Methods of treating small cell lung cancer with lurbinectedin formulations

Abstract

To satisfy a need for treatment for small cell lung cancer (SCLC) and other solid tumors.SOLUTION: Provided are methods for the treatment of SCLC patients by administering therapeutic amounts of lurbinectedin by intravenous infusion. Also provided are methods of treating cancer by administering lurbinectedin in combination with other anticancer drugs, in particular topoisomerase inhibitors. The invention further relates to the administration of lurbinectedin in combination with anti-emetic agents for effective control of symptoms related to nausea and vomiting, reduced lurbinectedin dosages to achieve a safer administration and an increase in the number of treatment cycles. Stable lyophilized formulations of lurbinectedin are also provided.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] Methods are provided for the treatment of SCLC patients by administering therapeutic amounts of lurbinectedin via intravenous infusion. Methods are also provided for treating cancer by administering lurbinectedin in combination with other anticancer drugs, particularly topoisomerase inhibitors. The invention further relates to the administration of lurbinectedin in combination with antiemetics for effective control of symptoms related to nausea and vomiting, reducing the dosage of lurbinectedin to achieve safer administration, and increasing the number of treatment cycles. Stable lyophilized formulations of lurbinectedin are also provided. [Background technology]

[0002] Lung cancer is the leading cause of cancer death for both men and women in the United States. In 1998, an estimated 171,500 new cases were diagnosed and approximately 160,100 deaths were attributable to the disease. More women die from lung cancer than from breast, ovarian, and uterine cancer combined, and four times as many men die from lung cancer than from prostate cancer.

[0003] Lung cancer is a disease in which malignant (cancer) cells form within 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 accounts for only about 13-15% of all lung cancers at the time of diagnosis, but is a more aggressive form of lung cancer. In SCLC, cancer cells tend to grow quickly and migrate, or metastasize, more easily to other parts of the body. Its incidence is associated with smoking, nearly two-thirds of patients present with advanced disease, and although response rates to chemotherapy are high, the benefits are short-lived. The median survival time for patients with untreated SCLC is 2-4 months (Clark, 1998; Glisson, 2003; Davies, 2004). 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 (Sundstrom, 2005; Jackman, 2005). The overall expected median survival after recurrence of untreated disease is 2-4 months (Huisman, 1999).

[0004] Treatment and survival have not changed substantially over the past 20 years. Even limited-stage disease is rarely cured with definitive local therapy (surgery or radiation therapy), and systemic chemotherapy (platinum and etoposide) remains the cornerstone of first-line treatment in SCLC.

[0005] Topotecan is the only drug approved for second-line treatment of patients with chemotherapy-free intervals longer than 60 days. Topotecan monotherapy improves survival and quality of life, as well as cancer-related symptoms in the second-line setting. Alternatively, doxorubicin-based combination therapy can be administered, with similar outcomes but slightly lower symptom control rates. In refractory patients, no standard therapy exists. Amrubicin, a novel anthracycline, has shown promising activity in refractory relapsed patients. Phase III trials are ongoing. Other agents with activity include paclitaxel, docetaxel, gemcitabine, bendamustine, and vinorelbine.

[0006] During the past few years, several clinical trials have evaluated the effect of adding immunotherapy to conventional chemotherapy in patients with extensive SCLC. Checkpoint inhibitors, especially CTLA-4 and PD-1 / PD-L1 inhibitors, are currently being investigated. Nivolumab and pembrolizumab were the first immunotherapy agents approved by the FDA for patients with metastatic SCLC with disease progression during or after platinum-based chemotherapy and at least one other prior line of chemotherapy.

[0007] Lurbinectedin (PM01183) is a synthetic tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one alkaloid analogue with antineoplastic activity. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand breaks that lead to apoptosis, and modulates the tumor microenvironment. For example, by inhibiting active transcription in tumor-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and VEGF.

[0008] Lurbinectedin has demonstrated very potent in vitro activity against solid and non-solid tumor cell lines, as well as significant in vivo activity in several xenografted human tumor cell lines in mice, such as those against breast, renal, and ovarian cancer. Preliminary clinical results indicate that lurbinectedin has activity as a second-line treatment as a single agent in SCLC. There is a need for treatments for SCLC and other solid tumors. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 7,763,615 [Patent Document 2] International Publication No. PCT WO2003 / 014127 [Non-patent literature]

[0010] [Non-Patent Document 1] National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (May 28, 2009) [Non-Patent Document 2] International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICHarmonisation Guidelines for Pharmaceuticals for Human Use) "Impurities: Residual Solvents Q3C(R6)" Summary of the Invention [Means for solving the problem]

[0011] Phase 2 clinical trial results show an overall response rate of at least 30% (35.2%) for SCLC patients with lurbinectedin as a second-line agent administered as a single agent. Results from a Phase 1b-2 study in solid tumor patients showed activity of the combination of lurbinectedin and irinotecan, particularly in SCLC, endometrial carcinoma, soft tissue sarcoma, and glioblastoma. Thus, provided herein is a method of treating SCLC, including metastatic SCLC, in patients in need thereof, particularly in patients whose SCLC has progressed after prior therapy, such as platinum-containing therapy or immunotherapy, including, among others, patients who have failed to respond or have failed to respond adequately to prior treatment, patients who have responded to prior treatment but may subsequently experience disease progression, and patients who may have multiple such responses followed by progression. Also provided is a method of treating solid tumors, particularly SCLC, endometrial carcinoma, soft tissue sarcoma, and glioblastoma, in a patient in need thereof, administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan or SN-38. Further provided is a stable lyophilized formulation.

[0012] The methods provided herein include administering an effective amount of lurbinectedin by intravenous infusion to patients, including adult patients, suffering from SCLC, including metastatic SCLC, particularly patients with SCLC that have progressed after prior platinum-based chemotherapy. In certain embodiments, methods are provided for administering an effective amount of lurbinectedin by intravenous infusion to patients suffering from SCLC, including metastatic SCLC that has progressed after prior immunotherapy, particularly atezolizumab, including a combination of carboplatin and etoposide, or nivolumab. Preferably, lurbinectedin is administered at a dose of 3.2 mg / m every 21 days (or 3 weeks) for a period of time typically of multiple months, often until disease progression and death, or until the patient experiences unacceptable toxicity, depending on the patient's response to administration. 2 is administered at a dose of

[0013] In certain embodiments, the therapeutically effective amount of lurbinectedin is 3.2 mg / m every 21 days or every 3 weeks. 2Administer to a patient as a 1-hour IV infusion using the dosing level to achieve an average total plasma Cmax of about 85.6 μg / L to 133.75 μg / L, preferably 107 μg / L, and an average AUC∞ of about 440.8 μg*h / L to 688.75 μg*h / L, preferably 551 μg*h / L. Treatment results in a median progression-free survival of 3.5 months (range 2.6 months to 4.3 months), including a complete response rate of greater than 30%, a median of 2.6 months in the resistant patient population (CFTI less than 90 days for prior chemotherapy treatment), and a median of 4.6 months in the sensitive patient population (CFTI greater than or equal to 90 days for prior chemotherapy treatment). A median overall survival of 9.3 months (5.0 months in the resistant patient population and 11.9 months in the sensitive patient population) can be achieved according to the methods disclosed herein.

[0014] In one embodiment, a method of managing hematologic adverse events associated with a lurbinectedin treatment regimen is provided by dose reduction and / or administration of G-CSF. The method provided is to administer a lurbinectedin formulation to an SCLC patient by IV infusion at a dose of 3.2 mg / m 2 ; after administration of lurbinectedin, evaluating whether the patient experiences an adverse reaction associated with lurbinectedin administration that is a grade 3 (severe) or greater non-hematologic toxicity, grade 4 thrombocytopenia (platelet count less than 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count less than 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction. Then, at the scheduled dose, preferably 3 weeks after the prior dose, once the patient's neutrophil count is greater than 1500 cells / mm 3 ; and the platelet count is about 100,000 cells / mm 3above; when the hemoglobin level is above about 9 g / dL, (i) if the adverse reaction consists of grade 4 isolated neutropenia, administer to the patient a dose of G-CSF and a dose of lurbinectedin that is the same as the previous dose, e.g., 3.2 mg / m 2 or (ii) if the adverse reaction is a hematologic abnormality other than grade 4 isolated neutropenia, administer a reduced dose, e.g., 80 - 85% of the previous dose, e.g., if the previous dose was 3.2 mg / m 2 then administer a dose of 2.6 mg / m 2 Optionally, if the adverse reaction is grade 4 isolated neutropenia, the dose can be reduced to the next scheduled dose, particularly 80 - 85% of the previous dose, e.g., if the previous dose was 3.2 mg / m 2 then administer a dose of 2.6 mg / m 2 In the case after receiving a reduced dose of lurbinectedin, the patient experiences an adverse event that is grade 3 (severe) or higher non-hematologic toxicity, grade 4 thrombocytopenia (platelet count < 25,000 cells / mm

[0015] ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count < 50,000 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction (except grade 4 isolated neutropenia in certain embodiments), and then, at the next scheduled dose, preferably 3 weeks after the previous dose, once the patient's neutrophil count is above 1500 cells / mm 3 and the platelet count is above about 100,000 cells / mm 3 and the hemoglobin level is above about 9 g / dL, administer a dose that is 60 - 65% of the first non-reduced dose, particularly 2.0 mg / m 3 (3.2 mg / m 2 was the first non-reduced dose) 2Optionally, if the adverse reaction following administration of the reduced dose of lurbinectedin is grade 4 isolated neutropenia, the dose is then reduced to 60-65% of the first non-reduced dose at the next scheduled dose, e.g., if the initial dose is 3.2 mg / m 2 When the 2 can be reduced to

[0016] In another embodiment, methods are provided for managing hematological toxicity, myelosuppressive effects, and / or hepatotoxicity that may be associated with lurbinectedin administration in the treatment of SCLC, including metastatic SCLC, in patients, including adult patients, by dose reduction and / or dose delay. 3 Absolute neutrophil count of at least 100,000 cells / mm 3 3.2 mg / m 2 In a further embodiment, a method of treating SCLC, including metastatic SCLC, is provided by administering a dose of lurbinectedin, preferably by infusion over 60 minutes. In a further embodiment, 21 days after the previous dose, the patient has at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 and a platelet count of 3.2 mg / m 2 A dose of lurbinectedin is administered, preferably by infusion over 60 minutes. In an embodiment, the patient is monitored for and free of hepatotoxicity prior to administration of lurbinectedin. Subsequent treatments are administered at 21 day (3 week) intervals at a dose of at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 The drug is administered to patients with a platelet count of 0.05 mg / kg or less and preferably without any grade 2 or higher adverse reactions.

[0017] In certain embodiments, lurbinectedin is administered at 3.2 mg / m 2The present invention provides a method of treating SCLC, including metastatic SCLC, in a patient in need thereof by administering at a dose of 3.2 mg / m 2 Patients receiving lurbinectedin at a dose of 10 mg / kg / day developed grade 4 neutropenia (< 500 cells / mm 3 If the patient develops Grade 1 or less neutropenia (neutrophil counts of at least 1500 cells / mm3) or any febrile neutropenia, subsequent doses of lurbinectedin should be administered 21 days after the previous dose or if the patient develops Grade 1 or less neutropenia (neutrophil counts of at least 1500 cells / mm3). 3 ) (which may be longer than 21 days past the previous dose), whichever is later, and then every 3 weeks a reduced dose of 2.6 mg / m 2 or lurbinectedin at 3.2 mg / m every 3 weeks with G-CSF prophylaxis. 2 or administer lurbinectedin at a dose of 3.2 mg / m 2 Patients receiving lurbinectedin at doses of 100 mg / kg / day or 100 mg / kg / day experienced grade 3 thrombocytopenia (25,000 to 50,000 platelets / mm) with bleeding. 3 ) or grade 4 thrombocytopenia (25,000 platelets / mm 3 <100,000 cells / mm 3 Subsequent doses of lurbinectedin will not be administered until the later of the patient achieving a platelet count of 2.6 mg / m or greater, and then the dose will be reduced to 2.6 mg / m every 3 weeks (21 days). 2 In the end, it was 3.2 mg / m 2 If a patient receiving a dose of lurbinectedin experiences hepatotoxicity or other adverse reactions that are either Grade 2 or Grade 3 or 4, then a subsequent dose of lurbinectedin will not be administered until 21 days after the previous dose or until the patient experiences Grade 1 or less hepatotoxicity (or other adverse reactions) whichever occurs later, and if the patient experiences Grade 2 hepatotoxicity (or other adverse reactions), subsequent doses will be 3.2 mg / m every 3 weeks (21 days). 2If a patient experiences grade 3 or 4 hepatotoxicity or other adverse reactions, the dose is then reduced to a 2.6 mg / m2 dose every 3 weeks (21 days). 2 If, after the dose reduction, a patient experiences grade 4 neutropenia, or any grade of febrile neutropenia, grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding, or grade 3 or 4 hepatotoxicity or one of the other adverse reactions, subsequent doses will not be administered until the later of 21 days or when the patient has recovered as detailed above, at which point a further reduced dose of 2 mg / m2 will be administered every 3 weeks thereafter. 2 Patients will receive 2 mg / m lurbinectedin or, in the case of grade 4 neutropenia, the same dose of lurbinectedin as the previous dose with G-CSF prophylaxis. 2 Treatment will be discontinued if the patient does not tolerate lurbinectedin at this dose (i.e., develops grade 4 neutropenia, or any grade febrile neutropenia, grade 3 thrombocytopenia or grade 4 thrombocytopenia with hemorrhage, or grade 3 or 4 hepatotoxicity or one of the other adverse reactions after lurbinectedin administration) or if the delay in administration is longer than 2 weeks past the scheduled dose (21 days after the prior dose) in order for the patient to recover and meet the criteria for lurbinectedin administration.

[0018] 2-3.2 mg / m 2 and avoiding co-administration with a strong or moderate CYP3A inhibitor or a strong or moderate CYP3A inducer. In certain embodiments, a method of treating SCLC or solid tumors in a patient in need thereof is provided, in which the patient is also administered a moderate CYP3A inhibitor, followed by administration of a reduced dose of lurbinectedin, e.g., 2.6 mg / m every 3 weeks (21 days). 2 or 2 mg / m 2 to said patient.

[0019] In an embodiment, an antiemetic agent is administered prophylactically prior to lurbinectedin administration-related (acute or delayed phase) nausea and / or vomiting, and the antiemetic agent is administered in the range of 2 to 3.2 mg / m 2 Also provided are embodiments that include administering an antiemetic prophylactic dose on the day and prior to administering lurbinectedin at a dose of 1 mg / kg / day to the patient, in particular, the antiemetic comprises a corticosteroid and a serotonin antagonist. The treatment may be for SCLC or any other solid tumor, including metastatic SCLC, in a patient in need of such treatment. In certain embodiments, the corticosteroid is dexamethasone, preferably at a dose of 8 mg administered intravenously, or a corticosteroid dose equivalent to 8 mg of dexamethasone intravenously, and the serotonin antagonist is ondansetron, preferably at a dose of 8 mg administered intravenously, or a serotonin antagonist dose equivalent to 8 mg of ondansetron administered intravenously. In certain embodiments, antiemetic therapy is administered post-infusion, preferably on the day of administration of lurbinectedin, including a corticosteroid, a serotonin antagonist, and metoclopramide, or 2, 3, or 4 days after administration. In a specific embodiment, the corticosteroid is dexamethasone administered orally at a dose of 4 mg, or a corticosteroid dose equivalent to 4 mg oral dexamethasone; the serotonin antagonist is ondansetron administered orally at a dose of 8 mg, or a serotonin antagonist equivalent to 8 mg oral ondansetron; and metoclopramide is administered either intravenously or orally at a dose of 10 mg, or a dose equivalent to 10 mg oral or intravenous metoclopramide, and metoclopramide is administered every 8 hours.

[0020] One aspect of the invention is a method of treating a patient with a solid tumor in need thereof by administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan. In a particular embodiment, a patient with a solid tumor receives lurbinectedin at a dose of 1-2.5 mg / m on day 1 of a treatment cycle. 2 75 mg / m administered on days 1 and 8. 2The first treatment cycle is administered at a dose of 1 to 2.5 mg / m in the second treatment cycle, and the second treatment cycle is administered at a dose of 1 to 2.5 mg / m in the third treatment cycle. 2 lurbinectedin at a dose of 75 mg / m on day 22 2 and irinotecan at a dose of 75 mg / m 2 A dose of irinotecan is administered 7 days after the initial treatment, generally on day 29, and then on day 21. Subsequent treatments are every 3 weeks, with 1 to 2.5 mg / m administered on day 1 of the cycle. 2 of lurbinectedin and 75 mg / m 2 of irinotecan and 75 mg / m2 administered on day 8 with G-CSF. 2 In certain embodiments, if a patient exhibits hematological toxicity following the combination dose on day 1, no dose of irinotecan is administered on day 8. In some embodiments, the solid cancer is selected from endometrial cancer, SCLC, soft tissue sarcoma (including Ewing's sarcoma and synovial sarcoma), glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, and epithelial ovarian cancer. In preferred embodiments, the solid tumor is endometrial cancer, SCLC, soft tissue sarcoma (including Ewing's sarcoma or synovial sarcoma), or glioblastoma.

[0021] In one aspect, a stable lyophilized formulation of lurbinectedin is provided that includes lurbinectedin, an organic acid derived buffer (e.g., an organic carboxylic acid, e.g., a lactate buffer), and a disaccharide, the formulation having a pH of 3.8 to 4.5 when reconstituted with 8 mL of water. A reference to reconstitution of 4 mg lurbinectedin in 8 mL having a concentration of 0.5 mg / mL can be based on a calculated concentration of 0.47 mg / mL in 8.55 mL.

[0022] In some embodiments, the lyophilized composition comprises or consists of 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide, and 800 mg sucrose (or comprises or consists of these components in this ratio). The composition is preferably packaged in a 30 ml vial and can be reconstituted with 8 ml water to obtain a solution containing 0.5 mg / ml lurbinectedin.

[0023] In some embodiments, the lyophilized composition can be stored at 5° C.±3° C. for 24 months or 36 months or longer, during which time lurbinectedin retains its therapeutic efficacy and exhibits minimal chemical degradation. For example, after 24 or 36 months of storage, the amount of impurity D (lurbinectedin degradation product resulting from deacetylation of lurbinectedin) present in the composition is less than or equal to 0.8% wt. / wt. of the total lurbinectedin mass. In certain embodiments, the stored formulation does not contain more than 2.0%, 1.5%, or 1.3% (area or wt / wt) of total degradation products.

[0024] Methods for storing the lurbinectedin lyophilized formulations, as well as methods for treating SCLC and solid tumors by administration of a lurbinectedin infusion solution prepared from the stored stable lyophilized lurbinectedin formulations, are also provided.

[0025] The present invention identifies methods of treatment using lurbinectedin alone or in combination with additional agents. When referring to methods of treatment, the present invention also encompasses lurbinectedin and / or said additional agents in the manufacture of a medicament for the treatment of cancer, as well as lurbinectedin and / or said additional agents for use in the treatment of cancer as disclosed herein. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is an X-ray powder diffractogram (XRPD) of lurbinectedin form A (batch R05). [Figure 2a]1 is an X-ray powder diffractogram (XRPD) of two batches of lurbinectedin form B, batches 1924128-LT (top) and 1924129-LT. [Figure 2b] Figure 1 is an X-ray powder diffractogram (XRPD) of lurbinectedin form B made by mixing 15 mg of batch 1711182-2 (form B partially crystalline) and 15 mg of batch P02 (amorphous) with 1 ml of water. The suspension was stirred at rt for 24 hours. The resulting solid was filtered off. [Diagram 3] FIG. 2 is a TG-FTIR of lurbinectedin form B (batch 1711182-2). [Figure 4] DSC of lurbinectedin form B (batch 1711182-2). [Diagram 5] DVS of lurbinectedin form B (batch P05). [Figure 6] From top to bottom, multiple XRPD patterns of lurbinectedin form B after 6 hours of phase equilibration in water in an initial 1:1 mixture of lurbinectedin forms A and B, and after 24 hours of phase equilibration in water. (Lurbinectedin form A (batch P02) and lurbinectedin form B (batch 1711182-2) were mixed to prepare the mixture.) [Figure 7a] IR of lurbinectedin form A (batch P04). [Figure 7b] IR of lurbinectedin form B (batch 1711182-2). [Figure 8] FIG. 1 is a schematic diagram of a Faraday cage. [Figure 9a] FIG. 1 is a diagram of the electrostatic charge (nC) of various amounts of lurbinectedin form A (batch P04) and lurbinectedin form B (batch 1924129-LT). [Figure 9b] FIG. 1 is a diagram of the electrostatic charge (nC) of various amounts of lurbinectedin form A (batch R05) and lurbinectedin form B (batch 1924128-LT). [Figure 10a]FIG. 1 is a diagram of charge density of lurbinectedin form A (batch P04) and lurbinectedin form B (batch 1924129-LT). [Figure 10b] FIG. 1 is a diagram of charge density of lurbinectedin form A (batch R05) and lurbinectedin form B (batch 1924128-LT). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Provided herein is a method for the effective treatment of small cell lung cancer (SCLC) based on the administration of lurbinectedin as a monotherapy. Also provided is a method for treating solid tumors by the administration of a combination of lurbinectedin and irinotecan. Such methods may be carried out by the administration of lurbinectedin prepared from the stable lyophilized formulation disclosed herein.

