Lurbinectedin in combination with doxorubicin

Abstract

A combination therapy for the treatment of cancer, particularly soft tissue sarcoma, is described, which includes low doses of lurbinectedin and doxorubicin.

Description

[Technical Field]

[0001] The present invention relates to the therapeutic treatment of cancer, and in particular to dosing schedules useful in the treatment of cancer. In particular, the present invention relates to combination therapies using low doses of lurbinectedin and doxorubicin. [Background technology]

[0002] Lurbinectedin, also known as PM01183 and originally called tryptamicidine, is a synthetic alkaloid with antitumor activity and is the subject of International Publication No. 03 / 01427. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand breaks, causes apoptosis, and modulates the tumor microenvironment. For example, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF by inhibiting active transcription in tumor-associated macrophages.

[0003] The chemical structure of lurbinectedin is represented as follows: [ka]

[0004] It is a selective inhibitor of oncogenic transcriptional programs on which many tumors are particularly dependent. In addition to its effects on cancer cells, lurbinectedin inhibits oncogenic transcription in tumor-associated macrophages and downregulates the production of cytokines essential for tumor growth. Transcriptional addiction has been recognized as a target for many of these diseases, as many of these diseases lack other actionable targets.

[0005] Lurbinectedin was approved in the United States in 2020 and is marketed there for the treatment of adult patients with metastatic small cell lung cancer (SCLC) who have disease progression during or after platinum-based chemotherapy. The recommended dose is 3.2 mg / m2 administered intravenously every 21 days. In 2021, lurbinectedin also received marketing authorization in the United Arab Emirates, Canada, Australia, and Singapore.

[0006] Doxorubicin is a cytotoxic anthracycline topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, doxorubicin hydrochloride is 5,12-naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis).

[0007] The cytotoxic effect of doxorubicin on malignant cells is related to its nucleotide base intercalating and cell membrane lipid binding activities. The interaction of doxorubicin with topoisomerase II to form a complex capable of DNA cleavage is an important mechanism for the cytocidal activity of doxorubicin HCl.

[0008] Doxorubicin is FDA-approved and marketed for use in the treatment of acute lymphocytic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic osteosarcoma, metastatic ovarian cancer, metastatic transitional cell bladder cancer, metastatic thyroid cancer, metastatic gastric cancer, and metastatic bronchogenic carcinoma. As a single agent, the recommended standard starting dose of doxorubicin per cycle in adults is 60–75 mg / m2 of body surface area, and the standard doxorubicin treatment cycle is limited to six cycles.

[0009] The combination of lurbinectedin and doxorubicin has been investigated in various clinical trials.

[0010] A closed-phase, multicenter, open-label clinical and pharmacokinetic study (PM1183-A-003-10, NCT01970540) of PM01183 in combination with immobilized doxorubicin (DOX) in heavily pretreated patients with selected advanced solid tumors determined the recommended dose (RD) of lurbinectedin to be administered as a 1-hour infusion on Day 1 of every 3 weeks (D1 q3wk) in combination with doxorubicin (DOX) in patients with selected advanced solid tumors. Lurbinectedin was administered at a dose of 2.0 mg and doxorubicin at 50.0 mg / m². 2 was administered every 3 weeks (q3wk).

[0011] Meanwhile, the completed phase III trial PM1183-C-003-14 ([ATLANTIS]) compared the combination of lurbinectedin and doxorubicin with either CAV or topotecan in patients with small cell lung cancer (SCLC) who had received one prior platinum-containing line of therapy but no more than one chemotherapy-containing line of therapy. Patients received 40 mg / m 2 Doxorubicin at a dose of 2.0 mg / m 2 Lurbinectedin at a dose of 3.2 mg / m administered intravenously (iv) on D1 q3wk for up to 10 cycles, followed by single-agent lurbinectedin 3.2 mg / m 2 was infused intravenously on D1 q3wk.

[0012] Regarding the treatment of sarcoma, Cote et al. Eur, J. Cancer 126 (2020) p. 21-32 disclosed a phase 2 multi-level trial using a combination of doxorubicin and lurbinectedin for the treatment of metastatic and / or resectable sarcomas, such as leiomyosarcoma (LMS). Patients received doxorubicin 50 mg / m² followed by lurbinectedin 2 mg / m² on day 1 of a 21-day cycle. 2 After six cycles, patients with controlled disease received lurbinectedin alone at 3.2 mg / m 2 The administration continued.

[0013] There is a continuing need for more effective cancer therapies that are safe and effective. Summary of the Invention [Means for solving the problem]

[0014] The present inventors have determined the dosing regimen for the combination of lurbinectedin and doxorubicin in the treatment of cancer.

[0015] In one aspect, there is provided lurbinectedin for use in treating cancer in a patient in need thereof, wherein the lurbinectedin is administered in combination with doxorubicin, wherein the doxorubicin is administered at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0016] In a further aspect, there is provided lurbinectedin for use in treating cancer in a patient in need thereof, wherein the lurbinectedin is administered in combination with doxorubicin, wherein the doxorubicin is administered at a low dose.

[0017] In a further aspect, there is provided lurbinectedin for use in treating cancer in a patient in need thereof, said treatment comprising: i) in a first phase, administering lurbinectedin in combination with doxorubicin to the patient for one or more cycles, wherein the doxorubicin is administered at a low dose; ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0018] In a further aspect, there is provided lurbinectedin for use in treating cancer in a patient in need thereof, said treatment comprising: i) In the first phase, lurbinectedin is administered to patients in combination with doxorubicin for one or more cycles, wherein the doxorubicin is administered at a dose of 30 mg / m during each cycle. 2 administering at the following doses: ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0019] In a further aspect, there is provided doxorubicin for use in treating cancer in a patient in need thereof, said treatment comprising administering lurbinectedin to the patient in combination with doxorubicin, wherein the lurbinectedin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0020] In a further aspect, there is provided lurbinectedin and doxorubicin for use in treating cancer in a patient in need thereof, said treatment comprising administering to the patient a combination of lurbinectedin and doxorubicin, wherein doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0021] In a further aspect, there is provided doxorubicin for use in the treatment of cancer in a patient in need thereof, said treatment comprising: i) In the first phase, doxorubicin is administered to patients in combination with lurbinectedin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 administering at the following doses: ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0022] In a further aspect, there is provided lurbinectedin and doxorubicin for use in treating cancer in a patient in need thereof, said treatment comprising: i) In the first phase, lurbinectedin is administered to patients in combination with doxorubicin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 administering at the following doses: ii) administering lurbinectedin to the patient in a second administration cycle.

[0023] In a further aspect, a pharmaceutical package is provided comprising lurbinectedin together with instructions for use in combination with doxorubicin, wherein the doxorubicin is administered at a low dose.

[0024] In a further aspect, a pharmaceutical package is provided comprising lurbinectedin together with instructions for use in combination with doxorubicin, wherein the doxorubicin is administered at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0025] In a further aspect, a pharmaceutical package is provided comprising doxorubicin together with instructions for use in combination with lurbinectedin, wherein the doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0026] In a further aspect, a pharmaceutical package is provided comprising lurbinectedin and doxorubicin together with instructions for their combined use, wherein doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0027] In a further aspect, a method of treating cancer is provided, the method comprising administering to a patient in need of cancer treatment a combination therapy of lurbinectedin and doxorubicin, wherein the doxorubicin is administered at a low dose.

[0028] In a further aspect, a method of treating cancer is provided, the method comprising administering to a patient in need of cancer treatment a combination therapy of lurbinectedin and doxorubicin, wherein the doxorubicin is administered at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0029] In a further aspect, a method of treating cancer is provided, the method comprising administering a combination therapy of lurbinectedin and doxorubicin to a patient in need of cancer treatment according to the following schedule: i) In the first phase, patients are administered lurbinectedin in combination with doxorubicin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses: ii) In the second phase, patients will receive lurbinectedin alone for one or more cycles.

