WO2008135792A1 - Pm00104 compound for use in cancer therapy - Google Patents

Pm00104 compound for use in cancer therapy Download PDF

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Publication number
WO2008135792A1
WO2008135792A1 PCT/GB2008/050330 GB2008050330W WO2008135792A1 WO 2008135792 A1 WO2008135792 A1 WO 2008135792A1 GB 2008050330 W GB2008050330 W GB 2008050330W WO 2008135792 A1 WO2008135792 A1 WO 2008135792A1
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WO
WIPO (PCT)
Prior art keywords
pmoo
cancer
dose
administered
patient
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Application number
PCT/GB2008/050330
Other languages
French (fr)
Inventor
Johann De Bono
Luis Paz-Ares
Josep Tabernero
John Smyth
Begoña DE LAS HERAS
Original Assignee
Pharma Mar S.A.
Williams, Gareth
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Pharma Mar S.A., Williams, Gareth filed Critical Pharma Mar S.A.
Publication of WO2008135792A1 publication Critical patent/WO2008135792A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the treatment of cancers and, in particular, to the effective treatment of human cancers using compound PMOO 104.
  • Cancer develops when cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Epithelial cells, which cover internal and external surfaces of the body, including organs and lining of vessels, may give rise to a carcinoma. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
  • cancer is invasive and tends to metastasise to new sites. It spreads directly into surrounding tissues and also may be disseminated through the lymphatic and circulatory systems.
  • Chemotherapy in its classic form, has been focused primarily on killing rapidly proliferating cancer cells by targeting general cellular metabolic processes, including DNA, RNA, and protein biosynthesis.
  • PMOO 104 is a novel synthetic alkaloid related to Jorumycin and Renieramycins, and also to safracin and saframycin compounds.
  • Jorumycin is a natural compound isolated from the skin and from the mucus of the Pacific nudibranch Jorunna funebris (Fontana A., et al, Tetrahedron (2000), 56, 7305-8).
  • the family of Renieramycins is disclosed as being isolated from sponges and tunicates (James M. F. et al. J. Am. Chem. Soc. ( 1982), 104, 265-269; Oku N., et al. Journal Natural Products (2003), 66, 1136-9).
  • PMOO 104 has demonstrated a significant in vitro activity against solid and non-solid tumour cell lines as well as significant in vivo activity in several xenografted human cell lines in mice, such as breast and prostate.
  • Preliminary insights into the mechanism of action of PMOO 104 suggested cell cycle changes, DNA binding properties and transcriptional inhibition.
  • This compound shows the following chemical structure:
  • the present invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of PMOO 104, or a pharmaceutical composition thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of PMOO 104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods of this invention.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods of this invention.
  • the present invention provides a method for treating a human patient afflicted with cancer, comprising administering PMOO 104 to said patient, using a cyclical dosing protocol and a predetermined cycle.
  • Typical dosing protocols for PMOO 104 administration are provided.
  • the administration of PMOO 104 in humans in accordance with the methods and compositions of this invention is tolerable and provides antitumor activity at the dosage and regimens given.
  • a medical kit for administering PMOO 104 comprising printed instructions for administering PMOO 104 according to the procedures and methods of treatment set forth herein, and a supply of PMOO 104 in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of PMOO 104 for the treatments as defined above and a pharmaceutically acceptable carrier.
  • PMOO 104 is a novel synthetic alkaloid related to the marine compounds Jorumycin and Renieramycins, and also to safracin and saframycin compounds, having the following structure:
  • PM00104 is intended here to cover any pharmaceutically acceptable salt, ester, solvate, hydrate or any other compound which, upon administration to the patient is capable of providing (directly or indirectly) the compound as described herein.
  • non- pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts and prodrugs and derivatives can be carried out by methods known in the art. In particular, we incorporate by reference the disclosure of WO 01/87894 with regard to PMOO 104 and compositions comprising it.
  • compositions of PMOO 104 that can be used include solutions, suspensions, emulsions, lyophilised compositions, etc., with suitable excipients for intravenous administration.
  • PMOO 104 may be supplied and stored as a sterile lyophilized product, comprising PMOO 104 and excipients in a formulation adequate for therapeutic use.
  • a formulation comprising sucrose and a phosphate salt buffered to an adequate pH is preferred.
  • Further guidance on PMOO 104 formulations is given in PCT/GB2006/050362 which is incorporated herein by reference in its entirety.
  • Administration of the compounds or compositions of the present invention is by intravenous infusion. Infusion times of up to 72 hours can be used, more preferably between 1 and 24 hours, with either about 1 , about 3 or about 24 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be around 24 hours or even longer if required.
  • the administration of PMOO 104 is performed in cycles, in accordance with the methods of the invention.
  • An intravenous infusion of PMOO 104 is given to the patients typically the first day of each cycle and then the patients are allowed to recover for the remainder of the cycle.
  • the preferred duration of each cycle is typically of 3 or 4 weeks; multiple cycles can be given as needed. Dose delays and/ or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance to treatments.
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of PMOO 104, or a pharmaceutical composition thereof, by intravenous infusion once per cycle and with an infusion time of up to 72 hours.
  • the infusion times are preferably between 1 and 24 hours, with about 1, about 3 and about 24 hours more preferred.
  • the preferred duration of each cycle is of either 3 or 4 weeks, being 3 weeks the most preferred; and multiple cycles can be given as needed.
  • the PMOO 104 is administered at a dose below 3600 ⁇ g/m 2 , preferably about 3200 ⁇ g/m 2 , about 3000 ⁇ g/m 2 , about 1800 ⁇ g/m 2 , about 1600 ⁇ g/m 2 and about 900 ⁇ g/m 2 .
  • the dose is at least about 3000 ⁇ g/m 2 .
  • the dose is in the range of 900-3600 ⁇ g/m 2 .
  • the PMOO 104 is administered at a dose at or below 8100 ⁇ g/m 2 , preferably at or below 5400 ⁇ g/m 2 , or about 3600 ⁇ g/m 2 , or about 1800 ⁇ g/m 2 .