[0028] Lurbinectedin Lurbinectedin is a synthetic alkaloid and an ecteinascidin analogue having the following chemical structure:

[0029] [ka]

[0030] This is described, for example, in U.S. Patent No. 7,763,615, which is incorporated herein by reference in its entirety. Lurbinectedin can be prepared according to methods known in the art, for example, the process disclosed in International Publication No. PCT WO2003 / 014127, which is incorporated herein by reference.

[0031] Any lurbinectedin compound referred to herein is intended to represent hydrate, solvate, amorphous, and crystalline or partially crystalline forms, and mixtures thereof, when such forms exist in a medium.In addition, the lurbinectedin compound referred to herein may exist in isotopically labeled forms.All geometric hydrates, solvates, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the formulations and methodologies of the present invention.

[0032] In this application, "cancer" is meant to include tumors, neoplasias, and any other malignant disease that gives rise to malignant tissues or cells.

[0033] The term "treating" as used herein means, unless otherwise indicated, to reverse, alleviate, or inhibit 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 means, unless otherwise indicated, the act of treating as "treating" is defined immediately above. In particular, the method of "treatment" or "treating" herein can be used to alleviate one or more symptoms of solid tumors, delay progression of solid tumors, reduce tumor size in solid tumor patients, inhibit solid tumor growth, extend overall survival, extend progression-free survival, prevent or delay metastasis of solid tumors, reduce (e.g., eradicate) metastasis of existing solid tumors, reduce the incidence or burden of metastasis of existing solid tumors, or prevent recurrence of solid tumors.

[0034] The term "immunotherapy" as used herein refers to therapy that modulates the immune response, including promoting or blocking inhibition of the immune response to cancer cells, such as antibodies, proteins, or other agents that bind to checkpoint inhibitors, such as, but not limited to, CTLA-4, PD-1, PD-L1, and others with similar activity that promote an immune response to cancer cells. Examples of immunotherapies include, but are not limited to, atezolizumab, nivolumab, pembrolizumab, ipilimumab, cemiplimab, durvalumab, avelumab, and the like.

[0035] Adverse events such as neutropenia, thrombocytopenia, hepatotoxicity, and other adverse reactions are graded according to the criteria described in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (May 28, 2009). In general, the grades are as follows: Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated; Grade 2: moderate; minimal, local, or non-invasive intervention indicated; limitation of age-appropriate assisted activities of daily living such as food preparation; Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or extended hospitalization indicated; disability; limitation of self-care activities of daily living such as dressing, defecation, etc., not bedridden; Grade 4: life-threatening consequences; urgent intervention indicated; Grade 5: death related to the adverse event.

[0036] Treatment of SCLC

[0013] Embodiments of the present invention include methods of treating metastatic small cell lung cancer (SCLC), including SCLC, in a patient suffering therefrom by administering to the patient a therapeutically effective amount of lurbinectedin according to a dosing regimen of one or more treatment cycles using a pharmaceutical formulation of lurbinectedin described herein. Lurbinectedin therapy is, in certain embodiments, a second line therapy, such that the patient has previously been administered and has progressed in response to a therapy, such as a platinum-containing or platinum-based chemotherapy, and / or an immuno-oncology therapy. Preferably, such a treatment regimen is administered to a patient with SCLC at a dose of 2.0-3.2 mg / m 2, and in a preferred embodiment, for at least the initial dose, 3.2 mg / m 2 The preferred method of administering lurbinectedin is by intravenous infusion at a dose of 2.0 mg / m every 3 weeks (or 21 days), preferably over 1 hour, although the dose may be reduced and / or delayed depending on the occurrence of adverse events, particularly the hematological abnormalities and hepatotoxicity disclosed herein. In some embodiments, SCLC patients experience disease progression or unacceptable toxicity (e.g., the patient does not recover until criteria are met for more than 5 weeks of dosing after the prior dose, or the patient is not administered a second reduced dose of 2.0 mg / m). 2 3.2 mg / m 2 is administered by intravenous infusion over 60 minutes, repeated every 3 weeks. In embodiments of the invention, treatment results in an overall response rate of greater than 30%, including greater than 35% or 35.2%, a median progression-free survival of 3.5 months, including 2.6 to 4.6 months, or 2.6 months (resistant patient population (CTFI < 90 days))) to 4.6 months (sensitive patient population (CTFI ≥ 90 days)); and a median overall survival of 9.3 months (resistant patient population (CTFI < 90 days) at 5.0 months and sensitive patient population (CTFI ≥ 90 days) at 11.9 months).

[0037] In various embodiments, the present invention provides methods for treating SCLC, including metastatic SCLC, in patients in need thereof, particularly patients whose SCLC has progressed after prior therapy, such as platinum-containing or platinum-based chemotherapy, immunotherapy, or both, including, among others, patients who have failed or failed to respond adequately to prior treatment, patients who have responded to prior treatment but may subsequently experience disease progression, and patients who may have multiple such responses followed by progression.

[0038] In some embodiments, the present disclosure provides a method for treating metastatic SCLC. In some embodiments, the present disclosure provides a method for treating an adult patient with metastatic SCLC with disease progression after platinum-based chemotherapy.

[0039] SCLC patient SCLC patients, including metastatic SCLC, who fail to respond or progress through first-line platinum-containing chemotherapy and / or immunotherapy are considered to be "non-responsive." Patients who relapse / progress within 90 days (3 months) after initially responding to initial or "first-line" chemotherapy containing a platinum agent are considered to be "resistant." Patients who respond to initial treatment but subsequently relapse, or whose tumors progress within about 91-180 days (3-6 months) after discontinuation of first-line therapy with a platinum agent, are considered to be sensitive and are considered herein to have "91-180 day progressive" SCLC. Patients who respond to first relapse or whose tumors progress after 180 days are "sensitive."

[0040] Lurbinectedin therapy can be a second-line therapy, and the SCLC patient has been previously treated with one or more other chemotherapeutic agents, such as carboplatin or cisplatin (platinum-based chemotherapy), and etoposide. In particular, the treatment is suitable for SCLC patients who have relapsed or are refractory to previous chemotherapy. In some embodiments, the SCLC patient has discontinued in response to a prior platinum-containing therapy, or discontinued in response to a suitable therapy, or has not responded to a prior platinum-containing therapy. More specifically, lurbinectedin therapy can be used when the SCLC patient is refractory, resistant, or recurrent / progressive within 0-90 days or 91-180 days after discontinuation of first-line platinum-containing chemotherapy and, optionally, radiation treatment, in certain embodiments. Patients with SCLC who progress within 0-90 days or 91-180 days after discontinuation of first-line therapy, as well as patients whose SCLC is refractory to treatment and progresses at any time, including within 90 days, 180 days, or any time, or patients whose SCLC responds to initial treatment and then progresses within 90 days, 180 days, or any time after discontinuation of initial treatment, can be advantageously treated with lurbinectedin to increase one or more of progression-free survival, overall survival, or length of time of response. In some embodiments, the SCLC patient has had a chemotherapy-free period of at least 90 days, at least 120 days, at least 150 days, or at least 180 days after prior administration of a prior platinum-containing therapy. In specific embodiments, the patient has not received a platinum-containing therapy at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. In some embodiments, the present disclosure provides a method of treating a patient with SCLC who has progressed after a prior platinum-containing therapy. In some embodiments, the present disclosure provides methods of treating adult patients with metastatic SCLC with disease progression following platinum-based chemotherapy.

[0041] Lurbinectedin therapy can also be administered following first-line platinum-based chemotherapy such as carboplatin or cisplatin and etoposide in combination with checkpoint inhibitors such as atezolizumab, pembrolizumab, ipilimumab, durvalumab, or combinations thereof, or following second-line therapy with other immunotherapies such as nivolumab, or atezolizumab, pembrolizumab, ipilimumab, or durvalumab. In particular, treatment is suitable for SCLC patients who have relapsed or are refractory to prior immunotherapy. For example, in some embodiments, lurbinectedin treatment is suitable for SCLC patients who have relapsed or are refractory to prior first-line carboplatin / etoposide / atezolizumab combination therapy, or second-line immunotherapy with nivolumab. In some embodiments, the SCLC patient has discontinued in response to prior immunotherapy, or discontinued in response to adequate therapy, or has not responded to prior immunotherapy. More specifically, lurbinectedin therapy can be used when the SCLC patient is refractory, resistant, sensitive, or recurrent / progressive within 91-180 days after discontinuation of first-line platinum-containing chemotherapy or second-line nivolumab in combination with immunotherapy, and in certain embodiments, the patient has undergone radiation treatment. SCLC patients who progress after discontinuation of first-line immunotherapy (including in combination with platinum-containing therapy) or second-line immunotherapy any time after therapy (including within 90 days or within 180 days of treatment in certain embodiments), as well as patients whose SCLC is refractory to treatment (having a chemotherapy-free period of less than 90 days) and progresses within 180 days, or patients whose SCLC responds to initial treatment and then progresses within 180 days of discontinuation of initial treatment, can be advantageously treated with lurbinectedin to increase one or more of progression-free survival, overall survival, or duration of response. In some embodiments, the SCLC patient has had a chemotherapy-free period, including immunotherapy, of less than 90 days relative to prior treatment, and in other embodiments, the SCLC has had a chemotherapy-free period of at least 90 days, at least 120 days, at least 150 days, or at least 180 days, but in certain embodiments, not more than 120 days, 150 days, or 180 days.In specific embodiments, the patient has not received first-line immunotherapy (in combination with a platinum-containing therapy) or second-line immunotherapy at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin.

[0042] When the treatments disclosed herein are administered to SCLC patients, including metastatic SCLC patients in need of such treatment, the treatments are expected to produce benefits as measured by the extent of anti-cancer effect, (overall) response rate, time to disease progression, or survival rate. In one embodiment, the overall response rate is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 60%. In some embodiments, the overall response rate is at least 11%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, for patients with less than 90 days of chemotherapy-free period, or the overall response rate is at least 30%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, for patients with at least 90 days of chemotherapy-free period. In some embodiments, the duration of response is at least 5.3 months (4.1 months to 6.4 months) or at least 4.7 months (2.6 months to 5.6 months) for resistant patients (less than 90 days of chemotherapy free period), or the duration of response is at least 6.2 months (3.5 months to 7.3 months) for sensitive patients with at least 90 days of chemotherapy free period.

[0043] In certain embodiments, SCLC patients treated with lurbinectedin disclosed herein have a progression free survival of at least 3.5 months (2.6 months to 4.3 months), for resistant patients, a progression free survival of 2.6 months (1.3 months to 3.9 months), and for sensitive patients, a progression free survival of 4.6 months (2.8 months to 6.5 months). In other embodiments, SCLC patients treated with lurbinectedin disclosed herein have an overall survival of 9.3 months (6.3 months to 11.8 months), for resistant patients, an overall survival of 5.0 months (4.1 months to 6.3 months), and for sensitive patients, an overall survival of 11.9 months (9.7 months to 16.2 months).

[0044] Alternatively, the treatment can be a second-line therapy for SCLC with widespread or limited disease that is refractory to initial chemotherapy or that progresses within less than 90 days (3 months) of completing first-line platinum-containing therapy. SCLC patients who progress after discontinuation of first-line therapy (any time, including within 30-90 days of treatment), as well as patients whose SCLC is refractory to treatment and progresses within 90 days, or whose SCLC responds to initial treatment and then progresses within 90 days of discontinuation of initial treatment, can be advantageously treated with lurbinectedin to increase one or more of progression-free survival, overall survival, or duration of response. In some embodiments, the SCLC patient has had a chemotherapy-free period of less than 90 days, e.g., less than 30 days, less than 60 days, or less than 90 days, relative to prior treatment.

[0045] In various embodiments, SCLC patients are initially treated with platinum-based chemotherapy and immunotherapy, either given simultaneously or sequentially, followed by chemotherapy at 3.2 mg / m every 3 weeks. 2The patient is administered an effective amount of lurbinectedin or a cycle of lurbinectedin treatment as disclosed herein, including administering 3.2 mg / m every 3 weeks (or delayed or reduced for patients who exhibit hematological toxicity). For example, in some embodiments, the SCLC patient has received prior immunotherapy including administering an antibody targeting PD-L1, CTLA-4, or PD-1, where the antibody is selected from atezolizumab, nivolumab, pembrolizumab, ipilimumab, durvalumab, or combinations thereof. In some embodiments, the patient has previously received atezolizumab in combination with a platinum-containing therapy and etoposide. In some embodiments, the patient has received nivolumab. Thus, 3.2 mg / m every 3 weeks may be administered 3.2 mg / m every 3 weeks. 2 Methods are provided for treating SCLC patients progressing on atezolizumab (including in combination with carboplatin and etoposide), or nivolumab, with lurbinectedin at 0.5 mg / kg (or delayed or reduced for patients experiencing hematological toxicity).

[0046] In some embodiments, the patient receiving lurbinectedin is an adult.

[0047] Treatment Cycle The administration of the pharmaceutical composition comprising lurbinectedin is preferably by intravenous infusion. Infusion times of up to 72 hours can be used, but are preferably 1 to 24 hours, typically about 1 hour. Short infusion times are particularly desirable, allowing the procedure to be performed without overnight hospitalization. In a preferred embodiment, lurbinectedin is administered by infusion over 1 hour (60 minutes).

[0048] Preferably, administration of lurbinectedin is performed in cycles. In a preferred administration schedule, intravenous infusion of lurbinectedin is given to the patient on the first day of each cycle, and the patient is allowed to recover for the remainder of the cycle. The preferred duration of each cycle is 3 weeks or 21 days. However, the treatment cycle can be increased or decreased by, for example, 1-6 days, 1 week, or 2 weeks, or more than 3 weeks, for example, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 days, or more, depending on the patient's response to treatment. In certain embodiments, if the treatment cycle is delayed for more than 2 weeks because the patient does not recover from an adverse event and does not meet the hematological criteria for lurbinectedin treatment, treatment with lurbinectedin can be interrupted. Administration of lurbinectedin by intravenous infusion over approximately one hour once every three weeks is the most preferred administration schedule, although other protocols can be devised as variations. Multiple cycles can be performed as needed. Over the course of treatment for SCLC, 1-24 doses of lurbinectedin can be administered, with 4-8 doses typically administered at intervals of approximately 21 days (3 weeks). Intervals of up to 6 weeks, e.g., 3-4 weeks, can be utilized if the treatment schedule needs to be modified, e.g., to reduce or manage side effects (described in more detail below). Over the course of treatment for cancer, 1-24 treatments of lurbinectedin can be administered, with 4-8 treatments typically administered at intervals of approximately 21 days (3 weeks). In some embodiments, one dose of lurbinectedin is administered per treatment cycle and the patient receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 treatment cycles. In embodiments, lurbinectedin is administered in 3 week treatment cycles until disease progression or unacceptable toxicity occurs, or delayed to allow the patient to recover from adverse events.

[0049] Drug bioavailability is defined as the proportion of a drug or other substance that is introduced into the body and enters the circulation where it can have an active effect. Measurements of bioavailability well known in the art include the area under the plasma concentration-time curve (AUC) and the concentration maximum (Cmax). Cmax is the maximum plasma concentration achieved after administration of the drug.

[0050] Provided herein are methods for dosing lurbinectedin according to one or more pharmacokinetic parameters, where administration of said doses is effective to treat resistant, refractory, or progressive SCLC. In exemplary embodiments, the one or more pharmacokinetic parameters are peak concentration (Cmax) or area under the curve (AUC). In one embodiment, lurbinectedin is administered at a dose of 3.2 mg / m 2 Lurbinectedin is administered to SCLC patients in need thereof as a 1-hour infusion to achieve a mean total plasma Cmax within 80%-125% of about 107 μg / L and a mean AUC∞ within 80%-125% of about 551 μg*h / L. In some embodiments, lurbinectedin is administered to SCLC patients in cycles of 1 day on and 20 days off (1 / 20 cycle). In one embodiment, the administration cycle is 1 / 20 cycle and the target mean AUC∞ is about 551 μg*h / L. In one embodiment, the administration cycle is 1 / 20 cycle and the target mean AUC∞ is about 551 μg*h / L ± 5%, about 551 μg*h / L ± 10%, about 551 μg*h / L ± 20%, or about 551 μg*h / L ± 25%. In a preferred embodiment, the administration cycle is 1 / 20 cycle and the target mean AUC∞ is within 80%-125% of about 551 μg*h / L. In one embodiment, the administration cycle is 1 / 20 cycle and the mean target Cmax is about 107 μg / L. In one embodiment, the administration cycle is 1 / 20 cycle and the mean target Cmax is about 107 μg / L ± 5%, about 107 μg / L ± 10%, about 107 μg / L ± 20%, or about 107 μg / L ± 25%. In a preferred embodiment, the administration cycle is 1 / 20 cycle and the mean target Cmax is within 80%-125% of about 107 μg / L.

[0051] Renal, hepatic, and hematological disorders must be ruled out prior to administration of lurbinectedin to patients afflicted with SCLC. In one embodiment, patients afflicted with SCLC have a pulmonary function of at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 and optionally a hemoglobin level of at least 9 g / dL (with transfusion as needed), but 2 In another embodiment, a patient afflicted with SCLC is determined to have an estimated hepatic clearance of greater than 30 mL / min and an AST or ALT less than 3×ULN, or a bilirubin less than 1.5×ULN and an estimated creatinine clearance of greater than 30 mL / min, but is administered a first dose of about 3.2 mg / m 2 The second dose is about 3.2 mg / m 2 Lurbinectedin is administered to the patient about 21 days after the first dose, and continues at this level of dosing if hematological, renal, and hepatic parameters remain stable. In certain embodiments, the patient is administered lurbinectedin at a dose of at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 and a platelet count of 3.2 mg / m 2 To achieve the preferred dosing, lurbinectedin is preferably administered at about 3.2 mg / m 2 is administered per dose, e.g., per intravenous infusion. The dosing of lurbinectedin is about 3.2 mg / m lurbinectedin per dose, e.g., per intravenous infusion. 2 , or at reduced doses thereof as discussed below.

[0052] Antiemetic Treatment Best supportive care for the treatment of SCLC, including metastatic SCLC, and solid tumors in adult patients includes several palliative measures. For example, in one embodiment of the present invention, best supportive care includes one or more, and preferably all, of the administration of analgesics to control pain, management of constipation, and treatment of dyspnea, and treatment of anemia, for example, with transfusions to maintain hemoglobin levels (i.e., above 9 g / dL).

[0053] In other embodiments, the therapy is administered to specifically prevent, treat or manage nausea and / or vomiting associated with lurbinectedin administration, as described below.

[0054] Chemotherapy agents vary in their emetogenicity: those associated with a risk of emesis of >90% in the absence of antiemetic prophylaxis are classified as highly emetogenic chemotherapy, and those associated with a risk of emesis of 30%-90% are classified as moderately emetogenic.

[0055] Aspects include methods of prevention and treatment of lurbinectedin-induced nausea and / or vomiting (either acute or delayed phase), where an antiemetic effective amount of a serotonin antagonist or a corticosteroid, or a combination thereof, is administered to a patient prior to administration of lurbinectedin, and in particular immediately prior to administration of lurbinectedin, to reduce the nausea and vomiting side effects that may be associated with administration of lurbinectedin. A preferred embodiment is a method for treating SCLC, including metastatic SCLC, in a patient in need thereof, or reducing the side effects of administration of lurbinectedin to a patient, comprising the steps of: (1) administering one or more antiemetic agents effective to reduce nausea associated with administration of lurbinectedin to the patient on the day and prior to administration of lurbinectedin to the patient; and (2) administering lurbinectedin at a dose of 2 to 3.2 mg / m 2 In certain embodiments, lurbinectedin is administered as a single agent chemotherapy agent and / or is not administered in combination with doxorubicin. In other embodiments, the patient is administered irinotecan 75 mg / m 2in combination with lurbinectedin 2 mg / m 2 and in certain embodiments, 75 mg / m on day 8 of the treatment cycle. 2 The compound may be administered with irinotecan at a dose of 1:1.

[0056] In some embodiments, the antiemetic agent is administered intravenously or orally. If the antiemetic agent or agents are administered intravenously, the agent or agents are administered 30-90 minutes prior to administration of lurbinectedin, or about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, or about 90 minutes, preferably 30 or 60 minutes, prior to administration of lurbinectedin. If the antiemetic agent or agents are administered orally, the agent or agents are administered 30-60 minutes prior to administration of lurbinectedin, about 3 hours to 9 hours prior to administration of lurbinectedin, or about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or about 9 hours prior to administration of lurbinectedin. In some embodiments, the antiemetic agent comprises a corticosteroid and a serotonin antagonist, the corticosteroid being selected from the group consisting of dexamethasone, hydrocortisone, or methylprednisolone, and the serotonin antagonist being selected from the group consisting of ondansetron, granisetron, and palonosetron. The dose of the corticosteroid is about 4 mg to 20 mg of dexamethasone delivered intravenously, preferably 8 mg delivered intravenously, or the equivalent. The dose of the serotonin antagonist is about 8 mg to 16 mg of ondansetron delivered intravenously, preferably 8 mg delivered intravenously, or the equivalent. When given orally, the dose can be increased up to a dose equivalent to 24 mg of ondansetron. In a preferred embodiment, the prophylactic antiemetic agent comprises dexamethasone administered intravenously at 8 mg, ondansetron administered intravenously at 8 mg, or a combination thereof.