[0030] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating cancer, said treatment comprising administering to a patient in need of treatment for cancer a combination therapy of lurbinectedin and doxorubicin, wherein doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0031] In a further aspect, there is provided a use of doxorubicin in the manufacture of a medicament for treating cancer, said treatment comprising administering to a patient in need of treatment for cancer a combination therapy of lurbinectedin and doxorubicin, wherein doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0032] In a further aspect, there is provided a use of lurbinectedin and doxorubicin in the manufacture of a medicament for treating cancer, said treatment comprising administering to a patient in need of treatment for cancer a combination therapy of lurbinectedin and doxorubicin, wherein doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 It is administered in the following doses:

[0033] In a further aspect, there is provided the use of lurbinectedin in the manufacture of a medicament for the treatment of cancer, said treatment comprising: i) In the first phase, lurbinectedin is administered to patients in combination with doxorubicin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 administering at the following doses: ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0034] In a further aspect, there is provided the use of doxorubicin in the manufacture of a medicament for the treatment of cancer, said treatment comprising: i) In the first phase, lurbinectedin is administered to patients in combination with doxorubicin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 administering at the following doses: ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0035] In a further aspect, there is provided the use of lurbinectedin and doxorubicin in the manufacture of a medicament for the treatment of cancer, said treatment comprising: i) In the first phase, lurbinectedin is administered to patients in combination with doxorubicin for one or more cycles, where doxorubicin is administered at a low dose or at a dose of 30 mg / m during each administration cycle. 2 administering at the following doses: ii) in a second phase, administering lurbinectedin alone to the patient for one or more cycles.

[0036] The following embodiments apply to all aspects of the present invention.

[0037] In one embodiment of the present invention, doxorubicin is administered at a dose of 30 mg / m during each administration cycle. 2 The following dosages may be administered:

[0038] In one embodiment of the present invention, doxorubicin is administered at a dose of 30 mg / m during each administration cycle. 2 It may be administered in doses less than 100 mg / kg.

[0039] In a further embodiment, doxorubicin is administered at a dose of 15-30 mg / m during each administration cycle. 2 may be administered at a dose of

[0040] In a further embodiment, doxorubicin is administered at a dose of 20-30 mg / m during each administration cycle. 2 may be administered at a dose of

[0041] In a further embodiment, doxorubicin is administered at a dose of 15-30 mg / m during each administration cycle. 2 It may be administered in doses less than 100 mg / kg.

[0042] In a further embodiment, doxorubicin is administered at a dose of 20-30 mg / m during each administration cycle. 2 It may be administered in doses less than 100 mg / kg.

[0043] In a further embodiment, doxorubicin is administered at a dose of 15-25 mg / m during each administration cycle. 2 may be administered at a dose of

[0044] In a further embodiment, doxorubicin is administered at a dose of 20-25 mg / m during each administration cycle. 2 may be administered at a dose of

[0045] In a further embodiment, doxorubicin is administered at a dose of about 25 mg / m during each administration cycle. 2 may be administered at a dose of

[0046] In a further embodiment, doxorubicin is administered at a dose of 25 mg / m during each administration cycle. 2 may be administered at a dose of

[0047] In a further embodiment, a single dose of doxorubicin is administered in each administration cycle.

[0048] In a further embodiment, a single dose of doxorubicin is administered on day 1 of each administration cycle.

[0049] In a further embodiment, about 25 mg / m 2 A single dose of doxorubicin is administered in each dosing cycle.

[0050] In a further embodiment, 25 mg / m 2 A single dose of doxorubicin is administered in each dosing cycle.

[0051] In a further embodiment, lurbinectedin is administered at a dose of 2 mg / m2 of body surface area during each administration cycle. 2 ~4mg / m 2 may be administered at a dose of

[0052] In a further embodiment, lurbinectedin is administered at a dose of 2 mg / m2 of body surface area during each administration cycle. 2 May be administered at more than 4 mg / m2.

[0053] In a further embodiment, lurbinectedin is administered at a dose of 2.5 to 3.5 mg / m2 of body surface area during each administration cycle. 2 may be administered at a dose of

[0054] In a further embodiment of the invention, lurbinectedin may be administered on day 1 (D1) of each administration cycle.

[0055] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 of body surface area during each administration cycle. 2 may be administered at a dose of

[0056] In a further embodiment, lurbinectedin is administered at a dose of 3.2 mg / m2 of body surface area during each administration cycle. 2 may be administered at a dose of

[0057] In a further embodiment, lurbinectedin may be administered on day 1 (D1) of each administration cycle.

[0058] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 of body surface area during each administration cycle. 2 and doxorubicin may be administered at a lower dose of 30 mg / m during each dosing cycle. 2 15-30 mg / m during each cycle at the following doses: 2at a dose of 20-30 mg / m during each dosing cycle 2 at a dose of 15-25 mg / m during each dosing cycle. 2 at a dose of 20-25 mg / m during each dosing cycle. 2 at a dose of approximately 25 mg / m during each dosing cycle 2 or 25 mg / m during each dosing cycle 2 may be administered at a dose of

[0059] In a further embodiment, the method further comprises administration of granulocyte colony-stimulating factor (G-CSF).

[0060] In a further embodiment, G-CSF may be administered on day 1 of the administration cycle.

[0061] In a further embodiment, the patient may receive primary prophylaxis with G-CSF beginning 24-72 hours after day 1 of the dosing cycle. Dosing may be for 5 days.

[0062] In a further embodiment, G-CSF may be administered during one or more subsequent administration cycles.

[0063] In a further embodiment, each dosing cycle is 3 to 4 weeks.

[0064] In a further embodiment, each administration cycle is for 21 consecutive days.

[0065] In a further embodiment, lurbinectedin may be administered on day 1 (D1) of each administration cycle.

[0066] In a further embodiment, lurbinectedin and doxorubicin may be administered on day 1 (D1) of each administration cycle.

[0067] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 body surface area on day 1 (D1) of each administration cycle. 2and doxorubicin may be administered at a lower dose of 30 mg / m on day 1 (D1) of each administration cycle. 2 At the following doses: 15-30 mg / m 2 At a dose of 20-30 mg / m 2 at a dose of 15-25 mg / m 2 at a dose of 20-25 mg / m 2 At a dose of approximately 25 mg / m 2 or at a dose of 25 mg / m 2 may be administered at a dose of

[0068] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 body surface area on day 1 (D1) of each administration cycle. 2 and doxorubicin may be administered at a lower dose of 30 mg / m on day 1 (D1) of each administration cycle. 2 At the following doses: 15-30 mg / m 2 At a dose of 20-30 mg / m 2 at a dose of 15-25 mg / m 2 at a dose of 20-25 mg / m 2 At a dose of approximately 25 mg / m 2 or at a dose of 25 mg / m 2 may be administered at a dose of 0.01 mg / kg / day, with each administration cycle lasting 3 to 4 weeks.

[0069] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 body surface area on day 1 (D1) of each administration cycle. 2 and doxorubicin may be administered at a lower dose of 30 mg / m on day 1 (D1) of each administration cycle. 2 At the following doses: 15-30 mg / m 2 At a dose of 20-30 mg / m 2 at a dose of 15-25 mg / m 2 at a dose of 20-25 mg / m 2 At a dose of approximately 25 mg / m 2 or at a dose of 25 mg / m 2 and each dosing cycle is for 21 days.