  • the dose is about 15-25% lower than about 3600 ⁇ g/m 2 , and is thus preferably about 2700 ⁇ g/m 2 , about 2800 ⁇ g/m 2 , about 2900 ⁇ g/m 2 , about 3000 ⁇ g/m 2 . about 3100 ⁇ g/m 2 , or about 3200 ⁇ g/m 2 , particularly preferably about 3000 ⁇ g/m 2 .
  • the dose is about 15-25% lower than about 5400 ⁇ g/m 2 , and is thus preferably about 4000 ⁇ g/m 2 , about 4100 ⁇ g/m 2 , about 4200 ⁇ g/m 2 , about 4300 ⁇ g/m 2 , about 4400 ⁇ g/m 2 , or about 4500 ⁇ g/m 2 .
  • the dose is about 15-20% lower than about 8100 ⁇ g/m 2 , and is thus preferably about 6300 ⁇ g/m 2 , about 6400 ⁇ g/m 2 , about 6500 ⁇ g/m 2 , about 6600 ⁇ g/m 2 , about 6700 ⁇ g/m 2 , about 6800 ⁇ g/m 2 , or about 6900 ⁇ g/m 2 .
  • the PM00104 is administered at a dose of or below 4800 ⁇ g/m 2 , preferably about 4200 ⁇ g/m 2 , about 4000 ⁇ g/m 2 , about 3800 ⁇ g/m 2 , about 3600 ⁇ g/m 2 , about 3200 ⁇ g/m 2 , about 3000 ⁇ g/m 2 , about 2400 ⁇ g/m 2 , about 1600 ⁇ g/m 2 , about 800 ⁇ g/m 2 .
  • the dose is at least about 3200 ⁇ g/m 2 .
  • the dose is in the range of 1600-4800 ⁇ g/m 2 (particularly preferably 2000-4400 ⁇ g/m 2 , 2400-4000 ⁇ g/m 2 , or 2800-3600 ⁇ g/m 2 ), 1600- 3200 ⁇ g/m 2 (particularly preferably 1800-3000 ⁇ g/m 2 , 2000-2800 ⁇ g/m 2 , or 2200-2600 ⁇ g/m 2 ) or 3200-4800 ⁇ g/m 2 (particularly preferably 3400-4600 ⁇ g/m 2 , 3600-4400 ⁇ g/m 2 , 3800-4200 ⁇ g/m 2 , 3900-4100 ⁇ g/m 2 , or about 4000 ⁇ g/m 2 ).
  • the dose may be about 3000 ⁇ g/m 2 , about 3200 ⁇ g/m 2 , or about 4000 ⁇ g/m 2
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose below 3600 ⁇ g/m 2 , every 3 to 4 weeks.
  • the dose is preferably about 3000 ⁇ g/m 2
  • the treatment is preferably repeated every 21 days.
  • Suitable doses for a 1 hour infusion time include doses below 3600 ⁇ g/m 2 , preferably about 3200 ⁇ g/m 2 , about 3000 ⁇ g/m 2 , about 1800 ⁇ g/m 2 , about 1600 ⁇ g/m 2 and about 900 ⁇ g/m 2 .
  • the dose is at least about 3000 ⁇ g/m 2 .
  • the dose is in the range of 900-3600 ⁇ g/m 2 .
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose of or below 5400 ⁇ g/m 2 , every 3 to 4 weeks.
  • the dose is preferably about 5400 ⁇ g/m 2 (or 15-25% lower including 4000-4500 ⁇ g/m 2 , preferably about 4000 ⁇ g/m 2 , about 4100 ⁇ g/m 2 , about 4200 ⁇ g/m 2 , about 4300 ⁇ g/m 2 , about 4400 ⁇ g/m 2 , or about 4500 ⁇ g/m 2 ), about 3500 ⁇ g/m 2 or about 3600 ⁇ g/m 2 (or 15-25% lower including 2700-3200 ⁇ g/m 2 , preferably about 2700 ⁇ g/m 2 , about 2800 ⁇ g/m 2 , about 2900 ⁇ g/m 2 , about 3000 ⁇ g/m 2 , about 3100 ⁇ g/m 2 , or about 3200 ⁇ g/m 2 ), and the treatment is preferably repeated every 21 days.
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose of or below 4800 ⁇ g/m 2 , every 3 to 4 weeks.
  • the dose is preferably in the range of 1600-4800 ⁇ g/m 2 (particularly preferably 2000-4400 ⁇ g/m 2 , 2400-4000 ⁇ g/m 2 , 2800-3600 ⁇ g/m 2 , about 3200 ⁇ g/m 2 , or about 3000 ⁇ g/m 2 ), 1600- 3200 ⁇ g/m 2 (particularly preferably 1800-3000 ⁇ g/m 2 , 2000-2800 ⁇ g/m 2 , or 2200-2600 ⁇ g/m 2 ) or 3200-4800 ⁇ g/m 2 (particularly preferably 3400-4600 ⁇ g/m 2 , 3600-4400 ⁇ g/m 2 , 3800-4200 ⁇ g/m 2 , 3900-4100 ⁇ g/m 2 , or about 4000 ⁇ g/m 2 ), and the treatment is preferably repeated every 21 days.
  • the present invention is directed to a medical kit for administering PMOO 104, comprising printed instructions for administering PMOO 104 according to the dosages and schedules set forth above, and a supply of PMOO 104 in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of PMOO 104 for the treatments as defined above and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of PMOO 104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods as defined above.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods as defined above.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the formulation of one or more dosage units of PMOO 104, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, said dosage units formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
  • the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for use in the procedures and methods as defined herein.
  • the invention further provides a medicament, dosage unit(s), formulation or composition of PMOO 104, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/or schedules given herein.
  • This specific configuration is carried out during the preparation process of the final medicament, and is not part of the actions carried out by the doctor when treating the patient.
  • the invention provides a dosage unit(s), medicament, formulation or composition comprising PMOO 104, or a pharmaceutically acceptable salt thereof, specifically adapted to be administered in the dosages and/ or schedules given herein.
  • the invention provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
  • the invention provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
  • the invention provides PMOO 104 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein PMOO 104 is administered at the dosages and /or schedules given herein.