[0057] In some embodiments, the method further comprises administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient, e.g., administered on the same day after lurbinectedin administration, e.g., within 2, 3, 4, 5, 6, 7, or 8 hours after lurbinectedin administration, and / or on the 1, 2, 3, or 4th day after lurbinectedin administration. The one or more antiemetic agents administered after lurbinectedin administration are selected from the group consisting of corticosteroids, where the corticosteroids are selected from dexamethasone, hydrocortisone, and methylprednisolone, serotonin antagonists, where the serotonin antagonists are selected from ondansetron, granisetron, and palonosetron, and metoclopramide. In a preferred embodiment, the post-infusion antiemetic treatment is dexamethasone 4 mg (orally), ondansetron 8 mg (orally), or metoclopramide 10 mg (orally or as an infusion), or a combination thereof. Metoclopramide may be administered at 8 hour intervals. In some embodiments, the post-infusion antiemetic is administered intravenously. In some embodiments, the first dose of post-infusion antiemetic is given the night or 1, 2, 3, 4, 5, 6, 7, or 8 hours after lurbinectedin administration and continues for up to 1, 2, 3, or 4 days after infusion. In some embodiments, a corticosteroid, such as dexamethasone, is given at a dose equivalent to dexamethasone 4 mg the night or 1, 2, 3, 4, 5, 6, 7, or 8 hours after chemotherapy, and then given twice daily for up to 1, 2, 3, or 4 days. In some embodiments, metoclopramide is administered orally at a dose of 10-20 mg every 8 hours after chemotherapy for up to 1, 2, 3, or 4 days. In other embodiments, a serotonin antagonist, such as ondansetron, is given orally at a dose equivalent to 8 mg or 16 mg of ondansetron every 12 or 24 hours, respectively, for up to 1, 2, or 3 days after lurbinectedin administration.

[0058] In some embodiments, the antiemetic prophylaxis and optionally post-infusion antiemetic treatment is about 2.0 mg / m lurbinectedin. 2 , about 2.6mg / m 2 , or about 3.2 mg / m2 Lurbinectedin is administered by intravenous infusion to patients with SCLC who are given 1.0 to 2.0 mg / m 2 in combination with irinotecan. Antiemetic prophylaxis and optional post-infusion antiemetic treatment are administered at 1.0 to 2.0 mg / m 2 in combination with irinotecan. 2 is administered to patients with solid tumors receiving

[0059] Dosage and Dose Reduction Additional embodiments of the invention include a first dose of 3.2 mg / m2 with a dose delay of more than a 21 day treatment cycle (e.g., more than 2 weeks) for lurbinectedin dosed on day 1. 2 This includes dose modifications upon identification of grade 2 or higher adverse events (AEs) when administering lurbinectedin to patients with SCLC, particularly adult patients with metastatic SCLC.

[0060] In some embodiments, a smaller amount of lurbinectedin is used compared to the amount commonly used for the respective therapy. In some embodiments, the same or greater therapeutic effect is achieved by using a smaller amount of lurbinectedin (e.g., a lower dose or a less frequent dosing schedule) than the amount commonly used for the respective therapy. For example, the use of a smaller amount of lurbinectedin may result in a reduction in the number, severity, frequency, or duration of one or more side effects associated with lurbinectedin infusion. For example, in a preferred embodiment, the first dose modification is about 3.2 mg / m of lurbinectedin. 2 to about 2.6 mg / m 2 (or 80-85% of the initial dose), and the second dose modification is approximately 2.6 mg / m 2 to about 2.0 mg / m 2A dose reduction to (or 60 - 65% of the initial dose). After the second dose reduction, if the patient experiences an adverse event that requires further dose reduction, treatment can be terminated. Adverse events that require frequent or prolonged (more than 2 weeks) dose delays include, but are not limited to, any hematological toxicity that is grade 3 or 4, or any adverse reaction such as non - hematological toxicity or hepatotoxicity of any grade 2, grade 3, or grade 4. In the case of grade 2, grade 3, or grade 4 non - hematological toxicity, the following cycle is delayed until the non - hematological parameters improve to grade 1 or 0. Administration of two doses of lurbinectedin is always spaced at least 21 days apart.

[0061] The treatment cycle does not start until hematological parameters such as neutrophil count, platelet count, and optionally hemoglobin level improve such that the absolute neutrophil count is 1500 cells / mm 3 or more, the platelet count is 100,000 cells / mm 3 or more, and optionally, in certain embodiments, the hemoglobin level is 9 g / dL or more (with transfusion if necessary). For example, after the first occurrence of any adverse reaction such as non - hematological toxicity above grade 3 (severe), grade 4 thrombocytopenia (platelet count < 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count < 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count < 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN), or frequent or prolonged (more than 2 weeks) dose delays, the lurbinectedin dose is reduced from 3.2 mg / m 2 to 2.6 mg / m 2 (or 80 - 85% of the initial dose), and the next cycle is when the patient's neutrophil count is > 1500 cells / mm 3 ; the platelet count is approximately 100,000 cells / mm 3until hemoglobin levels exceed about 9 g / dL. In certain embodiments, if the identified adverse event consists of grade 4 isolated neutropenia, the method comprises administering a dose of G-CSF as prophylactic administration to manage grade 4 isolated neutropenia (“secondary G-CSF prophylactic administration”), and then administering to the patient a dose of lurbinectedin equal to the previous dose rather than reducing the subsequent lurbinectedin dose. After the first dose reduction, if the patient develops one of the adverse events requiring dose reduction (non-hematological toxicity above grade 3 (severe), grade 4 thrombocytopenia (platelet count < 25,000 cells / mm 3 platelet count), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count < 50,000 cells / mm 3 platelet count), grade 4 neutropenia (neutrophil count < 500 cells / mm 3 neutrophil count), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN), or any adverse reaction requiring frequent or prolonged (more than 2 weeks) dose delay), once the patient has recovered to a neutrophil count of 1500 cells / mm 3 or more, a platelet count of 100,000 cells / mm 3 or more, and a hemoglobin level of about 9 g / dL or more (with transfusion if necessary), the subsequent dose 3 weeks later is reduced to 2.0 mg / m 2 (60 - 65% of the initial dose). After the second dose reduction, if the patient again has an adverse event requiring dose reduction, treatment is discontinued. If the absolute neutrophil count does not rise to 1500 cells / mm 3 or more and the platelet count does not rise to 100,000 cells / mm 3 or more, such that the dose is delayed for more than 2 weeks, treatment can be discontinued.

[0062] If the identified adverse reaction is not only grade 4 isolated neutropenia, the method comprises administering to the patient a reduced dose of lurbinectedin. Administration of two doses of lurbinectedin must be spaced at least 21 days apart, regardless of the dose of lurbinectedin.

[0063] A preferred embodiment is the treatment of small cell lung cancer (SCLC) including metastatic SCLC in a patient in need thereof, comprising: (1) administering to the patient by intravenous infusion a first dose of 3.2 mg / m 2 of lurbinectedin; (2) identifying an adverse reaction in the patient, wherein the adverse reaction is selected from the group consisting of non-hematological toxicity of grade 3 (severe) or higher, grade 4 thrombocytopenia (platelet count less than 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count less than 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN), or any other adverse reaction; and (3) after identifying the adverse reaction, when the patient's neutrophil count exceeds 1500 cells / mm 3 ; the platelet count exceeds about 100,000 cells / mm 3 ; and the hemoglobin level exceeds about 9 g / dL: (i) if the identified adverse reaction consists of grade 4 isolated neutropenia (neutrophil count less than 500 cells / mm 3 ), administering to the patient a dose of G-CSF and a dose of lurbinectedin equal to the previous dose; or (ii) if the identified adverse reaction is not only grade 4 isolated neutropenia, administering to the patient a reduced dose of lurbinectedin, wherein the administration of two doses of lurbinectedin is spaced 21 days, or 20 - 23 days, or at least 18, 19, 20, 21, 22, or 23 days apart.

[0064] In some embodiments, after the first occurrence of an adverse reaction that is not only grade 4 isolated neutropenia, the first dose reduction is 80 - 85% of the first dose, or after the first occurrence of an adverse reaction that is not only grade 4 isolated neutropenia, the first reduced dose is 2.6 mg / m 2In some embodiments, after a second occurrence of an adverse reaction that is not solely grade 4 isolated neutropenia, the second reduced dose is 60-65% of the first dose, or after a second occurrence of an adverse reaction that is not solely grade 4 isolated neutropenia, the second reduced dose is 2.0 mg / m 2 and the second reduced dose is administered to the patient. Administration of lurbinectedin is discontinued following identification of an adverse reaction following administration of the second reduced dose.

[0065] Prior to administration of the first or subsequent dose of lurbinectedin, patients, including adult patients with SCLC, particularly metastatic SCLC, should have a ≥ 1,500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 Therefore, for SCLC, including metastatic SCLC, the platelet count should be at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 Patients with platelet counts of 3.2 mg / m2 or lower were treated with 3.2 mg / m2 every 3 weeks, with dose delays or reductions if patients experience adverse events. 2 Methods of treatment are provided by administration of lurbinectedin at a dose of

[0066] Methods are provided for managing hematological toxicity, myelosuppressive effects, and / or hepatotoxicity that may be associated with lurbinectedin administration in the treatment of SCLC, including metastatic SCLC, by dose reduction and / or dose delay. Adverse events that may cause dose delay or reduction include febrile neutropenia of grade 4 or any grade (grade 4 neutropenia is 500 cells / mm 3 neutrophil count less than 0.001), grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia (grade 3 thrombocytopenia is 25,000 to 50,000 platelets / mm 3 and grade 4 thrombocytopenia is 25,000 platelets / mm 3In the event of any of these adverse reactions, subsequent doses should be reduced until the patient has Grade 1 or less neutropenia (< 1500 cells / mm 3 >100,000 cells / mm 3 Treatment may be delayed until the patient has recovered to have a platelet count of 0.01 mg / m2 or hepatotoxicity or other adverse reactions that are Grade 1 or less. Patients who after recovery develop Grade 4 neutropenia, or febrile neutropenia of any grade, Grade 3 or Grade 4 thrombocytopenia with hemorrhage, or Grade 3 or greater hepatotoxicity or other adverse reactions will receive a reduced dose for the subsequent treatment cycle. 2 If the dose was 2.6 mg / m 2 and a prior dose of 2.6 mg / m 2 If the dose was 1.0 mg / m every 3 weeks, the reduced dose was 2.0 mg / m every 3 weeks. 2 The patient was 2.0 mg / m 2 If a patient experiences an adverse event indicating a dose reduction after the first dose, treatment may be terminated. For patients with grade 4 neutropenia, the subsequent dose may not be reduced once the patient recovers, i.e., if the patient receives G-CSF prophylaxis, it may be the same as the previous dose every 3 weeks. For patients with grade 2 hepatotoxicity or other adverse reactions, the subsequent dose is the same as the previous dose every 3 weeks after the patient recovers to grade 1 or less toxicity.

[0067] Therefore, at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 3.2 mg / m 2 In a further embodiment, a method of treating SCLC, including metastatic SCLC, is provided by administering a dose of lurbinectedin, preferably by infusion over 60 minutes. In a further embodiment, 21 days after the previous dose, the patient has at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3and a platelet count of 3.2 mg / m 2 A dose of lurbinectedin is administered, preferably by infusion over 60 minutes. In an embodiment, the patient is monitored for and free of hepatotoxicity prior to administration of lurbinectedin. Subsequent treatments are administered at 21 day (3 week) intervals at a dose of at least 1500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 It is administered to patients with platelet counts of

[0068] In certain embodiments, lurbinectedin is administered at 3.2 mg / m 2 The present invention provides a method of treating SCLC, including metastatic SCLC, in a patient in need thereof by administering at a dose of 3.2 mg / m 2 Patients receiving lurbinectedin at a dose of 10 mg / kg / day developed grade 4 neutropenia (< 500 cells / mm 3 If the patient develops Grade 1 or less neutropenia (neutrophil counts of at least 1500 cells / mm3) or any febrile neutropenia, subsequent doses of lurbinectedin should be administered 21 days after the previous dose or if the patient develops Grade 1 or less neutropenia (neutrophil counts of at least 1500 cells / mm3). 3 ) (which may be longer than 21 days past the previous dose), whichever is later, and then every 3 weeks a reduced dose of 2.6 mg / m 2 or lurbinectedin at 3.2 mg / m every 3 weeks with G-CSF prophylaxis. 2 or administer lurbinectedin at a dose of 3.2 mg / m 2 Patients receiving lurbinectedin at doses of 100 mg / kg / day or 100 mg / kg / day experienced grade 3 thrombocytopenia (25,000 to 50,000 platelets / mm) with bleeding. 3 ) or grade 4 thrombocytopenia (25,000 platelets / mm 3 <100,000 cells / mm 3Subsequent doses of lurbinectedin will not be administered until the later of the patient achieving a platelet count of 2.6 mg / m or greater, and thereafter doses will be reduced to 2.6 mg / m every 3 weeks (21 days). 2 In the end, it was 3.2 mg / m 2 If a patient receiving lurbinectedin at a dose of 3.2 mg / m2 experiences hepatotoxicity or other adverse reactions that are either Grade 2 or Grade 3 or 4, then a subsequent dose of lurbinectedin is not administered until 21 days after the previous dose or until the patient experiences Grade 1 or less hepatotoxicity (or other adverse reactions), whichever is later, and if the patient experiences Grade 2 hepatotoxicity (or other adverse reactions of Grade 2), then the subsequent dose is 3.2 mg / m2 every 3 weeks. 2 If a patient experiences grade 3 or 4 hepatotoxicity or other adverse reactions, the dose is then increased to 2.6 mg / m every 3 weeks (21 days). 2 If, after the dose reduction, the patient experiences grade 4 neutropenia, or any grade of febrile neutropenia, grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding, or grade 3 or 4 hepatotoxicity or one of the other adverse reactions, then subsequent doses will not be administered until the later of 21 days or when the patient has recovered as detailed above, and then every 3 weeks thereafter a further reduced dose of 2 mg / m 2 Patients will receive 2 mg / m lurbinectedin or, in the case of grade 4 neutropenia, the same dose of lurbinectedin as the previous dose with G-CSF prophylaxis. 2 Treatment will be discontinued if the patient does not tolerate lurbinectedin at this dose (i.e., develops grade 4 neutropenia, or any grade febrile neutropenia, grade 3 thrombocytopenia or grade 4 thrombocytopenia with hemorrhage, or grade 3 or 4 hepatotoxicity or one of the other adverse reactions after lurbinectedin administration) or if the delay in dosing is longer than 2 weeks past the scheduled dose (21 days after the prior dose).

[0069] Coadministration with strong or moderate CYP3A inhibitors increases the systemic exposure of lurbinectedin, and patients taking CYP3A inhibitors should either be advised to remove or discontinue the CYP3A inhibitor, or the dose of lurbinectedin should be reduced to, for example, 3.2 mg / m 2 or 2.6 mg / m 2 or 2.0 mg / m 2 Examples of CYP3A inhibitors include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, and grapefruit. Thus, if the patient is not taking a CYP3A inhibitor (remove the CYP3A inhibitor prior to dosing with lurbinectedin to avoid drug interactions), the dose of lurbinectedin is reduced from 3.2 mg / m every 3 weeks. 2 or 2.6 mg / m if the patient is also taking a CYP3A inhibitor. 2 or 2.0 mg / m 2 Contains 3.2 mg / m 2 Administration of lurbinectedin at doses less than 100 mg / kg provides a method of treating patients with SCLC, particularly metastatic SCLC, or solid tumors.

[0070] Coadministration with strong CYP3A inducers reduces the systemic exposure of lurbinectedin, which may reduce efficacy. Examples of CYP3A inducers include phenobarbital, phenytoin, rifampicin, St. John's wort, and glucocorticoids. Thus, lurbinectedin 3.2 mg / m every 3 weeks is recommended. 2 Administration of lurbinectedin at a dose comprising:

[0071] Combination therapy for solid tumors In other embodiments, the present invention relates to the combination of lurbinectedin with a topoisomerase I and / or II inhibitor in the treatment of cancer, more specifically in the treatment of solid tumors, particularly endometrial cancer, SCLC, soft tissue sarcoma (including Ewing's sarcoma and synovial sarcoma), glioblastoma (including supratentorial or intratentorial tumors), pancreatic adenocarcinoma, mesothelioma, colorectal cancer, and epithelial ovarian cancer. In preferred embodiments, the solid tumor is endometrial cancer, SCLC, soft tissue sarcoma (including Ewing's sarcoma and synovial sarcoma), or glioblastoma. In some embodiments, the method of treating patients with solid tumors comprises administering lurbinectedin at a dose of 1-2.5 mg / m in combination with another anticancer agent, e.g., a topoisomerase inhibitor selected from SN-38 or irinotecan. 2 and lurbinectedin is administered at a dose of 1 to 2.5 mg / m 2 , especially 2.0 mg / m 2 The topoisomerase inhibitor is irinotecan 50-75 mg / m 2 The chemotherapeutic group of topoisomerase I and / or II inhibitors includes, but is not limited to, topotecan, SN-38, irinotecan, camptothecin, rubitecan, etoposide, amsacrine, and teniposide. Particularly preferred is the combination of lurbinectedin and irinotecan in the treatment of cancer, especially solid tumors, more particularly in the treatment of endometrial cancer, SCLC, soft tissue sarcoma (including Ewing's sarcoma and synovial sarcoma), glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, and epithelial ovarian cancer.

[0072] In some embodiments, lurbinectedin is administered at 1, 1.5, 2, or 2.4 mg / m 2 The topoisomerase inhibitor is irinotecan 50-75 mg / m 2 In a preferred embodiment, lurbinectedin is administered at a dose equivalent to 2 mg / m 2 and irinotecan was administered at a dose of 75 mg / m 2 G-CSF is administered to the patient in combination.

[0073] In some embodiments, the lurbinectedin and topoisomerase inhibitor are administered on day 1 of the treatment cycle. In some embodiments, the method further comprises administering G-CSF to the patient to manage the myelosuppressive effects of the therapy. In another embodiment, the topoisomerase inhibitor is further administered to the patient on day 7, 8, 9, or 10 of the treatment cycle. In some embodiments, the treatment cycle is an 18, 19, 20, 21, 22, 23, 24, or 25 day cycle.

[0074] In certain embodiments, a dose of 2.0 mg / m2 is administered on day 1 of a treatment cycle, with G-CSF administration managing the myelosuppressive effects of the therapy. 2 and lurbinectedin at a dose of 75 mg / m 2 on day 8 of the treatment cycle, followed by irinotecan at a dose of 75 mg / m 2 A method of treating solid tumors in a patient in need thereof by administering a dose of irinotecan to the patient in need thereof. The treatment cycle may be a 3-week (21 day) cycle, with the subsequent treatment cycle beginning on day 22. In certain embodiments, a patient who exhibits hematological toxicity (including grade 3-4 adverse events) after a combination dose administered on day 1 of a treatment cycle may not receive an irinotecan dose on day 8 (or at any other time during the treatment cycle) or may receive a reduced dose of irinotecan on day 8 of a treatment cycle or at any other time during the treatment cycle. Treatment may include multiple treatment cycles until disease progression or unacceptable toxicity occurs. In particular, a patient may be administered 1, 2, 3, 4, 5, or more, including 8, 10, 12, 15, 20, or 30, or more, cycles of combination treatment.

[0075] In certain embodiments, the combination treatment method results in a reduction in tumor size and a median progression-free survival of at least 4.3 months (particularly for SCLC), at least 7.1 months (particularly for endometrial cancer), at least 2.6 months (particularly for soft tissue sarcoma), or at least 1.4 months (particularly for glioblastoma).

[0076] In one embodiment, the method further comprises administering one or more antiemetic agents on day 1 of a treatment cycle (detailed above for treatment of SCLC with lurbinectedin) and a post-infusion antiemetic treatment as described herein for treatment of SCLC.

[0077] Pharmaceutical compositions and methods of preparation Pharmaceutical compositions of lurbinectedin that can be used include solutions, lyophilized compositions, and the like, containing excipients suitable for intravenous administration.

[0078] In one aspect, lurbinectedin is supplied and stored as a stable, sterile, lyophilized product containing lurbinectedin, an organic acid derived buffer (e.g., an organic carboxylic acid buffer), a disaccharide, and sufficient base to provide a suitable pH for injection when the composition is reconstituted in an appropriate solvent.