[0070] In a further embodiment, lurbinectedin is administered at about 3.2 mg / m2 body surface area on day 1 (D1) of each administration cycle. 2 and doxorubicin may be administered at a lower dose of 30 mg / m on day 1 (D1) of each administration cycle. 2 At the following doses: 15-30 mg / m 2 At a dose of 20-30 mg / m 2 at a dose of 15-25 mg / m 2 at a dose of 20-25 mg / m 2 At a dose of approximately 25 mg / m 2 or at a dose of 25 mg / m 2 and the method further comprises administration of granulocyte colony-stimulating factor (G-CSF), wherein G-CSF may be administered on day 1 of the administration cycle, or the patient may receive primary prophylaxis with G-CSF for 5 days starting 24 to 72 hours after day 1 of the administration cycle, and optionally G-CSF is administered during one or more subsequent administration cycles, optionally each administration cycle being 3 to 4 weeks or 21 days.

[0071] In further embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 administration cycles are administered.

[0072] In further embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 administration cycles are administered.

[0073] In a further embodiment, the patient's lifetime doxorubicin limit is 450 mg / m 2 may be.

[0074] In a further embodiment, 7 or more cycles are administered. In a further embodiment, 8 or more cycles are administered. In a further embodiment, 9 or more cycles are administered. In a further embodiment, 10 or more cycles are administered. In a further embodiment, 11 or more cycles are administered. In a further embodiment, 12 or more cycles are administered. In a further embodiment, 13 or more cycles are administered. In a further embodiment, 14 or more cycles are administered. In a further embodiment, 15 or more cycles are administered. In a further embodiment, 16 or more cycles are administered. In a further embodiment, 17 or more cycles are administered.

[0075] In a further embodiment, 7 to 18 cycles are administered. In a further embodiment, 8 to 18 cycles are administered. In a further embodiment, 9 to 18 cycles are administered. In a further embodiment, 10 to 18 cycles are administered. In a further embodiment, 11 to 18 cycles are administered. In a further embodiment, 12 to 18 cycles are administered. In a further embodiment, 13 to 18 cycles are administered. In a further embodiment, 14 to 18 cycles are administered. In a further embodiment, 15 to 18 cycles are administered. In a further embodiment, 16 to 18 cycles are administered. In a further embodiment, 17 to 18 cycles are administered. In a further embodiment, 18 cycles are administered.

[0076] In a further embodiment, lurbinectedin and doxorubicin may be administered as a 1-hour intravenous infusion during each administration cycle.

[0077] In a further embodiment, doxorubicin is administered first, followed by lurbinectedin.

[0078] In a further embodiment, one or more cycles of a combination of lurbinectedin and doxorubicin are administered in a first phase, followed by one or more cycles of lurbinectedin alone in a second phase. [Brief explanation of the drawings]

[0079] [Figure 1] FIG. 1 shows best response according to RECIST 1.1 as progressive, stable, and partial response in 10 patients with different sarcomas (leiomyosarcoma (LMS including uterine leiomyosarcoma (uLMS)), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), solitary fibrous tumor (SFT), endometrial stromal sarcoma (ESS), and myxofibrosarcoma (myxFS)). [Figure 2]

[0023] Figure 1 shows the duration of each patient's study. PR means partial response, PD means progressive disease, and the arrow indicates treatment is still being administered. DETAILED DESCRIPTION OF THE INVENTION

[0080] In this application, some general terms and phrases are used, which should be interpreted as follows:

[0081] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, ameliorating, or inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, unless otherwise indicated, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0082] A "patient" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.), and non-mammals (e.g., birds, etc.), preferably humans.

[0083] In order to provide a more concise explanation, some quantitative expressions set forth herein are not quantified using the term "about". Regardless of whether the term "about" is explicitly used, it is understood that all quantities set forth herein are intended to refer to the actual given value, and also to refer to approximations to the given value that can be reasonably inferred based on ordinary skill in the art, including equivalents and approximations based on experimental and / or measurement conditions for the given value.

[0084] The term "administration cycle" refers to a treatment period during which a single anticancer drug or a combination of drugs is administered, usually followed by a drug-free period. In the present invention, a treatment cycle is a period of 4 weeks, preferably 3 weeks, and more preferably 21 consecutive days.

[0085] The term "phase" in the present invention refers to a treatment period comprising various administration cycles.

[0086] "Lurbinectedin" or PM01183 is a new synthetic alkaloid that binds to the DNA minor groove, causing spatial distortion of DNA and protein complexes, leading to the formation of DNA double-strand breaks (DSBs), thus inducing apoptosis and delaying progression through the S / G2 phase of the cell cycle. Lurbinectedin has the following structure: [ka]

[0087] Lurbinectedin was negative in the COMPARE analysis when compared with 98 other standard anticancer drugs in a standard National Cancer Institute (NCI) panel of 36 cell lines. Therefore, its mechanism of action is likely to be significantly different from that of other drugs. It showed a positive correlation (S rank > 0.8) only with trabectedin.

[0088] In vitro, lurbinectedin exhibited cytotoxic effects against a wide range of tumor-derived cell lines, with half-maximal inhibitory concentrations (IC50 ) values ​​in the low to very low nanomolar range (IC 50 The median value was approximately 1E-10M.

[0089] Further information regarding the clinical development of PM01183 (lurbinectedin) can be found below. -Elez,ME.et.al.Clin.Cancer Res.2014,20(8),2205-2214, -50 th ASCO Annual Meeting,May 30-June 3,2014,Chicago,IL,Abstract 5505, -26 th EORTC-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, -51 th 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), -54 th ASCO Annual Meeting,June 1-5,2018,Chicago,IL,Abstract No.11519,published in J.Clin.Oncol.36,2018(suppl), -Cruz,C.et al.J.Clin.Oncol.2018,36(31),3134-3143, -54 thASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 8570, published in J. Clin. Oncol. 36, 2018 (suppl).

[0090] Further information can be found in Xie et al. Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity, Oncoimmunology, 2019, Vol. 8, No. 11, e1656502 (9 pages).

[0091] Furthermore, any drug referred to herein may be in crystalline or amorphous form, either as a free compound or as a solvate (e.g., hydrate), and all forms are intended to be within the scope of the present invention. Methods of solvation are generally known in the art.

[0092] Preferred routes of administration are parenteral, including but not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal, or transdermal. The preferred method of administration is left to the discretion of the physician and will depend, in part, on the site of the medical condition. In a more preferred embodiment, lurbinectedin and doxorubicin according to the present invention are administered intravenously.

[0093] In specific embodiments, it may be desirable to administer lurbinectedin and / or doxorubicin locally to the site in need of treatment, hi one embodiment, administration can be by direct injection at the site (or former site) of a cancer, tumor, or neoplastic or precancerous tissue.

[0094] In certain embodiments, lurbinectedin and / or doxorubicin for use in treating cancer may be administered by infusion, with infusion times of up to 24 hours, 1 to 12 hours, 1 to 6 hours, and most preferably 1 hour. In embodiments, administration may occur between -5 minutes and +20 minutes of the stated infusion time.

[0095] Lurbinectedin may be administered in a dosing cycle of every 3 weeks or every 4 weeks, preferably every 3 weeks.

[0096] "Low-dose" doxorubicin means a dose lower than the dose typically used for doxorubicin. Low-dose may mean a dose lower than the dose currently listed in the product information for doxorubicin for the relevant indication.

[0097] mg / m 2 References to unit doses refer to doses based on body surface area (BSA).

