Combination of lurbinectedin and atezolizumab

Abstract

A combination therapy for the treatment of small cell lung cancer is described that includes lurbinectedin and atezolizumab.

Description

[Technical Field]

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

[0002] Atezolizumab (MPDL3280A) is a humanized IgG1 monoclonal antibody composed of two heavy chains (448 amino acid residues each) and two light chains (214 amino acid residues each) produced in Chinese hamster ovary cells. Atezolizumab targets human PD-L1 and inhibits its interaction with its receptors, programmed cell death protein 1 (PD-1) and B7.1 (CD80, B7-1). Both of these interactions have been reported to provide inhibitory signals to T cells. Atezolizumab is approved in the United States and Europe for the treatment of patients with metastatic NSCLC that has progressed during or after platinum-containing chemotherapy.

[0003] Lurbinectedin, also known as PM01183 and originally called tryptamicidine, is a synthetic tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one alkaloid analog with antineoplastic activity and is the subject of International Publication No. 03 / 014127. Lurbinectedin is a selective inhibitor of oncogenic transcription, inducing DNA double-strand breaks, causing apoptosis, and modulating the tumor microenvironment. For example, by inhibiting active transcription in tumor-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF.

[0004] The chemical structure of lurbinectedin is represented as follows:

[0005] [ka]

[0006] Lurbinectedin has demonstrated highly potent in vitro activity against solid and non-solid tumor cell lines, as well as significant in vivo activity in several xenograft human tumor cell lines in mice, including those of breast, renal, and ovarian cancers. 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 dependence is a commonly recognized target in these diseases, many of which lack other viable targets. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 03 / 014127 [Non-patent literature]

[0008] [Non-Patent Document 1] 100th AACR Annual Meeting, April 18-22, 2009, Denver, CO, Abstract Nr. 2679 [Non-patent document 2] 100th AACR Annual Meeting, April 18-22, 2009, Denver, CO, Abstract Nr. 4525 [Non-patent document 3] Leal JFM et al., Br. J. Pharmacol. 2010, 161, pp. 1099-1110 [Non-patent document 4] Belgiovine, C et al., Br. J. Cancer, 2017; 117(5): pp. 628-638 [Non-patent document 5] Elez, ME. et al., Clin. Cancer Res. 2014, 20(8), pp. 2205-2214 [Non-licensed Document 6] 50th ASCO Annual Meeting, May 30th - June 3rd, 2014, Chicago, IL, Abstract 5505 [Non-licensed Document 7] 26th EORTC - 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; November 18-21, 2014, Barcelona, ​​Spain; Eur. J. Cancer 2014, 50 (Addendum. 6), pp. 13-14, published in Abs. No. 23. [Non-licensed Document 8] Published at the 51st ASCO Annual Meeting, May 29 – June 2, 2015, Chicago, IL, Abstract No. TPS2604 and Abstract No. 7509; J. Clin. Oncol. 33, 2015 (Addendum). [Non-licensed Document 9] 54th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 11519; J. Clin. Oncol. 36, published in 2018 (Addendum). [Non-licensed Document 10] Cruz, C. He, J. Clin. Oncol. 2018, 36(31), pp. 3134-3143 [Non-licensed Document 11] 54th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 8570; J. Clin. Oncol. 36, published in 2018 (addendum). [Non-licensed Document 12] Xie et al., Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer; immunity ONCOIMMUNOLOGY, 2019, Vol. 8, No. 11, e1656502 (page 9) [Non-Patent Document 13] Burger, "Medicinal Chemistry and Drug Discovery" 6th ed. (Donald J. Abraham, ed., 2001, Wiley) [Non-Patent Document 14] "Design and Application of Prodrugs" (ed. H. Bundgaard, 1985, Harwood Academic Publishers) [Non-Patent Document 15] "Remington's Pharmaceutical Sciences", E.W. Martin Summary of the Invention [Problem to be solved by the invention]

[0009] More effective cancer treatments are needed. [Means for solving the problem]

[0010] The present inventors have surprisingly determined a dosing regimen of lurbinectedin and atezolizumab that is effective in treating small cell lung cancer.

[0011] In view of the above, in an embodiment of the present invention there is provided lurbinectedin and atezolizumab for use in the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination of lurbinectedin and atezolizumab, wherein lurbinectedin is administered at a dose of 3.2 mg / m 2wherein lurbinectedin and atezolizumab are administered at a dose of 1200 mg, and wherein lurbinectedin and atezolizumab are administered on day 1 of a 21 day cycle.

[0012] In a further aspect, lurbinectedin and atezolizumab for use in the treatment of small cell lung cancer, said treatment comprising administering a combination of lurbinectedin and atezolizumab to a patient in need thereof, and optionally, after progression of the small cell lung cancer. Type Provided are lurbinectedin and atezolizumab for use in the treatment of small cell lung cancer (ES-SCLC).

[0013] In a further embodiment, a method of treating cancer comprises administering to a patient in need thereof a combination of lurbinectedin and atezolizumab, wherein the lurbinectedin is 3.2 mg / m 2 wherein lurbinectedin is administered at a dose of 1200 mg, atezolizumab is administered at a dose of 1200 mg, and lurbinectedin and atezolizumab are administered on day 1 of a 21-day cycle.

[0014] In a further aspect, a method of treating small cell lung cancer, comprising administering a combination therapy of lurbinectedin and atezolizumab, optionally after progression of the small cell lung cancer. Type The method is for treating small cell lung cancer (ES-SCLC).

[0015] In a further embodiment, there is provided a use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination of lurbinectedin and atezolizumab, wherein the lurbinectedin is 3.2 mg / m 2 wherein atezolizumab is administered at a dose of 1200 mg, and wherein lurbinectedin and atezolizumab are administered on day 1 of a 21-day cycle.

[0016] In a further aspect, there is provided a use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of small cell lung cancer, said treatment comprising administering a combination of lurbinectedin and atezolizumab to a patient in need thereof, and optionally, after progression of the small cell lung cancer. Type The present invention provides a method for treating small cell lung cancer (ES-SCLC).

[0017] In a further aspect, a method of inhibiting cancer cell proliferation is provided, comprising contacting cancer cells with a combination of lurbinectedin and atezolizumab, wherein the cancer cells are selected from the group consisting of small cell lung cancer cells, and optionally advanced lung cancer cells. Type The method is provided in which the cells are small cell lung cancer (ES-SCLC) cells.

[0018] In a further embodiment, a method of treating cancer comprises administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg, thereby treating cancer. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0019] In a further embodiment, there is provided a use of lurbinectedin in the manufacture of a medicament for the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0020] In a further embodiment, there is provided use of atezolizumab in the manufacture of a medicament for the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0021] In a further embodiment, there is provided a use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0022] In a further embodiment, there is provided lurbinectedin for use in the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m. In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m. 2 and atezolizumab is administered at a dose of 1200 mg.

[0023] In a further embodiment, there is provided atezolizumab for use in the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0024] In a further embodiment, there is provided lurbinectedin and atezolizumab for use in the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, the atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, the lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0025] In a further embodiment, lurbinectedin for use in the treatment of cancer, wherein the lurbinectedin is administered to a patient in need thereof in combination with atezolizumab, and the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m. In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m. 2 and atezolizumab is administered at a dose of 1200 mg.

[0026] In a further embodiment, atezolizumab for use in the treatment of cancer, wherein the atezolizumab is administered to a patient in need thereof in combination with lurbinectedin, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0027] In a further embodiment, lurbinectedin and atezolizumab for use in the treatment of cancer, wherein lurbinectedin is administered to a patient in need thereof in combination with atezolizumab, and wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 In certain embodiments, the atezolizumab is administered at a dose of 840 mg to 1680 mg. In certain embodiments, the lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0028] In a further aspect, there is provided a method of treating small cell lung cancer, wherein a patient, preferably a human patient, in need thereof is administered a combination therapy of lurbinectedin and atezolizumab, thereby treating the small cell lung cancer. Type It can be small cell lung cancer (ES-SCLC).

[0029] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer, wherein the treatment comprises administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0030] In a further aspect, there is provided a use of atezolizumab in the manufacture of a medicament for the treatment of small cell lung cancer, wherein the treatment comprises administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0031] In a further aspect, there is provided a use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of small cell lung cancer, wherein the treatment comprises administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0032] In a further aspect, there is provided lurbinectedin for use in the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. Type It can be small cell lung cancer (ES-SCLC).

[0033] In a further aspect, there is provided atezolizumab for use in treating small cell lung cancer, wherein the treatment comprises administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0034] In a further aspect, there is provided lurbinectedin and atezolizumab for use in treating small cell lung cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0035] In a further aspect, there is provided lurbinectedin for use in the treatment of small cell lung cancer, wherein the lurbinectedin is administered in combination with atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0036] In a further aspect, there is provided atezolizumab for use in the treatment of small cell lung cancer, wherein the atezolizumab is administered in combination with lurbinectedin to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0037] In a further aspect, there is provided lurbinectedin and atezolizumab for use in the treatment of small cell lung cancer, wherein the lurbinectedin is administered in combination with atezolizumab to a patient in need thereof. The small cell lung cancer can be ES-SCLC.

[0038] Dosage forms, pharmaceutical packages and formulations, and kits of parts are also provided by the present invention. These may include lurbinectedin and / or atezolizumab packaged for use in a method for treating small cell lung cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof according to the present invention. The dosage forms, packages, formulations, and kits may further include instructions for providing the treatment to a patient according to the present invention.

[0039] The following embodiments apply to all aspects of the present invention.

[0040] Lurbinectedin and atezolizumab can be administered simultaneously, separately, or sequentially. Multiple administrations of lurbinectedin, atezolizumab, or both can be administered.