[0079] In some embodiments, the organic carboxylic acid buffer is derived from an organic acid selected from the group consisting of lactic acid, butyric acid, propionic acid, acetic acid, succinic acid, citric acid, ascorbic acid, tartaric acid, malic acid, maleic acid, fumaric acid, glutamic acid, aspartic acid, gluconic acid, and α-ketoglutaric acid. In some embodiments, the organic carboxylic acid buffer is derived from an organic acid selected from lactic acid or succinic acid. In some embodiments, the organic carboxylic acid buffer is derived from lactic acid. In certain embodiments, the buffer is not a phosphate buffer.

[0080] In some embodiments, the disaccharide is selected from the group consisting of sucrose, trehalose, or lactose, or a combination thereof, hi some embodiments, the disaccharide is sucrose.

[0081] In some embodiments, the base is selected from the group consisting of carbonates, hydroxides, bicarbonates, and ammonium salts. Particularly preferred bases are sodium carbonate, potassium carbonate, calcium carbonate, NH4OH, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, and calcium bicarbonate. In some embodiments, the base is sodium hydroxide.

[0082] In some embodiments, the pH of the reconstituted lyophilized composition is about 4. In some embodiments, the pH of the reconstituted lyophilized composition is about 3 to about 5. In some embodiments, the pH of the reconstituted lyophilized composition is about 3.5 to about 4.5. In some embodiments, the pH of the reconstituted lyophilized composition is 3.8 to 4.1.

[0083] In some embodiments, the stable lyophilized product comprises lurbinectedin; lactic acid; sodium hydroxide; and sucrose, and the pH of the reconstituted lyophilized composition is 3.8 to 4.1. In some embodiments, the stable lyophilized product comprises 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or containing about 0.25 mmol of lactate); and 800 mg sucrose. In some embodiments, the stable lyophilized product consists essentially of 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or containing about 0.25 mmol of lactate); and 800 mg sucrose.

[0084] The lurbinectedin-containing formulation of the present invention can be prepared by lyophilizing the composition of the present invention in the form of a buffered bulk solution containing lurbinectedin, an organic acid-derived buffer such as a lactate buffer or a succinate buffer, and a disaccharide. The disaccharide is preferably sucrose. Typically, the bulk solution is buffered to a pH of, for example, about 3 to 5, preferably about 3.5 to 4.5, more preferably about 3.8 to 4.1. A preferred buffering agent is sodium lactate buffer. In a preferred embodiment, the lactate buffer contains lactic acid and a base, preferably an inorganic pharma- ceutically acceptable base such as sodium hydroxide.

[0085] Thus, in embodiments of the present invention, a buffered lyophilized composition is provided that includes lurbinectedin, a buffer derived from an organic acid, such as a lactate buffer or a succinate buffer, and a disaccharide; the buffer is configured such that, upon reconstitution, the pH of the reconstituted lyophilized composition is about 3 to about 5, about 3.5 to about 4.5, or 3.8 to 4.1.

[0086] The present invention has identified a methodology that allows complete dissolution of lurbinectedin in a desired buffer while minimizing impurity generation. In an embodiment, the use of an organic acid buffer allows for direct dissolution of lurbinectedin in the organic acid buffer (preferably at a pH of about 1-5, about 2-4.5, about 3-4.5, or about 4) followed by addition of a bulking agent such as a disaccharide, preferably sucrose. Such a formulation strategy allows for direct dissolution in a bulk formulation and avoids the need for a pre-dissolution step. In one embodiment, direct dissolution of lurbinectedin is provided, which includes dissolving lurbinectedin in an organic acid buffer (preferably at a pH of about 1-5, about 2-4.5, about 3-4.5, or about 4) followed by addition of a bulking agent such as a disaccharide, preferably sucrose, to form a bulk solution. The bulk solution can be sterile filtered. The bulk solution can then be filled into vials according to the desired dose. The bulk solution in the vial can then be lyophilized to form a lyophilized buffered lurbinectedin formulation. The lyophilized formulation can then be reconstituted to form a reconstituted solution. The reconstituted solution can be diluted to form an injection solution. Preferably, upon direct dissolution, the lurbinectedin is amorphous or substantially amorphous.

[0087] As described herein, lurbinectedin has limited aqueous solubility. It has been found that lurbinectedin solubility can be improved in bulk solution by first forming a concentrated pre-solution of lurbinectedin in a buffer derived from an organic acid, such as lactic acid, succinic acid, citric acid, or acetic acid, which is further diluted with water for injection. The disaccharide is then dissolved in an aqueous solution containing a basic component, such as aqueous sodium hydroxide, and when the pH is adjusted to a set value, the pre-solution of lurbinectedin and the buffer containing the disaccharide are mixed to obtain a bulk solution of lurbinectedin in an organic buffer containing a disaccharide (e.g., sucrose) at pH=4. Following this process, the lurbinectedin concentration can be increased in the bulk solution, allowing the filling volume of the vial to be reduced. In these embodiments of the present invention, the filling volume is usually reduced by about 80% relative to that of conventional filling volumes. By way of example and not limitation, embodiments of the present invention provide a fill volume of 1 mg lurbinectedin in 2 ml of solution in a 10 ml vial; or 4 mg lurbinectedin in 8 ml of solution in a 30 ml vial. Fill volumes can optionally be further reduced in other embodiments of the present invention by increasing the lurbinectedin concentration.

[0088] A method useful for improving the solubility of lurbinectedin in bulk solution is provided, which includes dissolving lurbinectedin in lactic acid, for example 0.31M lactic acid (25mg / mL), then diluting the solution with water for injection to obtain a concentrated solution of lurbinectedin in 0.1M lactic acid, mixing the solution containing pre-dissolved lurbinectedin with a buffer salt solution comprising sodium lactate buffer and a disaccharide, and optionally adjusting the pH. In some exemplary but non-limiting embodiments of the present invention, the pH adjustment is achieved with a lactate buffer.

[0089] An exemplary embodiment of a bulk solution for lyophilization according to the present invention is provided by a solution of lurbinectedin buffered at pH 4 with sodium hydroxide and lactic acid along with sucrose as a bulking agent.

[0090] An exemplary embodiment of the methodology according to the present invention provides the following: Lurbinectedin is dissolved in 0.31M lactic acid at a pH of about 3, and then diluted with water for injection to obtain a concentrated solution of 8.3 mg / mL lurbinectedin in 0.1M lactic acid at a pH of about 3. A sodium lactate buffer salt solution is prepared by mixing a 0.31M lactic acid solution with a 0.01M sodium hydroxide solution to create a 0.05M lactate buffer salt solution. Sucrose is then added to the sodium lactate buffer salt solution. The 0.05M lactate buffer salt solution containing sucrose is diluted with water for injection to obtain a 0.04M sodium lactate buffer containing 17% sucrose, pH about 4.2. Then, both solutions of 8.3 mg / mL lurbinectedin in 0.1 M lactic acid at pH about 3 and 0.04 M sodium lactate buffer at pH about 4.2 containing 17% sucrose are mixed. Dissolution is visually checked at every step before continuing and is considered complete when visually seen to be so. The pH of the solution is checked and the value is adjusted by slow addition of a suitable acid or base to a pH value in the range of about 1 to about 5, more preferably in the range of about 2 to about 4.5, even more preferably in the range of about 3 to about 4.5, and most preferably about 4.0. A preferred embodiment of such an acid is lactic acid, in which case the preferred concentration is about 0.1 M. A suitable base is optionally added for pH control. A preferred embodiment of such a base is sodium hydroxide, preferably in solution, in which case the preferred concentration is about 0.1 M. The volume is finally adjusted by addition of a suitable biocompatible fluid, preferably water for injection. The resulting bulk solution preferably contains 0.5 mg of lurbinectedin in 0.03 M sodium lactate buffer containing 10% (w / v) sucrose at pH = 4. The bulk solution is then filled into vials according to the desired doses.

[0091] In an embodiment, the dissolvable lurbinectedin is at least partially crystalline. The dissolvable lurbinectedin can be in a solid state as described herein. Crystalline lurbinectedin (including partially crystalline lurbinectedin) is found to be less soluble than amorphous lurbinectedin. As an example, direct dissolution of amorphous lurbinectedin at 0.5 mg / mL in 0.03 M sodium lactate buffer at pH 4 was complete in approximately 30 minutes, while partially crystalline lurbinectedin only reached 60-70% of the target concentration at 2 hours, which means it has even slower dissolution kinetics.

[0092] It has been found that lowering the pH accelerates the dissolution kinetics of partially crystalline lurbinectedin. Therefore, in an embodiment, a concentrated lurbinectedin solution is prepared with an organic acid before adding other additives. In a preferred embodiment, the organic acid has a pH of less than 4, preferably less than 3.5, more preferably less than 3, or approximately 3. The maximum solubility of lurbinectedin was investigated at different molar concentrations of the organic acid lactic acid. The solubility was high and increased linearly from 7.2 mg / ml in 0.05 M lactic acid to 90.4 mg / ml in 0.5 M lactic acid. In a preferred embodiment, lurbinectedin is soluble in an organic acid having a molar concentration of the organic acid of approximately 0.1 M to 0.5 M, preferably approximately 0.2 M to 0.4 M, more preferably approximately 0.3 M. An exemplary molar concentration is 0.31 M organic acid.

[0093] Lurbinectedin can be pre-dissolved with high concentration organic acid. In preferred embodiments, the pre-dissolution step is at least 30 minutes, at least 60 minutes, or at least 90 minutes, 30-90 minutes, 60-90 minutes, 60-70 minutes, or approximately 60 minutes. Following dissolution, the pre-dissolved solution can be diluted to form the required concentration, for example, 8.3 mg / ml. Dilution can include 1-fold, 2-fold, 3-fold, or more dilutions with WFI to obtain the target concentration. In embodiments, dilution is performed to achieve the desired concentration at the appropriate molar concentration. As an example, a 3-fold dilution adding 2 times the initial volume of organic acid can achieve 8.3 mg / mL in 0.1 M organic acid (e.g., lactic acid).

[0094] During manufacturing, there may be a limited internal dose for the dissolution step, and thus lurbinectedin dissolution is advantageously achieved with limited organic acid, so that by using organic acid with a high molar concentration, a high lurbinectedin concentration can be achieved in a limited organic acid volume.

[0095] In an embodiment, lurbinectedin is prepared using a multi-step synthesis strategy. Step 1 is the pre-dissolution step described above, for example: pre-dissolving partially crystalline lurbinectedin in 0.31 M lactic acid at 25 mg / mL, and diluting 3-fold with WFI to obtain a concentrated solution at 8.3 mg / mL in 0.1 M lactic acid. To avoid lurbinectedin precipitation, the remaining additives need to have an acidic pH when added to the formulation to be synthesized. It has been found that a highly concentrated lurbinectedin solution can be mixed with a buffer at a pH of 5.6 or less, for example 4-5.6 or 4.2-5.6, without lurbinectedin precipitation. Therefore, in step 2, an organic buffer containing a bulking agent (e.g., a disaccharide) can be prepared at a suitable pH. As an example, this can include the preparation of a 0.04 M sodium lactate buffer at a pH of approximately 4.2 containing sucrose. In step 3, the solutions from step 1 and step 2 are combined to form a final bulk solution. The final bulk solution can be adjusted with WFI to achieve a final target mass. As an example, in step 3, 8.3 mg / mL lurbinectedin concentrated solution in 0.1 M lactic acid at pH ≈ 3 is diluted with 0.04 M sodium lactate buffer at pH ≈ 4.2 containing sucrose. The final bulk solution composition after WFI adjustment to the final mass can be, as an example, 0.5 mg / mL lurbinectedin in 0.03 M sodium lactate buffer at pH = 4 + 10% (w / v) sucrose. Thus, the present invention identifies a synthetic strategy for formulating partially crystalline lurbinectedin.

[0096] In one embodiment, the lyophilized composition comprises or consists of 4 mg of lurbinectedin, 800 mg of sucrose, 22.1 mg of lactic acid, and 5.1 mg of sodium hydroxide. In some embodiments, the mass ratio of the lyophilized composition is 0.4%-0.6% (w / w) of the active compound, 96%-98% (w / w) of sucrose, 2%-3% (w / w) of lactic acid, and 0.5%-0.7% (w / w) of sodium hydroxide. In a preferred embodiment, the mass ratio of the lyophilized composition is 0.5% (w / w) of the active compound, 96.2% (w / w) of sucrose, 2.7% (w / w) of lactic acid, and 0.6% (w / w) of sodium hydroxide. The lyophilized formulation contains about 0.25 mmol of lactate ion per 4 mg of lurbinectedin. When reconstituted to 8 ml in a vial, the resulting solution is approximately pH 4.0 (range pH 3.5-4.5, preferably 3.8-4.5), 0.5 mg / ml lurbinectedin, 0.03 M sodium lactate buffer, 10% w / v sucrose.

[0097] The lyophilized material is typically present in a vial containing a fixed amount of lurbinectedin. Preferably, the lyophilized composition of lurbinectedin is provided in a 30 mL vial. The fixed amount of lurbinectedin in the lyophilized composition can be 0.2-5 mg, or about 1 mg, about 2 mg, about 3 mg, or about 4 mg. The fixed amount of lurbinectedin in the lyophilized composition is preferably 4 mg. In the lyophilized embodiment, the composition contains 0.4%-0.6% by weight of lurbinectedin, preferably 0.5%.

[0098] It is necessary to ensure that lurbinectedin is sterile and filled aseptically into vials, which is important for parenteral drugs. According to an embodiment of the present invention, terminal sterilization by heating or gamma irradiation is not used to avoid degradation of lurbinectedin. Instead, according to an embodiment of the present invention, sterile filtration of the bulk solution of lurbinectedin is performed before aseptic filling into vials. In an embodiment, the filter can be a filter such as PVDF or PES. In an embodiment, the filter can be a 0.2 μm filter.

[0099] Storage of lurbinectedin pharmaceutical formulations The present invention also provides a method for storing the lyophilized lurbinectedin composition. It is necessary to ensure that lurbinectedin is stable for at least 24 months. The lyophilized lurbinectedin formulation is storage stable such that lurbinectedin retains its therapeutic efficacy and exhibits minimal chemical degradation after long-term storage at 5°C±3°C (e.g., degradation is minimal and within acceptable tolerance; e.g., the profile of impurities and degradation products of lurbinectedin, the amount of each of the impurities and degradation products, and the lurbinectedin content, as determined by HPLC analysis, are substantially the same before and after long-term storage).

[0100] In one aspect, the lyophilized lurbinectedin compositions of the present disclosure minimize the amount of lurbinectedin degradation product resulting from deacetylation of lurbinectedin ("impurity D") (having a relative retention time of 0.87-0.88 by commercially available HPLC assay) when the compositions are stored for extended periods of time (e.g., at least 24 months). In some embodiments, the amount of impurity D present is less than 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, or 0.8% wt / wt of the total lurbinectedin mass in the formulation after extended storage at 5° C.±3° C. Impurities B, D, and G have the following structures:

[0101] [ka]

[0102] In a preferred embodiment, a method for storing a lyophilized lurbinectedin composition comprises storing a lyophilized composition comprising 4 mg of lurbinectedin; a lactate buffer; and a disaccharide at a temperature of 5°C ± 3°C for at least 24 months, wherein the lyophilized composition is formulated such that upon reconstitution with 8 mL of water, a solution having a pH of 3.5 to 4.5 and a lurbinectedin concentration of 0.5 mg / ml is obtained, and after storage for at least 24 months, the amount of impurity D present in the composition is less than or equal to 0.8% wt. / wt. of the total lurbinectedin mass. In some embodiments, the lyophilized lurbinectedin composition is stored at a temperature of 5° C.±3° C. for at least 24 months, 30 months, 36 months, 42 months, 48 ​​months, or 60 months, or for at least these periods, and after 24 months, 30 months, 36 months, 42 months, 48 ​​months, or 60 months of storage, the amount of lurbinectedin degradation product impurity D present in the composition is less than or equal to 0.8% wt. / wt. of the total lurbinectedin mass. In some embodiments, after 60 months of storage at about 5° C.±3° C., the amount of impurity D present in the composition is less than or equal to 0.8% wt. / wt. of the total lurbinectedin mass, or less than 0.7% wt. / wt., less than 0.6% wt. / wt., less than 0.5% wt. / wt., or less than 0.4% wt. / wt. In one embodiment, the amount of impurity D, a degradation product of lurbinectedin, present in the composition is 0.8% wt. / wt. or less of the total lurbinectedin mass after at least 36 months of storage. In some embodiments, the total % of impurities and degradation products (as % area) after 24 months, 30 months, or 36 months of storage at about 5° C.±3° C. is 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% (% area) or less. In some embodiments, the initial amount of impurity D present in the composition (i.e., on the first day of lyophilization) is less than 0.4% wt. / wt. of the total lurbinectedin mass. In some embodiments, the initial amount of impurity D present in the composition is at least 0.05% wt. / wt. or at least 0.1% wt. / wt. of the total lurbinectedin mass. In some embodiments, the initial amount of impurity D present in the composition is 0.8% wt. / wt. or less, 0.5% wt. / wt. or less, or 0.1% wt. / wt. or less of the total lurbinectedin mass.In some embodiments, after 24 months, 30 months, 36 months, 48 ​​months, or 60 months of storage at about 5°C ± 3°C, the stable lyophilized lurbinectedin formulations exhibit negligible degradation of the contents of the lurbinectedin assay, e.g., a reduction in the amount of lurbinectedin compared to the amount of lurbinectedin within 1.0%, 0.5%, or 0.2% of the total lurbinectedin mass compared to the bulk solution from which the formulation is made.

[0103] Thus, there is provided a stable lyophilized lurbinectedin formulation comprising an organic acid-derived buffer (e.g., an organic carboxylic acid buffer, such as a succinate buffer, a citrate buffer, an acetate buffer, or a lactate buffer) in a molar ratio of buffer to lurbinectedin of about 48, including a molar ratio of 52-46, 54-44, 50-48, 52-58, or a molar ratio of 51-48, as well as sucrose as a bulking agent, which upon reconstitution with 8 mL of water has a pH of about 4.0, including pH 3.5-4.5 or pH 3.8-4.1, and a pH of 0.8% wt / wt or less of the total mass of lurbinectedin. or less than 0.7% wt. / wt., less than 0.6% wt. / wt., less than 0.5% wt. / wt., or less than 0.4% wt. / wt., and preferably impurity D does not increase to more than 0.8% wt / wt of the total mass of lurbinectedin after 12 months, 24 months, 30 months, 36 months, 48 ​​months, or 60 months of storage at 5° C.±3° C.; or 3 months, 6 months, 9 months, 12 months, or 18 months of storage at 25° C. / 60% RH; or 1 month, 3 months, 6 months, or 12 months of storage at 40° C. / 60% RH. In these embodiments, the lurbinectedin is 95-105% or 97-103% of the amount of lurbinectedin assayed at lurbinectedin 4 mg or day 1.

[0104] Impurity D in the drug product is, in particular, lurbinectedin 4 mg or less per day by assay after 12 months, 24 months, 30 months, 36 months, 48 ​​months, or 60 months of storage at 5°C ± 3°C; or after 3 months, 6 months, 9 months, 12 months, or 18 months of storage at 25°C / 60% RH; or after 1 month, 3 months, 6 months, or 12 months of storage at 40°C / 60% RH. Also provided is a method for reducing decomposition of lurbinectedin in a lyophilized formulation comprising lurbinectedin by incorporating a buffer derived from an organic acid, preferably a lactate buffer or a succinate buffer, so that the amount of lurbinectedin in the lyophilized formulation does not exceed 0.5% wt / wt, 0.6% wt / wt, 0.7% wt / wt, or 0.8% wt / wt of the total mass of lurbinectedin when the amount of lurbinectedin in the lyophilized formulation is 95-105% or 97-103% of the total mass of lurbinectedin.

[0105] Other impurities or degradation products that may be minimized upon storage of the stable lyophilized lurbinectedin formulation may be degradation products having the following relative retention times in the commercial HPLC method: rrt 0.68, rrt 0.80, rrt 1.11 (impurity G), and rrt 1.12.

[0106] In a further embodiment, the total residual water content of the lyophilized lurbinectedin formulation is 3% (w / w) or less, preferably 1.5% (w / w) or less, preferably 1% (w / w) or less, preferably 0.5-0.7% (w / w).

[0107] An embodiment of the present invention further provides a pharmaceutical product comprising a vial containing a lyophilized lurbinectedin composition. In a preferred embodiment, the pharmaceutical product comprises a vial containing a lyophilized composition consisting of 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide (or containing about 0.25 mmol lactate); and 800 mg sucrose; and a label attached to the vial containing a use-by date that is at least 48 months from the date of manufacture. In some embodiments, the label attached to the vial contains a use-by date that is at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months from the date of manufacture. In some embodiments, the vial has a size of 30 mL to 50 mL, such as 30 mL, 35 mL, 40 mL, 45 mL, or 50 mL. In a preferred embodiment, the vial is a 30 mL vial. The 30 mL vial size is optimized to overcome the limitations of larger vial sizes that result in reduced production capacity by reducing the lyophilizer capacity, and the limitations of suitable extractable volume due to size. The 30 mL vial size overcomes both of these limitations.