[0098] In a preferred embodiment, the treatment of the present invention comprises: i) In Phase 1, 3.2 mg / m on D1 of each dosing cycle 2 Lurbinectedin at a dose of approximately 25 mg / m administered on D1 of each dosing cycle 2 to the patient for one or more cycles in combination with doxorubicin at a dose of ii) In the second phase, lurbinectedin alone at 3.2 mg / m on D1 of each dosing cycle 2 and administering to the patient one or more cycles at a dose of

[0099] In a further embodiment, the patient may receive antiemetic prophylaxis prior to each infusion, preferably 1 minute, more preferably 45 minutes, more preferably 30 minutes. The antiemetic prophylaxis includes a corticosteroid and a 5-HT3 antagonist. Preferably, the corticosteroid is dexamethasone and the 5-HT3 antagonist is ondansetron.

[0100] Patients may also receive prophylactic medications before receiving the infusion therapy described in the present invention. Prophylactic medications include corticosteroids and 5-HT3 receptor antagonists. Specific corticosteroids include dexamethasone. Specific 5-HT3 receptor antagonists include ondansetron. Specific dosages include 8 mg iv dexamethasone (or an equivalent dose of another iv corticosteroid) and 8 mg iv ondansetron (or an equivalent dose of another iv 5-HT3 receptor antagonist). Prophylactic medications may be administered on day 1 of each cycle. Furthermore, additional prophylactic medications may be administered as needed. An example is metoclopramide or equivalent, which, in embodiments, may be administered every 8 hours. After days 1 and 8 of each cycle, extended administration of oral corticosteroids (e.g., dexamethasone, not to exceed 20 mg / day) and / or 5-HT3 receptor antagonists (e.g., oral (or intravenous) ondansetron 4-8 mg (or equivalent)) may be permitted.

[0101] Patients may also receive granulocyte colony-stimulating factor (G-CSF). One example of G-CSF is non-pegylated filgrastim. By way of example, patients may receive primary prophylaxis with G-CSF for 5 days, starting 24-72 hours after day 1 of cycle 1. In embodiments, primary G-CSF prophylaxis for additional cycles may also be administered using the same regimen. G-CSF prophylaxis may also be administered at the physician's discretion.

[0102] The present invention has identified dosing regimens useful in the treatment of cancer.

[0103] In one embodiment, the cancer is a sarcoma.

[0104] In one embodiment, the cancer is a soft tissue sarcoma.

[0105] Sarcomas are rare cancers that begin in muscle, bone, nerves, cartilage, tendons, blood vessels, fatty tissue, and fibrous tissue. Sarcomas can affect almost any part of the body, inside or out. Sarcomas commonly affect the arms, legs, and trunk. Sarcomas can also appear in the stomach and intestines, as well as the back of the abdomen (retroperitoneal sarcoma) and female reproductive system (gynecologic sarcoma).

[0106] "Soft tissue sarcomas" can affect any part of the body. They arise in supportive or connective tissues, such as muscles, nerves, fatty tissue, and blood vessels. Soft tissue sarcomas include GIST, a common type of sarcoma that arises in the gastrointestinal (GI) tract; gynecological sarcomas, which arise in the female reproductive system (uterus (womb), ovaries, vagina, vulva, and fallopian tubes); and retroperitoneal sarcomas, which arise in the retroperitoneum.

[0107] There are over 50 different types of soft tissue sarcoma, including:

[0108] Leiomyosarcoma is a type of cancer that begins in smooth muscle tissue. These tumors often begin in the abdomen, but can also begin in other parts of the body, such as the arms or legs, or in the uterus.

[0109] Liposarcomas are malignant tumors of adipose tissue. They can start anywhere in the body, but most often begin in the thighs, behind the knees, and inside the back of the abdomen. They primarily occur in adults between the ages of 50 and 65.

[0110] Synovial sarcoma is a malignant tumor of the tissues surrounding joints. The most common sites are the hip, knee, ankle, and shoulder. This tumor is more common in children or young adults, but can also occur in middle-aged and older people.

[0111] In preferred embodiments, the soft tissue sarcoma is selected from leiomyosarcoma (LMS), gastrointestinal stromal tumor (GIST), liposarcoma (LPS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma, hemangioendothelioma (EHE), solitary fibrous tumor (SFT), fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), low-grade fibromyxoid sarcoma (LGFMS), endometrial stromal sarcoma (ESS), myxofibrosarcoma (myxFS), fibromatosis, follicular dendritic cell sarcoma (FDCS), desmoplastic small round cell tumor (DSRC), pleomorphic liposarcoma (PLS), and synovial sarcoma.

[0112] In a more preferred embodiment, the cancer may be advanced or metastatic leiomyosarcoma. The leiomyosarcoma may be selected from somatic soft tissue leiomyosarcoma, cutaneous or subcutaneous leiomyosarcoma, leiomyosarcoma of vascular origin, and leiomyosarcoma of uterine (uLMS) or non-uterine origin.

[0113] In certain embodiments, for use in treating leiomyosarcoma, about 25 mg / m on D1 of each dosing cycle 2 A single dose of doxorubicin at approximately 3.2 mg / m 2 It is administered in combination with lurbinectedin at a dose of

[0114] Pharmaceutical compositions can be prepared by methods well known in the pharmaceutical field.For example, the composition for injection can be prepared by mixing lurbinectedin with water or other physiologically suitable diluents (such as phosphate buffered saline) to form a solution.A surfactant can be added to promote the formation of a uniform solution or suspension.

[0115] Preferred compositions containing lurbinectedin in the present invention include the following: A pharmaceutical composition comprising lurbinectedin and a disaccharide, particularly preferably selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosucrose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof. A lyophilized pharmaceutical composition comprising lurbinectedin and a disaccharide, particularly preferably selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosucrose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.

[0116] In embodiments of the present invention, the ratio of lurbinectedin to disaccharide is determined according to the solubility of the disaccharide and, if the formulation is lyophilized, according to the lyophilizability of the disaccharide. It is contemplated that the lurbinectedin:disaccharide ratio (w / w) may be about 1:10 in some embodiments, about 1:20 in other embodiments, and about 1:50 in yet other embodiments. In other embodiments, such ratios are contemplated to be in the range of about 1:5 to about 1:500, and in yet other embodiments, such ratios are contemplated to be in the range of about 1:10 to about 1:500.

[0117] Compositions containing lurbinectedin may be lyophilized. Compositions containing lurbinectedin are typically provided in vials containing a specific amount of the compound.

[0118] Lurbinectedin may be a concentrated lyophilized powder for a 4 mg / vial solution for injection. Prior to use, the 4 mg vial may be reconstituted with 8 mL of sterile water for injection to obtain a solution containing 0.5 mg / mL of lurbinectedin. For intravenous administration to patients, the reconstituted vial may be diluted with a 50 mg / mL glucose (5%) or 9 mg / mL sodium chloride (0.9%) solution for infusion.

[0119] PM01183 The total composition of the 4 mg vial and reconstituted solution per 1 mL may be as follows: [Table 1]

[0120] In one embodiment of the present invention, a pharmaceutical package includes lurbinectedin, optionally in combination with doxorubicin, together with instructions for use, wherein lurbinectedin is administered at a dose of 30 mg / m administered on D1 of each administration cycle. 2 2 mg / m on D1 of each cycle in combination with doxorubicin at the following doses: 2 Super~4mg / m 2 It is administered in doses less than 100 mg / kg.

[0121] In another embodiment of the present invention, a pharmaceutical package comprises lurbinectedin and doxorubicin, optionally together with instructions for their combined use, wherein lurbinectedin is administered at a dose of 30 mg / m on D1 of each administration cycle. 2 2 mg / m on D1 of each cycle in combination with doxorubicin at the following doses: 2 Super~4mg / m 2 It is administered in doses less than 100 mg / kg.