[0041] Lurbinectedin is 2.5 to 3.2 mg / m2 In a preferred embodiment, lurbinectedin may be administered at a dose of 2.5 mg / m 2 at a dose of 2.8 mg / m 2 More preferably at a dose of 3.0 mg / m 2 and even more preferably at a dose of 3.1 mg / m 2 and most preferably at a dose of 3.2 mg / m 2 In a preferred embodiment, lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 , preferably 2.8 to 3.2 mg / m 2 , more preferably 3.0 to 3.2 mg / m 2 , and even more preferably 3.1 to 3.2 mg / m 2 , most preferably 3.2 mg / m 2 is administered at a dose of

[0042] Lurbinectedin and atezolizumab may be administered in a cycle of once every 1 to 4 weeks, preferably once every 3 weeks or once every 4 weeks. A specific administration cycle is every 21 days. Day 1 q3wk.

[0043] Any suitable route of administration may be used, for example, subcutaneous, intravenous, or intraperitoneal. Different routes of administration may be used for lurbinectedin and atezolizumab.

[0044] Lurbinectedin may be administered by intravenous infusion. Lurbinectedin may be administered after atezolizumab.

[0045] Lurbinectedin may be administered as an infusion, preferably with an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours, and most preferably 1 hour. In embodiments, administration may be from -5 minutes to +20 minutes of the stated infusion time.

[0046] Lurbinectedin may be administered on day 1. Lurbinectedin may be administered on day 1 of a 21-day cycle. A window of + / - 2 days may be allowed for administration on day 1 of the cycle. No window may be allowed for the first cycle.

[0047] Lurbinectedin may be administered in the form of a pharmaceutically acceptable salt selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, calcium salt, and ammonium salt, ethylenediamine salt, ethanolamine salt, N,N-dialkyleneethanolamine salt, triethanolamine salt, and basic amino acid salt.

[0048] Atezolizumab may be administered at a dose of 840 mg to 1680 mg, preferably 900 mg to 1500 mg, 1000 mg to 1400 mg, or 1100 mg to 1300 mg. In a preferred embodiment, atezolizumab is administered at a dose of 1200 mg. In embodiments, atezolizumab may be administered at 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every four weeks. 1200 mg every three weeks is particularly preferred.

[0049] Atezolizumab may be administered by intravenous infusion. Atezolizumab may be administered before lurbinectedin.

[0050] Atezolizumab may be administered as an infusion, preferably over a maximum infusion time of 24 hours, 1 to 12 hours, 1 to 6 hours, most preferably a 60 minute infusion, or for subsequent infusions, a 30 minute infusion. In embodiments, administration may be from -5 minutes to +30 minutes of the stated infusion time.

[0051] Atezolizumab may be administered on day 1. Atezolizumab may be administered on day 1 of a 21-day cycle. A window of + / - 2 days may be allowed for administration on day 1 of the cycle. No window may be allowed for the first cycle.

[0052] In embodiments, the patient may also receive granulocyte colony-stimulating factor G-CSF. In embodiments, in cycle 1, the patient may receive G-CSF primary prophylaxis for 5 days beginning 24-72 hours after day 1 of cycle 1. Stated another way, the patient may receive G-CSF daily for 5 days, with the first administration beginning 24-72 hours after day 1. In further embodiments, additional cycles of G-CSF primary prophylaxis are administered with the same regimen. In further embodiments, additional cycles of G-CSF primary prophylaxis are administered with the same regimen.

[0053] Multiple cycles may be used in accordance with the present invention, in embodiments, treatment comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more cycles.

[0054] The present invention has identified advantageous dosage regimens useful in the treatment of cancer.

[0055] The cancer can be a solid tumor.

[0056] The solid tumor may be selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head / neck cancer, renal cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, and sarcoma.

[0057] The lung cancer may be selected from mesothelioma, malignant mesothelioma, malignant pleural mesothelioma, malignant peritoneal mesothelioma, preferably malignant pleural mesothelioma.

[0058] The lung cancer can be non-small cell lung cancer.

[0059] The lung cancer can be small cell lung cancer.

[0060] Small cell lung cancer progresses Type It can be small cell lung cancer (ES-SCLC).

[0061] The patient may have progressed, including having progressed on first-line therapy. The patient may be a pre-treated patient. The patient may be a heavily pre-treated patient. The patient may be a progressive patient.

[0062] The cancer can be advanced cancer.

[0063] The patient may have progressed from prior platinum treatment.

[0064] Patients may not have been immunotherapy-naive.

[0065] The treatment can be a secondary treatment.

[0066] Treatment can result in one or more of the following outcomes: a reduction in tumor size; a delay in tumor growth; an extension of the patient's lifespan; or remission. These outcomes can be compared with control subjects (or hypothetical control subjects) who received no treatment or an alternative treatment.

[0067] Patients may have progressed from prior immunotherapy.

[0068] Patients may have progressed from standard of care treatments, including immunotherapy.

[0069] Patients may have progressed from platinum-etoposide, eg, cisplatin-etoposide or carboplatin-etoposide; carboplatin-oral topotecan; cisplatin-irinotecan; or carboplatin-gemcitabine.

[0070] Patients may have progressed from immune checkpoint inhibitors and platinum agents and etoposide, including (but not limited to) carboplatin-etoposide-atezolizumab or platinum-etoposide-durvalumab.

[0071] Patients may have progressed from nivolumab-ipilimumab. [Brief explanation of the drawings]

[0072] [Figure 1] 1 is a graph showing progression-free survival (PFS) results in advanced small cell lung cancer that progressed after prior treatment with platinum-based chemotherapy. DETAILED DESCRIPTION OF THE INVENTION

[0073] In this application, several general terms and phrases are used, which should be interpreted as follows:

[0074] The term "treating," as used herein, unless otherwise indicated, means to reverse, attenuate, alleviate, or inhibit the progression of the disease or condition to which such term applies or one or more symptoms of such disorder or condition. The term "treatment," as used herein, unless otherwise indicated, refers to the act of treating, as "treating" is defined immediately above.

[0075] A "patient" includes humans, non-human mammals (eg, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.), and non-mammals (eg, birds, etc.).

[0076] Lurbinectedin (PM01183) is a novel synthetic tetrahydroisoquinoline alkaloid that binds the DNA minor groove, causing spatial distortion of DNA and protein complexes, forming DNA double-strand breaks (DSBs), and thus inducing apoptosis and delaying progression through the S / G2 phase of the cell cycle. Lurbinectedin has the following structure:

[0077] [ka]

[0078] In vitro, lurbinectedin demonstrated cytotoxic effects against a broad selection of tumor-derived cell lines, with half-maximal inhibitory concentrations (IC 50 ) values ​​range from low nanomolar to very low nanomolar (IC 50 Approximately the median of 1 × 10 -10 Lurbinectedin also exhibits in vivo antitumor activity against a variety of mouse models of xenografted human-derived tumor types.

[0079] The in vitro antineoplastic activity of lurbinectedin was evaluated in a panel of solid tumor cell lines (some of which are shown in Table 1) exposed to various lurbinectedin concentrations for 72 hours and then assayed for viability by the MTT short-term assay.

[0080] [Table 1]

[0081] The in vivo antineoplastic activity of lurbinectedin was demonstrated in a panel of different human-derived tumor types, namely breast, colon, lung, ovarian, and prostate (Table 2). The resulting tumor sensitivity was analyzed in xenografts grown in athymic mice, where unformulated lurbinectedin inhibited tumors at the maximum tolerated dose in rodents [0.3 mg / kg (0.9 mg / m)]. 2 Lurbinectedin was administered as a single bolus intravenous (iv) injection at various time points during the study. Lurbinectedin demonstrated statistically significant antitumor activity (p<0.05) against breast, lung, and ovarian xenografts, but had a more modest antitumor profile against bladder, pancreas, and prostate.

[0082] [Table 2]

[0083] Toxicological studies in rats and dogs have shown that the primary target organs are bone marrow and liver. The effects of a single bolus injection of PM01183 on cardiovascular parameters [arterial blood pressure (ABP), heart rate (HR), and lead II electrocardiogram (ECG)] were evaluated for 6 hours in dogs. The study was conducted at 0.01 mg / kg (0.2 mg / m 2 In dogs treated with PM01183 at doses up to 0.05 mg / kg (1 mg / m), PM01183 had no effect on the heart, ABP, lead II ECG variables (PR, QT, QTcF and QTcV intervals, and QRS duration), ECG gross morphology, or rhythm. Furthermore, two separate toxicity studies demonstrated no effect on the heart, ABP, lead II ECG variables (PR, QT, QTcF and QTcV intervals, and QRS duration), ECG gross morphology, or rhythm. 2 ) revealed no electrophysiological changes in HR and ECG in dogs after single or repeated administration of lurbinectedin.

[0084] Clinical Data Based on these positive preclinical results, the clinical development program for lurbinectedin was initiated in March 2009. Currently, the program includes four phase I single-agent studies (three in solid tumors and one in acute leukemia); six phase Ib combination studies (studies using gemcitabine, capecitabine, doxorubicin, cisplatin, irinotecan, or paclitaxel with or without bevacizumab in selected advanced solid tumors); five phase II studies (four studies using lurbinectedin as a single agent in second-line pancreatic cancer, BRCA-mutated or BRCA-unselected metastatic breast cancer patients, and platinum-resistant / refractory ovarian cancer, as well as selected advanced solid tumors, and one study using lurbinectedin in combination with gemcitabine as second-line treatment in advanced non-small cell lung cancer [NSCLC]); and two phase III studies (single-agent lurbinectedin versus pegylated liposomal lurbinectedin in platinum-resistant ovarian cancer). These include a study comparing doxorubicin [PLD] or topotecan, and a study comparing lurbinectedin in combination with doxorubicin versus cyclophosphamide, doxorubicin, and vincristine [CAV] or topotecan in small cell lung cancer [SCLC]; one thorough QT study in patients with normal cardiac conduction and function, systolic blood pressure of 90 to 150 mmHg, and normal serum electrolyte levels who were already participating in the Phase 2 trial PM1183-B-005-14; and two investigator-sponsored studies (IST: a study using PM01183 in combination with olaparib in advanced solid tumors, and a study using lurbinectedin alone or in combination with doxorubicin or gemcitabine in soft tissue sarcoma). As of January 15, 2017 (cutoff date for IB version 9.0), 1515 patients had been enrolled in lurbinectedin clinical studies, and 1204 had been treated with lurbinectedin-containing therapy (460 in phase I, 448 in phase II, 234 in phase III, and 62 in IST).