  • Example 1 the results of a phase I clinical trial wherein PMOO 104 is administered intravenously either as a 1-hour infusion or 3-hour infusion every 3 weeks are shown.
  • MTD maximum tolerated dose
  • RD recommended dose
  • Example 2 it is showed the results of a phase I clinical trial wherein PMOO 104 is administered intravenously as a 24-hour infusion every 3 weeks.
  • Premedication and supportive medication can be given.
  • a prophylactic antiemetic therapy by using for example dexamethasone and/ or metoclopramide can be useful to avoid the side effects due to the administration of the chemotherapeutic agent. Therefore, it is preferred to administer one or several antiemetic agents, such as dexamethasone and metoclopramide, to the patient typically before PMOO 104 infusions, and after the emetic events and the DLT observed. Coadministration of both dexamethasone and metoclopramide as antiemetic medication is particularly preferred in the method of the invention.
  • the treatments of the invention are useful in promoting tumour regression, in stopping tumour growth and/or in preventing metastasis.
  • the method of the invention is suited for human patients, especially those who are relapsing or refractory to previous chemotherapy. First line therapy is also envisaged.
  • the method of the invention is used according to the above schedules and dosages for the treatment of lung cancer (NSCLC and SCLC), sarcoma, especially soft tissue sarcoma, malignant melanoma, pleural mesotelioma, osteosarcoma, bladder cancer, prostate cancer, pancreas cancer, colorectal cancer, kidney cancer, esophageal cancer, suprarenal cancer, parotid gland cancer, head & neck carcinoma, hepatocarcinoma, cervix cancer, and neuroendocrine lung carcinoma.
  • lung cancer NSCLC and SCLC
  • sarcoma especially soft tissue sarcoma, malignant melanoma, pleural mesotelioma, osteosarcoma
  • bladder cancer prostate cancer
  • pancreas cancer colorectal cancer
  • kidney cancer esophageal cancer
  • suprarenal cancer esophageal cancer
  • parotid gland cancer head & neck carcinoma
  • the method of the invention is used for the treatment of NSCLC, submaxilar carcinoma, bladder cancer, pancreas cancer, hepatocarcinoma, esophageal cancer, cervix cancer, and pleural mesotelioma.
  • a phase I trial administering PMOO 104 was conducted.
  • the main objective of this study was to determine the safety, tolerability and identify the maximum tolerated dose (MTD) and recommended dose (RD) of PMOO 104 as 1-hour intravenous (iv) infusion every 3 weeks (this was considered a treatment cycle) to subjects with advanced solid tumours or lymphoma. Since there was evidence that dose limiting toxicities were related to C ma ⁇ , drug escalation was resumed by increasing the duration of the infusion from 1 hour to 3 hours.
  • Other secondary objectives of the trial were to determine the preliminary pharmacokinetics of PMOO 104 in this schedule and evaluate the preliminary antitumor activity of PMOO 104.
  • the maximum tolerated dose relates to the highest dose at which at least 2 out of 3-6 subjects experience a dose limiting toxicity (DLT) at any given dose level, being this dose level considered the MTD.
  • the recommended dose is intended to relate to the highest dose at which less than 2 of 6 subjects experience DLT during the first cycle.
  • PM00104 doses 225, 450, 900, 1800, 3000 and 3600 ⁇ g/m 2
  • PMOO 104 drug product was provided as a lyophilized powder containing PMOO 104, sucrose and potassium dihydrogen phosphate, and it was reconstituted with sterile water for injection.
  • Subjects enrolled in this clinical trial were adult patients with confirmed malignant solid tumour or lymphoma for which no standard therapy would reasonable be expected to result in cure or palliation.
  • Inclusion criteria included recovery from any drug-related adverse event derived from prior therapies excluding alopecia and NCI-CTCAE grade ⁇ 2 symptomatic peripheral neuropathy, life expectancy of at least 12 weeks, adequate cardiac function (Left ventricular ejection fraction (LVEF) of at least 50%), adequate renal, liver and bone marrow functions, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1 or 2, no uncontrolled central nervous system metastasis, no active infection or serious intercurrent illness, and no active cardiac disease, no chemotherapy, radiotherapy or biologies within four weeks prior to entry (eight weeks in extensive radiotherapy and 6 weeks in nitrosourea or mitomycin C), and measurable or non measurable disease using the RECIST criteria.
  • DLT Dose limiting toxicities
  • Grade 4 neutropenia concomitant with fever i.e. body temperature > 38.5°C
  • fever should not be disease-related Grade 4 neutropenia and sepsis or other severe infection - Platelets ⁇ 25 x 10 9 /L
  • NSCLC non-senorized regional lung cancer
  • soft tissue sarcoma (4) malignant melanoma (3)
  • pleural mesotelioma (3) pleural mesotelioma (3)
  • osteosarcoma (2) and other types (10) such as of bladder cancer, prostate cancer, pancreas cancer, colorectal cancer, kidney cancer, esophageal cancer, suprarenal cancer, parotid gland cancer, head & neck carcinoma and neuroendocrine lung carcinoma.
  • Table I it is summarised the dose cohorts, number of patients in each cohort and adverse events (DLTs) observed during the study.
  • PK pharmacokinetics
  • the scheme was changed in order to increase the infusion time from 1 hour to 3 hours every 3 weeks.
  • the starting dose for this new scheme was 1800 ⁇ g/m 2 administered in 3 hours, followed by a dose level of 2250 ⁇ g/m 2 and another one of 2800 ⁇ g/m 2 .
  • One DLT consisting of G3 hypotension was observed at the dose level of 1800 ⁇ g/m 2 . So, the administration of PMOO 104 during 3 hours every 21 days was also safe and well tolerated.
  • PMOO 104 Another phase I trial administering PMOO 104 was conducted.
  • the main objective of this study was to determine the safety, tolerability and identify the maximum tolerated dose (MTD) and recommended dose (RD) of PMOO 104 as 24-hour intravenous (iv) infusion every 3 weeks (this was considered a treatment cycle) to subjects with advanced solid tumours or lymphoma.