[0122] In a preferred embodiment of the present invention, the pharmaceutical package contains lurbinectedin, optionally in combination with doxorubicin, together with instructions for use, wherein lurbinectedin is administered at a dose of about 25 mg / m on D1 of each administration cycle. 2 3.2 mg / m on D1 of each dosing cycle in combination with doxorubicin at a dose of 2 is administered at a dose of

[0123] The present invention will now be further described with reference to the following examples. [Example]

[0124] Phase 1b Induction to Randomized Phase 2 Trial of Lurbinectedin Plus Doxorubicin in Leiomyosarcoma Test Purpose The objective of the Phase 1b study is to investigate the safety and efficacy of lurbinectedin in combination with doxorubicin. Once the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) have been determined, a randomized phase 2 study will be initiated in participants with advanced leiomyosarcoma (LMS).

[0125] Phase Ib Main purpose: To determine the MTD and RDP2 of lurbinectedin in combination with doxorubicin in patients with advanced soft tissue sarcoma.

[0126] Secondary Objectives: To evaluate the preliminary antitumor activity of the combination, including disease control rates (DCR) at 6 and 12 months as assessed by RECIST version 1.1, as well as PFS, overall survival (OS), and objective response (OR) rates. To evaluate the safety and tolerability of lurbinectedin in combination with doxorubicin.

[0127] Phase II Main purpose: · To determine the progression-free survival (PFS) rate of lurbinectedin in combination with doxorubicin compared with doxorubicin alone in patients with advanced leiomyosarcoma.

[0128] Secondary Objectives: To evaluate the antitumor activity of the combination (including disease control rate (DCR) at 6 and 12 months as assessed by RECIST version 1.1, as well as OS and OR rates). To evaluate the safety and tolerability of lurbinectedin in combination with doxorubicin.

[0129] Exploratory objectives of both phases: Collect archival tumor, germline DNA, and CtDNA for correlation studies to explore genomic markers of susceptibility / resistance.

[0130] Study design The study is divided into two parts: Phase 1b is being conducted to determine the maximum tolerated dose (MTD) of the combination of lurbinectedin and doxorubicin in patients with soft tissue sarcomas and to determine the recommended dose for Phase II. Phase II is a randomized (1:1) trial comparing lurbinectedin plus doxorubicin with doxorubicin alone in patients with anthracycline-naïve leiomyosarcoma.

[0131] Phase Ib Phase 1b induction follows a standard 3+3 design. Patients receive two dose levels of doxorubicin (the first dose level is 25 mg / m on day 1 only). 2 doxorubicin, and the second dose level was 25 mg / m on days 1 and 8. 2 of doxorubicin) administered as a 60-minute intravenous infusion, followed by PM01183 at 3.2 mg / m on day 1 every 3 weeks (q3wk). 2 The treatment will be administered as a fixed dose intravenous infusion over 1 hour. One cycle is defined as a 3-week interval. Phase 1b induction will follow a standard 3+3 design, with dose escalation occurring if 0 of 3 or 1 of 6 patients experience dose-limiting toxicity (DLT).

[0132] Phase II Fifty patients with leiomyosarcoma will be randomized 1:1 and enrolled in one of two treatment arms: Arm 1: Lurbinectedin + doxorubicin vs. doxorubicin monotherapy. Randomization will be stratified by uterine vs. non-uterine origin of leiomyosarcoma. Participants in Arm 1 will receive lurbinectedin and doxorubicin at the RP2D defined in Phase 1b. Participants enrolled in Arm 2 will receive single-agent doxorubicin 75 mg / m on day 1 of each cycle. 2 at a dose of 450 mg / m 2 The maximum lifetime dose of

[0133] After progress Patients in Arm 2 who experienced radiological disease progression received lurbinectedin monotherapy at 3.2 mg / m on day 1 of each 21-day cycle. 2 will be permitted to transition to receiving

[0134] Study population Inclusion criteria Phase Ib 1) Patients with locally advanced or metastatic soft tissue sarcoma for whom there are no curative multidisciplinary treatment options 2) Freely signed and dated written informed consent has been obtained prior to any specific study procedure. 3) Be over 18 years old. 4) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 (Karnofsky score ≥ 60%). 7) Measurable disease per RECIST v.1.1. Note: Irradiated lesions may be eligible as targets if progression is confirmed. 9) Adequate bone marrow, renal, hepatic, and metabolic function (assessed within 7 days prior to study entry). a) Platelet count ≥ 100x109 / L, hemoglobin ≥ 9.0g / dL, absolute neutrophil count (ANC) ≥ 1.5x109 / L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN) with or without liver metastases. c) alkaline phosphatase (AP) ≤ 2.5xULN. d) Total bilirubin ≤ 1.5xULN or direct bilirubin ≤ ULN. e) International normalized ratio (INR) < 1.5 (unless the patient is receiving oral anticoagulation therapy). f) Calculated creatinine clearance (CrCL) ≥ 30 mL / min (using the Cockcroft-Gault formula). g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN. h) Albumin ≥ 3.0 g / dL. Albumin infusion to meet the inclusion criteria is prohibited. i) Thyroid-stimulating hormone (TSH) must be within the normal range at the facility. If TSH exceeds the ULN, it is acceptable as long as free T4 is within the normal range at the facility. 10) For women of childbearing potential (WOCBP), evidence of non-pregnancy. Both men and women must agree to use highly effective contraception before study enrollment, throughout the study, and for at least 6 months after study drug treatment is discontinued. Male patients of reproductive potential with a WOCBP partner must agree to refrain from fathering children or donating sperm during the study and for up to 5 months after treatment discontinuation. Acceptable contraceptive methods include abstinence, intrauterine devices (IUDs), oral contraceptives, subdermal implants, and / or double barrier contraception. 11) For participants with known chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable with suppressive therapy, if necessary. 12) Participants with a history of hepatitis C virus (HCV) infection must be on treatment and cured. Participants with known HCV infection and currently receiving treatment are eligible if they have an undetectable HCV viral load. 13) Left ventricular ejection fraction (LVEF) ≥ 50% on screening echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan. 14) Participants must have archival tissue available for analysis in the form of formalin-fixed, paraffin-embedded (FFPE) blocks or unstained slides. Participants without available archival tissue may be enrolled with sponsor-investigator approval. Note: Verification of archival tissue availability is the only requirement for eligibility; archival tissue does not need to be received by the study team or site prior to enrollment. 15) Patients with a history of prior or concurrent malignancy may be included with the sponsor-investigator's approval if the treating investigator assesses that the natural history or treatment of the patient is not likely to interfere with the safety or efficacy evaluation of the investigational regimen.

[0135] Phase II Participants must have histologically confirmed advanced or metastatic leiomyosarcoma (LMS) with no curative multimodality treatment options.

