed at DL1 was moderate to high. As a result, it was decided to escalate to DL2 (lurbinectedin 3.0 mg/m2 + irinotecan 30 mg/m2) but giving primary G-CSF prophylaxis. Six patients were treated at DL2, of whom five were evaluated for DLTs and one had a DLT (grade 3 ALT increase) that prevented administration of irinotecan on D8. It was then decided to escalate dose first to DL3 (lurbinectedin 3.0 mg/m2 + irinotecan 40 mg/m2), with one of five evaluable patients having a DLT (grade 4 neutropenia lasting >3 days), and then to DL4 (lurbinectedin 3.0 mg/m2 + irinotecan 50 mg/m2), all with primary G-CSF prophylaxis. Two of three patients treated at DL4 had DLTs (grade 3/4 neutropenia; and grade 3 thrombocytopenia, both of which prevented administration of irinotecan on D8). As a result, the MTD for this combination with primary G-CSF prophylaxis in this group was defined at DL4 (lurbinectedin 3.0 mg/m2 + irinotecan 50 mg/m2), whereas the RD was defined at DL3 (lurbinectedin 3.0 mg/m2 + irinotecan 40 mg/m2). Patient accrual in this escalation group was completed at cutoff.

Dose Adjustment

None of the patients discontinued treatment due to a treatment-related adverse event. No treatment-related deaths occurred. 5 patients (22%) had dose reductions (100% of the dose reductions were due to day 8 IRI omissions related to adverse events). 39/192 (20%) of day 8 IRI infusions were omitted (56% of them due to hematological toxicity).

Efficacy

*1 PR in cohort A; 1 PR in cohort B

CBR, clinical benefit rate; DCR, disease control rate; mo, months; ORR, overall response rate; PFS, progression-free survival; PR, partial response; SD, stable disease; STS, soft tissue sarcoma. + patients ongoing

In relation to STS, Progression Free Survival (PFS) is shown in Figure 1.

Changes in tumour size in all STS patients is shown in Figure 2.

The number of cycles in all STS patients is shown in Figure 3.

In the Cohort B (Irinotecan escalation group), the following patient responses have been seen:

DL1 : Lurbinectedin 3 mg/m2 + Irinotecan 15 mg/m2 (2/9 DLT): 1 PR in synovial sarcoma with 27cycles of treatment. 1 SD in Ewing sarcoma. 1 SD in mesothelioma. 3 SD in pancreatic adrenocarcinoma. 1 SD in SCLC.

DL2: Lurbinectedin 3 mg/m2 + Irinotecan 30 mg/m2 (1/6 DLT): PR in gastric carcinoma.

Long stabilization in glioblastoma. Patients at DL2 also received G-CSF.

DL3: Lurbinectedin 3 mg/m2 + Irinotecan 40 mg/m2 (1/6 DLT): 1 PR in SCLC. 2 SD in SCLC. 1 SD in mesothelioma. 1 SD in leiomyosarcoma. Patients at DL3 also received

G-CSF.

DL4: . Lurbinectedin 3 mg/m2 + Irinotecan 50 mg/m2: 1 SD in leiomyosarcoma with 10 cycles and ongoing. 1 SD in chondrosarcoma with 13 cycles and ongoing. Patients at

DL4 also received G-CSF. Following evaluation of the patient responses, the Maximum tolerated dose (MTD) was found to be irinotecan 50mg/m2 + LUR 3mg/m2 +G-CSF and the Recommended dose (RD) was found to be irinotecan 40mg/m2 + LUR 3mg/m2 +G-CSF.

It can be seen that dosage regimens according to the present invention are effective in the treatment of solid tumours.

Conclusion

The combination of lurbinectedin and irinotecan has been tested in patients with solid tumours in 2 different cohorts: cohort A with fixed doses of Irinotecan (75 mg/m²) and cohort B with fixed doses of Lurbinectedin (3 mg/m²).

The combination was well tolerated in both cohorts; main adverse event was related with neutropenia, and it was known, predictable and manageable.

Non-hematological toxicity was related to fatigue and gastrointestinal adverse events, being all of them mild (grade 1 -2) and transient, except one case of diarrea grade 3.

Activity has been demonstrated in both cohorts, especially based on long-lasting stabilizations, and with progression-free times longer than the time-to-progression observed with the last prior therapy line.

Particular efficacy has been seen in patients with soft tissue sarcoma, notably synovial sarcoma (most of them heavily pretareated). Efficacy has also been seen in Ewing sarcoma, gastric carcinoma, glioblastoma, SCLC and mesothelioma.

Dosing regimens comprising lurbinectedin at 3 mg/m² and irinotecan at between 15 to 60 mg/m² have been seen to be effective in various solid tumours. In the Cohort B (Irinotecan escalation group), the Maximum tolerated dose (MTD) was found to be irinotecan 50mg/m2 + LUR 3mg/m2 +G-CSF and the Recommended dose (RD) was found to be irinotecan 40mg/m2 + LUR 3mg/m2 +G-CSF.