[0085] The completed PM1183-A-001-08 Phase I study evaluated intravenous lurbinectedin for the first time in human patients, when it was infused over 1 hour (h) every 3 weeks (q3wk) in 31 patients with advanced and refractory solid tumors. Of these, 15 (48.4%) patients were treated at the defined recommended dose (RD). The RD for the Phase II study was 4.0 mg / m q3wk. 2 The PM01183 dose was defined as 0.001 mg / kg q3wk, equivalent to a fixed dose (FD) of 7.0 mg. Treatment with RD was generally well tolerated with standard antiemetic prophylaxis. The most significant toxicity in RD was reversible short-term myelosuppression. One patient had grade 4 thrombocytopenia, the only dose-limiting toxicity (DLT) in RD. No signs of cumulative toxicity were observed. Antitumor activity was observed in RD. Pharmacokinetic (PK) analysis demonstrated high interpatient variability (area under the curve [AUC] >50.0%) and linearity across all doses explored. Linear regression analysis demonstrated a correlation between neutropenia and AUC (r 2 =0.452).

[0086] Two other phase I trials have been completed: one using single-agent lurbinectedin on a q3wk day 1 and day 8 schedule in solid tumors (PM1183-A-005-11), and one using lurbinectedin in combination with gemcitabine in selected advanced solid tumors (PM1183-A-004-10). Antitumor activity was observed in both studies.

[0087] Additionally, recruitment has closed in five phase I trials: one using single-agent lurbinectedin in acute relapsed / refractory adult leukemia and myelodysplastic syndromes (PM1183-A-002-10), and four using lurbinectedin in combination with doxorubicin (PM1183-A-003-10), capecitabine (PM1183-A-006-12), paclitaxel with or without bevacizumab (PM1183-A-007-13), and cisplatin (PM1183-A-008-13) in selected solid tumors. Recruitment is currently ongoing in two phase I trials. A study using single-agent lurbinectedin in Japanese patients with unresectable / advanced solid tumors (PM1183-A-013-15), and this study using lurbinectedin in combination with irinotecan in selected advanced solid tumors (PM1183-A-014-15).

[0088] Of the five phase II trials, two have been completed, one evaluating lurbinectedin as a second-line treatment in advanced pancreatic cancer (PM1183-B-001-10) and one evaluating lurbinectedin in platinum-resistant and platinum-refractory ovarian cancer (PM1183-B-002-11). Three other phase II trials are ongoing (one trial is closed to recruitment) evaluating lurbinectedin as second-line treatment in BRCA 1 / 2-associated or unselected breast cancer (PM1183-B-003-11), alone or in combination with gemcitabine in NSCLC (PM1183-B-004-13), and in several selected advanced solid tumors: SCLC, head and neck cancer (H&N), neuroendocrine tumors (NETs), biliary tract cancer, endometrial cancer, BRCA 1 / 2-associated metastatic breast cancer, cancer of unknown primary site, germ cell tumors (GCTs), and Ewing's family of tumors (EFTs) (PM1183-B-005-14).

[0089] Both phase III trials are ongoing: recruitment has closed for a trial comparing single-agent lurbinectedin versus PLD or topotecan in platinum-resistant ovarian cancer (PM1183-C-004-14 [CORAIL]) and is ongoing for a trial comparing lurbinectedin in combination with doxorubicin versus CAV or topotecan in SCLC (PM1183-C-003-14 [ATLANTIS]).

[0090] Recruitment has also closed for the QT evaluation study (PM1183-B-005-14-QT) and is ongoing in both ISTs (IST POLA / ACOG1401 in advanced solid tumors, and IST 15-083 in soft tissue sarcomas).

[0091] Pooled logistic regression analysis of phase II data suggested that grade 3 / 4 neutropenia and thrombocytopenia may be related to body surface area (BSA). Based on these findings, all planned studies that are actively recruiting will now use BSA-based dosing to limit severe myelosuppression. The original RD of 4.0 mg / m 2 q3wk was reviewed and for the same reasons, 3.2 mg / m 2 It was reduced to q3wk.

[0092] Further information regarding the mechanism of action and in vivo efficacy of lurbinectedin is available at th AACR Annual Meeting, April 18-22, 2009, Denver, CO, Abstract Nr. 2679 and Abstract Nr. 4525; Leal JFM et al., Br. J. Pharmacol. 2010, 161, 1099-1110; and Belgiovine, C et al., Br. J. Cancer, 2017; 117(5): 628-638.

[0093] Further information regarding the clinical development of PM01183 (lurbinectedin) can be found below. - Elez, ME. 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; Eur. J. Cancer 2014, 50 (Addendum. 6), pages 13-14, Abs. No. 23. - 51 th Published at the ASCO Annual Meeting, May 29 – June 2, 2015, Chicago, IL, Abstract No. TPS2604 and Abstract No. 7509; J. Clin. Oncol. 33, 2015 (Addendum); - 54 th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 11519; published in J. Clin. Oncol. 36, 2018 (Addendum). - Cruz, C., J. Clin. Oncol. 2018, 36(31), pp. 3134-3143; - 54 th ASCO Annual Meeting, June 1-5, 2018, Chicago, IL, Abstract No. 8570; J. Clin. Oncol. 36, 2018 (Addendum).

[0094] 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 (page 9).

[0095] The term "lurbinectedin" is intended herein to encompass any pharmaceutically acceptable salt, ester, solvate, hydrate, prodrug, or any other compound that, upon administration to a patient, is capable of providing (directly or indirectly) a compound described herein. However, it is recognized that non-pharmaceutically acceptable salts also fall within the scope of the present invention, as these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts can be carried out by methods known in the art.

[0096] For example, pharmaceutically acceptable salts of the compounds provided herein can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by, for example, reacting the free acid or base of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, as well as organic acid addition salts such as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as sodium salts, potassium salts, calcium salts and ammonium salts, as well as organic alkali salts such as ethylenediamine salts, ethanolamine salts, N,N-dialkyleneethanolamine salts, triethanolamine salts and basic amino acid salts.

[0097] Any compound that is a prodrug of lurbinectedin is within the scope and spirit of the present invention. The term "prodrug" is used in its broadest sense and includes those derivatives that are converted to PM01183 in vivo. Prodrugs can hydrolyze, oxidize, or otherwise react under biological conditions to provide PM01183. Examples of prodrugs include, but are not limited to, derivatives and metabolites of PM01183 that contain biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Prodrugs can typically be prepared using well-known methods, such as those described by Burger, "Medicinal Chemistry and Drug Discovery," 6th Edition (Donald J. Abraham, ed., 2001, Wiley), and "Design and Application of Prodrugs" (H. Bundgaard, ed., 1985, Harwood Academic Publishers).

[0098] Additionally, 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 within the art.

[0099] Additionally, lurbinectedin for use in the present invention may be prepared according to synthetic processes such as those disclosed in WO 03 / 014127, which is incorporated herein by reference.

[0100] Atezolizumab (MPDL3280A) is a humanized IgG1 monoclonal antibody composed of two heavy chains (448 amino acid residues each) and two light chains (214 amino acid residues each) produced in Chinese hamster ovary cells. Atezolizumab was designed to eliminate Fc-effector function via a single amino acid substitution at position 298 of the heavy chain, resulting in an aglycosylated antibody that has minimal binding to Fc receptors in humans and prevents Fc-effector function at expected concentrations.

[0101] Atezolizumab targets human DP-L1 and inhibits its interaction with its receptors, programmed cell death protein 1 (PD-1) and B7.1 (CD80, B7-1), both of which are reported to provide inhibitory signals to T cells.

[0102] Atezolizumab is under investigation as a potential treatment for solid tumors and hematologic malignancies in humans.

[0103] The US FDA approved atezolizumab on March 18, 2016, and the EMA on September 21, 2017, for the treatment of patients with metastatic NSCLC who have progressed during or after platinum-containing chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tumor genomic aberrations must have disease progression on FDA-approved treatment for these aberrations before receiving atezolizumab.

[0104] The approval was based on two international, randomized, open-label clinical trials (Study GO28915 [OAK] and Study GO28753 [POPLAR]) that demonstrated consistent efficacy and safety results in a total of 1,137 patients with NSCLC.

[0105] Atezolizumab in combination with carboplatin and etoposide progressed in Europe in 2019 Type It is approved for the first-line treatment of adult patients with small-cell lung cancer (ES-SCLC).

[0106] The combination of the present invention has been found to be useful in the treatment of small cell lung cancer.

[0107] Small cell lung cancer (SCLC) is a fast-growing form of lung cancer. It is sometimes called oat cell carcinoma. Lung cancer is the leading cause of cancer death in the United States for both men and women. In 1998, an estimated 171,500 new cases were diagnosed, and approximately 160,100 deaths were attributed to the disease. More women died from lung cancer than from breast, ovarian, and uterine cancer combined, and men died from lung cancer four times as often as prostate cancer.

[0108] Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC, while accounting for only approximately 13–15% of all lung cancers at diagnosis, is a more aggressive form of lung cancer. In SCLC, cancer cells tend to grow rapidly and migrate, or metastasize, more easily to other parts of the body. Its incidence is associated with smoking, and nearly two-thirds of patients present with advanced disease. While response rates to chemotherapy are high, the benefits are short-lived. The median survival time for untreated SCLC patients is 2–4 months. The most common regimens include cisplatin or carboplatin and etoposide. Unfortunately, despite response rates of 40–90% to first-line chemotherapy, long-term survival is uncommon, as patients develop resistance to chemotherapy and relapse. The expected median overall survival after disease recurrence without treatment is typically 2–4 months.