  • Other secondary objectives of the trial were to determine the preliminary pharmacokinetics of PMOO 104 in this schedule and evaluate the preliminary antitumor activity of PMOO 104.
  • the maximum tolerated dose relates to the highest dose at which at least 2 out of 3-6 subjects experience a dose limiting toxicity (DLT) at any given dose level, being this dose level considered the MTD.
  • the recommended dose is intended to relate to the highest dose at which less than 2 of 6 subjects experience DLT during the first cycle.
  • PMOO 104 drug product was provided as a lyophilized powder containing PMOO 104, sucrose and potassium dihydrogen phosphate, and it was reconstituted with sterile water for injection.
  • Subjects enrolled in this clinical trial were adult patients with confirmed malignant solid tumour or lymphoma for which no standard therapy would reasonable be expected to result in cure or palliation.
  • Inclusion criteria included recovery from any drug-related adverse event derived from prior therapies excluding alopecia and NCI-CTCAE grade ⁇ 2 symptomatic peripheral neuropathy, life expectancy of at least 12 weeks, adequate cardiac function (Left ventricular ejection fraction (LVEF) of at least 50%), adequate renal, liver and bone marrow functions, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1 or 2, no uncontrolled central nervous system metastasis, no active infection or serious intercurrent illness, and no active cardiac disease, no chemotherapy, radiotherapy or biologies within four weeks prior to entry (eight weeks in extensive radiotherapy and 6 weeks in nitrosourea or mitomycin C), and measurable or non measurable disease using the RECIST criteria.
  • DLT Dose limiting toxicities
  • Grade 4 neutropenia concomitant with fever i.e. body temperature > 38.5°C
  • fever should not be disease-related Grade 4 neutropenia and sepsis or other severe infection
  • Table III it is summarised the dose cohorts, number of patients in each cohort and adverse events observed during the study.

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Abstract

Treatment of human patients afflicted with cancer with a therapeutically effective amount of PM00104.

Description

PMOO 104 COMPOUND FOR USE IN CANCER THERAPY
The present invention relates to the treatment of cancers and, in particular, to the effective treatment of human cancers using compound PMOO 104.
BACKGROUND OF THE INVENTION
Cancer develops when cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Epithelial cells, which cover internal and external surfaces of the body, including organs and lining of vessels, may give rise to a carcinoma. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
In addition, cancer is invasive and tends to metastasise to new sites. It spreads directly into surrounding tissues and also may be disseminated through the lymphatic and circulatory systems.
Many treatments are available for cancer, including surgery and radiation for localised disease, and chemotherapy. However, the efficacy of available treatments for many cancer types is limited, and new, improved forms of treatment showing clinical benefit are needed. This is especially true for those patients presenting with advanced and/ or metastatic disease and for patients relapsing with progressive disease after having been previously treated with established therapies which become ineffective or intolerable due to acquisition of resistance or to limitations in administration of the therapies due to associated toxicities.
Since the 1950s, significant advances have been made in the chemotherapeutic management of cancer. Unfortunately, more than 50% of all cancer patients either do not respond to initial therapy or experience relapse after an initial response to treatment and ultimately die from progressive metastatic disease. Thus, the ongoing commitment to the design and discovery of new anticancer agents is critically important. Chemotherapy, in its classic form, has been focused primarily on killing rapidly proliferating cancer cells by targeting general cellular metabolic processes, including DNA, RNA, and protein biosynthesis.
PMOO 104 is a novel synthetic alkaloid related to Jorumycin and Renieramycins, and also to safracin and saframycin compounds. Jorumycin is a natural compound isolated from the skin and from the mucus of the Pacific nudibranch Jorunna funebris (Fontana A., et al, Tetrahedron (2000), 56, 7305-8). In addition, the family of Renieramycins is disclosed as being isolated from sponges and tunicates (James M. F. et al. J. Am. Chem. Soc. ( 1982), 104, 265-269; Oku N., et al. Journal Natural Products (2003), 66, 1136-9). Safracin and saframycin compounds are disclosed in Manzanares L, et al. Curr. Med. Chem. Anti-Cancer Agents (2001), 1 , 257-276, as well as in WO 00/ 18233 and WO 01 /87894. Because of the detailed description provided in such references and citations therein, the structural characterizations of such compounds are not given again explicitly herein; any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources.
PMOO 104 has demonstrated a significant in vitro activity against solid and non-solid tumour cell lines as well as significant in vivo activity in several xenografted human cell lines in mice, such as breast and prostate. Preliminary insights into the mechanism of action of PMOO 104 suggested cell cycle changes, DNA binding properties and transcriptional inhibition. For further details of PMOO 104 see WO 01/87894. This compound shows the following chemical structure:
Figure imgf000004_0001
Additionally, the reader is referred to PCT/ GB2006/ 050362 and incorporated herein by specific reference, for pharmaceutical compositions of PM00104.
It is an object of the present invention to provide new and improved forms of treatment using PMOO 104 showing clinical benefit.
In particular, it is an object of the invention to provide dosages and schedules of PMOO 104 that can be used for cancer therapy in humans, avoiding toxicities while maintaining the desired antineoplastic effects.
It is another object of the present invention to provide new uses in cancer therapy for PMOO 104.
It is yet another object of the invention to provide new products comprising PMOO 104 for administration in the treatment of cancer.
SUMMARY OF THE INVENTION We have developed a method to treat human patients with PMOO 104, or a pharmaceutical composition thereof, avoiding toxicity and leading to clinical improvement.
The present invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of PMOO 104, or a pharmaceutical composition thereof.
The present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of PMOO 104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods of this invention.
The invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods of this invention.
In one aspect, the present invention provides a method for treating a human patient afflicted with cancer, comprising administering PMOO 104 to said patient, using a cyclical dosing protocol and a predetermined cycle. Typical dosing protocols for PMOO 104 administration are provided. The administration of PMOO 104 in humans in accordance with the methods and compositions of this invention is tolerable and provides antitumor activity at the dosage and regimens given.