[0108] Solid forms of lurbinectedin and uses thereof In an embodiment according to the present invention, the pre-lyophilized lurbinectedin comprises at least some crystalline material. The pre-lyophilized lurbinectedin can be partially crystalline. The use of partially crystalline pre-lyophilized lurbinectedin provides advantages, including better control of impurities and / or degradation products.

[0109] The present invention identifies a novel solid state of lurbinectedin that is easier to handle under typical pharmaceutical processing conditions than the known amorphous form (hereinafter, form A). Amorphous form A can be obtained by the method described in WO03 / 014127. Form A becomes electrostatically charged during its operation, causing production problems. Therefore, there is a need to obtain a form of lurbinectedin that is easier to handle under typical pharmaceutical processing conditions.

[0110] In an embodiment according to the present invention, a novel solid state of lurbinectedin is provided, hereinafter referred to as Form B of lurbinectedin. Form B exhibits advantageous physical properties compared to the known Form A. For example, Form B exhibits improved triboelectric properties over known forms of lurbinectedin. Triboelectric charging is the process by which a certain material becomes electrically charged after contacting a different material through friction. In many pharmaceutical operations, uncontrolled static electricity can cause significant production problems. These problems include product contamination, product loss, cleaning, and safety, and the problems can be exacerbated with nanomolar sized cytotoxic drugs such as lurbinectedin. Even in the most rigorous clean rooms, it is important to take appropriate measures to ensure that static charges are kept to a minimum, as they attract particulates from people, processes, and equipment.

[0111] Form B exhibits a lower average charge density than known forms of lurbinectedin. Form B also exhibits a narrower charge density distribution than known forms of lurbinectedin. Form B of lurbinectedin has less residual solvent than known forms of lurbinectedin. Form B also has a simplified impurity profile compared to known forms of lurbinectedin. These characteristics are particularly suitable for the preparation of pharmaceuticals. Pre-lyophilized lurbinectedin may contain Form B. The amount of Form B may vary and may be considered a crystalline mixture (partially crystalline). In other embodiments, the crystalline mixture may contain other crystalline lurbinectedin (e.g., crystalline lurbinectedin that is not Form B).

[0112] In a further embodiment, the present invention relates to a method for preparing lurbinectedin form B, comprising the steps of: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or a basic buffer to precipitate lurbinectedin form B. Lurbinectedin form B can be substantially converted into a different physical form, preferably an amorphous form. Form B can be used in the manufacturing process to prepare a lyophilized bulk product.

[0113] In a further embodiment, the present invention relates to a pharmaceutical composition comprising lurbinectedin Form B and a pharma- ceutically acceptable carrier. Such a composition may be a pre-lyophilized composition.

[0114] In a further embodiment, the invention relates to a pharmaceutical composition comprising lurbinectedin, prepared using lurbinectedin form B and a pharma- ceutically acceptable carrier. The pharmaceutical composition may no longer contain any form B of lurbinectedin, but the process for preparing the composition utilized at least some form B in one or more steps. In a further embodiment, the invention relates to form B of lurbinectedin for use in preparing a pharmaceutical composition comprising lurbinectedin. In yet a further embodiment, the invention relates to the use of form B of lurbinectedin in preparing a pharmaceutical composition comprising lurbinectedin. In yet a further embodiment, the invention relates to form B of lurbinectedin for use as a pharmaceutical. Again, form B may no longer be present in the final composition, but may be utilized during preparation.

[0115] In a further embodiment, the present invention relates to a composition comprising lurbinectedin form B and a pharma- ceutically acceptable carrier for use as a medicament. In a further embodiment, the present invention relates to lurbinectedin form B for use as a medicament for treating cancer. In a further embodiment, the present invention relates to a composition comprising lurbinectedin form B and a pharma- ceutically acceptable carrier for use as a medicament for treating cancer.

[0116] In a further embodiment, the present invention relates to a method for the preparation of a pharmaceutical composition comprising lurbinectedin, preferably utilizing lurbinectedin form B as a starting material.

[0117] In a further embodiment, the present invention also relates to the use of lurbinectedin form B, or a pharmaceutical composition comprising lurbinectedin form B and a pharmaceutically acceptable carrier, in the treatment of cancer. In a further embodiment, the present invention also relates to the use of lurbinectedin form B, or a pharmaceutical composition comprising lurbinectedin form B and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating cancer. Another embodiment of the present invention is lurbinectedin form B for use in these methods of treatment. Thus, the present invention further provides a method of treating any mammal, particularly a human, affected by cancer, comprising administering to the affected individual a therapeutically effective amount of lurbinectedin form B, or a pharmaceutical composition comprising lurbinectedin form B and a pharmaceutically acceptable carrier; or a pharmaceutical composition made from a method utilizing lurbinectedin form B.

[0118] The present invention further provides a method of treating any mammal, particularly a human, affected by cancer, comprising administering to the affected individual a therapeutically effective amount of lurbinectedin, which has been prepared via lurbinectedin form B. The present invention further provides a method of treating any mammal, particularly a human, affected by cancer, comprising administering to the affected individual a therapeutically effective amount of a pharmaceutical composition comprising lurbinectedin, which has been prepared via lurbinectedin form B, and a pharma- ceutically acceptable carrier.

[0119] In further embodiments, the present invention relates to lurbinectedin having a water content of 1%, 0.5%, 0.1% or less, or substantially no detectable residual solvent. In further embodiments, the present invention relates to lurbinectedin having a water content of greater than 1.6% w / w, or between 1.7-5% w / w. In further embodiments, the present invention relates to lurbinectedin having a water content of 5%, 4%, or 3% w / w or less.

[0120] For the solid state of lurbinectedin, the alkanes of the present invention can be branched or unbranched and have about 5 to about 10 carbon atoms. One more preferred class of alkanes has 5 to 9 carbon atoms. Even more preferred are alkanes having 5, 6, or 7 carbon atoms. Particularly preferred alkanes of the present invention are n-pentane, n-hexane, n-heptane, cyclohexane, and methylcyclohexane. As used herein, the term alkane refers to both cyclic and non-cyclic alkanes, unless otherwise indicated.

[0121] Pharmaceutically acceptable solvents for the solid state of lurbinectedin are those classified as Class 2 and Class 3 in the International Council for Harmonisation (ICHarmonisation) guidelines "Impurities: Residual Solvents Q3C(R6)".

[0122] In one embodiment, the present invention relates to form B of lurbinectedin.

[0123] Form B of lurbinectedin may be characterized by exhibiting an X-ray powder diffractogram pattern that includes four or more characteristic peaks at 2-theta angles selected from 6.2±0.2°, 7.6±0.2°, 9.0±0.2°, 10.9±0.2°, 14.9±0.2°, and 15.3±0.2°. Alternatively, form B may be characterized by exhibiting an X-ray powder diffractogram pattern that includes five or more of said characteristic peaks. Alternatively, form B may be characterized by exhibiting an X-ray powder diffractogram pattern that includes all six of said characteristic peaks.

[0124] In particular, lurbinectedin form B can be characterized by an X-ray powder diffraction pattern comprising the peaks and intensities shown in the table below.

[0125] [Table 1]

[0126] In a preferred embodiment, additional peaks can be found at 2-theta angles of 12.4±0.2°, 19.2±0.2°, and 26.5±0.2°. In particular, lurbinectedin form B can be characterized by an X-ray powder diffraction pattern comprising the characteristic peaks and intensities shown in the table below.

[0127] [Table 2]

[0128] In a more preferred embodiment, additional peaks can be found at 2-theta angles of 18.4±0.2°, 20.7±0.2°, and 24.9±0.2°. In particular, lurbinectedin form B can be characterized by an X-ray powder diffraction pattern comprising the characteristic peaks and intensities shown in the table below.

[0129] [Table 3]

[0130] In a most preferred embodiment, the present invention relates to Form B of lurbinectedin, which exhibits an X-ray powder diffraction pattern substantially the same as any one of the X-ray powder diffraction patterns shown in Figure 2a or Figure 2b.

[0131] Additionally, lurbinectedin form B can be characterized by exhibiting an IR spectrum that includes peaks at wavelengths of 2928, 1755, 1626, 1485, 1456, 1370, 1197, 1150, 1088, 1003, 959, 916, and 587. An exemplary IR spectrum is shown in Figure 7b.

[0132] Additionally, lurbinectedin form B can be characterized by TG-FTIR decomposition above 150° C. Alternatively, or in addition, lurbinectedin form B can be characterized by TG-FTIR mass change due to loss of water up to 150° C. The loss of water can be less than about 5%, less than about 4%, or less than about 3%. Alternatively, or in addition, lurbinectedin form B can be characterized by TG-FTIR showing loss of water, preferably approximately 2-3% water by weight, more preferably 2.6% water by weight. An exemplary TG-FTIR is shown in FIG. 3.

[0133] In addition, lurbinectedin form B can be characterized by DSC, with decomposition beginning above 130° C. An exemplary DSC thermogram is shown in FIG.

[0134] In one embodiment, lurbinectedin form B has an average charge density of about 30 nC / g or less, about 20 nC / g or less, about 10 nC / g or less, about 6 nC / g or less, about 5 nC / g or less, about 5±2 nC / g, about 4±2 nC / g, about 4-5 nC / g, about 5 nC / g, or about 4 nC / g. In one embodiment, lurbinectedin form B has a charge density variance of less than 4.8 nC / g, between about 0.7 nC / g and less than 4.8 nC / g, or 2.4±2 nC / g. In one embodiment, lurbinectedin form B has a water content of greater than 1.6% w / w, or between 1.7-5% w / w. In one embodiment, lurbinectedin form B has less than 1%, 0.5%, 0.1%, or substantially no residual solvent.

[0135] The present invention encompasses lurbinectedin comprising at least a detectable amount of form B, up to 1% w / w of form B, up to 5% w / w of form B, up to 10% w / w of form B, up to 20% w / w of form B, up to 30% w / w of form B, up to 40% w / w of form B, up to 50% w / w of form B, up to 60% w / w of form B, up to 70% w / w of form B, up to 80% w / w of form B, up to 90% w / w of form B, up to 95% w / w of form B, up to 98% w / w of form B, or substantially pure form B. In one embodiment, the partially crystalline lurbinectedin described herein may contain at least a detectable amount of form B, up to 1% w / w of form B, up to 5% w / w of form B, up to 10% w / w of form B, up to 20% w / w of form B, up to 30% w / w of form B, up to 40% w / w of form B, up to 50% w / w of form B, up to 60% w / w of form B, up to 70% w / w of form B, up to 80% w / w of form B, up to 90% w / w of form B, up to 95% w / w of form B, up to 98% w / w of form B, or may be substantially pure form B. W / w is intended to refer to the amount of lurbinectedin that is in form B. Thus, purely by way of example, 50% w / w means that the lurbinectedin API contains 50% form B and 50% by weight of another form, such as amorphous form A.

[0136] In one embodiment, the present invention provides a method for preparing lurbinectedin form B, comprising: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or buffer to precipitate lurbinectedin form B. The present invention relates to a method comprising the steps of:

[0137] In step a), a solution of lurbinectedin in acidic water is provided.Examples of methods for preparing such a solution include, but are not limited to, dissolving any solid form of lurbinectedin in acidic water; or extracting lurbinectedin from a solution containing lurbinectedin in a water-immiscible organic phase into acidic water.In a preferred embodiment, the acidic aqueous solution of lurbinectedin is obtained by dissolving lurbinectedin in acidic water.

[0138] Any form of lurbinectedin, such as amorphous lurbinectedin, can be used to form crystalline lurbinectedin. The concentration of lurbinectedin in acidic water can range from about 10 to about 50 g / L. Particularly preferred is a concentration of about 15 to about 40 g / L, and more preferably a concentration of about 20 to about 30 g / L. The most preferred concentration of lurbinectedin in acidic water is about 26 g / L.

[0139] The preferred pH of the acidic water may range from about 1 to about 4, more preferably from about 1 to about 3, even more preferably from about 1 to about 2, and most preferably about 1. The acidic conditions may be provided by an acid or a buffer. Suitable pharma- ceutically acceptable acids include carboxylic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, aliphatic and aromatic carboxylic acids. More preferred acids include hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, nitrobenzoic acid, and citric acid. A suitable acidic buffering agent provides a pH of about 1 to about 4. Examples of suitable acidic buffering agents include, but are not limited to, phosphate buffers, citrate buffers, lactate buffers, ascorbic acid buffers, tartaric acid / citric acid buffers, bicarbonate / hydrochloric acid buffers, acetate buffers, succinic acid buffers, and glycine / hydrochloric acid buffers. More preferably, the acidic conditions are provided by an acid, and most preferably, the acid is hydrochloric acid. The preferred pH of a solution of lurbinectedin in acidic water can range from about 1 to about 4, from about 1 to about 3, or from about 2 to about 3.

[0140] In step b), the resulting acidic aqueous solution is treated with an excess of base or buffer to basify it and precipitate lurbinectedin form B. The basification can be carried out with a base or buffer. The preferred pH of the resulting basic solution can range from about 8 to about 11, most preferably from about 9 to about 11. Suitable pharma- ceutically acceptable bases include carbonates, hydroxides, bicarbonates, and ammonium salts. Particularly preferred bases are sodium carbonate, potassium carbonate, NH4OH, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate. Suitable basic buffers provide a pH of about 8 to about 11. Examples of suitable basic buffers include ammonium and phosphate buffers, such as KH2PO4 buffers, Na2HPO4 / citric acid, and NH4Cl-NH4OH. In a preferred embodiment, the basification is carried out with a buffer, and in a most preferred embodiment, the basification is carried out with NH4Cl-NH4OH buffers.

[0141] The obtained lurbinectedin form B can be separated by an isolation procedure such as filtration or centrifugation, preferably filtration. Furthermore, after separation, the separated solid can be subjected to a drying treatment by any known method. The precipitate can be dried, preferably under vacuum, at a temperature preferably in the range of about 15 to 35°C, more preferably about 20 to 30°C, most preferably about 25°C, for a time preferably in the range of about 10 to 24 hours, more preferably about 16 to 20 hours, most preferably about 18 hours.

[0142] In a preferred embodiment, the acidic aqueous solution obtained after step a) is washed one or more times with a pharma- ceutically acceptable, water-immiscible polar solvent and one or more times with a pharma-ceutically acceptable, water-immiscible non-polar solvent, and then treated with an excess of base or buffer in step b).

[0143] Examples of pharma- ceutically acceptable, water-immiscible polar solvents suitable for this wash include chloroform, 1-butanol, 2-butanol, butyl acetate, ethyl acetate, methyl acetate, 1-pentanol, propyl acetate, and dichloromethane. More preferred pharma-ceutically acceptable, water-immiscible polar solvents for this wash are chloroform, ethyl acetate, and dichloromethane, and most preferred is dichloromethane.

[0144] Preferred pharma- ceutically acceptable, water-immiscible non-polar solvents suitable for this wash include C5-C7 alkanes, such as n-heptane, n-hexane, n-pentane, cyclohexane, and methylcyclohexane; most preferred is n-pentane.

[0145] In one embodiment, the present invention relates to a pharmaceutical composition comprising lurbinectedin form B and a pharma- ceutically acceptable carrier, or a pharmaceutical composition prepared from lurbinectedin comprising form B. The lurbinectedin used in the composition or used during preparation of the composition may comprise lurbinectedin that comprises at least a detectable amount of form B, up to 1% w / w of form B, up to 5% w / w of form B, up to 10% w / w of form B, up to 20% w / w of form B, up to 30% w / w of form B, up to 40% w / w of form B, up to 50% w / w of form B, up to 60% w / w of form B, up to 70% w / w of form B, up to 80% w / w of form B, up to 90% w / w of form B, up to 95% w / w of form B, up to 98% w / w of form B, or is substantially pure form B.

[0146] The partially crystalline lurbinectedin disclosed herein, in embodiments, may comprise at least a detectable amount of Form B, up to 1% w / w of Form B, up to 5% w / w of Form B, up to 10% w / w of Form B, up to 20% w / w of Form B, up to 30% w / w of Form B, up to 40% w / w of Form B, up to 50% w / w of Form B, up to 60% w / w of Form B, up to 70% w / w of Form B, up to 80% w / w of Form B, up to 90% w / w of Form B, up to 95% w / w of Form B, up to 98% w / w of Form B, or may be substantially pure Form B. In alternative embodiments, other non-Form B crystalline lurbinectedin may form partially crystalline lurbinectedin in the same w / w amount.

[0147] Partially crystalline lurbinectedin disclosed herein can be used to form a pharmaceutical composition according to the present invention. Thus, in an embodiment, partially crystalline lurbinectedin is used to prepare a bulk solution of lurbinectedin that is then lyophilized to form a lyophilized lurbinectedin formulation. Partially crystalline lurbinectedin can include Form B disclosed herein.

[0148] Even if partially crystalline lurbinectedin may not be present in the final dosage form (due to the dissolution and subsequent lyophilization steps), it may nevertheless affect the properties of the final dosage form. As an example, the use of partially crystalline lurbinectedin may reduce and / or simplify the total impurities, including degradation products. A characteristic impurity profile may indicate the use of partially crystalline lurbinectedin during manufacturing. According to one embodiment, the total degradation products in the final lyophilized product may be not more than 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, or 1.3% (NMT). In a preferred embodiment, the total degradation products may be 1.3% NMT. ​​According to a further embodiment, the final lyophilized product contains 0.8% NMT of impurity D. According to a further embodiment, the final lyophilized product contains 0.3% NMT of any unspecified impurity.

[0149] The use of partially crystalline lurbinectedin can also advantageously control residual solvents, hi one embodiment, lurbinectedin contains 0.2% or less residual solvents, preferably 0.1% or less residual solvents, preferably substantially no detectable residual solvents.

[0150] In one embodiment, the partially crystalline lurbinectedin used in the manufacture of the compositions disclosed herein may have an Assay (%) in the range of 94.0-102.0% and an impurity level of less than 1.0%. The specific impurities and their limits may be Impurity B (0.20% or less), Impurity D (0.50% or less), and / or Impurity G (0.50% or less). Any other individual unspecified impurities may have a limit of 0.20% or less.

[0151] Use of lurbinectedin pharmaceutical formulations The present invention identifies several methods of treatment using lurbinectedin alone or in combination with additional agents.When referring to methods of treatment, the present invention also includes lurbinectedin and / or said additional agents in the manufacture of a medicament for the treatment of cancer, and lurbinectedin and / or said additional agents for use in the treatment of cancer.The following methods can utilize the compositions of the present invention as defined herein.

[0152] In some embodiments, the method of treating SCLC in a patient in need thereof thus comprises: (1) administering lurbinectedin to the patient at 3.2 mg / m 2 (or reduced dose of 2.6 mg / m 2 or 2.0 mg / m 2The method includes administering by intravenous infusion of a lurbinectedin infusion solution at about 3.8 to about 4.5, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg lurbinectedin to be reconstituted, a lactate buffer, and a disaccharide to form a reconstituted solution at a pH of 3.8 to 4.5. In a preferred embodiment, the disaccharide is sucrose. In a preferred embodiment, the lyophilized composition comprises 4 mg lurbinectedin, a lactate buffer (preferably obtained from a solution comprising 22.1 mg lactic acid and 5.1 mg sodium hydroxide, containing about 0.25 mmol of lactate), and a disaccharide (preferably sucrose, particularly 800 mg sucrose), and reconstitution of the lyophilized composition with about 8 mL of aqueous solution produces a lurbinectedin solution at 0.5 mg / mL lurbinectedin having a pH of about 3.8 to about 4.5. In some embodiments, the lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution, which is a 0.9% sodium chloride solution or a 5% dextrose solution. In some embodiments, the reconstituted solution is diluted with at least 100 mL or at least 250 mL of an isotonic solution to prepare the lurbinectedin infusion solution. In some embodiments, after reconstitution or dilution, the solution can be stored under either room temperature (i.e., about 23° C.) / light or refrigerated (5° C.±3° C.) conditions for up to 24 hours (including the time of infusion) following reconstitution. In certain embodiments, the % wt / wt of impurity D relative to lurbinectedin does not increase higher than 0.1%, 0.2%, or 0.3% wt / wt upon storage of the reconstituted or diluted solution under either room temperature (i.e., about 23° C.) / light or refrigerated (5° C.±3° C.) conditions for 24, 48, or 72 hours.

[0153] Some embodiments provide a method of administering a pharmaceutical composition to a patient in need thereof, e.g., a patient suffering from SCLC refractory to first line treatment, comprising the steps of: (1) reconstituting a lyophilized pharmaceutical composition in a vial after storing the composition for 30-36, or 48 months, where the lyophilized pharmaceutical composition is prepared by lyophilizing a stock solution containing lurbinectedin, lactic acid, sodium hydroxide, and sucrose in a ratio of 4 mg lurbinectedin: 22.1 mg lactic acid: 5.1 mg sodium hydroxide: 800 mg sucrose: 8 mL water; and (2) administering the reconstituted solution to the patient, where the reconstituted solution may be diluted with an isotonic solution, such as 0.9% sodium chloride solution or 5% dextrose solution, from a volume of 100 ml to 250 ml for administration to the patient as an infusion solution.