[0109] However, on March 18, 2019, the US FDA approved atezolizumab in combination with carboplatin and etoposide as an advanced treatment. Type Approved for the first-line treatment of adult patients with small-cell lung cancer (ES-SCLC).

[0110] Approval is progress TypeThe study was based on IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC who had not received prior chemotherapy for their disease and had an ECOG performance status of 0 or 1. Patients were randomized to one of the following: Atezolizumab 1200 mg and carboplatin AUC 5 mg / mL / min on day 1 of each 21-day cycle, and etoposide 100 mg / m on days 1, 2, and 3. 2 intravenously for up to 4 cycles, followed by atezolizumab 1200 mg intravenously once every 3 weeks until disease progression or unacceptable toxicity, or Placebo and carboplatin AUC 5 mg / mL / min on day 1 and etoposide 100 mg / m on days 1, 2, and 3 of each 21-day cycle 2 will be administered intravenously for up to four cycles, followed by placebo once every three weeks until disease progression or unacceptable toxicity.

[0111] The primary efficacy outcome measures were investigator-assessed overall survival (OS) and progression-free survival (PFS) according to RECIST 1.1 in the intention-to-treat population. Median OS was 12.3 months (10.8, 15.9) in patients receiving atezolizumab with chemotherapy and 10.3 months (9.3, 11.3) in patients receiving placebo with chemotherapy (hazard ratio 0.70; 95% CI: 0.54, 0.91; p=0.0069). Median PFS was 5.2 months (4.4, 5.6) compared with 4.3 months (4.2, 4.5) in the atezolizumab and placebo groups, respectively (HR 0.77; 0.62, 0.96; p=0.0170).

[0112] The most common adverse reactions reported in 20% or more of patients receiving atezolizumab in IMpower133 were fatigue / asthenia, nausea, alopecia, constipation, and decreased appetite.

[0113] Additionally, in June 2020, the FDA approved lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) who had disease progression during or after platinum-based chemotherapy. Efficacy was demonstrated in the multicenter, open-label, multicohort study PM1183-B-005-14 (Study B-005; NCT02454972), which enrolled 105 patients with metastatic SCLC who had disease progression during or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg / m 2 Patients received lurbinectedin by intravenous infusion every 21 days until disease progression or unacceptable toxicity. The primary efficacy endpoints were confirmed overall response rate (ORR) as determined by investigator assessment using RECIST 1.1 and duration of response. Among 105 patients, the ORR was 35% (95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). According to an involved independent review, the ORR was 30% (95% CI: 22%, 40%), with a median response duration of 5.1 months (95% CI: 4.9, 6.4). The recommended dose of lurbinectedin is 3.2 mg / m every 21 days. 2 is.

[0114] In some embodiments, the cancer progresses Type In one embodiment, the cancer is small cell lung cancer (ES-SCLC). Type It is small cell lung cancer (ES-SCLC) and the cancer has spread beyond a single area that can be treated with radiation therapy. It may have spread within the chest (widely throughout the lung, to one lung, or to lymph nodes further from the cancer), or to other parts of the body. Or cancer cells may be present in the fluid around the lung (malignant pleural effusion).

[0115] "Malignant mesothelioma" is a disease in which malignant (cancer) cells are found in the pleura (a thin layer of tissue that lines the chest cavity and covers both lungs) or peritoneum (a thin layer of tissue that lines the abdomen and covers most of its organs). Malignant mesothelioma can also form in the heart or testicles, but this is rare. The four types of mesothelioma are therefore pleural (lung lining), peritoneal (peritoneal cavity lining), pericardial (heart cardia), and testicular mesothelioma.

[0116] Mesothelioma can be identified by three cancer cell types: epithelioid, sarcomatoid, and biphasic. Therefore, it can be defined as epithelioid mesothelioma (epithelioid cells), sarcomatoid mesothelioma (sarcomatoid cells), or biphasic mesothelioma (epithelioid and sarcomatoid cells). The pleura is the most common form of mesothelioma. Approximately 70% to 75% of cases occur in the pleura. Peritoneal disease accounts for 10% to 20% of mesothelioma cases. Compared to the pleura, fewer studies are available on the peritoneum; however, this tumor type has a good prognosis. Pericardial mesothelioma is extremely rare. Approximately 200 cases have been reported in the medical literature. Testicular mesothelioma develops in the lining of the testicles. This form of mesothelioma is the rarest. Fewer than 100 cases have been reported in the medical literature.

[0117] The three types of mesothelioma cells are epithelioid, sarcomatoid, and biphasic. Biphasic mesothelioma is a mix of the first two cell types. Different mesothelioma tumors respond differently to treatment. Epithelioid or epithelioid cells typically respond best to treatment, while sarcomatoid cells are typically more resistant to treatment. Epithelioid mesothelioma constitutes approximately 70% to 75% of all cases of asbestos-related mesothelioma cancer. Epithelioid cells typically have the best prognosis. They tend to be less aggressive and do not spread as quickly as sarcomatoid and biphasic cell disease. Approximately 50% of pleural disease is epithelioid. Approximately 75% of peritoneal tumors are composed of epithelioid cells. Sarcomatoid is an extremely rare mesothelioma cell category. It is typically the most aggressive and difficult to treat. It accounts for approximately 10% to 20% of all mesothelioma diagnoses. Approximately 20% of pleural tumors are sarcomatoid, while only 1% of peritoneal mesotheliomas are sarcomatoid. Biphasic mesothelioma refers to tumors containing epithelial and sarcomatoid cells. Life expectancy after diagnosis of biphasic mesothelioma depends on the cells that predominate in the tumor. More epithelioid cells generally indicate a better prognosis. Tumors that are predominantly sarcomatoid are more difficult to treat and have a shorter life expectancy. Approximately 30% of pleural tumors and 25% of peritoneal tumors are biphasic.

[0118] [Table 3]

[0119] Based on the limited number of cases reported in the medical literature, pericardial mesothelioma shows a roughly equal distribution of the three mesothelioma cell types. Approximately two-thirds of testicular mesothelioma cases are epithelioid. The remainder of testicular cases are biphasic. Only one case of purely sarcomatoid cell disease has been reported for testicular mesothelioma.

[0120] In embodiments, the present invention is useful in the treatment of malignant pleural mesothelioma (MPM).

[0121] The malignant mesothelioma to be treated can be epithelioid. The malignant mesothelioma to be treated can be sarcomatoid. The malignant mesothelioma to be treated can be biphasic.

[0122] Patients may not have been immunotherapy-naive.

[0123] The patient may have progressed from prior immunotherapy. "Progressed from prior immunotherapy" means that the patient has previously received immunotherapy.

[0124] The immunotherapy can be an immune checkpoint inhibitor. The immune checkpoint inhibitor can be (but is not limited to) a PD-1 inhibitor, such as pembrolizumab, nivolumab, or cemiplimab. The immune checkpoint inhibitor can be (but is not limited to) a PD-L1 inhibitor, such as atezolizumab, avelumab, or durvalumab. The immune checkpoint inhibitor can be (but is not limited to) a CTLA-4 inhibitor, such as ipilimumab. The immune checkpoint inhibitor can be (but is not limited to) a LAG-3 inhibitor, such as leratolimab.

[0125] The treatment can be a secondary treatment.

[0126] Patients may have progressed after receiving standard treatment, which can be platinum-etoposide, such as cisplatin-etoposide or carboplatin-etoposide; carboplatin-oral topotecan; cisplatin-irinotecan; or carboplatin-gemcitabine.

[0127] Patients may have progressed from platinum-etoposide, such as cisplatin-etoposide or carboplatin-etoposide; carboplatin-oral topotecan; cisplatin-irinotecan; or carboplatin-gemcitabine.

[0128] Patients may have progressed after receiving standard treatments, including immunotherapy.

[0129] The standard of care for ES-SCLC can be immune checkpoint inhibitors and platinum agents and etoposide. Examples include (but are not limited to) carboplatin-etoposide-atezolizumab or platinum-etoposide-durvalumab. The standard of care for malignant pleural mesothelioma can be nivolumab-ipilimumab.

[0130] Patients may have progressed from immune checkpoint inhibitors and platinum agents and etoposide, including (but not limited to) carboplatin-etoposide-atezolizumab or platinum-etoposide-durvalumab.

[0131] Patients may have progressed from nivolumab-ipilimumab.

[0132] In embodiments, the present invention provides dosing schedules for treating cancer as defined herein.

[0133] In a preferred embodiment, lurbinectedin is administered at a dose of 2.5 mg / m 2 at a dose of 2.8 mg / m 2 More preferably at a dose of 3.0 mg / m 2and even more preferably at a dose of 3.1 mg / m 2 and most preferably at a dose of 3.2 mg / m 2 is administered at a dose of

[0134] In a preferred embodiment, lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 , preferably 2.8 to 3.2 mg / m 2 , more preferably 3.0 to 3.2 mg / m 2 , and even more preferably 3.1 to 3.2 mg / m 2 , most preferably 3.2 mg / m 2 is administered at a dose of

[0135] In a preferred embodiment, atezolizumab may be administered at a dose of 840 mg to 1680 mg, preferably 900 mg to 1500 mg, 1000 mg to 1400 mg, or 1100 mg to 1300 mg. In a particularly preferred embodiment, atezolizumab is administered at a dose of 1200 mg. In an embodiment, atezolizumab may be administered at 840 mg every two weeks, 1200 mg every three weeks, or 1680 mg every four weeks. 1200 mg every three weeks is particularly preferred.

[0136] In a particularly preferred embodiment, lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0137] In a particularly preferred embodiment, lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg.

[0138] Patients may also receive prophylactic medications while undergoing the treatment 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 medications include intravenous administration of 8 mg of dexamethasone (or an equivalent dose of another intravenous corticosteroid) and intravenous administration of 8 mg of ondansetron (or an equivalent dose of another intravenous 5-HT3 receptor antagonist). Prophylactic medications may be administered on day 1 of each cycle. Further, additional prophylactic medications may be administered as needed. Examples include metoclopramide or an equivalent, which may be administered every 8 hours in an embodiment. After days 1 and 8 of each cycle, broad-spectrum 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 administered.