Claims

64 CLAIMS

1 . A method of treatment of a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, thereby treating the solid tumour; wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

2. The method of claim 1 wherein lurbinectedin and irinotecan are administered concurrently, separately or sequentially.

3. The method of claim 2 wherein lurbinectedin is administered initially, followed by irinotecan.

4. The method of any preceding claim wherein multiple administrations of either lurbinectedin, or irinotecan, or both, are given.

5. The method of any preceding claim, wherein lurbinectedin is administered by subcutaneous, intravenous, or intraperitoneal route; preferably intravenous infusion.

6. The method of any preceding claim, wherein lurbinectedin is administered with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours and most preferably 1 hour; optionally allowing - 5 minutes to +20 minutes.

7. The method of any preceding claim, wherein irinotecan is administered by subcutaneous, intravenous, or intraperitoneal route; preferably intravenous infusion.

8. The method of any preceding claim, wherein irinotecan is administered with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours and most preferably 90 minutes; optionally allowing - 5 minutes to +30 minutes.

9. The method of any preceding claim, having an administration cycle of once every one to four weeks; preferably once every three weeks.

10. The method of claim 9, having an administration cycle of once every 21 days.

1 1 . The method of any preceding claim, wherein lurbinectedin is administered on day

65

12. The method of any preceding claim, wherein irinotecan is administered on day 1 of a cycle.

13. The method of any preceding claim, wherein irinotecan is administered on day 8 of a cycle.

14. The method of any preceding claim, wherein irinotecan is administered on day 1 and day 8 of a cycle.

15. The method of any preceding claim, wherein the method further comprises administration of granulocyte-colony stimulating factor (G-CSF).

16. The method of claim 15, wherein in Cycle 1 , the patient receives primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days.

17. The method of claim 15 or claim 16, wherein G-CSF is administered during one or more subsequent cycles.

18. The method of any preceding claim wherein the solid tumour is selected from the group consisting of sarcoma, carcinoma, lung cancer, gastric cancer, glioblastoma, and malignant mesothelioma.

19. The method of claim 18, wherein the solid tumour is sarcoma, wherein the sarcoma may be a soft tissue sarcoma, preferably synovial sarcoma or Ewing sarcoma.

20. The method of claim 18, wherein the solid tumour is lung cancer, wherein the lung cancer is small cell lung cancer (SCLC).

21 . The method of any preceding claim, wherein the treatment results in one or more of: reduction in tumour size; delay in growth of tumour; prolongation of life of the patient; delay in disease progression; remission.

22. A method of prolonging survival of a patient having a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby prolonging survival of the patient. 66

23. A method of delaying disease progression of a solid tumour in a patient, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of between 15 to 60 mg/m², thereby delaying disease progression of the solid tumour.

24. A method of reducing or delaying growth of a solid tumour, the method comprising administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m², thereby reducing or delaying growth of the solid tumour.

25. The method according to any one of claims 22 to 24, wherein the method further comprises administration of granulocyte-colony stimulating factor (G-CSF).

26. The method of claim 25, wherein in Cycle 1 , the patient receives primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days.

27. The method of claim 25 or claim 26, wherein G-CSF is administered during one or more subsequent cycles.

28. Use of lurbinectedin in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

29. Use of irinotecan in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

30. Use of lurbinectedin and irinotecan in the manufacture of a medicament for the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m². 67

31. The use according to any one of claims 28 to 30, wherein the method further comprises administration of granulocyte-colony stimulating factor (G-CSF).

32. The use of claim 31 , wherein in Cycle 1 , the patient receives primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days.

33. The use of claim 31 or claim 32, wherein G-CSF is administered during one or more subsequent cycles.

34. Lurbinectedin for use in the treatment of a solid tumour, wherein in said treatment lurbinectedin is administered in combination with irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

35. Irinotecan for use in the treatment of a solid tumour, wherein in said treatment irinotecan is administered in combination with lurbinectedin to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

36. Lurbinectedin and irinotecan for use in the treatment of a solid tumour, wherein said treatment comprises administering a combination therapy of lurbinectedin and irinotecan to a patient in need thereof, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².

37. The compounds for use according to any one of claims 34 to 36, wherein the method further comprises administration of granulocyte-colony stimulating factor (G- CSF).

38. The compounds for use of claim 37, wherein in Cycle 1 , the patient receives primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1 , and during five days.

39. The compounds for use of claim 37 or claim 38, wherein G-CSF is administered during one or more subsequent cycles.

40. A pharmaceutical package comprising lurbinectedin and irinotecan, wherein lurbinectedin is administered at a dose of 3 mg/m² and irinotecan is administered at a dose of 40 mg/m².