[0154] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of Uses are provided, including

[0155] In a further aspect, there is provided the use of a corticosteroid in the manufacture of a medicament for treating small cell lung cancer (SCLC), said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering a prophylactic dose of said corticosteroid and serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of Uses are provided, including

[0156] In a further aspect, use of a serotonin antagonist in the manufacture of a medicament for treating small cell lung cancer (SCLC), wherein the treatment comprises: (1) administering to the patient, on the day of and prior to administration of lurbinectedin, a prophylactic dose of corticosteroid and said serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) administering lurbinectedin to the patient by intravenous infusion at a dose of 2 - 3.2 mg / m 2 is provided.

[0157] In a further aspect, use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), wherein the method comprises: (1) administering to the patient by intravenous infusion a first dose of 3.2 mg / m 2 of lurbinectedin; and (2) identifying an adverse reaction in the patient, wherein the adverse reaction is selected from the group consisting of grade 3 (severe) or higher non - hematological toxicity, grade 4 thrombocytopenia (platelet count < 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count < 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count < 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction; (3) after identifying the adverse reaction, when the patient's neutrophil count is greater than 1500 cells / mm 3 ; platelet count is greater than about 100,000 cells / mm 3 ; and hemoglobin level is higher than about 9 g / dL: (i) if the identified adverse reaction is grade 4 neutropenia (500 cells / mm 3 ​If it consists of (number of neutrophils less than), administering to the patient a certain dose of G-CSF and a dose of lurbinectedin equal to the first dose; or (ii) If the identified adverse reaction is not only grade 4 neutropenia, administering to the patient a dose of lurbinectedin reduced compared to the first dose comprising The administration of two doses of lurbinectedin is spaced at least 21 days apart is provided for use

[0158] In a further aspect, the use of G-CSF in the manufacture of a medicament for treating small cell lung cancer (SCLC), wherein the method is (1) Administering to the patient by intravenous infusion a first dose of 3.2 mg / m 2 of lurbinectedin; and (2) Identifying an adverse reaction in the patient, wherein the adverse reaction is selected from the group consisting of grade 3 (severe) or higher non-hematological toxicity, grade 4 thrombocytopenia (number of platelets less than 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (number of platelets less than 50,000 cells / mm 3 ), grade 4 neutropenia (number of neutrophils less than 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction (3) After identifying the adverse reaction, when the patient's neutrophil count is greater than 1500 cells / mm 3 ; platelet count is greater than about 100,000 cells / mm 3 ; hemoglobin level is higher than about 9 g / dL: (i) If the identified adverse reaction consists of grade 4 neutropenia (number of neutrophils less than 500 cells / mm 3 ), administering to the patient a certain dose of G-CSF and a dose of lurbinectedin equal to the first dose; or (ii) administering to the patient a reduced dose of lurbinectedin compared to the first dose if the identified adverse reaction is not solely grade 4 neutropenia. Including, The two doses of lurbinectedin are administered at least 21 days apart. Use is provided.

[0159] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), the method comprising: Patients were administered lurbinectedin at 3.2 mg / m 2 by intravenous infusion of a lurbinectedin infusion solution at a dose of 4 mg of lurbinectedin, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a reconstituted solution at a pH of 3.5 to 4.5. Uses are provided, including

[0160] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer, said treatment comprising: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to Use is provided.

[0161] In a further aspect, the present invention relates to the use of a topoisomerase inhibitor selected from SN-38 and irinotecan in the manufacture of a medicament for treating endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer, said treatment comprising: administering to the patient lurbinectedin and said topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to Use is provided.

[0162] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating cancer, said treatment comprising: Reconstituting the lyophilized pharmaceutical composition in a vial after storing the composition for 30 to 60 months, A lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution containing 4 mg of lurbinectedin, a buffering agent derived from an organic carboxylic acid, and sucrose; the composition comprises lurbinectedin and a disaccharide in a ratio of 1 mol lurbinectedin to 455 to 465 mol sucrose disaccharide; The lyophilized composition is formulated so that upon reconstitution with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained; and Administering the reconstituting solution to the patient. Uses are provided, including

[0163] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), said treatment comprising: Lurbinectedin at 2–3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of Including, The patient is administered an immunotherapeutic antibody to treat SCLC prior to beginning a treatment cycle; the duration of response is at least 2, 3, 4, 5, or 6 months, or the overall response rate is at least 40%; Use is provided. In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), said treatment comprising: Lurbinectedin 2-3.2 mg / m every 3 weeks 2 to a patient by intravenous infusion at a dose of Lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, a lactic acid derived buffer, and sucrose, wherein the ratio of lurbinectedin:lactic acid:sucrose is 1 mol:46 mol:455 mol to 1 mol:50 mol:465 mol, and the formulation is stable at 5°C±3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months, such that deacetylation-derived lurbinectedin degradation products do not exceed 0.8% wt. / wt. of the total lurbinectedin mass. Use is provided.

[0164] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating small cell lung cancer (SCLC), said treatment comprising: 1) dissolving a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.5 to about 4.1; and 2) Approximately 2 to 3.2 mg / m every 3 weeks 2 administering lurbinectedin of formula (I) to patients whose SCLC has progressed after prior platinum-containing therapy by intravenous infusion. Including, the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage at about 5° C. for about 24, 36, or 48 months, the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin); Use is provided.

[0165] In a further aspect, lurbinectedin for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) 2 to 3.2 mg / m 2 administering lurbinectedin to the patient by intravenous infusion at a dose of Lurbinectedin is provided, comprising:

[0166] In a further aspect, a corticosteroid for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering a prophylactic dose of said corticosteroid and serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of Corticosteroids are provided, including

[0167] In a further aspect, a serotonin antagonist for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering a prophylactic dose of a corticosteroid and said serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of Serotonin antagonists are provided, including:

[0168] In a further aspect, there is provided lurbinectedin for use in treating small cell lung cancer (SCLC), the method comprising: (1) First dose 3.2 mg / m 2 administering lurbinectedin of the formula (I) to a patient by intravenous infusion; and (2) A step of identifying an adverse reaction in a patient, wherein the adverse reaction is a non-hematological toxicity of grade 3 (severe) or higher, grade 4 thrombocytopenia (platelet count less than 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count less than 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction, selected from the group consisting of; (3) After identifying the adverse reaction, when the patient's neutrophil count is greater than 1500 cells / mm 3 ; platelet count is greater than about 100,000 cells / mm 3 ; and hemoglobin level is higher than about 9 g / dL: (i) If the identified adverse reaction consists of grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), administering to the patient a dose of G-CSF and a dose of lurbinectedin equal to the first dose; or (ii) If the identified adverse reaction is not only grade 4 neutropenia, administering to the patient a dose of lurbinectedin reduced compared to the first dose comprising, administering two doses of lurbinectedin at least 21 days apart, lurbinectedin is provided.

[0169] In a further aspect, G-CSF for use in the treatment of small cell lung cancer (SCLC), wherein the method is (1) A step of intravenously injecting a patient with a first dose of 3.2 mg / m 2 of lurbinectedin; and (2) A step of identifying an adverse reaction in a patient, wherein the adverse reaction is a non-hematological toxicity of grade 3 (severe) or higher, grade 4 thrombocytopenia (platelet count less than 25,000 cells / mm 3Grade 3 thrombocytopenia (platelet count < 50,000 cells / mm) with bleeding requiring transfusion, 3 Grade 4 neutropenia (neutrophil count < 500 cells / mm), 3 or any grade of neutropenia (neutrophil count < LLN) associated with infection / sepsis or any other adverse reaction, a step selected from the group consisting of; (3) After identifying the adverse reaction, when the patient's neutrophil count is greater than 1500 cells / mm 3 ; platelet count is greater than about 100,000 cells / mm 3 ; and hemoglobin level is higher than about 9 g / dL: (i) If the identified adverse reaction consists of Grade 4 neutropenia (neutrophil count < 500 cells / mm), 3 administering to the patient a dose of G-CSF and a dose of lurbinectedin equal to the first dose; or (ii) If the identified adverse reaction is not only Grade 4 neutropenia, administering to the patient a reduced dose of lurbinectedin compared to the first dose comprising, administering two doses of lurbinectedin at least 21 days apart, G-CSF is provided.

[0170] In a further aspect, lurbinectedin for use in the treatment of small cell lung cancer (SCLC), wherein the method comprises administering lurbinectedin to a patient by intravenous infusion of a lurbinectedin infusion solution at a dose of 3.2 mg / m 2 , preparing the lurbinectedin infusion solution administered to the patient from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a solution reconstituted at a pH of 3.5 - 4.5, a step comprising, lurbinectedin is provided.

[0171] In a further aspect, lurbinectedin for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer, said treatment comprising: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to Lurbinectedin is provided.

[0172] In a further aspect, a topoisomerase inhibitor selected from SN-38 and irinotecan for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer, said treatment comprising: administering to the patient lurbinectedin and said topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to Topoisomerase inhibitors are provided.

[0173] In a further aspect, lurbinectedin for use in the treatment of cancer, said treatment comprising: Reconstituting the lyophilized pharmaceutical composition in a vial after storing the composition for 30 to 60 months, A lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution containing 4 mg of lurbinectedin, a buffering agent derived from an organic carboxylic acid, and sucrose; The composition comprises lurbinectedin and a disaccharide in a ratio of lurbinectedin 1 mol:sucrose 455-465 mol; The lyophilized composition is formulated so that upon reconstitution with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained; and Administering the reconstituting solution to the patient. Lurbinectedin is provided, comprising:

[0174] In a further aspect, lurbinectedin for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: Lurbinectedin at 2–3.2 mg / m 2 administering to a patient by intravenous infusion at a dose of Including, The patient is administered an immunotherapeutic antibody to treat SCLC prior to beginning a treatment cycle; the duration of response is at least 2, 3, 4, 5, or 6 months, or the overall response rate is at least 40%; Lurbinectedin is provided.

[0175] In a further aspect, lurbinectedin for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: Lurbinectedin 2-3.2 mg / m every 3 weeks 2 to a patient by intravenous infusion at a dose of Lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, and sucrose, wherein the ratio of lurbinectedin:lactic acid:sucrose is 1 mol:46 mol:455 mol to 1 mol:50 mol:465 mol, and the formulation is stable at 5°C ± 3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months, such that lurbinectedin degradation products derived from deacetylation do not exceed 0.8% wt. / wt. of the total lurbinectedin mass. Lurbinectedin is provided.

[0176] In a further aspect, lurbinectedin for use in the treatment of small cell lung cancer (SCLC), said treatment comprising: 1) dissolving a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.5 to about 4.1; and 2) Approximately 2 to 3.2 mg / m every 3 weeks 2 administering lurbinectedin of formula (I) to patients whose SCLC has progressed after prior platinum-containing therapy by intravenous infusion. Including, the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage at about 5° C. for about 24, 36, or 48 months, the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin); Lurbinectedin is provided.

[0177] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating a solid tumor, including SCLC, endometrial carcinoma, soft tissue sarcoma, or glioblastoma, said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) 2 mg / m 2 and lurbinectedin at a dose of 75 mg / m 2 administering the irinotecan to the patient by intravenous infusion. Uses are provided, including

[0178] In a further aspect, there is provided the use of a corticosteroid in the manufacture of a medicament for treating a solid tumor, said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering a prophylactic dose of said corticosteroid and serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) 2 mg / m 2 and lurbinectedin at a dose of 75 mg / m 2 administering irinotecan to the patient by intravenous infusion at a dose of Uses are provided, including

[0179] In a further aspect, the present invention relates to the use of a serotonin antagonist in the manufacture of a medicament for treating a solid tumor, including SCLC, endometrial carcinoma, soft tissue sarcoma, or glioblastoma, said treatment comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering a prophylactic dose of a corticosteroid and said serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) 2 mg / m 2 and lurbinectedin at a dose of 75 mg / m 2 administering irinotecan to the patient by intravenous infusion at a dose of Uses are provided, including

[0180] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating a solid tumor, including SCLC, endometrial carcinoma, soft tissue sarcoma, or glioblastoma, said treatment comprising: (1) 2 mg / m 2 and lurbinectedin at a dose of 75 mg / m 2 administering irinotecan to the patient by intravenous infusion at a dose of (2) 7 days later, irinotecan 75 mg / m 2 administering to the patient by intravenous infusion at a dose of (3) administering G-CSF to the patient to manage the myelosuppressive effects of the administration. Uses are provided, including

[0181] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating a solid tumor, including SCLC, endometrial carcinoma, soft tissue sarcoma, or glioblastoma, the method comprising: (1) 2 mg / m 2and lurbinectedin at a dose of 75 mg / m 2 administering irinotecan to the patient by intravenous infusion at a dose of (2) identifying whether the patient experiences grade 3 or 4 hematological toxicity following said administration; (3) 75 mg / m 2 on day 7 after step 1 if the patient is free of grade 3 or grade 4 hematological toxicity. 2 administering a dose of irinotecan to the patient by intravenous infusion. Uses are provided, including

[0182] In a further aspect, there is provided a use of lurbinectedin in the manufacture of a medicament for treating a solid tumor, said method comprising: Patients were administered lurbinectedin at 2.0 mg / m 2 and 75 mg / m 2 administering a dose of irinotecan to a patient by intravenous infusion, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a reconstituted solution at a pH of 3.5 to 4.5. Uses are provided, including EXAMPLES

[0183] Example 1 Preparation of lurbinectedin in various buffers Bulk lurbinectedin solutions containing 0.5 mg / mL (calculated reconstituted concentration of 0.47 mg / mL based on a final volume of 8.55 mL) were prepared in acetate, citrate, lactate, and succinate buffer solutions with buffer concentrations of 0.02-0.05 M, buffered with sodium hydroxide to pH 3, 4, and 5. An example of a lactate-containing lurbinectedin formulation buffered to pH=4 is shown in Table 1 below.

[0184] [Table 4]

[0185] Example 2 Solubility of lurbinectedin in various buffers Bulk solutions of phosphate, acetate, citrate, lactate and succinate buffers were prepared to determine the maximum solubility of lurbinectedin. Table 2 shows the maximum solubility of lurbinectedin in 0.02M-0.05M or 0.06-0.1M buffers at pH=4. The results show that lurbinectedin was not significantly solubilized in phosphate buffers. The results also suggest that the molar concentration of the buffer has little effect on the solubility.

[0186] [Table 5]

[0187] Example 3 Stability of lurbinectedin formulations with different organic carboxy buffers at different pH values Stability and solubility studies were performed to determine the pH at which lurbinectedin exhibits good stability. Table 3 shows the solubility and impurity and degradation product profile of lurbinectedin in different 0.02M to 0.05M buffers at pH 3, pH 4, and pH 5. The solubility was similar at pH 3 and pH 4, and decreased dramatically at pH 5. This decrease in solubility was accompanied by an increase in degradation products as the buffer pH increased.

[0188] [Table 6]

[0189] The stability of lurbinectedin in various buffers was further evaluated at 25° C. / 60% RH conditions on day 14. Lurbinectedin is relatively stable at pH 3 and 4, but a significant decrease in assay and purity is observed at pH=5 (Table 4).

[0190] [Table 7]

[0191] These results showed that organic carboxy buffers with a pH of 4.5 or less were most suitable for increasing the concentration of lurbinectedin in solution and maintaining adequate stability. Sodium lactate and sodium citrate buffers were considered to be the most suitable.

[0192] Example 4 Stability of lyophilized vials formulated in sodium lactate and sodium citrate buffer with pH=4.0 under stress conditions (50°C) To determine which of the two buffers is optimal for lurbinectedin, batches of lyophilized vials containing lurbinectedin 1 mg / vial were manufactured on a laboratory scale with lurbinectedin formulated at 0.5 mg / mL in 0.03 M sodium lactate pH=4 and 0.05 M sodium citrate pH=4. pH 4 was selected due to its greater physiological compatibility compared to pH 3. Sucrose was included at 10% (w / v) as a bulking agent. The stability of the active ingredient in the lyophilized product under stress conditions of temperature (50° C.) was evaluated. Lyophilized vials formulated in 0.05 M monopotassium phosphate buffer pH=4 were also included in these studies for comparison. The stability results of the lyophilized vials after one month at 50° C. are shown in Table 5. Due to the large number of degradation products that appear under these conditions, only those with an area of ​​0.20% or more are reported.

[0193] The three formulations showed comparable characteristics at t = 0. After storage at 50°C for 1 month, quality attributes such as appearance of the lyophilized solid, color and pH of the reconstituted solution, and water content were not altered.

[0194] For the three compositions, lurbinectedin assay was significantly decreased (11%-17%) relative to the starting content, with % degradants being the main difference observed. Vials formulated in sodium lactate or monopotassium phosphate buffers behaved very similarly, but sodium citrate buffer promoted more degradation after 1 month storage at 50°C. In all cases, the main degradants were impurities eluting at rrt 0.49-0.50 (HPLC development method), which were significantly more prevalent in the lyophilized vials formulated in sodium citrate buffer. Other degradants, also appearing in very significant percentages, were impurity D (rrt 0.73-0.74) and impurities with rrt 0.25, rrt 0.28, and rrt 1.09-1.10.

[0195] Based on the solubility and stability results, it was concluded that the most suitable dissolution medium for the optimized lurbinectedin formulation was 0.03 M sodium lactate buffer pH 4.

[0196] [Table 8]

[0197] Example 5 Effect of bulk solution pH on the stability of freeze-dried products. The stability of 4 mg of lyophilized product produced from various 0.03M sodium lactate buffer lurbinectedin bulk solutions was tested. The bulk solutions had a concentration of lurbinectedin 0.5 mg / mL at pH 3.6, pH 4.0, and pH 4.5 (8 mL fill in 30 mL glass vials) using 10% sucrose (w / v) as a bulking agent. The stability of these batches was evaluated under 25°C / 60% RH to determine whether small changes in pH could have a significant effect on the stability of the product.

[0198] The stability results of the lyophilized vials after 6 months at 25°C are shown in Table 6. All batches behaved similarly. Quality attributes such as appearance of the lyophilisate, appearance, colour and pH of the reconstituted solution, water content (%) and assay remained constant. Total decomposition products did not undergo significant changes.

[0199] In conclusion, and based on the solubility and stability data, lurbinectedin solution and lyophilized preparation presentation, 0.03 M sodium lactate buffer pH 4.0 was selected as the most suitable dissolution medium for lurbinectedin preparation.

[0200] [Table 9]

[0201] Example 6 Bulking Agent Concentration The stability of 4 mg of lyophilized product produced from various 0.03M sodium lactate buffer lurbinectedin bulk solutions was tested. The bulk solutions had a concentration of lurbinectedin 0.5 mg / mL at pH 3.6, pH 4.0, and pH 4.5 (8 mL fill in 30 mL glass vials) using 10% sucrose (w / v) as a bulking agent. The stability of these batches was evaluated under 25°C / 60% RH to determine whether small changes in pH could have a significant effect on the stability of the product.

[0202] Once the dissolution medium was selected, various bulking agents were screened at various concentrations: sucrose (5%, 7.5% and 10%), mannitol (5%), and a combination of sucrose and mannitol (5% sucrose + 2.5% mannitol).

[0203] For that purpose, several lyophilized batches of lurbinectedin were prepared at a concentration of 4 mg / vial incorporating various bulking agents at various concentrations. Lurbinectedin was dissolved at 0.5 mg / mL in 0.03 M sodium lactate buffer pH 4. The batch compositions are detailed in Table 7. The batches were characterized and their stability under stress conditions was evaluated (40° C. / 75% RH).

[0204] [Table 10]

[0205] Table 8 below shows the stability results of lyophilized batches with various bulking agents after storage at 40° C. / 75% RH for 3 months.

[0206] The batch formulated with 5% sucrose was stable as neither the appearance of the lyophilized cake nor the reconstituted solution underwent any changes and the lurbinectedin assay was maintained with only a slight increase in degradation products, with impurity D being the main degradation product observed (rrt 0.88 HPLC industrial method).

[0207] However, batches formulated with sucrose and mannitol mixture or mannitol alone degraded significantly during storage at 40°C. In both cases, the appearance of the lyophilized cake was different from batches with sucrose only (5% or 10%). The formulation containing 5% mannitol underwent a very significant decrease in the lurbinectedin assay (43% of the nominal target). Furthermore, the % degradants increased in both formulations (up to 57% in the formulation containing 5% mannitol). The two major degradants in the formulation containing mannitol are those eluting at rrt 0.67-0.68 and rrt 1.06).

[0208] [Table 11]

[0209] Table 9 shows the stability results of lyophilized vials formulated in 0.03 M sodium lactate buffer pH=4 with various concentrations of sucrose ranging from 5% to 10% under stress conditions (40° C. / 75% RH).

[0210] [Table 12]

[0211] Batches containing three different concentrations of sucrose behaved similarly and remained stable. They did not undergo significant changes in the appearance of the lyophilized cake and the lurbinectedin assay (%). A slight increase in the % decomposition products was observed. In particular, impurity D (rrt 0.88, HPLC industrial method) was the main decomposition product. The percentage of sucrose did not significantly affect the stability of the product, with 10% sucrose showing the least degradation.

[0212] In conclusion, sucrose exhibited a protective effect in preventing lurbinectedin degradation during storage at high temperature. Based on these results, sucrose was selected as the most suitable bulking agent, and a concentration of 10% (w / v) was the optimal amount for a suitable and stable lurbinectedin preparation.