[0139] Patients may also receive a granulocyte colony-stimulating factor (G-CSF), such as non-pegylated filgrastim. In embodiments, in cycle 1, patients may receive primary prophylaxis with G-CSF for 5 days beginning 24-72 hours after day 1 of cycle 1. Additional cycles of G-CSF primary prophylaxis may be administered using the same regimen, but may also be administered at the physician's discretion.

[0140] Pharmaceutical compositions containing lurbinectedin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier can be formulated according to the selected route of administration. Examples of dosage forms include, but are not limited to, oral, topical, parenteral, sublingual, rectal, intravaginal, ophthalmic, and intranasal administration. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Preferably, the composition is administered parenterally. The pharmaceutical composition can be formulated so that the compound becomes bioavailable upon administration of the composition to an animal, preferably a human. The composition can be in the form of one or more dosage units; for example, a tablet can be a single dosage unit, and the compound container can contain the compound in liquid or aerosol form and hold one or more dosage units.

[0141] The pharmaceutically acceptable carrier or vehicle can be particulate, so that the composition is in the form of, for example, a tablet or powder. The carrier can be liquid, such as an oral syrup or injectable liquid. Furthermore, the carrier can be gaseous or liquid, to provide an aerosol composition useful, for example, in inhalation administration. Powders can also be used in inhalation dosage forms. The term "carrier" refers to a diluent, adjuvant, or additive with which the compound according to the present invention is administered. Such pharmaceutical carriers can be liquids, such as water or oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, and coloring agents can be used. In one embodiment, when administered to animals, the compounds and compositions and pharmaceutically acceptable carriers are sterile. Water is a preferred carrier when the compound is administered intravenously. Physiological saline solution and aqueous dextrose and glycerol solution can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include additives such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat powdered milk, glycerol, propylene glycol, water, and ethanol. The composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0142] When intended for oral administration, the composition is preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included within the scope of forms considered solid or liquid herein.

[0143] As a solid composition for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer, or similar form. Such solid compositions typically contain one or more inert diluents. Additionally, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; additives such as starch, lactose, or dextrin; disintegrating agents such as alginic acid, sodium alginate, or corn starch; lubricants such as magnesium stearate; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavoring; and coloring agents.

[0144] When the composition is in the form of a capsule (eg, a gelatin capsule), it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or fatty oil.

[0145] The composition can be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. The liquid can be useful for oral administration or delivery by injection. When intended for oral administration, the composition can contain one or more of a sweetener, a preservative, a dye / colorant, and a flavor enhancer. The composition for administration by injection can also contain one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffer, a stabilizer, and an isotonic agent.

[0146] The preferred route of administration is parenteral, including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal, or transdermal administration. The preferred mode of administration is left to the discretion of the practitioner and will depend, in part, on the site of the pathological condition. In a more preferred embodiment, the compounds according to the present invention are administered intravenously. Infusion times of up to 24 hours are preferred for use, with 1 to 12 hours being more preferred, 1 to 6 hours being even more preferred, and 1 hour being most preferred. Short infusion times that allow treatment to be performed without an overnight stay in a hospital are particularly desirable. However, infusions can be 12 to 24 hours or even longer, as needed. Infusions can be administered at suitable intervals, for example, 1 to 4 weeks, preferably once every 3 weeks.

[0147] In a preferred embodiment, atezolizumab is administered intravenously (iv) at a flat dose of 1200 mg as a 60-minute infusion (second and subsequent infusions may be administered over 30 minutes), followed by lurbinectedin at 3.2 mg / m 2 Administered intravenously on day 1 of every 3 weeks (q3wk) as a 1-hour infusion at a dose of 1:1. A cycle is defined as a 3-week interval.

[0148] Liquid compositions, whether in solution, suspension, or other similar form, may contain one of the following: a sterile diluent, such as water for injection, physiological saline solution, preferably saline, Ringer's solution, isotonic saline, synthetic mono- or diglycerides, polyethylene glycol, fixed oils such as glycerin or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; and tonicity adjusters such as sodium chloride or dextrose. Parenteral compositions may be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass, plastic, or other materials. Saline is a preferred adjuvant.

[0149] The compositions contain an effective amount of lurbinectedin and / or atezolizumab to provide a suitable dosage regimen. Dosing can be performed sequentially or cyclically within the maximum tolerated dose.

[0150] In specific embodiments, it may be desirable to administer lurbinectedin or atezolizumab locally to the area requiring treatment. In one embodiment, administration may be by direct injection at the site (or former site) of the cancer, tumor, or neoplastic or pre-neoplastic tissue.

[0151] Pulmonary administration can be employed, for example, by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In some embodiments, lurbinectedin can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0152] The compositions can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use. Other examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences," by E.W. Martin.

[0153] Pharmaceutical compositions can be prepared using methods well known in the pharmaceutical arts. For example, compositions intended to be administered by injection can be prepared by combining 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 homogeneous solution or suspension.

[0154] Preferred compositions containing lurbinectedin include the following: A pharmaceutical composition comprising lurbinectedin and a disaccharide, particularly preferred disaccharides being 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 preferred disaccharides being selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosucrose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.

[0155] In embodiments of the present invention, the ratio of lurbinectedin to disaccharide is determined based on the solubility of the disaccharide and, when the formulation is lyophilized, the lyophilizability of the disaccharide. It is contemplated that the lurbinectedin:disaccharide ratio (w / w) can be about 1:10 in some embodiments, about 1:20 in other embodiments, and about 1:50 in still further embodiments. Other embodiments have such ratios in the range of about 1:5 to about 1:500, and still further embodiments have such ratios in the range of about 1:10 to about 1:500.

[0156] Lurbinectedin-containing compositions may be lyophilized. Lurbinectedin-containing compositions are typically provided in vials containing a specified amount of such compound.

[0157] Lurbinectedin can be provided as a lyophilized powder concentrate for an infusion solution of 4 mg per vial. Prior to use, the 4 mg vial can be reconstituted with 8 mL of sterile water for injection to obtain a solution containing 0.5 mg / mL of lurbinectedin. When administered to a patient as an intravenous infusion, the reconstituted vial can be diluted for infusion with a 50 mg / mL glucose (5%) or 9 mg / mL sodium chloride (0.9%) solution.

[0158] The total composition of a 4 mg vial of PM01183 and reconstituted solution / mL can be as follows:

[0159] [Table 4]

[0160] In order to provide a more concise description, some of the quantitative expressions described herein are not quantified using the term "about". Whether or not the term "about" is explicitly used, it is understood that any quantity described herein refers to the actual value described, and also refers to an approximation of such a described value that should be reasonably inferred based on ordinary knowledge in the art, including equivalent values ​​and approximations resulting from the experimental and / or measurement conditions of such a described value.

[0161] The present invention will now be further described with reference to the following examples. [Example]

[0162] A Phase I-II Study to Evaluate the Safety, Tolerability, and Efficacy of PM01183 and Atezolizumab in Patients with Advanced Small Cell Lung Cancer Whose Progression Has Been Treated After Prior Platinum-Based Chemotherapy Research objectives Phase I Main purpose: · To determine the maximum tolerated dose (MTD) and recommended dose for a phase II study (RD) of PM01183 in combination with atezolizumab in patients with advanced SCLC progressing after platinum-doublet chemotherapy. Secondary Objectives: Characterize the safety profile and feasibility of this combination. · To characterize the pharmacokinetics (PK) of PM01183 and detect major drug-PK interactions. Obtain preliminary information on the clinical antitumor activity of this combination. · To determine the MTD and RD of PM01183 in combination with atezolizumab with mandatory primary prophylaxis with G-CSF in patients with advanced SCLC when DLT is exclusively related to neutropenia. To assess pharmacogenetics (PGt) in germline DNA to identify factors that may explain interindividual variability in key PK parameters. Evaluating pharmacogenomics (PGx) in tumor and blood samples to identify potential markers of response and / or resistance.

[0163] Study design A prospective, open-label, non-comparative, multicenter phase I-II study in patients with SCLC and ECOG PS 0-1 who have failed one prior platinum-containing line but no more than one chemotherapy-containing line (reloading not allowed). The study will be divided into two parts: a dose-finding phase I with escalating doses of PM01183 in combination with a fixed dose of atezolizumab, followed by a single-arm phase II part with expansion in the RD determined in phase I.

[0164] Phase I Patients received atezolizumab at a fixed dose of 1200 mg administered intravenously (iv) as a 60-minute infusion (subsequent infusions may be administered over 30 minutes), followed by PM01183 at a starting dose of 2.5 mg / m 2 Patients will receive PM01183 intravenously on day 1 of each treatment period (q3wk) as a 1-hour infusion. A cycle is defined as a 3-week interval. The dose of PM01183 will be titrated in consecutive patient cohorts according to observed tolerability and safety following a modified Fibonacci scheme and a classic 3+3 design.