[0136] Exclusion criteria 1) Participants with a history of anthracycline or trabectedin (Yondelis, ET-743) administration (including a history of exposure to doxorubicin or liposomal doxorubicin). 2) Participants who have received more than two prior lines of cytotoxic chemotherapy in Phase 1b trials and no more than one prior line of cytotoxic chemotherapy in Phase 2 trials. There is no limit to the number of prior lines of non-cytotoxic chemotherapy (e.g., pazopanib, immunotherapy). 3) History of exposure to lurbinectedin (PM01183). 4) Participants who had previously received more than 45 Gy of radiation therapy to the pelvis. 5) Participants who received or have received chemotherapy within 14 days of Day 1 of Cycle 1, therapeutic radiotherapy within 21 days of Day 1 of Cycle 1, or major surgery within 21 days of Day 1 of Cycle 1. 6) Participants who had previously received palliative radiotherapy within 7 days of Day 1 of Cycle 1. 7) Participants who have received prior antibody-based therapy (e.g., nivolumab) within 4 weeks or 3 half-lives (whichever is shorter) of Day 1 of Cycle 1. 8) Participants who have received prior oral small molecule or tyrosine kinase inhibitor (TKI) therapy within 2 weeks or 3 half-lives (whichever is shorter) of Day 1 of Cycle 1. 9) Participants who have not recovered to baseline or grade 1 or less from adverse events attributable to any prior anticancer therapy, except for alopecia, controlled endocrine toxicity (e.g., hypothyroidism), and skin toxicity at grade 2. 10) Participants receiving any other investigational drug. 11) Participants with known CNS involvement, except for patients with previously treated brain metastases that remained stable on MRI ≥28 days prior to Day 1 of Cycle 1 without the use of steroids or antiepileptic drugs. 12) History of allergic reaction caused by compounds with similar chemical or biological compositions to lurbinectedin or doxorubicin. 13) Participants receiving any medication or substance that is a strong or moderate inhibitor or inducer of CYP3A, CYP2D6, or P-gp are ineligible. Because the list of these medications is constantly changing, it is important to regularly consult the frequently updated medical literature. As part of the enrollment / informed consent process, participants must be counseled about the risk of interactions with other medications and what to do if a new medication should be prescribed or if the participant is considering a new over-the-counter or herbal product. 14) Uncontrolled intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, chronic indwelling drains, or psychiatric / social circumstances that limit compliance with study requirements. 15) History of interstitial pneumonia or pulmonary fibrosis. 16) Known cardiomyopathy. 17) Pregnant women are excluded from this study because lurbinectedin and doxorubicin are anticancer drugs that may have teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to maternal treatment with lurbinectedin or doxorubicin, breastfeeding must be discontinued if the mother is treated with lurbinectedin or doxorubicin. Women of childbearing potential must have a negative pregnancy test before the first dose of study drug. 18) Immunocompromised patients (including patients known to be seropositive for human immunodeficiency virus (HIV) due to the increased risk of fatal infection when treated with myelosuppressive therapy). HIV testing is not required as part of screening.

[0137] Study population Expected number of patients Phase 1b follows a standard 3+3 design. Phase 1b studies will enroll a minimum of two and a maximum of 12 patients. The starting dose is dose level 1. At starting dose level 1, three participants can be enrolled. A minimum of six patients must be treated at the recommended phase II dose (R2PD). Phase 2 studies will randomize 50 patients 1:1 to one of two treatment arms, for an overall maximum sample size of 62 participants: Arm 1: lurbinectedin + doxorubicin; Arm 2: doxorubicin monotherapy. Participants enrolled in phase 2 will be stratified by uterine leiomyosarcoma and non-uterine leiomyosarcoma.

[0138] Test drug formulation PM01183 The PM01183 formulation is provided as a concentrated lyophilized powder for solution for infusion in 4 mg vials.

[0139] Prior to use, the 4 mg vial should be reconstituted with 8 mL of sterile water for injection to obtain a solution containing 0.5 mg / mL of PM01183. For administration to patients intravenously, the reconstituted vial should be diluted with glucose 50 mg / mL (5%) solution or sodium chloride 9 mg / mL (0.9%) solution for infusion.

[0140] The complete composition of the PM01183 4 mg vial and the reconstituted solution per mL is shown in Table 1. [Table 2]

[0141] Doxorubicin Doxorubicin hydrochloride formulations are supplied as concentrated lyophilized powders for solution for infusion in 10 mg, 20 mg, 50 mg, or 150 mg vials.

[0142] Prior to use, doxorubicin hydrochloride should be reconstituted with 0.9% Sodium Chloride Injection, USP to a final concentration of 2 mg / mL as follows: Reconstitute a 10 mg doxorubicin HCl vial with 5 mL 0.9% Sodium Chloride Injection, USP Reconstitute a 20 mg doxorubicin HCl vial with 10 mL 0.9% Sodium Chloride Injection, USP Reconstitute a 50 mg doxorubicin HCl vial with 25 mL 0.9% Sodium Chloride Injection, USP Reconstitute 150 mg doxorubicin HCl with 75 mL 0.9% Sodium Chloride Injection, USP

[0143] Treatment schedule Phase 1b Lurbinectedin PM01183 3.2 mg / m on day 1 of each treatment cycle 2 The drug is administered by intravenous infusion over 1 hour (±5 minutes) at a fixed dose of 0.01 mg / kg / day.

[0144] Doxorubicin will be administered by intravenous infusion according to institutional practice and / or FDA package insert. Dosage of doxorubicin will be 450 mg / m 2 After discontinuation of doxorubicin, participants will continue lurbinectedin monotherapy at 3.2 mg / m on day 1 of each dosing cycle until they meet other treatment discontinuation criteria. 2 Continue receiving this dose.

[0145] A dosing cycle is defined as 21 consecutive days.

[0146] Route of administration and dosage Phase Ib On days when both lurbinectedin and doxorubicin are administered, doxorubicin is administered first, followed by lurbinectedin. The lurbinectedin infusion is initiated within 1 hour of the end of the doxorubicin infusion.

[0147] The starting dose level is dose level 1. At dose level 1 (starting dose level), doxorubicin was administered at 25 mg / m on day 1 only. 2was administered by intravenous infusion over 1 hour at a dose of 3.2 mg / m followed by lurbinectedin at 3.2 mg / m 2 The drug is administered by intravenous infusion over 1 hour (±5 minutes) at a fixed dose of 0.01 mg / kg / day.

[0148] Dose level 2: doxorubicin 25 mg / m on days 1 and 8 2 administered by intravenous infusion over 1 hour at a dose of 3.2 mg / m followed by lurbinectedin at 3.2 mg / m 2 The drug is administered by intravenous infusion over 1 hour (±5 minutes) at a fixed dose of 0.01 mg / kg / day.

[0149] Dose-escalation plan (Phase Ib) Dose escalation will proceed in a standard 3+3 design according to the following criteria: [Table 3]

[0150] During Phase Ib, body surface area (BSA) will be calculated for each cycle according to the DuBois formula. The PM01183 dose will be recalculated before starting a new cycle. The dose will be rounded to two decimal places.

[0151] Prophylactic drugs On Day 1 of each cycle (prior to lurbinectedin administration), all patients will receive the following prophylactic medications: Dexamethasone 8 mg (intravenous) or equivalent, up to a maximum of 20 mg daily. If possible, the agent and dose administered in Cycle 1 should be maintained in Cycle 2. · 5-HT3 antagonists, i.e., ondansetron 8 mg (intravenous administration), not exceeding 16 mg.

[0152] Other possible preventive medications: Treatment with 5-HT3 antagonists and / or dexamethasone can be administered orally, i.e., 4-8 mg / day, extended for 3-5 consecutive days after drug infusion. If necessary, additional antiemetics may be used.

[0153] Permitted Drugs / Therapies Granulocyte colony-stimulating factor (G-GSF): Pegylated G-GSF is required for patients receiving lurbinectedin and doxorubicin. Pegylated G-GSF should be administered on day 2 at dose level 1 and on day 9 at dose level 2. Therapy for pre-existing medical conditions and conditions that emerge during treatment, including pain management and topical management of mucositis / stomatitis. · Blood products and transfusions (if clinically indicated). Bisphosphonates. In the event of nausea or vomiting, administer secondary prophylaxis and / or symptomatic treatment for vomiting according to the American Society of Clinical Oncology (ASCO) guidelines (considering the daily corticosteroid limit described above). Use of erythropoietin according to ASCO guidelines. Low molecular weight heparin (LMWH) and / or any other anticoagulant (if clinically indicated). Oral anticoagulants must be carefully monitored. Palliative limited-field bone RT (e.g., extrathoracic pain management). · Megestrol acetate for appetite stimulation. Contraceptives.