In a further aspect of the present invention, a medical kit for administering PMOO 104 is provided, comprising printed instructions for administering PMOO 104 according to the procedures and methods of treatment set forth herein, and a supply of PMOO 104 in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of PMOO 104 for the treatments as defined above and a pharmaceutically acceptable carrier.
EMBODIMENTS OF THE INVENTION
PMOO 104 is a novel synthetic alkaloid related to the marine compounds Jorumycin and Renieramycins, and also to safracin and saframycin compounds, having the following structure:
Figure imgf000006_0001
The term "PM00104" is intended here to cover any pharmaceutically acceptable salt, ester, solvate, hydrate 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 these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art. In particular, we incorporate by reference the disclosure of WO 01/87894 with regard to PMOO 104 and compositions comprising it.
Pharmaceutical compositions of PMOO 104 that can be used include solutions, suspensions, emulsions, lyophilised compositions, etc., with suitable excipients for intravenous administration. Preferably, PMOO 104 may be supplied and stored as a sterile lyophilized product, comprising PMOO 104 and excipients in a formulation adequate for therapeutic use. In particular a formulation comprising sucrose and a phosphate salt buffered to an adequate pH is preferred. Further guidance on PMOO 104 formulations is given in PCT/GB2006/050362 which is incorporated herein by reference in its entirety.
Administration of the compounds or compositions of the present invention is by intravenous infusion. Infusion times of up to 72 hours can be used, more preferably between 1 and 24 hours, with either about 1 , about 3 or about 24 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be around 24 hours or even longer if required.
In addition, the administration of PMOO 104 is performed in cycles, in accordance with the methods of the invention. An intravenous infusion of PMOO 104 is given to the patients typically the first day of each cycle and then the patients are allowed to recover for the remainder of the cycle. The preferred duration of each cycle is typically of 3 or 4 weeks; multiple cycles can be given as needed. Dose delays and/ or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance to treatments.
Therefore in one aspect the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of PMOO 104, or a pharmaceutical composition thereof, by intravenous infusion once per cycle and with an infusion time of up to 72 hours. The infusion times are preferably between 1 and 24 hours, with about 1, about 3 and about 24 hours more preferred. The preferred duration of each cycle is of either 3 or 4 weeks, being 3 weeks the most preferred; and multiple cycles can be given as needed.
In a further aspect of the present invention, the PMOO 104 is administered at a dose below 3600 μg/m2, preferably about 3200 μg/m2, about 3000 μg/m2, about 1800 μg/m2, about 1600 μg/m2 and about 900 μg/m2. Suitably the dose is at least about 3000 μg/m2. Preferably the dose is in the range of 900-3600 μg/m2.
Alternatively, the PMOO 104 is administered at a dose at or below 8100 μg/m2, preferably at or below 5400 μg/m2, or about 3600 μg/m2, or about 1800 μg/m2.
Alternatively, the dose is about 15-25% lower than about 3600 μg/m2, and is thus preferably about 2700 μg/m2, about 2800 μg/m2, about 2900 μg/m2, about 3000 μg/m2. about 3100 μg/m2, or about 3200 μg/m2, particularly preferably about 3000 μg/m2.
Alternatively, the dose is about 15-25% lower than about 5400 μg/m2, and is thus preferably about 4000 μg/m2, about 4100 μg/m2, about 4200 μg/m2, about 4300 μg/m2, about 4400 μg/m2, or about 4500 μg/m2.
Alternatively, the dose is about 15-20% lower than about 8100 μg/m2, and is thus preferably about 6300 μg/m2, about 6400 μg/m2, about 6500 μg/m2, about 6600 μg/m2, about 6700 μg/m2, about 6800 μg/m2, or about 6900 μg/m2.
Alternatively, in the present methods of the invention, the PM00104 is administered at a dose of or below 4800 μg/m2, preferably about 4200 μg/m2, about 4000 μg/m2, about 3800 μg/m2, about 3600 μg/m2, about 3200 μg/m2, about 3000 μg/m2, about 2400 μg/m2, about 1600 μg/m2, about 800 μg/m2. Suitably the dose is at least about 3200 μg/m2.
Preferably the dose is in the range of 1600-4800 μg/m2 (particularly preferably 2000-4400 μg/m2, 2400-4000 μg/m2, or 2800-3600 μg/m2), 1600- 3200 μg/m2 (particularly preferably 1800-3000 μg/m2, 2000-2800 μg/m2, or 2200-2600 μg/m2) or 3200-4800 μg/m2 (particularly preferably 3400-4600 μg/m2, 3600-4400 μg/m2, 3800-4200 μg/m2, 3900-4100 μg/m2, or about 4000 μg/m2). Suitably, the dose may be about 3000 μg/m2, about 3200 μg/m2, or about 4000 μg/m2
Therefore in another aspect, the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose below 3600 μg/m2, every 3 to 4 weeks. When the infusion time is about 1 hour the dose is preferably about 3000 μg/m2, and the treatment is preferably repeated every 21 days.
Other suitable doses for a 1 hour infusion time include doses below 3600 μg/m2, preferably about 3200 μg/m2, about 3000 μg/m2, about 1800 μg/m2, about 1600 μg/m2 and about 900 μg/m2. Suitably the dose is at least about 3000 μg/m2. Preferably the dose is in the range of 900-3600 μg/m2.
In another aspect the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose of or below 5400 μg/m2, every 3 to 4 weeks. When the infusion time is about 3 hours the dose is preferably about 5400 μg/m2 (or 15-25% lower including 4000-4500 μg/m2, preferably about 4000 μg/m2, about 4100 μg/m2, about 4200 μg/m2, about 4300 μg/m2, about 4400 μg/m2, or about 4500 μg/m2), about 3500 μg/m2 or about 3600 μg/m2 (or 15-25% lower including 2700-3200μg/m2, preferably about 2700 μg/m2, about 2800 μg/m2, about 2900 μg/m2, about 3000μg/m2, about 3100 μg/m2, or about 3200 μg/m2), and the treatment is preferably repeated every 21 days. In another aspect the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient PMOO 104, or a pharmaceutical composition thereof, for between 1 and 24 hours at a dose of or below 4800 μg/m2, every 3 to 4 weeks. When the infusion time is about 24 hours the dose is preferably in the range of 1600-4800 μg/m2 (particularly preferably 2000-4400 μg/m2, 2400-4000 μg/m2, 2800-3600 μg/m2, about 3200 μg/m2, or about 3000 μg/m2), 1600- 3200 μg/m2 (particularly preferably 1800-3000 μg/m2, 2000-2800 μg/m2, or 2200-2600 μg/m2) or 3200-4800 μg/m2 (particularly preferably 3400-4600 μg/m2, 3600-4400 μg/m2, 3800-4200 μg/m2, 3900-4100 μg/m2, or about 4000 μg/m2), and the treatment is preferably repeated every 21 days.