[0165] Study population Inclusion criteria 1) Voluntarily signed and dated written informed consent prior to any specific study procedure. 2) Age > 18 years. 3) Histologically or cytologically confirmed diagnosis of extensive or limited-stage SCLC. 4) progression to first-line platinum-based chemotherapy. 5) Tumor tissue blocks or slides available from previous surgery or biopsy. 6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 1. 7) Measurable disease per RECIST v.1.1. Note: Irradiated lesions may be targeted if progression is documented. 8) At least 3 weeks since the last prior anticancer treatment (including radiation therapy) and recovery from any adverse events (AEs) (all Grade ≤2 except sensory neuropathy, anemia, asthenia, and alopecia) related to the prior anticancer treatment to Grade ≤1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5). 9) Adequate bone marrow, renal, hepatic, and metabolic function (assessed within 7 days prior to study enrollment): a) Platelet count ≥ 100 × 10 9 / L, hemoglobin ≥ 9.0 g / dL and absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN), regardless of the presence of liver metastases. c) alkaline phosphatase (AP) ≤ 2.5 × ULN. d) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN. e) International normalized ratio (INR) < 1.5 (unless the patient is receiving oral anticoagulation therapy). f) Calculated creatinine clearance (CrCL) (using the Cockcroft and Gault formula) ≥ 30 mL / min. g) Creatine phosphokinase (CPK) ≤ 2.5 × ULN. h) Albumin ≥ 3.0 g / dL. Albumin infusion to meet the inclusion criteria is prohibited. i) Thyroid-stimulating hormone (TSH) within the institutional normal range. If TSH is above the ULN, free T4 within the institutional normal range is acceptable. 10) For women of childbearing potential (WOCBP), evidence of non-pregnancy. Both women and men must agree to use highly effective contraception during the study and for at least 5 months after the last atezolizumab dose and for at least 6 weeks (women) or 4 months (men) after the last PM01183 dose. Fertile male patients with WOCBP partners 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.

[0166] Exclusion criteria 1) Active or untreated central nervous system (CNS) complications. Treated CNS metastases must demonstrate radiographic stability (defined as no CNS progression for at least 3 weeks from the post-radiotherapy brain scan to the brain scan performed prior to study enrollment) and patients should not have neurological signs / symptoms associated with brain metastases or RT. Any steroid treatment must be completed ≥ 14 days before the first dose of study treatment. 2) More than one prior chemotherapy-containing line (reloading with the same initial regimen is not permitted). 3) Patients who received radiation therapy (RT) in more than 35% of the bone marrow. 4) History of previous bone marrow and / or stem cell transplant. 5) Imminent need for RT (e.g., painful bone metastases and / or risk of spinal cord compression). 6) History of allergy or hypersensitivity to the study drug or any of its excipients. 7) Prior treatment with antibodies against PM01183, PD-1, PD-L1, PD-L2, CD137, or cytotoxic T-lymphocyte antigen 4 (CTLA-4). 8) Live vaccines within 30 days prior to the start of study treatment and during treatment. 9) History of other previous malignancies, except for basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and intraepithelial cervical cancer. Patients with other previous malignancies and no disease recurrence for 3 years are eligible. 10) Concomitant diseases / conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure defined as an abnormal left ventricular ejection fraction (LVEF) of less than 50% as assessed by multi-gated acquisition scan (MUGA) or ultrasound (US) equivalent, or clinically significant valvular heart disease within 12 months prior to the first study dose. b) Symptomatic arrhythmias or any uncontrolled arrhythmias requiring ongoing treatment. c) Ongoing chronic alcohol use or Child-Pugh B or C cirrhosis. d) Uncontrolled active infection, serious non-healing wounds, ulcers or fractures. e) Diagnosis of immunodeficiency or receipt of systemic steroid treatment (greater than 10 mg per day of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first study dose. f) Active autoimmune disease that has required systemic treatment (i.e., with disease-modifying agents, corticosteroids, and immunosuppressants) within the last 2 years. Patients with vitiligo or self-limited childhood asthma / atopy are also eligible, as are patients requiring the intermittent use of bronchodilators or local steroid injections, patients with stable hypothyroidism on hormone replacement, and patients with insulin-controlled type 1 diabetes or Sjogren's syndrome. g) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on a screening chest computed tomography (CT) scan. A history of radiation pneumonitis (fibrosis) in the radiation field is permitted if asymptomatic and not requiring steroids. h) Known history of active tuberculosis (Mycobacterium tuberculosis). i) Non-neoplastic chronic liver disease of any origin requiring ongoing treatment. For hepatitis B, this includes a positive test for both hepatitis B surface antigen (HBsAg) and quantitative hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes a positive test for both hepatitis C antibody and quantitative hepatitis C PCR. Patients who have taken hepatitis-related antiviral treatment within 6 months prior to the first study dose will also be excluded. j) Known human immunodeficiency virus (HIV) infection. k) Myopathy or any clinical condition causing a marked and persistent elevation of CPK (>2.5 x ULN in two separate determinations taken 1 week apart). l) The patient's limited ability to comply with treatment or follow-up procedures. m) Any other serious illness that, in the investigator's judgment, substantially increases the risks associated with the patient's participation in this study.

[0167] Study population Expected number of patients The number of patients in the Phase I part may vary depending on the tolerability of PM01183 in combination with atezolizumab and the number of dose levels required to identify the MTD, with an estimated enrollment of approximately 24 patients in Phase I.

[0168] Study Drug formulation PM01183 PM01183 drug product is supplied as a lyophilized powder concentrate for solution for injection in 4 mg vials.

[0169] 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. When administered to patients as an IV infusion, the reconstituted vial should be diluted for infusion with glucose 50 mg / mL (5%) solution or sodium chloride 9 mg / mL (0.9%) solution.

[0170] The complete composition of the PM01183 4 mg vial and reconstituted solution / mL is shown in Table S1.

[0171] [Table 5]

[0172] Atezolizumab Commercial presentation of vials containing atezolizumab (1200 mg / 20 mL per vial) will be provided accordingly.

[0173] Treatment Schedule Atezolizumab will be administered as a fixed dose of 1200 mg as a 60-minute iv infusion (subsequent infusions over 30 minutes) followed by PM01183 as a 1-hour iv infusion, both q3wk on day 1.

[0174] Route of administration and dosage Phase I Patients will receive the following consecutively on day 1 every q3wk (3 weeks = 1 treatment cycle): Atezolizumab: IV infusion over 60 minutes (or subsequent infusions over 30 minutes) immediately followed by: · PM01183: Starting dose 2.5mg / m 2 Over a 1-hour period, a minimum of 100 mL of 5% glucose or 0.9% sodium chloride dilution is infused (at a fixed rate) intravenously via a pump device through a central line (or a minimum of 250 mL of dilution if a peripheral line is used).

[0175] During the Phase I part, body surface area (BSA) will be calculated for each cycle according to the DuBois formula. The PM01183 dose will be recalculated before a new cycle begins. The dose will be rounded to one decimal place.

[0176] Dose escalation scheme (Phase I) The dose escalation scheme follows predefined dose levels, starting at DL1 as summarized in the following table.

[0177] [Table 6]

[0178] Patients will be evaluated for DLTs (dose-limiting toxicities) during the complete initial treatment cycle (a 3-week period). Patients who are not sufficiently evaluable will be replaced. A cohort of at least three fully evaluable patients will be initially included at each dose level. o If the first patient at a dose level has no DLT (within a 3 week period), the second and third patients can be included simultaneously. If the first patient has a DLT, the third patient at the dose level will only be included if the second patient does not have a DLT. If one of these first three evaluable patients experiences a DLT during cycle 1, three more evaluable patients will be included at that dose level. If DLT does not occur in more than one-third of evaluable patients at a dose level, escalation will proceed to the next dose level. If more than one-third of evaluable patients at a given dose experience a DLT, that dose will be deemed the MTD (i.e., the lowest dose level explored during dose escalation at which more than one-third of evaluable patients experience a DLT). Dose escalation will be terminated unless all DLTs occurring at a given dose level are associated with neutropenia (i.e., febrile neutropenia, Grade 4 neutropenia lasting more than 3 days, Grade 3 neutropenia lasting more than 7 days, or neutropenic sepsis), in which case dose escalation may be resumed at the same dose level but with mandatory G-CSF primary prophylaxis. The dose level just below the MTD (or DL3 if the MTD is not reached) will be expanded (i.e., including escalation and expansion) so that at least 9 evaluable patients are treated at that dose level. This level will be confirmed as a RD if fewer than one-third of the first 9 evaluable patients experience a DLT (Table S3).

[0179] [Table 7]

[0180] Depending on the toxicity observed, intermediate dose levels may be explored if deemed appropriate.

[0181] Intra-patient dose escalation is not permitted under any circumstances.

[0182] For DLTs, frequency tables were used to characterize the DLT profile. First, all AEs and SAEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) and their Preferred Term (PT) version 23.0. Frequency tables were then obtained and displayed by dose level and use of primary G-CSFG prophylaxis.

[0183] Prophylactic medication On Day 1 of each cycle, all patients must receive the following prophylactic medications prior to the infusion of any study drug: dexamethasone 8 mg iv or equivalent, · Ondansetron 8 mg iv or equivalent, with or without metoclopramide 10 mg iv or equivalent.

[0184] Other possible preventive medications: Broad-spectrum oral prednisone and / or oral ondansetron 4-8 mg or equivalent, as needed, per investigator criteria, not to exceed 10 mg / day. Additional antiemetics may be used as needed. Aprepitant and equivalent agents (e.g., fosaprepitant) are prohibited in patients treated with PM01183.

[0185] If G-CSF primary prophylaxis is required in a particular patient cohort, it will consist of G-CSF (non-pegylated filgrastim) 300 μg / day subcutaneously for 5 consecutive days, starting at least 24 hours after treatment infusion.

[0186] Accepted medications / treatments Treatment of pre-existing and procedure-emergent medical conditions, including pain management. Blood products and transfusions, if clinically indicated. Bisphosphonates In case of nausea or vomiting, secondary prevention of vomiting and / or symptomatic treatment according to the American Society of Clinical Oncology (ASCO) guidelines (considering the above daily corticosteroid limits). Use of erythropoietin according to ASCO guidelines. Secondary prophylaxis or therapeutic use of G-CSF. Note: Patients who develop severe non-febrile neutropenia during cycle 1 of the Phase 1 study part should not receive therapeutic G-CSF unless DLT criteria for neutropenia are met or clinically indicated. Palliative limited field bone RT as needed (e.g., for pain control) after completion of cycle 1. · Megestrol acetate for appetite stimulation.