[0154] Prohibited Drugs / Therapies In combination with any other anti-tumor therapy. Other investigational drugs. Immunosuppressive therapy other than corticosteroids for antiemetic prophylaxis or pain control, or low-dose replacement therapy in patients who require this approach. Aprepitant or fosaprepitant or any other NK-1 antagonist or related substance P antagonist (except rolapitant). · CYP3A4 inhibitors (such as ketoconazole, fluconazole, voriconazole, telithromycin, clarithromycin, erythromycin, nafcillin, aprepitant, fosaprepitant, verapamil, modafinil, nefazodone, or grapefruit juice). · CYP3A enzyme inducers and / or inhibitors (unless strictly necessary and there are no therapeutic alternatives). Use of any prescription or non-prescription herbal and / or dietary supplements within 14 days prior to the first dose of medication and until 31 days after the last dose of lurbinectedin, unless the investigator, with the sponsor's consent, determines that this will not interfere with study procedures related to patient safety.

[0155] Drug-drug interactions Lurbinectedin In vitro studies using human microsomes indicated that the major CYP isoform involved in the metabolism of PM01183 is CYP3A4, followed by CYP2E1, CYP2D6, and CYP2C9. The estimated contribution of other CYP isoenzymes to the metabolism of PM01183 is considered negligible. For participants enrolled in the dose-escalation portion of the study, concomitant use of lurbinectedin with strong or moderate CYP3A inhibitors is strictly prohibited during Cycle 1. For all other participants, concomitant use of lurbinectedin with strong or moderate CYP3A inhibitors should be avoided if clinically feasible. Do not use lurbinectedin in combination with aprepitant or any other NK-1 antagonist or related substance P antagonist (except rolapitant).

[0156] Doxorubicin Doxorubicin is a major substrate of cytochrome P450 (CYP3A4 and CYP2D6) and P-glycoprotein (P-gp). Clinically significant interactions with CYP3A4, CYP2D6, and / or P-gp inhibitors (e.g., verapamil) have been reported, resulting in increased doxorubicin concentrations and clinical effects. CYP3A4 inducers (e.g., phenobarbital, phenytoin, St. John's wort) and P-gp inducers may decrease doxorubicin concentrations. Therefore, concomitant use of doxorubicin HCl with CYP3A4, CYP2D6, or P-gp inhibitors and inducers should be avoided.

[0157] Patient evaluability Phase Ib Evaluable patients for the primary objective of this Phase 1b (determination of MTD and RP2D) should have received at least one complete infusion of doxorubicin and PM01183 and been followed for at least one complete cycle (i.e., 3 weeks = 21 days). Patients who discontinue early or have missed / delayed doses and / or have clinically relevant evaluations (i.e., hematology, etc.) will be evaluable if these events are the result of treatment-related toxicity (excluding hypersensitivity reactions and / or extravasation).

[0158] Evaluation criteria Primary endpoint Phase Ib Determination of MTD and MAD: The maximum administered dose (MAD) of study drug is defined as the dose level at which at least two participants experience DLT-defined toxicities.

[0159] The dose level just below the MAD is defined as the MTD.

[0160] If no two or more DLTs are observed at any dose level, the MTD will be the highest dose administered (i.e., dose level 2).

[0161] If dose level 1 proves to be intolerable (DLTs observed in 2 of 3 or 2 of 6 or more patients), the Phase 1b trial will be stopped.

[0162] Alternative doses and / or schedules may be considered by protocol amendment (e.g., lurbinectedin 2 mg / m 2 and doxorubicin 50 mg / m 2 , known tolerated dose schedule).

[0163] The MTD will be established in a minimum of 6 participants. Once the MTD is assigned, available safety and efficacy data generated during Phase 1b will be reviewed to confirm the RP2D of the combination therapy.

[0164] Secondary endpoints Safety: Patients who received at least one infusion of doxorubicin and PM01183 will be evaluable for safety. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. Efficacy: The antitumor activity of the combination therapy will be evaluated from the following perspectives: Progression-free survival (PFS) was defined as the time from the date of enrollment to the date of documented progression according to RECIST v.1.1 or death (any cause). If patients receive further antineoplastic therapy or are lost to follow-up before PD, PFS will be censored at the date of the last tumor assessment before the date of subsequent antineoplastic therapy. Duration of response (DoR) will be calculated from the date of first documented response (complete or partial response, whichever occurs first) according to RECIST v.1.1 to the date of documented PD or death. The censoring rules defined above for PFS will be used for DoR. Clinical benefit is defined as the proportion (%) of evaluable patients with a complete response, partial response, or stable disease lasting ≥3 months as defined by RECIST v1.1. Overall survival (OS): Calculated from the date of enrollment to the date of death (fatal event) or last contact (in which case survival is censored on that date). Intermediate- and long-term survival rates (OS at 12, 18, and 24 months) are Kaplan-Meier estimates of the probability of being alive at these time points. Pharmacokinetics: PK parameters are assessed in plasma using standard non-compartmental methods (compartmental modeling may be performed where appropriate). Pharmacogenetics: Extracted leukocyte DNA will be analyzed for the presence of germline mutations or polymorphisms that may be involved in the metabolism and / or transport of PM01183, factors that may help explain interindividual variability in key PK parameters. Pharmacogenomics: To determine predictive / prognostic markers of response and / or resistance to PM01183 and doxorubicin, available tumor samples at baseline will be evaluated in all patients. Additionally, for patients who consent to the PGx substudy, blood samples (day 1 of each cycle) and on-treatment tumor biopsies (weeks 4-6 after treatment initiation) will be collected and evaluated.

[0165] result In Phase 1b, a total of 10 patients were treated, including 3 men (30%) and 7 women (70%), with a median age of 59 years. The median ECOG PS (range) was 0. The median number of prior lines of therapy was 0.5.

[0166] Of the 10 patients enrolled, 5 had leiomyosarcoma (1 patient with LMS and 4 patients with uterine leiomyosarcoma (uLMS)), 1 had dedifferentiated liposarcoma (DDLPS), 1 had undifferentiated pleomorphic sarcoma (UPS), 1 had solitary fibrous tumor (SFT), 1 had endometrial stromal sarcoma (ESS), and 1 had myxofibrosarcoma (myxFS).

[0167] Dose level 1 (day 1 only, lurbinectedin 3.2 mg / m 2 + doxorubicin 25 mg / m 2 ) enrolled three patients and no DLTs were observed.

[0168] Dose level 2 (3.2 mg / m on days 1 and 8) 2 + doxorubicin 25 mg / m 2 In the 2016 study, one patient (1 of 3 patients) experienced a DLT (grade 3 neutropenia on day 8, leading to discontinuation of doxorubicin), which resolved to grade 1 within 7 days.

[0169] A fourth patient enrolled at dose level 2 experienced a DLT (grade 2 alanine aminotransferase (ALT) / aspartate transferase (AST) elevation) on day 8, resulting in discontinuation of doxorubicin. The DLT resolved to grade 1 within 7 days.

[0170] Three additional slots were available for confirmation of dose level 1. One of three patients experienced a grade 3 ALT elevation, which improved to grade 1 within 4 days.

[0171] No other grade 3 or 4 adverse events occurred. Most treatment-related adverse events were grade 1 or 2 nausea, fatigue, reversible cytopenias, alopecia, anemia, and dehydration, typical of the doxorubicin and lurbinectedin drugs.