In another aspect, the present invention is directed to a medical kit for administering PMOO 104, comprising printed instructions for administering PMOO 104 according to the dosages and schedules set forth above, and a supply of PMOO 104 in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of PMOO 104 for the treatments as defined above and a pharmaceutically acceptable carrier.
In another aspect, the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of PMOO 104, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the procedures and methods as defined above.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition for use in the procedures and methods as defined above.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, as a medicament formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
In another aspect, the invention further provides for the formulation of one or more dosage units of PMOO 104, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, said dosage units formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for the treatment of cancer.
In another aspect, the invention further provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a composition, formulated to be provided in or suitable to be administered at a dosage and/ or schedule as defined herein for use in the procedures and methods as defined herein.
In another aspect, the invention further provides a medicament, dosage unit(s), formulation or composition of PMOO 104, or a pharmaceutically acceptable salt thereof, specifically configured to the dosages and/or schedules given herein. This specific configuration is carried out during the preparation process of the final medicament, and is not part of the actions carried out by the doctor when treating the patient.
In a further aspect, the invention provides a dosage unit(s), medicament, formulation or composition comprising PMOO 104, or a pharmaceutically acceptable salt thereof, specifically adapted to be administered in the dosages and/ or schedules given herein.
In a further aspect, the invention provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, in a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
In a further aspect, the invention provides for the use of PMOO 104, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer wherein the medicament is configured for administration at the dosages and/ or schedules given herein.
In a further aspect, the invention provides PMOO 104 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein PMOO 104 is administered at the dosages and /or schedules given herein.
In one of the preferred embodiments, Example 1, the results of a phase I clinical trial wherein PMOO 104 is administered intravenously either as a 1-hour infusion or 3-hour infusion every 3 weeks are shown. According to said study the maximum tolerated dose (MTD) of PMOO 104 was established at 3600 μg/m2 in the course of treatments, and the recommended dose (RD) was determined as 3000 μg/m2, when PMOO 104 was administered intravenously as a 1-hour infusion every 3 weeks. In another preferred embodiment, Example 2, it is showed the results of a phase I clinical trial wherein PMOO 104 is administered intravenously as a 24-hour infusion every 3 weeks.
Premedication and supportive medication can be given. As disclosed in Example 1, a prophylactic antiemetic therapy, by using for example dexamethasone and/ or metoclopramide can be useful to avoid the side effects due to the administration of the chemotherapeutic agent. Therefore, it is preferred to administer one or several antiemetic agents, such as dexamethasone and metoclopramide, to the patient typically before PMOO 104 infusions, and after the emetic events and the DLT observed. Coadministration of both dexamethasone and metoclopramide as antiemetic medication is particularly preferred in the method of the invention.
Depending on the type of tumour and the development stage of the disease, the treatments of the invention are useful in promoting tumour regression, in stopping tumour growth and/or in preventing metastasis. In particular, the method of the invention is suited for human patients, especially those who are relapsing or refractory to previous chemotherapy. First line therapy is also envisaged.
Preferably, the method of the invention is used according to the above schedules and dosages for the treatment of lung cancer (NSCLC and SCLC), sarcoma, especially soft tissue sarcoma, malignant melanoma, pleural mesotelioma, osteosarcoma, bladder cancer, prostate cancer, pancreas cancer, colorectal cancer, kidney cancer, esophageal cancer, suprarenal cancer, parotid gland cancer, head & neck carcinoma, hepatocarcinoma, cervix cancer, and neuroendocrine lung carcinoma. Most preferably the method of the invention is used for the treatment of NSCLC, submaxilar carcinoma, bladder cancer, pancreas cancer, hepatocarcinoma, esophageal cancer, cervix cancer, and pleural mesotelioma. The following examples further illustrate the invention. They should not be interpreted as a limitation of the scope of the invention.
To 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. In addition, unless otherwise stated, where values are given as ranges, the upper and lower values are specifically contemplated as preferred values.
Examples of the invention
Example 1
A phase I trial administering PMOO 104 was conducted. The main objective of this study was to determine the safety, tolerability and identify the maximum tolerated dose (MTD) and recommended dose (RD) of PMOO 104 as 1-hour intravenous (iv) infusion every 3 weeks (this was considered a treatment cycle) to subjects with advanced solid tumours or lymphoma. Since there was evidence that dose limiting toxicities were related to Cmaχ, drug escalation was resumed by increasing the duration of the infusion from 1 hour to 3 hours. Other secondary objectives of the trial were to determine the preliminary pharmacokinetics of PMOO 104 in this schedule and evaluate the preliminary antitumor activity of PMOO 104.
The maximum tolerated dose (MTD) relates to the highest dose at which at least 2 out of 3-6 subjects experience a dose limiting toxicity (DLT) at any given dose level, being this dose level considered the MTD. On the other hand, the recommended dose (RD) is intended to relate to the highest dose at which less than 2 of 6 subjects experience DLT during the first cycle. We designed a dose finding trial wherein cohorts of 3-6 patients were treated at increasing PM00104 doses (225, 450, 900, 1800, 3000 and 3600 μg/m2) administered intravenously over 1 hour. This treatment was repeated every 21 days. A prophylactic antiemetic therapy with dexamethasone (20 mg iv) plus metoclopramide (10 mg iv) was administered before PMOO 104 infusions, and after the emetic events and the DLT observed.