[0187] Prohibited Drugs / Medications · Concomitant administration of any other antineoplastic treatment. Other investigational drugs. Aprepitant or directly related substances (e.g., fosaprepitant). · Corticosteroids at doses >10 mg / day of prednisone or equivalent (except for pre-medication for chemotherapy vs. iv). · Immunosuppressive treatments other than corticosteroids. Primary prophylaxis and / or treatment with colony-stimulating factors (G-CSF) during cycle 1 (unless one or more patients are treated within a specific cohort that resumes dose escalation with G-CSF primary prophylaxis, in which case use is not only permitted but mandatory). Secondary prophylaxis is permitted as needed during subsequent cycles, exclusively for febrile neutropenia or Grade 4 neutropenia, or in agreement with the sponsor, in lieu of dose reduction.

[0188] Drug interactions In vitro studies of human microsomes have shown that CYP3A4 is the major CYP isoform involved in the metabolism of PM01183, followed by CYP2E1, CYP2D6, and CYP2C9. The estimated contribution of other CYP isoenzymes to PM01183 metabolism is judged to be negligible. Therefore, combinations of drugs that induce or inhibit any of these cytochromes, especially CYP3A4, should be carefully monitored or avoided whenever possible.

[0189] A significant interaction with aprepitant (a CYP3A4 inhibitor) is suggested by available phase I data from the PM1183-A-008-13 study. PM01183 clearance was reduced by approximately 50% in the presence of aprepitant. Although all patients ultimately recovered, the use of aprepitant is currently prohibited in all PM01183 studies.

[0190] Patient evaluability Phase I Evaluable patients for the primary objective of this Phase I part (i.e., determination of MTD and RD) were to receive at least one complete infusion of atezolizumab and PM01183 and be followed for at least one complete cycle (i.e., 3 weeks = 21 days). Patients who discontinue prematurely or lose / delay dosing and / or clinically important assessments (i.e., Hematology and Biochemistry-A) are evaluable if these events are the result of treatment-related toxicity (excluding hypersensitivity reactions and / or extravasation).

[0191] Evaluation criteria Primary endpoint Phase I Determination of MTD and RD: The MTD is the lowest dose level explored during dose escalation at which more than one-third of evaluable patients experience a DLT during the first cycle. The RD is the highest dose level explored during dose escalation at which fewer than one-third of evaluable patients experience a DLT during cycle 1.

[0192] If DLTs observed with the combination of PM01183 and atezolizumab without G-CSF prophylaxis are exclusively related to neutropenia, the MTD and RD will also be determined with G-CSF primary prophylaxis.

[0193] Secondary endpoints Safety: Patients will be evaluable for safety if they receive at least one partial infusion of atezolizumab and PM01183. 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 will be evaluated in terms of: Progression-free survival defined as the time from enrollment to the date of documented progression or death (regardless of cause) according to RECIST v.1.1. If patients receive additional antineoplastic treatment or are lost to follow-up before PD, PFS will be censored at the date of the last tumor assessment prior to the date of subsequent antineoplastic treatment. Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death. The censoring rules defined above for PFS will be used for DoR. Clinical benefit, defined as the percentage of evaluable patients experiencing a complete response, partial response, or stable disease lasting at least 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 (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 by standard non-compartmental methods (compartmental modeling may be performed where appropriate). Pharmacogenetics: Factors that may help explain individual variability in key PK parameters, the presence or absence of germline mutations or genetic polymorphisms that may be involved in the metabolism and / or transport of PM01183, will be analyzed in extracted leukocyte DNA. Pharmacogenomics: To determine predictive / prognostic markers of response and / or resistance to PM01183 and atezolizumab, available tumor specimens at baseline will be evaluated in all patients. Additionally, blood samples (day 1 of each cycle and end of treatment) and on-treatment tumor specimens from biopsies (weeks 4-6 after treatment initiation) will be obtained and evaluated for patients who consent to the PGx substudy.

[0194] result A total of 26 patients were treated, including 14 male (53.8%) and 12 female (46.2%) patients with a median age of 60.6 years.

[0195] Five patients received lurbinectedin 2.5 mg / m 2 Three patients received atezolizumab 1200 mg and were evaluable without DLT.

[0196] Lurbinectedin 3.2 mg / m 2 Of the 21 patients who received atezolizumab 1200 mg, 6 patients had primary G-CSF and 5 patients (20.8%) developed DTL. · 2 patients G3 febrile neutropenia (9.5%) (1 patient G4 thrombocytopenia) 2 patients had Grade 4 neutropenia lasting longer than 72 hours (9.5%) · 1 patient G4 thrombocytopenia (4.8%).

[0197] The most common hematologic adverse events ≥ grade 2 in the DL2 cohort (21 patients) were: · 9 patients neutropenia (42.9%) · 6 patients thrombocytopenia (28.6%) · 4 patients anemia (19.1%) 1 patient had lymphopenia (4.8%) One patient developed febrile neutropenia (4.8%)

[0198] The most common non-hematologic treatment-related adverse event ≥ grade 2 was asthenia in 30.8% (8 patients) (Table 1). No treatment-related deaths were reported.

[0199] The MTD could not be calculated because the proportion of patients who experienced DLT was less than one-third (20.8%).

[0200] Objective response (ORR) was observed in 15 patients (57.7%), including two patients (7.7%) with complete response (CR) and 13 patients (50%) with partial response (PR). Stable disease (SD) was observed in seven patients (26.9%), and three patients (11.54%) with progressive disease (PD). The disease control rate (DC) was 84.61%.

[0201] Eight patients were censored due to progression, and the median PFS was 4.93 months (range 3.37–7.47 months).

[0202] conclusion The combination of lurbinectedin and atezolizumab was well tolerated without unexpected toxicities. Transient hematologic toxicity was the dose-limiting toxicity. RD was lurbinectedin 3.2 mg / m on day 1 with G-CSF. 2 Atezolizumab 1200 mg on day +1. Preliminary antitumor activity is significant. Significant antitumor activity of the combination was observed in more than half of all patients (RR 57.7%), including two complete responses. This activity is not currently expected in this population with approved drugs. The data support synergy between the two compounds.