[0213] Example 7 Stability of lurbinectedin under long-term storage conditions The stability of lyophilized lurbinectedin composition (4 mg) was evaluated for 36 months under conditions proposed for long-term storage (5° C.±3° C.). A batch with a high residual moisture content was selected as it was considered the worst case.

[0214] The product remained stable for the 36 months of study (Table 10). None of the quality attributes underwent significant changes. Lurbinectedin content underwent minor changes due to analytical variability over the first 24 months. Total degradation products did not change over storage time. The only related substance observed at reportable levels was impurity D, which remained constant and at the level present in the active ingredient used to manufacture the batches.

[0215] [Table 13]

[0216] Example 8 Clinical Trial - Treatment of SCLC Patients with Lurbinectedin A clinical trial of lurbinectedin monotherapy for patients suffering from SCLC in a population with refractory or resistant disease as defined herein was conducted. In this single-arm, multicenter, open-label, Phase 2 trial, a cohort of 105 patients who had measurable disease, including patients whose SCLC was non-responsive to first-line platinum-containing chemotherapy (cisplatin, carboplatin, or oxaliplatin) (refractory), and patients whose SCLC recurred within 90 days after cessation of first-line therapy (resistant), were treated with lurbinectedin at a dose of 3.2 mg / m administered intravenously over a 1-hour period every 21 days. 2 The patients were treated with lurbinectedin, which was prepared as a sterile, isotonic aqueous solution for IV infusion as described below.

[0217] Study population Adult patients at least 18 years of age with a pathologically proven diagnosis of SCLC were included if they had only one prior chemotherapy-containing treatment line (immunotherapy in combination with chemotherapy or alone was permitted); a measurable response by Response Criteria in Solid Tumors (RECIST version 1.1) and documented progression prior to study entry; and an Eastern Cooperative Oncology Group (ECOG) activity status of 2 or less. Patients were required to have adequate bone marrow function (assessed by laboratory tests of absolute neutrophil count, platelet count, and hemoglobin), kidney (assessed by serum creatinine and creatine kinase), and liver (assessed by total bilirubin, albumin, and aminotransferases). The minimum time between prior treatment and study initiation had to be 3 weeks for chemotherapy, 4 weeks for immunotherapy or radiation therapy, and 2 weeks for any investigational or symptomatic treatment. Only patients with grade 1 or less toxicity from prior therapy were included, except for cases with alopecia and peripheral sensory neuropathy (both grade 2), which were also permitted. Women of childbearing age were required to use adequate contraception during the study and for at least 3 months after its completion.

[0218] Patients were excluded if they had previously received lurbinectedin or trabectedin; had previous or concurrent malignancies unless in complete remission for more than 5 years; had known CNS involvement (screening for CNS metastases at baseline was mandatory); had concurrent unstable or serious medical conditions within the past year (unstable angina, myocardial infarction, congestive heart failure, valvular heart disease, arrhythmia, severe dyspnea, or history or presence of active infections such as hepatitis or HIV); had an urgent need for radiation therapy; or had no or limited ability to comply with the study protocol. More details on the inclusion and exclusion criteria can be found in Table 11 (Table 14).

[0219] [Table 14]

[0220] Investigational Drug Formulations - Preparation and Administration Lurbinectedin was provided as a 4 mg vial and as a lyophilized powder for the concentration of infusion solution. Prior to use, the 4 mg vial was reconstituted with 8 mL of water for injection to yield a solution containing 0.5 mg / mL of lurbinectedin. For administration to patients as an iv infusion, the reconstituted vial was diluted with glucose for injection 50 mg / mL (5%) solution or sodium chloride for injection 9 mg / mL (0.9%) solution. The total composition and per mL of the reconstituted solution was as shown in Table 12.

[0221] [Table 15]

[0222] Dosage and Administration Lurbinectedin was administered via a central venous catheter with a minimum total volume of 100 mL of infusion solution (either 5% glucose or 0.9% sodium chloride) or, if administered via a peripheral line, with a minimum total volume of 250 mL, always at a predetermined infusion rate over 1 hour.

[0223] Starting dose is 3.2 mg / m 2 The dose was 2.0 mg / m2 of body surface area. 2 (e.g., doses were not allowed to exceed 6.4 mg). Patients received lurbinectedin iv as a 1-h infusion on day 1 of every 3 weeks until disease progression or unacceptable toxicity. Three weeks was defined as one treatment cycle.

[0224] Premedication All patients received antiemetic prophylaxis before each treatment infusion. The iv formulations of these drugs were used as follows: corticosteroids (dexamethasone 8 mg or equivalent), serotonin antagonists (ondansetron 8 mg or equivalent), chronic treatment with oral serotonin antagonists, and oral dexamethasone for 2 consecutive days. If necessary and in addition to the above, oral or iv metoclopramide (or equivalent) 10 mg was administered every 8 hours. Aprepitant and equivalent drugs were prohibited in patients treated with lurbinectedin.

[0225] Criteria for continuing treatment If a patient met all treatment criteria listed in Table 13, additional treatment cycles were administered q3wk (±48 hours).

[0226] [Table 16]

[0227] Patients received packed red blood cell transfusions and / or erythropoietin treatment to increase / maintain adequate hemoglobin levels if clinically indicated. If a patient did not meet the requirement for retreatment on day 1 of the next cycle, regardless of the reason, reassessment was performed at least every 48-72 hours. In that case, treatment was withheld until suitable recovery, up to 3 weeks beyond the due date. Patients not meeting retreatment criteria after a delay of up to 3 weeks had to be withdrawn from the study. In delays due to treatment-related adverse events lasting more than 1 week, dose reductions were performed upon recovery according to the rules described in the next section.

[0228] Dose Modifications for Adverse Reactions Patients continued treatment if they presented with any of the following: (1) Grade 3 or higher treatment-related non-hematological toxicity. Exceptions were Grade 3 or higher nausea and / or vomiting not optimally treated, Grade 3 asthenia lasting 3 days or less, Grade 3 diarrhea lasting 2 days or less or not optimally treated, Grade 3 transient elevation of ALT / AST that rapidly reversed and did not lead to a subsequent delay, and non-clinically relevant biochemical abnormalities. (2) Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia concomitant with Grade 3 or higher bleeding. (3) Grade 4 neutropenia, any grade febrile neutropenia, or neutropenia associated with infection / sepsis. (4) Frequent prolonged (>1 week) dose delays due to treatment-related adverse events. Patients who experienced Grade 3 or 4 hypersensitivity reactions discontinued study treatment.

[0229] Previous analysis of lurbinectedin administered according to body surface area-based dosing showed that the incidence of febrile neutropenia with lurbinectedin was less than 10%. Therefore, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was not permitted (secondary prophylaxis with G-CSF for neutropenia was permitted) in accordance with the American Society of Clinical Oncology and European Society for Medical Oncology guidelines.

[0230] The dose reduction levels are shown in Table 14 below.

[0231] [Table 17]

[0232] A maximum of two dose reductions were allowed per patient. Patients who continued to experience treatment-related toxicity and / or frequent dosing delays after permitted dose reductions were withdrawn from the study. They could continue to receive study medication if objective clinical benefit was appropriately documented. Once the dose was reduced for an individual patient, it was not re-escalated under any circumstances.

[0233] Efficacy evaluation The primary objective of this study was to evaluate the antitumor activity of lurbinectedin in terms of overall response rate (ORR) as the primary endpoint, supported by duration of response (DOR) as a secondary endpoint. ORR was assessed for a set of measurable lesions identified at baseline as target lesions or non-target lesions (if any) using RECIST v1.1 and followed until disease progression (PD) by appropriate methods.

[0234] Radiological tumor assessments (CT scan or MRI) were performed at baseline and every 6 weeks from the start of study treatment until cycle 6 or evidence of PD, and every 9 weeks thereafter. If an objective response was observed, this had to be confirmed by the same method at least 4 weeks after the date of first documentation of response, according to RECIST v1.1.

[0235] ORR was defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial response (PR), from the start of treatment to the date of progression or the start of subsequent therapy or end of patient follow-up according to RECIST v1.1. DOR was calculated from the date of first documented PD, relapse, or death from any cause in responder patients. The dates of response as assessed by the investigator and independently assessed by the Independent Review Committee (IRC), the date of radiological or clinical PD, and the date of death were noted and recorded, as appropriate. The IRC determined the patient's best response and assigned the dates of first documented response and progression / censoring according to RECIST v1.1.

[0236] For binomial endpoints (i.e. ORR, clinical benefit), numbers and percentages with corresponding exact 95% confidence intervals were calculated. Time-to-event variables (OS, PFS, and DOR) and their set time estimates (i.e. PFS4 / 6 and OS6 / 12) were analyzed according to the Kaplan-Meier method. Efficacy endpoint assessments assessed by IA and IRC were analyzed and compared.

[0237] Pharmacokinetic evaluation Plasma PK of lurbinectedin was evaluated in all treated patients during cycles 1 and 2. Sampling schedules are shown in Tables 15 and 16, respectively.

[0238] PK analysis of lurbinectedin plasma-concentration-time data was performed using nonlinear mixed-effects modeling and / or noncompartmental analysis.

[0239] [Table 18]

[0240] [Table 19]

[0241] Safety assessment Patients were evaluated for safety when they received a partial or complete infusion of lurbinectedin. All adverse events were graded according to the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE, v4). Patient safety profiles were monitored throughout the treatment and up to 30 days after the last lurbinectedin infusion (end of treatment), or until the patient started a new antitumor therapy, or until the date of death, whichever occurred first. Treatment delays, dose reduction requests, transfusions, and reasons for treatment interruption were monitored throughout the study. Treatment-related adverse events were tracked until recovery to at least grade 1 or stabilization of symptoms, or initiation of a new antitumor therapy, whichever occurred first.

[0242] Study Evaluation Items

[0243] [Table 20]

[0244] statistical methods This phase II trial was designed to evaluate the antitumor activity of lurbinectedin in terms of ORR according to RECIST v.1.1, as assessed by IA, with tumor assessment also performed by IRC.

[0245] A maximum of 100 evaluable patients were recruited to test the null hypothesis of a response in 15% or less patients (p less than 0.15) versus the alternative hypothesis of a response in 30% or more patients (p 0.30 or greater). Standardized test variance was based on the null hypothesis. The type I error (alpha) associated with this one-sided test is 0.025 and the type II error (beta) is 0.051 (normal approximation; approximately 0.05, for exact binomial distribution). Hence, the power is 95% (normal approximation; approximately 95%, for exact binomial distribution). With these assumptions, if the number of patients achieving a confirmed response is 23 or greater, this allows rejection of the null hypothesis. The determination of patient evaluability and replacement of non-evaluable patients in each cohort at the interim analysis was guided by investigator assessment.

[0246] Test period Patients were evaluated at scheduled visits within three study periods: (1) pretreatment: signs of IC to first infusion of study treatment; (2) treatment: first infusion of study treatment to end of treatment; and (3) follow-up: after end of treatment. Patients were followed up every 4 weeks until resolution or stabilization of all drug-related adverse events, if any, or until initiation of new antitumor therapy. Patients were followed up for at least 1 year after the first lurbinectedin infusion. Patients who completed treatment without PD were followed every 2 months for the first 6 months and every 3 months thereafter until PD, initiation of new antitumor therapy, death, or end of study date.

[0247] result One hundred and five patients with SCLC were enrolled in the study. All 105 patients were treated and included in the analysis for the primary endpoint. Of the 105 treated patients, 60% were male, 75% were white, 92% had ECOG PS 0 or 1, and the median age was 60 years (range, 40-83 years; 35.2% were 65 years or older). Two of the 105 treated patients (1.9%) had undergone previous surgery (curative resection in one patient). Prior radiation therapy had been administered in 75 patients (71.4%). Patients had received a median of one prior line of chemotherapy for advanced disease (range, 1-2 lines). The chemotherapy-free interval was <30 days in 21 patients (21%), <90 days in 45 patients (43%), and >90 days in 60 patients (57%). One patient had CNS metastases at baseline, and another had rechallenge with carboplatin plus etoposide and atezolizumab as a previous line of therapy; these two cases were considered protocol deviations, but they were small and were included in the primary analysis.

[0248] A total of 618 treatment cycles were administered with a median of 4 cycles per patient, with 46 patients (44%) receiving ≥6 cycles. The median relative dose intensity of study drug was 97.4% of the highest planned dose. Treatment-related adverse events led to dose delays in 23 patients (22%) and reductions in 28 patients (26%) (neutropenia was the most common cause of both dose delays in 13 patients (12%) and reductions in 17 patients (16%)).

[0249] Efficacy of lurbinectedin in patients with SCLC At the time of data cutoff, the median follow-up was 17.1 months. According to investigator assessment of all treated patients, 37 (35.2%) had an overall response, as shown in Table 17.

[0250] [Table 21]

[0251] In a preplanned analysis of overall response by chemotherapy-free interval (≥90 days vs. <90 days) in 60 patients with ≥90 days of chemotherapy-free interval (i.e., patients with chemotherapy-sensitive disease), 27 (45.0%) had an overall response with a median response duration of 6.2 months, whereas in 45 patients with <90 days of chemotherapy-free interval (i.e., chemotherapy-resistant disease), 10 (22.2%) had an overall response with a median response duration of 4.7 months.

[0252] Progression-free survival Median progression-free survival as assessed by the investigator was 3.5 months (95% CI 2.6-4.3) in the overall population, 4.6 months in patients with ≥90 chemotherapy-free days, and 2.6 months in patients with <90 chemotherapy-free days. Eight of 94 patients (9%) who discontinued lurbinectedin treatment had disease progression with new lesions in the CNS. Thus, no increased incidence of CNS metastases was observed.

[0253] overall survival With censoring of 37.1% (39 of 105 patients alive at data cutoff), median overall survival was 9.3 months (95% CI 6.3-11.8) for the entire population, 11.9 months (9.7-16.2) for patients with ≥90 chemotherapy-free days, and 5.0 months (4.1-6.3) for patients with <90 chemotherapy-free days. Notably, 29 (48%) of 60 patients with ≥90 chemotherapy-free days and 7 (16%) of 45 patients with <90 chemotherapy-free days were alive 1 year after first dose administration.

[0254] In a post hoc analysis of 37 patients with an objective response at baseline, median overall survival was greater than 1 year in the overall population (12.6 months, 95% CI 10.8-15.8) and in patients with sensitive disease (15.8 months, 10.2-not reached) and 10.9 months in patients with resistant disease (10.9 months, 6.3-14.0).

[0255] safety All 105 treated patients were evaluable for safety (Table 18). The most common grade 3-4 adverse events and laboratory abnormalities (in ≥2% of patients) were hematological disorders, including anemia (9 patients [9%]), leukopenia (30 [29%]), neutropenia (48 [46%]), thrombocytopenia (7 [7%]), and febrile neutropenia (5 [5%]); of these, only febrile neutropenia was considered treatment-related (Table 18). Notably, no cases of drug-induced liver injury were reported. Twenty-three of the 105 patients (22%) received G-CSF secondary prophylaxis or therapy for neutropenia. Serious treatment-related adverse events occurred in 11 of 105 patients (10%), with neutropenia and febrile neutropenia being the most common (five patients [5%] each). Grade 3 pneumonia was reported in two patients (2%); these episodes were associated with grade 3 febrile neutropenia and grade 4 neutropenia, lasted 3 days in one patient and 13 days in the other, and resolved without clinical consequences. One patient had a grade 3 skin ulcer due to extravasation without clinical consequences. Only two patients (2%) discontinued lurbinectedin therapy due to treatment-related adverse events. No treatment-related deaths occurred, but 66 of 105 patients (63%) died from disease progression.

[0256] [Table 22]

[0257] Prior immunotherapy A post-hoc exploratory analysis was performed on response in patients who had previously received immunotherapy (n=8). Data from this group of patients showed a trend towards better response to single-agent lurbinectedin after first-line platinum-containing chemotherapy in combination with a checkpoint inhibitor or second-line with nivolumab (Table 19). This is an important finding in light of the recent approval of atezolizumab in first-line SCLC in combination with carboplatin / etoposide. Thus, lurbinectedin may provide a viable option in patients who have progressed on immunotherapy.

[0258] [Table 23]

[0259] Summary and Conclusion One hundred and five patients with SCLC were enrolled and treated with lurbinectedin. Median follow-up was 17.1 months (IQR 6.5-25.3). Investigator-assessed overall response was observed in 37 patients (35.2%; 95% CI 26.2-45.2). The most common grade 3-4 adverse events (irrespective of causality) were hematological abnormalities, namely anemia (nine patients [9%]), leukopenia (30 patients [29%]), neutropenia (48 patients [46%]), and thrombocytopenia (seven patients [7%]). Serious treatment-related adverse events occurred in 11 patients (10%), of which neutropenia and febrile neutropenia were the most common (five patients [5%] each). No treatment-related deaths were reported.

[0260] Lurbinectedin was effective as a second-line therapy for SCLC in terms of overall response and had a tolerable and manageable safety profile. Lurbinectedin may represent a promising new treatment for SCLC patients who have few options, especially in the event of recurrence.

[0261] Example 8 Clinical Trial - Treatment of Solid Cancer Patients with Lurbinectedin and Irinotecan A clinical trial of lurbinectedin in combination with irinotecan for patients suffering from solid tumors was conducted. In patients with advanced solid tumors, lurbinectedin was administered at an escalating dose on day 1 (D) plus a fixed dose of irinotecan 75 mg / m2 on D1 and D8 every 3 weeks (q3w). 2 A Phase 1 trial to evaluate. Patients were enrolled according to a standard 3+3 dose escalation design. A Phase Ib / II expansion portion at the recommended dose (RD) was conducted to explore efficacy in indications where antitumor activity signals were observed.

[0262] Study population Details of the inclusion and exclusion criteria can be found in Table 20.

[0263] [Table 24A]

[0264] [Table 24B]

[0265] Investigational Drug Formulations - Preparation and Administration Lurbinectedin was provided as a 4 mg vial and as a lyophilized powder for the concentration of infusion solution. Prior to use, the 4 mg vial was reconstituted with 8 mL of water for injection to yield a solution containing 0.5 mg / mL of lurbinectedin. For administration to patients as an iv infusion, the reconstituted vial was diluted with glucose for injection 50 mg / mL (5%) solution or sodium chloride for injection 9 mg / mL (0.9%) solution. The total composition and per mL of the reconstituted solution was as shown in Table 12 above.

[0266] Irinotecan was provided as 40 mg, 100 mg, or 300 mg vials and as a lyophilized powder for infusion strength.

[0267] Dosage and Administration Lurbinectedin was administered via a central venous catheter with a minimum total volume of 100 mL of infusion solution (either 5% glucose or 0.9% sodium chloride) or, if administered via a peripheral line, with a minimum total volume of 250 mL, always at a predetermined infusion rate over 1 hour.

[0268] Dose levels for patients in the titration phase (n=39) were as shown in Table 21. Patients received lurbinectedin iv as a 1-hour infusion on day 1 and irinotecan iv as a 90-minute infusion on days 1 and 8 every 3 weeks. Three weeks was defined as one treatment cycle.

[0269] [Table 25]

[0270] Outcome measures The primary outcome measures were (1) maximum tolerated dose (MTD) and (2) recommended dose (RD). The MTD was defined as the lowest dose explored during dose escalation at which ≥1 / 3 of evaluable patients developed a DLT in cycle 1. The RD was defined as the highest dose level explored during dose escalation at which <1 / 3 of evaluable patients developed a DLT during cycle 1.

[0271] Secondary outcome measures included safety assessments, peak plasma concentration (Cmax), area under the plasma concentration versus time curve (AUC), volume of distribution based on terminal half-life (Vz), volume of distribution at steady state (Vss), clearance (CL), half-life (t1 / 2), assessment of antitumor response (RECIST v1.1, from start of treatment to PD, other antitumor therapy, death, or 12 months from enrollment of the last evaluable patient in the study (end of study), whichever occurred first), progression-free survival (from date of first infusion of study treatment to date of progression or death, or 12 months from end of study, whichever occurred first), and overall survival (from date of first infusion of study treatment to date of death, or 12 months from end of study, whichever occurred first).

[0272] Pharmacokinetic evaluation Patients underwent PK sampling for evaluation of lurbinectedin, irinotecan, and SN38 (the active metabolite of irinotecan) with the aim of ruling out major drug-drug interactions.

[0273] Safety assessment Patients were evaluated for safety when they received partial or complete infusion of lurbinectedin and irinotecan. All adverse events were graded according to the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE, v4). Patient safety profiles were monitored throughout the treatment and up to 30 days after the last study treatment administration (end of treatment), or until the patient started a new antitumor therapy, or until the date of death, whichever occurred first. Reasons for treatment delays, dose reduction requests, transfusions, and treatment interruptions were monitored throughout the study. Treatment-related adverse events were tracked until recovery to at least grade 1 or stabilization of symptoms, or initiation of a new antitumor therapy, whichever occurred first.