PMOO 104 drug product was provided as a lyophilized powder containing PMOO 104, sucrose and potassium dihydrogen phosphate, and it was reconstituted with sterile water for injection.
Subjects enrolled in this clinical trial were adult patients with confirmed malignant solid tumour or lymphoma for which no standard therapy would reasonable be expected to result in cure or palliation. Inclusion criteria included recovery from any drug-related adverse event derived from prior therapies excluding alopecia and NCI-CTCAE grade < 2 symptomatic peripheral neuropathy, life expectancy of at least 12 weeks, adequate cardiac function (Left ventricular ejection fraction (LVEF) of at least 50%), adequate renal, liver and bone marrow functions, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1 or 2, no uncontrolled central nervous system metastasis, no active infection or serious intercurrent illness, and no active cardiac disease, no chemotherapy, radiotherapy or biologies within four weeks prior to entry (eight weeks in extensive radiotherapy and 6 weeks in nitrosourea or mitomycin C), and measurable or non measurable disease using the RECIST criteria.
Dose limiting toxicities (DLT) were defined as follows: • Hematological drug-related adverse events:
Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x 109/L) lasting more than 5 days
Grade 4 neutropenia concomitant with fever (i.e. body temperature > 38.5°C), and fever should not be disease-related Grade 4 neutropenia and sepsis or other severe infection - Platelets < 25 x 109/L
® Any other grade 3-4 non-hemato logical adverse event suspected to be related to study drug, and any increase of troponin I > 0.1 ng/mL together with evidence of cardiac damage by ECG or ECHO, except nausea/ vomiting (unless the subject is receiving an optimal anti-emetic regimen) and hypersensitivity reactions
• Delay in the administration of a subsequent dose of PMOO 104 exceeding 2 weeks, due to an adverse event suspected to be related to the study drug
• Decrease in LVEF > 20% from the patient baseline values and/ or LVEF < 50%
Twenty seven patients were included in the clinical trial. These patients were suffering from different types of cancers, such as NSCLC (5), soft tissue sarcoma (4), malignant melanoma (3), pleural mesotelioma (3), osteosarcoma (2) and other types (10) such as of bladder cancer, prostate cancer, pancreas cancer, colorectal cancer, kidney cancer, esophageal cancer, suprarenal cancer, parotid gland cancer, head & neck carcinoma and neuroendocrine lung carcinoma.
In Table I it is summarised the dose cohorts, number of patients in each cohort and adverse events (DLTs) observed during the study.
Table I
Figure imgf000016_0001
Figure imgf000017_0001
* 1 patient with adrenal carcinoma developed G3 nausea, vomiting and asthenia despite of antiemetic treatment, and another patient with colorectal cancer and extensive liver metastases developed G4 thrombocytopenia and neutropenia, G3 transaminase elevation, and G4 troponin I rise without cardiac symptoms or electrocardiogram (ECG) alterations.
On the other hand, regarding the antitumor activity observed during the study, four patients had stable disease (SD) for more than 3 months (Table II).
Table II
Figure imgf000017_0002
The most frequent adverse events related reported were: nausea, vomiting, asthenia, and injection site reaction, being most of them of grade ≤ 2. Additionally, haematological toxicity (neutropenia and leukopenia) was observed more frequently at the highest dose levels (3000-3600 μg/m2), and increased transaminases of grade < 2 were the most frequent biochemistry alteration.
From this study it was concluded that administration of PMOO 104 was safe and well tolerated. In addition, the MTD was established at 3600 μg/m2 (at level 6), and the RD was established at 3000 μg/m2 (at level 5) when PMOO 104 is administered intravenously over 1 hour every 21 days.
On the other hand, preliminary pharmacokinetics (PK) was characterised by relatively long half life (up to 50 hours), wide distribution (500 L/m2), moderate interpatient variability. In addition, profiles appeared to have 3 exponential components and the drug infused during 1 hour showed linear PK up to 3000 μg/m2 (RD).
In view of the fact that the DLTs were related to Cmax, drug escalation was resumed by increasing the duration of the infusion. The pharmacokinetic evaluation of the patients treated showed that there was an overproportional increase in Cmax and AUC when doses of 3000 μg/m2 and higher were administered. The increase in AUC appeared related to the period of time immediately posterior to the start of the infusion. Additionally, the half-life did not change as the dose increases. Taking all together, the nonlinearity phenomenon was more likely related to a limitation in the distribution rather than to a saturation of the elimination processes. Therefore, there was a possibility that an increase in the infusion time from 1 hour to 3 hours would permit to increase the dose administered. Accordingly, after the expanded cohort at the RD was completed, the scheme was changed in order to increase the infusion time from 1 hour to 3 hours every 3 weeks. The starting dose for this new scheme was 1800 μg/m2 administered in 3 hours, followed by a dose level of 2250 μg/m2 and another one of 2800 μg/m2. One DLT consisting of G3 hypotension was observed at the dose level of 1800 μg/m2. So, the administration of PMOO 104 during 3 hours every 21 days was also safe and well tolerated. Example 2
Another phase I trial administering PMOO 104 was conducted. The main objective of this study was to determine the safety, tolerability and identify the maximum tolerated dose (MTD) and recommended dose (RD) of PMOO 104 as 24-hour intravenous (iv) infusion every 3 weeks (this was considered a treatment cycle) to subjects with advanced solid tumours or lymphoma. Other secondary objectives of the trial were to determine the preliminary pharmacokinetics of PMOO 104 in this schedule and evaluate the preliminary antitumor activity of PMOO 104.
The maximum tolerated dose (MTD) relates to the highest dose at which at least 2 out of 3-6 subjects experience a dose limiting toxicity (DLT) at any given dose level, being this dose level considered the MTD. On the other hand, the recommended dose (RD) is intended to relate to the highest dose at which less than 2 of 6 subjects experience DLT during the first cycle.
We designed a dose finding trial wherein cohorts of 3-6 patients were to be treated at increasing PMOO 104 doses (for instance 133, 266, 400, 800, 1600, 3200 and 4000 μg/m2) administered intravenously over 24 hour, with the exception of the first cohort wherein only 1 patient was treated at the corresponding dose.