[0203] item 1. A method for treating cancer, comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 wherein the compound is administered at a dose of 0.05% by weight, thereby treating cancer. 2. Lurbinectedin is 2.5 mg / m 2 2. The method of claim 1, wherein the compound is administered at a dose of 3. Lurbinectedin at 2.8 mg / m 2 2. The method of claim 1, wherein the compound is administered at a dose of 4. Lurbinectedin is 3.0 mg / m 2 2. The method of claim 1, wherein the compound is administered at a dose of 5. Lurbinectedin at 3.1 mg / m 2 2. The method of claim 1, wherein the compound is administered at a dose of 6. Lurbinectedin is 3.2 mg / m 2 2. The method of claim 1, wherein the compound is administered at a dose of 7. Lurbinectedin 2.8-3.2 mg / m 2 , or 3.0 to 3.2 mg / m 2 , or 3.1 to 3.2 mg / m 2 2. The method of claim 1, wherein the patient is administered 8. The method of any one of items 1 to 7, wherein atezolizumab is administered at a dose of 840 mg to 1680 mg, preferably 900 mg to 1500 mg, 1000 mg to 1400 mg, 1100 mg to 1300 mg, or 1200 mg. 9. The method of item 8, wherein atezolizumab is administered at a dose of 1200 mg. 10. Lurbinectedin 3.2 mg / m 2and atezolizumab is administered at a dose of 1200 mg. 11. The method of any one of items 1 to 10, wherein lurbinectedin and atezolizumab are administered simultaneously, separately or sequentially. 12. The method of item 11, wherein atezolizumab is administered first, followed immediately by lurbinectedin. 13. The method of any one of items 1 to 12, wherein multiple doses of lurbinectedin, atezolizumab, or both are administered. 14. The method of any one of items 1 to 13, wherein lurbinectedin is administered by subcutaneous, intravenous or intraperitoneal route, preferably by intravenous infusion. 15. The method of any one of items 1 to 14, wherein lurbinectedin is administered over an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours, most preferably 1 hour. 16. The method of any one of items 1 to 15, wherein atezolizumab is administered by subcutaneous, intravenous, or intraperitoneal route, preferably by intravenous infusion. 17. The method of any one of items 1 to 16, wherein atezolizumab is administered over a 1 hour infusion, or for second and subsequent infusions, over a 30 minute infusion. 18. The method according to any one of items 1 to 17, having an administration cycle of once every 1 to 4 weeks, preferably once every 3 or 4 weeks. 19. The method of any one of items 1 to 18, having one administration cycle every 21 days. 20. The method of any one of items 1 to 19, wherein lurbinectedin is administered on day 1 of the cycle. 21. The method of any one of items 1 to 20, wherein atezolizumab is administered on day 1 of the cycle. 22. The method of any one of items 1 to 21, further comprising administering granulocyte colony-stimulating factor (G-CSF). 23. The method according to item 22, wherein in cycle 1, the patient receives 5 days of G-CSF primary prophylaxis starting 24 to 72 hours after day 1 of cycle 1. 24. The method according to item 23, wherein G-CSF is administered in one or more subsequent cycles. 25. The method of any one of items 1 to 24, wherein the cancer is a solid tumor. 26. The method of item 25, wherein the solid tumor is selected from the group consisting of prostate cancer, breast cancer, lung cancer, colorectal cancer, melanoma, bladder cancer, brain / CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head / neck cancer, renal cancer, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, and sarcoma. 27. The method according to item 26, wherein the lung cancer is mesothelioma, malignant mesothelioma, malignant pleural mesothelioma, or malignant peritoneal mesothelioma, preferably malignant pleural mesothelioma. 28. The method according to item 26, wherein the lung cancer is non-small cell lung cancer. 29. The method according to item 26, wherein the lung cancer is small cell lung cancer. 30. Small cell lung cancer progresses Type 30. The method according to item 29, wherein the cancer is small cell lung cancer (ES-SCLC). 31. The method of any one of items 1 to 30, wherein the patient has progressed, including the patient has progressed from first-line therapy. 32. The method of any one of items 1 to 31, wherein the patient has progressed from prior platinum treatment. 33. The method of any one of items 1 to 32, wherein the patient is immunotherapy naive. 34. The method of any one of items 1 to 33, wherein the treatment is a secondary treatment. 35. A method for treating small cell lung cancer, comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, thereby treating the small cell lung cancer. 36. Lurbinectedin is 2.5-3.2 mg / m 2 36. The method of claim 35, wherein the dose is 37. Lurbinectedin is administered at 2.5 mg / m 236. The method of claim 35, wherein the dose is 38. Lurbinectedin is 2.8 mg / m 2 36. The method of claim 35, wherein the dose is 39. Lurbinectedin is administered at 3.0 mg / m 2 36. The method of claim 35, wherein the dose is 40. Lurbinectedin is administered at 3.1 mg / m 2 36. The method of claim 35, wherein the dose is 41. Lurbinectedin is administered at 3.2 mg / m 2 36. The method of claim 35, wherein the dose is 42. Lurbinectedin is 2.8-3.2 mg / m 2 , or 3.0 to 3.2 mg / m 2 , or 3.1 to 3.2 mg / m 2 36. The method of claim 35, wherein the administration 43. The method of any one of items 35 to 42, wherein atezolizumab is administered at a dose of 1200 mg. 44. Small cell lung cancer progresses Type 44. The method of any one of items 35 to 43, wherein the cancer is small cell lung cancer (ES-SCLC). 45. The method of any one of items 35 to 44, wherein the patient has progressed, including has progressed from first-line therapy. 46. ​​The method of any one of items 35 to 45, wherein the patient has progressed from prior platinum treatment. 47. The method of any one of items 35 to 46, wherein the patient has not received immunotherapy. 48. The method of any one of items 35 to 47, wherein the treatment is a secondary treatment. 49. The method of any one of items 35 to 48, wherein lurbinectedin and atezolizumab are administered simultaneously, separately, or sequentially. 50. The method of item 49, wherein atezolizumab is administered first, followed immediately by lurbinectedin. 51. The method of any one of items 35 to 50, wherein multiple doses of lurbinectedin, atezolizumab, or both are administered. 52. The method of any one of items 35 to 51, wherein lurbinectedin is administered by subcutaneous, intravenous, or intraperitoneal route, preferably by intravenous infusion. 53. The method of any one of items 35 to 52, wherein lurbinectedin is administered over an infusion time of up to 24 hours, 1 to 12 hours, 1 to 6 hours, and most preferably 1 hour. 54. The method of any one of items 35 to 53, wherein atezolizumab is administered by subcutaneous, intravenous, or intraperitoneal route, preferably by intravenous infusion. 55. The method of any one of items 35 to 54, wherein atezolizumab is administered over a 1-hour infusion time, or for second and subsequent infusions, over a 30-minute infusion time. 56. The method according to any one of items 35 to 55, having an administration cycle of once every 1 to 4 weeks, preferably once every 3 weeks. 57. The method of any one of items 35 to 56, having one administration cycle every 21 days. 58. The method of any one of items 35 to 57, wherein lurbinectedin is administered on day 1 of the cycle. 59. The method of any one of items 35 to 58, wherein atezolizumab is administered on day 1 of the cycle. 60. The method of any one of items 35 to 59, further comprising administering granulocyte colony-stimulating factor (G-CSF). 61. The method according to item 60, wherein in the first cycle, the patient receives 5 days of G-CSF primary prophylaxis beginning 24 to 72 hours after day 1 of the first cycle. 62. The method of any one of items 35 to 61, wherein the treatment results in one or more of: a reduction in tumor size; a delay in tumor growth; an increase in patient lifespan; a delay in disease progression; or remission. 63. Use of lurbinectedin in the manufacture of a medicament for the treatment of cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 Administered at a dose of, use. 64. Use of atezolizumab in the manufacture of a medicament for the treatment of cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 Administered at a dose of, use. 65. Use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 Administered at a dose of, use. 66. Lurbinectedin for use in the treatment of cancer, the treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 Lurbinectedin for use, wherein the lurbinectedin is administered at a dose of 67. Atezolizumab for use in the treatment of cancer, said treatment comprising administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab, wherein the lurbinectedin is 2.5 to 3.2 mg / m 2 2. The method of claim 1, wherein atezolizumab is administered at a dose of 68. Lurbinectedin and atezolizumab for use in the treatment of cancer, the treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 10. The method of claim 1, wherein lurbinectedin and atezolizumab are administered at a dose of 69. Lurbinectedin for use in the treatment of cancer, wherein the lurbinectedin is administered to a patient in need thereof in combination with atezolizumab, and the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 Lurbinectedin for use, wherein the lurbinectedin is administered at a dose of 70. Atezolizumab for use in the treatment of cancer, wherein the atezolizumab is administered to a patient in need thereof in combination with lurbinectedin, wherein the lurbinectedin is administered at a dose of 2.5 to 3.2 mg / m 2 2. The method of claim 1, wherein atezolizumab is administered at a dose of 71. A pharmaceutical package comprising lurbinectedin and atezolizumab, optionally together with instructions for their combined use, wherein lurbinectedin is 2.5 to 3.2 mg / m 2 A pharmaceutical package, administered at a dose of 72. Use of lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. 73. Use of atezolizumab in the manufacture of a medicament for the treatment of small cell lung cancer, wherein the treatment comprises administering to a patient in need thereof a combination therapy of lurbinectedin and atezolizumab. 74. Use of lurbinectedin and atezolizumab in the manufacture of a medicament for the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. 75. Lurbinectedin for use in the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. 76. Atezolizumab for use in the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. 77. Lurbinectedin and atezolizumab for use in the treatment of small cell lung cancer, said treatment comprising administering a combination therapy of lurbinectedin and atezolizumab to a patient in need thereof. 78. Lurbinectedin for use in the treatment of small cell lung cancer, wherein the lurbinectedin is administered to a patient in need thereof in combination with atezolizumab. 79. Atezolizumab for use in the treatment of small cell lung cancer, wherein atezolizumab is administered in combination with lurbinectedin to a patient in need thereof. 80. A pharmaceutical package comprising lurbinectedin and atezolizumab, optionally together with instructions for their combined use. 81. A kit comprising atezolizumab together with instructions for use in combination with lurbinectedin as defined in any one of items 1 to 80.

Claims

1. A pharmaceutical composition comprising a combination of lurbinectedin and atezolizumab, used for the treatment of extensive-stage small cell lung cancer (ES-SCLC), wherein the pharmaceutical composition is administered to a patient in need thereof, and the lurbinectedin is administered at a dose of 3.2 mg / m 2 and atezolizumab is administered at a dose of 1200 mg, and lurbinectedin and atezolizumab are administered on day 1 of a 21-day cycle.

2. A pharmaceutical comprising lurbinectedin used for the treatment of extensive-stage small cell lung cancer (ES-SCLC), administered in combination with atezolizumab, wherein lurbinectedin is administered by intravenous infusion at a dose of 3.2 mg / m2 and atezolizumab is administered at a dose of 1200 mg, and wherein lurbinectedin and atezolizumab are administered on day 1 of a 21-day cycle.

3. A pharmaceutical comprising atezolizumab used for the treatment of extensive-stage small cell lung cancer (ES-SCLC), administered in combination with lurbinectedin, wherein lurbinectedin is administered by intravenous infusion at a dose of 3.2 mg / m2 and atezolizumab is administered at a dose of 1200 mg, and wherein lurbinectedin and atezolizumab are administered on day 1 of a 21-day cycle.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein lurbinectedin and atezolizumab are administered simultaneously, separately or sequentially.

5. A pharmaceutical described in any one of claims 1 to 3, wherein atezolizumab is administered first, followed immediately by lurbinectedin.

6. The pharmaceutical composition of any one of claims 1 to 3, wherein multiple doses of lurbinectedin, atezolizumab, or both are administered.

7. A pharmaceutical composition described in any one of claims 1 to 3, wherein lurbinectedin is administered over an infusion time of up to 24 hours, 1 to 12 hours, or 1 to 6 hours.

8. A pharmaceutical described in any one of claims 1 to 3, wherein lurbinectedin is administered over an infusion time of 1 hour.

9. 4. The method of claim 1, wherein atezolizumab is administered by subcutaneous route.

10. A pharmaceutical described in any one of claims 1 to 3, wherein atezolizumab is administered by intravenous route.

11. The pharmaceutical composition of claim 9, wherein atezolizumab is administered over a 1-hour infusion period, or for second and subsequent infusions, over a 30-minute infusion period.

12. The pharmaceutical composition of claim 10, wherein atezolizumab is administered over a 1-hour infusion period, or for second and subsequent infusions, over a 30-minute infusion period.

13. A pharmaceutical described in any one of claims 1 to 3, wherein the treatment further comprises administration of granulocyte colony-stimulating factor (G-CSF).

14. The method of claim 13, wherein G-CSF is administered on day 1 of a 21-day cycle.

15. 14. The method of claim 13, wherein the patient receives G-CSF primary prophylaxis for 5 days starting 24 to 72 hours after day 1 of each cycle.

16. 4. The medicament of any one of claims 1 to 3, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more cycles.

17. 4. The method of claim 1, wherein the treatment results in a reduction in tumor size.

18. A pharmaceutical described in any one of claims 1 to 3, wherein treatment results in a delay in tumor growth.

19. A pharmaceutical described in any one of claims 1 to 3, wherein treatment results in an extension of the patient's lifespan.

20. A pharmaceutical described in any one of claims 1 to 3, wherein treatment results in a delay in disease progression.

21. A pharmaceutical described in any one of claims 1 to 3, wherein the treatment results in remission.

22. 4. A kit comprising lurbinectedin together with instructions for the combined use of lurbinectedin and atezolizumab in the treatment of extensive-stage small cell lung cancer (ES-SCLC) as defined in any one of claims 1 to 3.

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