[0172] Adverse events that occurred during treatment are shown in Table 2. [Table 4]

[0173] Updated Results Adverse events occurring during the most recent treatment are shown in Table 3. [Table 5]

[0174] DLT: 1. Treatment criteria not met on day 8 (G2 ALT / AST) 2. Treatment criteria were not met on day 8 (G3 neutropenia) 3.G3 ALT

[0175] Dose delay: 1. Neutropenia 2.SBO / Surgery 3. Viral respiratory infections (r / o coronavirus infection)

[0176] Weight loss: 1.DL2→DL1 n=2 (G2 LFT, G3 neutropenia, same DTL ot as above) 2. DL1 n=2 (neutropenia, fatigue)

[0177] The median progression-free treatment period was 330 days (range 42–617 days), and three patients remained on study at the time of data cutoff.

[0178] The median time to response was 81 days (range 43-207 days), and the median duration of response was 169 days (range 126-364 days).

[0179] Eight of 10 patients had been on treatment for more than 6 months, four of 10 for more than 12 months, and three for more than 500 days.

[0180] The median time to partial response was 81 days (range 46-207 days).

[0181] Response assessment (Figure 1): Six patients had a RECIST 1.1 partial response in: -Undifferentiated pleomorphic sarcoma - Leiomyosarcoma, including uterine leiomyosarcoma -Dedifferentiated liposarcoma -Myxofibrosarcoma Three patients demonstrated stable disease according to RECIST 1.1 in: -Leiomyosarcoma (uterine leiomyosarcoma) -endometrial stromal sarcoma -Solitary fibrous tumor

[0182] The recommended dose is lurbinectedin 3.2 mg / m on day 1 of a 21-day cycle. 2 and doxorubicin 25 mg / m 2 It was decided to administer

[0183] conclusion Full-dose lurbinectedin and low-dose doxorubicin are a feasible, well-tolerated, and effective combination. Six partial responses and two long-term stable disease (>430 days) were achieved in 10 patients.

[0184] Overall, the present invention has identified the superior activity of lurbinectedin plus doxorubicin in cancer treatment. The present invention has identified particularly well-tolerated dosing regimens. Among other advantages, these regimens allow for an increased number of cycles to be administered to patients, prolonging the duration of disease control. Furthermore, these regimens can improve response rates / disease control rates. Furthermore, these regimens can reduce the high level of toxicity typically associated with doxorubicin.

Claims

1. 1. Lurbinectedin for use in the treatment of cancer in a patient in need thereof, wherein the lurbinectedin is administered in combination with doxorubicin, and the doxorubicin is administered at a dose of 30 mg / m during each administration cycle. ２ or 30 mg / m during each dosing cycle ２ Lurbinectedin, administered in doses less than

2. Lurbinectedin is administered in combination with doxorubicin, and the doxorubicin is administered at a dose of 15-30 mg / m during each administration cycle. ２ , or 20 to 30 mg / m ２ , or 15 to 30 mg / m ２ Less than or 20-30 mg / m ２ 2. The method of claim 1, wherein the lurbinectedin is administered at a dose of less than 100 mg / kg.

3. Lurbinectedin is administered in combination with doxorubicin, and the doxorubicin is administered at a dose of 15-25 mg / m during each administration cycle. ２ , or 20 to 25 mg / m ２ , preferably about 25 mg / m ２ , preferably 25 mg / m ２ 10. Lurbinectedin for use according to any one of the preceding claims, administered at a dose of

4. Doxorubicin at about 25 mg / m ２ 10. Lurbinectedin for use according to any one of the preceding claims, administered at a dose of

5. 10. Lurbinectedin for use according to any one of the preceding claims, wherein a single dose of doxorubicin is administered in each administration cycle.

6. Lurbinectedin is administered at a dose of 2 mg / m2 per body surface area during each dosing cycle. ２ ~4 mg / m ２ , 2 mg / m ２ Super ~4mg / m ２ Less than 2.5-3.5 mg / m ２ , preferably about 3.2 mg / m ２ , preferably 3.2 mg / m ２ 10. Lurbinectedin for use according to any one of the preceding claims, administered at a dose of

7. Lurbinectedin at about 3.2 mg / m ２ 10. Lurbinectedin for use according to any one of the preceding claims, administered at a dose of

8. Lurbinectedin for use according to any one of the preceding claims, wherein the administration cycle is every 3 to 4 weeks, preferably every 21 days.

9. 10. Lurbinectedin for use according to any one of the preceding claims, wherein lurbinectedin is administered on day 1 (D1) of each cycle, or doxorubicin is administered on day 1 (D1) of each cycle, or lurbinectedin and doxorubicin are administered on day 1 (D1) of each cycle.

10. 10. Lurbinectedin for use according to any one of the preceding claims, wherein in combination with doxorubicin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles, preferably 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles are administered.

11. 10. Lurbinectedin for use according to any one of the preceding claims, wherein doxorubicin is administered first, followed by lurbinectedin.

12. 10. Lurbinectedin for use according to any one of the preceding claims, wherein lurbinectedin is administered as a one-hour intravenous infusion during each administration cycle, or doxorubicin is administered as a one-hour intravenous infusion during each administration cycle, or lurbinectedin and doxorubicin are administered as one-hour intravenous infusions during each administration cycle.

13. Lurbinectedin is administered in combination with doxorubicin, and lurbinectedin is administered at about 3.2 mg / m on D1 of each administration cycle. ２ and doxorubicin is administered at a dose of about 25 mg / m on D1 of each dosing cycle. ２ and each administration cycle is for 21 days.

14. Lurbinectedin for use according to any one of the preceding claims, wherein the method further comprises the administration of granulocyte colony-stimulating factor (G-CSF).

15. 15. The lurbinectedin for use according to claim 14, wherein G-CSF is administered on day 1 of the administration cycle, or the patient receives primary prophylaxis with G-CSF for 5 days starting 24 to 72 hours after day 1 of the administration cycle.

16. 16. Lurbinectedin for use according to claim 14 or claim 15, wherein G-CSF is administered during a first dosing cycle, and optionally G-CSF is administered during one or more subsequent dosing cycles.

17. 18. Lurbinectedin for use according to any one of the preceding claims, wherein lurbinectedin and doxorubicin are administered in combination during a first phase, followed by one or more cycles of lurbinectedin administered alone during a second phase, wherein the lurbinectedin may be administered according to one or more of claims 6 to 9, 12, or 14 to 16.

18. Lurbinectedin for use according to any one of the preceding claims, wherein the cancer is a sarcoma, preferably a soft tissue sarcoma.

19. 19. Lurbinectedin for use according to claim 18, wherein the soft tissue sarcoma is selected from leiomyosarcoma, gastrointestinal stromal tumor, liposarcoma, dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, hemangioendothelioma, solitary fibrous tumor, fibrosarcoma, dermatofibrosarcoma protuberances, low-grade fibromyxoid sarcoma, endometrial stromal sarcoma, myxofibrosarcoma, fibromatosis, follicular dendritic cell sarcoma, desmoplastic small round cell tumor, pleomorphic liposarcoma, and synovial sarcoma.

20. 20. The method of claim 19, wherein the soft tissue sarcoma is an advanced or metastatic leiomyosarcoma selected from somatic soft tissue leiomyosarcoma, cutaneous or subcutaneous leiomyosarcoma, leiomyosarcoma of vascular origin, and leiomyosarcoma of uterine or non-uterine origin.

21. 1. Lurbinectedin for use in the treatment of cancer in a patient in need thereof, said treatment comprising: i) administering in a first step to the patient one or more cycles of lurbinectedin in combination with doxorubicin according to any one of claims 1 to 20; ii) in a second phase, administering lurbinectedin alone to said patient for one or more cycles, wherein lurbinectedin may be administered according to one or more of claims 6 to 9, 12, or 14 to 16.

22. A pharmaceutical package comprising lurbinectedin together with instructions for use in combination with doxorubicin according to any one of claims 1 to 21.

Images