PMOO 104 drug product was provided as a lyophilized powder containing PMOO 104, sucrose and potassium dihydrogen phosphate, and it was reconstituted with sterile water for injection.
Subjects enrolled in this clinical trial were adult patients with confirmed malignant solid tumour or lymphoma for which no standard therapy would reasonable be expected to result in cure or palliation. Inclusion criteria included recovery from any drug-related adverse event derived from prior therapies excluding alopecia and NCI-CTCAE grade < 2 symptomatic peripheral neuropathy, life expectancy of at least 12 weeks, adequate cardiac function (Left ventricular ejection fraction (LVEF) of at least 50%), adequate renal, liver and bone marrow functions, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0, 1 or 2, no uncontrolled central nervous system metastasis, no active infection or serious intercurrent illness, and no active cardiac disease, no chemotherapy, radiotherapy or biologies within four weeks prior to entry (eight weeks in extensive radiotherapy and 6 weeks in nitrosourea or mitomycin C), and measurable or non measurable disease using the RECIST criteria.
Dose limiting toxicities (DLT) were defined as follows: » Hematological drug-related adverse events:
- Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 x 109/L) lasting more than 5 days
Grade 4 neutropenia concomitant with fever (i.e. body temperature > 38.5°C), and fever should not be disease-related Grade 4 neutropenia and sepsis or other severe infection
- Platelets < 25 x 109/L β Any other grade 3-4 non-hematological adverse event suspected to be related to study drug, and any increase of troponin I ≥ 0.1 ng/mL together with evidence of cardiac damage by ECG or ECHO, except nausea/ vomiting (unless the subject is receiving an optimal anti-emetic regimen) and hypersensitivity reactions
• Delay in the administration of a subsequent dose of PMOO 104 exceeding 2 weeks, due to adverse event suspected to be related to study drug
® Decrease in LVEF > 20% from the patient baseline values and/ or LVEF < 50%
Twenty five patients have been included in the study. These patients were suffering of different types of cancers. In Table III it is summarised the dose cohorts, number of patients in each cohort and adverse events observed during the study. Table III
Figure imgf000021_0001
* 1 patient developed G3 transaminase increase lasting less than 7 days. ** 1 patient developed G3 tumor pain, muscle pain and muscle stiffness. *** 1 patient developed G3 asthenia, G4 neutropenia, and G3 trombocytopenia.
On the other hand, regarding the antitumor activity observed during the study, three patients had stable disease (SD) for more than 3 months. These patients were suffering from different types of cancers, specifically one patient was suffering from pancreas adenocarcinoma, another one from hepatocarcinoma and the last one from lower aesophagus adenocarcinoma.
The most frequent adverse events related reported were: nausea, vomiting, asthenia, anorexia, and diarrhea, being most of them of grade ≤ 2.
From this study it was concluded that PMOO 104 was safe and well tolerated when administered during 24 hours every 21 days.

Claims

Claims: c
1. A method for treating a human patient afflicted with cancer, which comprises administering to the patient PMOO 104, or a pharmaceutically acceptable salt thereof, by intravenous infusion once per cycle at a dose of between 1600 to 4800 μg/m2, wherein the infusion time is up to 72 hours and the duration of each cycle is either 3 or 4 weeks.
2. A method according to claim 1, wherein the infusion time is between 1 and 24 hours.
3. A method according to claim 2, wherein the infusion time is about 1 hour.
4. A method according to claim 3, wherein PMOO 104 is administered at a dose below 3600 μg/m2.
5. A method according to claim 4, wherein PMOO 104 is administered at a dose of about 3000 μg/m2.
6. A method according to claim 2, wherein the infusion time is about 3 hours.
7. A method according to claim 6, wherein PMOO 104 is administered at a dose of about 3500 μg/m2.
8. A method according to claim 6, wherein PMOO 104 is administered at a dose of between 2700 to 3200 μg/m2.
9. A method according to claim 8, wherein PMOO 104 is administered at a dose of about 2800 μg/m2.
10. A method according to claim 2, wherein the infusion time is about 24 hours.
11. A method according to claim 10, wherein PMOO 104 is administered at a dose of about 4000 μg/m2.
12. A method according to claim 10, wherein PMOO 104 is administered at a dose of about 3200 μg/m2.
13. A method according to any preceding claim, wherein the method further comprises administering a prophylactic antiemetic therapy.
14. A method according to any preceding claim, wherein the duration of each cycle is 3 weeks.
15. The method according to any preceding claim, in which the patient is relapsing or refractory to previous chemotherapy.
16. The method according to any preceding claim, in which the patient has a cancer selected from lung cancer, sarcoma, malignant melanoma, pleural mesotelioma, osteosarcoma, bladder cancer, prostate cancer, pancreas cancer, colorectal cancer, kidney cancer, esophageal cancer, suprarenal cancer, parotid gland cancer, head & neck carcinoma, and neuroendocrine lung carcinoma.
17. The method according to any of claims 1 to 15, in which the patient has a cancer selected from NSCLC, submaxilar carcinoma, bladder cancer, pancreas cancer, hepatocarcinorna, esophageal cancer, cervix cancer, and pleural mesotelioma.
18. The method according to claim 17, in which the patient has a cancer selected from NSCLC, submaxilar carcinoma, bladder cancer, pancreas cancer, esophageal cancer, and pleural mesotelioma.
19. The use of PMOO 104, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for a method according to any of claims 1 to 18.
20. A formulation of one or more dosage units of PMOO 104, or a pharmaceutically acceptable salt thereof, wherein said dosage units are formulated to be provided for a method according to any of claims 1 to 18.
21. A medical kit for administering PMOO 104, comprising printed instructions for administering PMOO 104 in a method according to any of claims 1 to 18, and a supply of PMOO 104 in dosage units for at least one cycle, wherein each dosage unit comprises the appropriate amount of PMOO 104 for a method according to any of claims 1 to 18 and a pharmaceutically acceptable carrier.
22. PMOO 104 or a pharmaceutically acceptable salt thereof for use in a method according to any of claims 1 to 18.
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