[0274] result Thirty-nine patients were initially treated at five dose levels (DL, see Table 21 above) and 13 were treated at the recommended dose (RD). Fifty-six percent were female, 69% had ECOG PS=1, median age was 58 years, and had received a median of 2 prior chemotherapy lines for progressive disease (range, 0-4). RD was determined by lurbinectedin 2.0 mg / m on D1. 2 + irinotecan 75 mg / m on D1 and D8 q3w 2 + G-CSF. Dose-limiting toxicities in cycle 1 were observed in 2 / 3 evaluable patients at maximum tolerated dose (MTD) and in 3 / 13 evaluable patients at RD. At MTD and RD, DLTs included omission of the irinotecan D8 dose due to grade (G) 3-4 neutropenia (n=3 patients) or G2-4 thrombocytopenia (n=2). In RD, common G1 / 2 toxicities were nausea, vomiting, fatigue, diarrhea, anorexia, and neuropathy, and G3 / 4 hematologic abnormalities included neutropenia (33%) but not thrombocytopenia.

[0275] Pharmacokinetic data Concentration-time data for lurbinectedin, irinotecan, and SN-38 were available for 39 patients. Means (±SD) of key PK parameters are shown in the table below, along with parameters reported elsewhere for lurbinectedin alone, and irinotecan and SN-38 (Camptosar label).

[0276] Based on comparability with reference PK data, these PK results for the three analytes evaluated do not suggest any type of major drug-drug interactions, thus indicating that the drug combination of lurbinectedin and irinotecan is safe to administer from a PK perspective.

[0277] [Table 26]

[0278] Efficacy Data Promising activity was observed in patients with SCLC, including some cases as third-line treatment. Signals of activity were also observed in endometrial cancer and soft tissue sarcoma (STS) and glioblastoma (GBM). This resulted in a Phase II expansion with RD to further explore efficacy and safety in SCLC, GBM, STS, and endometrial cancer. A total of 59 patients were treated with RD, including patients n=15 SCLC, n=11 endometrial cancer, n=10 STS, and n=20 GBM. Efficacy data by tumor type at all doses is shown in the table below.

[0279] [Table 27]

[0280] safety Two patients (3.4%) discontinued treatment due to treatment-related adverse events (bilirubin G2, weakness G3). Seventeen patients (28.8%) had dose reductions (76% of reductions were due to omission of irinotecan on day 8 related to adverse events). 19.8% of irinotecan infusions on day 8 were omitted in RD (mostly due to hematological toxicity). No treatment-related deaths occurred. A detailed description of adverse events and laboratory abnormalities observed in patients in RD is shown in Table 24.

[0281] [Table 28]

[0282] Summary and Conclusion RD included lurbinectedin 2.0 mg / m on day 1 with GCS-F in solid tumors. 2 and irinotecan 75 mg / m on days 1 and 8 q3wk 2DLTs were mostly omission of irinotecan on day 8 in cycle 1 due to hematologic toxicity. The main toxicities observed were myelosuppression, GI, and fatigue. GI and myelosuppression were predictable and manageable. Promising activity was observed in SCLC. Notable activity was observed in endometrial cancer, and signs of activity were seen in STS (especially Ewing and synovial sarcoma). Moderate activity was observed in glioblastoma patients. Expansion cohorts in SCLC, endometrial cancer, and STS patients are still ongoing to enroll a total of 20 patients in each indication.

[0283] Examples of lurbinectedin solid forms Abbreviation

[0284] [Table 29]

[0285] X-ray powder diffractograms (XRPD) were obtained using a Stadi P diffractometer (Stoe & Cie GmbH) in transmission geometry equipped with a curved Ge-crystal monochromator, a Cu-Kα1 source and a Mythen 1K detector in step-scan detector mode. Patterns were recorded at a tube voltage of 40 kV and a tube current of 40 mA, applying a step size of 0.02° 2-theta with 12 seconds per step in the angular range of 1.5° to 50.5° 2-theta. The detector step was 1° 2-theta. The typical accuracy of the 2-theta values ​​is in the range of about ±0.2° 2-theta. Thus, a diffraction peak appearing at 5.0° 2-theta may appear between 4.8 and 5.2 2-theta on most X-ray diffractometers under standard conditions.

[0286] TG-FTIR experiments were carried out using a Thermo-Microbalance TG-209 (Netzsch) equipped with an FT-IR Spectrometer Vector 22 (Bruker) using Al crucibles (open or with a small hole) under N2 atmosphere with a heating range of 25–250 °C and a heating rate of 10 °C / min.

[0287] DSC experiments were carried out using a Perkin Elmer DSC 7 using closed Au crucibles with a heating range of −50 to 250° C. and heating rates of 10 or 20° C. / min.

[0288] DVS experiments were carried out using a Projekt Messtechnik SPS 11-100n multi-sample water vapor sorption analyzer. Samples were allowed to equilibrate at 50% rh before initiating a predefined humidity program. The program consisted of: - 2 hours at 50%rh - 50~0%rh(5% / h) - 5 hours at 0%rh - 0~95%rh(5% / h) - 5 hours at 95%rh - 95~50%(5% / h) - 2 hours at 50%rh It was.

[0289] Example 9 Preparation of Amorphous Form A of Lurbinectedin

[0290] [ka]

[0291] Lurbinectedin form A was obtained according to the procedure described in WO 03 / 014127. The XRPD pattern of lurbinectedin form A confirmed that the form was amorphous. See FIG. 1. Several batches of lurbinectedin form A were produced by this method. The analytical results of five of them are shown in Table 25.

[0292] [Table 30]

[0293] Table 26 shows the impurity profiles of several batches of lurbinectedin form A.

[0294] [Table 31]

[0295] Example 10 Preparation of lurbinectedin form B Crude lurbinectedin (10 g) obtained as described in Example 1 was dissolved in aqueous HCl (0.1 M, 390 mL). The aqueous solution was washed with CHCl (2×335 mL) and with n-pentane (1×335 mL), and treated with aqueous NHCl / NHOH (prepared by dissolving 17.5 g NHCl and 20 mL NHOH in 250 mL water, 68 mL) to precipitate lurbinectedin form B, which was filtered, washed with water, and dried under vacuum to yield 7.5 g, 9.45 mmol, 81% yield of lurbinectedin form B.

[0296] Several batches of lurbinectedin form B were produced by this method, and the analytical results of 10 of these are shown in Table 27.

[0297] [Table 32]

[0298] A further advantage of lurbinectedin form B over lurbinectedin form A is the absence of residual solvent.

[0299] Table 28 shows the impurity profile (% area) of several batches of lurbinectedin form B.

[0300] [Table 33]

[0301] A comparison between the impurity profiles of lurbinectedin forms A and B clearly shows that lurbinectedin form B consistently exhibits fewer impurities than lurbinectedin form A.

[0302] Solid State Characterization - Lurbinectedin form B was characterized by XRPD, IR, TG-FTIR, DSC and DVS. XRPD patterns of several batches of lurbinectedin form B confirmed that the form is partially crystalline (broad peaks, amorphous background) and that the manufacturing process is reproducible. See Figures 2a and 2b. The XRPD angles 2-theta and their relative intensities of two batches of lurbinectedin form B are shown in Table 29.

[0303] [Table 34]

[0304] TG-FTIR shows decomposition above 150° C. for lurbinectedin form B. Release of 2.6% water was detected. See FIG. 3.

[0305] It was not possible to estimate the amorphous content by DSC. Decomposition was observed to begin above 130° C., see FIG. 4. No glass transition temperature or melting point was detected.

[0306] DVS shows continuous water uptake and release without steps and little hysteresis. This is due to the partially amorphous character of form B. The sample is not deliquescent. A mass change Δm (50-96% rh) ≈ 4% was observed, indicating that lurbinectedin form B is hygroscopic. Reducing the relative humidity again reduced the water content, almost returning to the original mass, see FIG. 5.

[0307] Relative stability of lurbinectedin form B - Three 1:1 mixtures of lurbinectedin forms A and B (15 mg each) were prepared and suspended in water (1 mL). Samples were taken after 6 and 24 hours. The powder patterns after 6 and 24 hours match those of the form B starting material. See Figure 6. Both patterns after phase equilibration show sharper peaks and higher peak resolution, which are indicative of improved crystallinity. Quantification of the amorphous content was not possible with the available data.

[0308] IR spectra were obtained for lurbinectedin form A shown in Figure 7a and for lurbinectedin form B shown in Figure 7b. The correlation coefficients between the IR of three batches of lurbinectedin form B and the IR of lurbinectedin form A vary from 0.81 to 0.86, while the correlation coefficients of several IR spectra of lurbinectedin form A vary from 0.97 to 0.99.

[0309] Example 11 Electrostatic charge measurement in air The electrostatic charge of two batches of lurbinectedin form A (batches P04 and R05) and lurbinectedin form B (batches 1924129-LT and 1924128-LT) was measured using a Faraday cage (see FIG. 8) constructed of stainless steel with concentric spheres with ratios of 10, 15 and 20 cm. The technique consists of placing the sample to be measured (q) inside the inner sphere (a) and measuring the potential difference induced between the sphere (a) and another reference conductor sphere (b). The outer sphere (c) is grounded to protect the device. The potential difference measurements were performed using a high-precision electrometer (Keithley 617, resolution 10 fC).

[0310] To avoid the influence of ambient humidity on the electrostatic charge of the samples, the measurements were carried out under a controlled dry nitrogen atmosphere. To avoid loss of electrostatic charge, the samples were introduced into the glass capsule using a non-conductive instrument. To avoid parasitic static charge in the glass capsule, the sample-filled capsule was introduced into the Faraday cage through a grounded conductive tube. To minimize the generation of electrostatic charge due to friction of insulating parts, the introduction and removal of the capsule was performed by a computer-controlled servo engine to ensure a constant speed of introduction and removal of the capsule for each measurement.

[0311] Results: For each batch of lurbinectedin in each form, several measurements with various amounts of material were performed. Before filling into capsules, they were washed and their residual electrostatic charge was measured to correct the level. Each sample was introduced and removed five times, and after each introduction several consecutive measurements were taken to average out possible drift effects. Figures 9a and 9b summarize the results of such measurements for each pair of batches of lurbinectedin forms A and B.

[0312] The measured charge Q increases with the amount of material analyzed. Both forms of lurbinectedin have a positive electrostatic charge. Lurbinectedin form A has a significantly higher total electrostatic charge than lurbinectedin form B. The data were fitted to a linear regression (dashed lines in Figures 9a and 9b) to obtain the charge density (Q / m) as the slope of the line. Extrapolation of the linear regression to a mass of 0 mg represents the residual electrostatic charge of the glass capsule and does not affect the value of Q / m. The results of this regression and the dispersion of the charge density are summarized in Table 30. All ranges are given at 95% confidence.

[0313] [Table 35]

[0314] 10a and 10b show the distribution of charge density for each pair of batches of lurbinectedin forms A and B.

[0315] It is shown that lurbinectedin form B has an average charge density that is an order of magnitude lower than lurbinectedin form A. This difference in triboelectrization was demonstrated using two different batches of each form.

[0316] Example 12 Exemplary Processes for the Preparation of Pharmaceutical Compositions Using Form B as the Starting Material Lurbinectedin form B was dissolved in concentrated lactic acid solution (0.31 M) at a concentration of 25 mg / ml. This solution was then diluted with water for injection (WFI) to a lactic acid solution (0.1 M) containing PM01183 at a concentration of 8.33 mg / ml.

[0317] This solution was then added under stirring to a previously prepared sucrose / buffer solution (pH=4.2) consisting of lactic acid (3.7 mg / ml), sodium hydroxide (1.1 mg / ml) and a bulking agent, sucrose (167.7 mg / ml). If necessary, the mixture was adjusted to pH=4.0 with lactic acid solution or sodium hydroxide solution.

[0318] The bulk solution was then brought to the final volume or mass (taking into account the density value of 1.04 g / cc) to produce the final bulk solution (0.5 mg / ml lurbinectedin, 2.76 mg / ml lactic acid, 0.64 mg / ml NaOH, 100 mg / ml sucrose).

[0319] The bulk solution was then filtered through a sterile PVDF filter (0.22 μm) and filled into 30 ml glass vials at 8 ml / vial.

[0320] The vials were lyophilized according to the cycle detailed in Table 31. After lyophilization, the vials were sealed with flip-off seals and stored at +5°C.

[0321] [Table 36]

[0322] Although the present invention has been described in detail with reference to specific embodiments thereof, it should be understood that functionally equivalent variations are within the scope of the present invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing specification and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims (and clauses). Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims (and clauses).

[0323] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0324] The invention will now be described with reference to the following sections. 1. A method of treating small cell lung cancer (SCLC) in a patient in need thereof, comprising: (1) on the day and prior to administering lurbinectedin to the patient, administering prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of The method includes: 2. The method of claim 1, wherein the corticosteroid is dexamethasone administered intravenously at a dose of 8 mg dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 3. The method of clause 1 or 2, wherein the serotonin antagonist is ondansetron administered intravenously at a dose of 8 mg ondansetron or at a dose of serotonin antagonist equivalent to 8 mg ondansetron administered intravenously. 4. The method of any one of paragraphs 1 to 3, further comprising administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient. 5. The method of claim 4, wherein the one or more antiemetic agents administered after lurbinectedin administration are selected from corticosteroids, serotonin antagonists, and metoclopramide. 6. The method of clause 5, wherein the one or more antiemetic agents are administered at a dose of dexamethasone 4 mg, ondansetron 8 mg, or metoclopramide 10 mg, or a combination thereof. 7. The method of any one of clauses 1 to 6, wherein the patient is not treated with doxorubicin in combination with lurbinectedin. 8. The method of any one of paragraphs 1 to 7, wherein the patient has progressed after prior platinum-containing therapy or prior immunotherapy. 9. A method of treating small cell lung cancer (SCLC), including metastatic SCLC, in a patient in need thereof, comprising: (1) Patients had at least 1,500 cells / mm 3 Absolute neutrophil count of at least 100,000 cells / mm 3 First dose 3.2 mg / m 2 administering lurbinectedin of the formula (I) to a patient by intravenous infusion; and (2) identifying an adverse reaction in the patient after said administration, the adverse reaction being selected from the group consisting of Grade 2 hepatotoxicity or other adverse reactions, Grade 3 (severe) or greater hepatotoxicity or other adverse reactions, Grade 4 thrombocytopenia (≥ 25,000 cells / mm 3 Platelet counts below 50,000 cells / mm3), and grade 3 thrombocytopenia with bleeding 3 Platelet count less than 500 cells / mm 3a step of having neutropenia (number of neutrophils < LLN), or febrile neutropenia of any grade (number of neutrophils < LLN); (3) After identifying an adverse reaction, on the 21st day after the first dose, or when the patient's neutrophil count is greater than 1500 cells / mm 3 ; the platelet count is greater than approximately 100,000 cells / mm 3 ; optionally, the hemoglobin level is higher than approximately 9 g / dL, and at the later of the two time points after the hepatotoxicity or other adverse reaction has reached grade 1 or lower, (i) If the identified adverse reaction consists of grade 4 isolated neutropenia (number of neutrophils < 500 cells / mm 3 ), administering to the patient, together with prophylactic G-CSF administration, lurbinectedin at a dose equal to the first dose every three weeks; (ii) If the identified adverse reaction consists of grade 2 hepatotoxicity or other adverse reaction, administering to the patient lurbinectedin at a dose equal to the first dose every three weeks; or (iii) If the identified adverse reaction is grade 3 (severe) or higher hepatotoxicity or other adverse reaction, grade 4 thrombocytopenia (number of platelets < 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding (number of platelets < 50,000 cells / mm 3 ), or febrile neutropenia of any grade, administering to the patient lurbinectedin at a dose reduced compared to the first dose every three weeks A method comprising. 10. The method according to item 9, wherein the first reduced dose is 2.6 mg / m 2 . 11. After the patient has been administered the reduced dose of 2.6 mg / m 2 , grade 3 (severe) or higher hepatotoxicity or other adverse reaction, grade 4 thrombocytopenia (number of platelets < 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding (number of platelets < 50,000 cells / mm 3If the patient experiences febrile neutropenia of any grade 21 days after administration of the prior dose, or if the patient's neutrophil count is below 1500 cells / mm 3 Larger; platelet count is approximately 100,000 cells / mm 3 and optionally, after hemoglobin levels are greater than about 9 g / dL and hepatotoxicity or other adverse reactions are less than or equal to Grade 1, whichever occurs later, patients may be administered a second reduced dose of 2.0 mg / m every 3 weeks. 2 The method according to item 10, wherein lurbinectedin is administered. 12. After identifying an adverse reaction following administration of the second, reduced dose, or if the patient achieves at least 1500 cells / mm within 2 weeks of the scheduled dose. 3 Absolute neutrophil count of at least 100,000 cells / mm 3 Item 12. The method according to item 11, further comprising the step of discontinuing administration of lurbinectedin if the platelet count does not recover to . 13. The method of any one of clauses 9 to 12, wherein lurbinectedin is administered as an infusion formulation prepared by diluting a reconstituted lyophilized formulation comprising 4 mg of lurbinectedin, a buffer derived from an organic carboxylic acid (e.g., lactic acid), and a disaccharide (e.g., sucrose), and having a pH of 3.5 to 4.5 when reconstituted. 14. A method of treating small cell lung cancer (SCLC) in a patient in need thereof, comprising: Patients were administered lurbinectedin at 3.2 mg / m 2 by intravenous infusion of a lurbinectedin infusion solution at a dose of 4 mg of lurbinectedin, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a reconstituted solution at a pH of 3.5 to 4.5. The method includes: 15. The method of claim 14, wherein the disaccharide is sucrose, and optionally the composition comprises lurbinectedin and sucrose in a ratio of 1 mol lurbinectedin:455-465 mol sucrose. 16. The method according to item 14 or 15, wherein the organic carboxylic acid is lactic acid, and optionally the composition comprises lurbinectedin and lactic acid in a ratio of 1 mol lurbinectedin:44 to 54 mol lactic acid. 17. The method according to any one of items 14 to 16, wherein the pH is 3.8 to 4.5. 18. The method according to any one of items 14 to 17, wherein the lyophilized composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted solution. 19. The method according to paragraph 18, wherein the lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 20. The method according to any one of paragraphs 14 to 19, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 21. The method according to item 20, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 22. The freeze-dried composition comprises: Lactic acid 22.1 mg; 5.1 mg sodium hydroxide; and Sucrose 800mg Including, Or, the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium; 22. The method according to any one of items 14 to 21. 23. The method of any one of paragraphs 14 to 22, wherein the lyophilized composition is provided in a 30 mL vial. 24. The method of any one of paragraphs 14 to 23, wherein the lyophilized composition contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 25. The method of any one of paragraphs 14 to 24, wherein the lyophilized composition does not contain a phosphate buffer. 26. The method of any one of paragraphs 14 to 25, wherein the reconstituted solution or lurbinectedin infusion solution contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 27. The method of any one of paragraphs 14 to 26, further comprising administering prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient on the day and prior to administration of lurbinectedin to the patient. 28. The method of paragraph 27, wherein the corticosteroid is dexamethasone administered intravenously at a dose of 8 mg dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 29. The method of paragraph 27 or 28, wherein the serotonin antagonist is ondansetron administered intravenously at a dose of 8 mg of ondansetron, or at a dose of serotonin antagonist equivalent to 8 mg of ondansetron administered intravenously. 30. The method of any one of paragraphs 27 to 29, further comprising administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient. 31. The method of claim 30, wherein the one or more antiemetic agents are selected from corticosteroids, serotonin antagonists, and metoclopramide. 32. The method of claim 31, wherein the one or more antiemetic agents is dexamethasone 4 mg, ondansetron 8 mg, or metoclopramide 10 mg, or a combination thereof. 33. G-CSF, 500 cells / mm 3 33. The method of any one of paragraphs 14 to 32, further comprising administering to a patient identified as having a neutrophil count below normal or any value below the normal range and associated with infection / sepsis. 34. The method of any one of clauses 14 to 33, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 35. The method of any one of clauses 14 to 34, wherein the overall response rate is at least 11% or at least 20% for patients with a CTFI interval of less than 90 days, or the overall response rate is at least 30% or at least 40% for patients with a CTFI interval of more than 90 days. 36. The method of any one of clauses 14 to 35, wherein the duration of response is at least 2.5 months or at least 4.5 months for patients with a CTFI interval of less than 90 days, or the duration of response is at least 3.5 months, 5 months, or 6 months for patients with a CTFI interval of more than 90 days. 37. The method of any one of clauses 14 to 36, wherein the patient has not received platinum-containing therapy at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 38. The method of any one of clauses 14 to 37, wherein the patient has discontinued platinum-containing therapy prior to administration of lurbinectedin. 39. The method of any one of clauses 14 to 38, wherein the patient has previously been administered immunotherapy. 40. The method of claim 39, wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 41. The method of clause 40, wherein the immunotherapy is atezolizumab, optionally in combination with carboplatin and etoposide, or nivolumab. 42. The method of any one of paragraphs 39 to 41, wherein the patient is progressing after receiving immunotherapy. 43. The method of any one of clauses 14 to 42, wherein the patient has an estimated creatinine clearance greater than 30 mL / min, AST or ALT less than 3×ULN, or bilirubin less than 1.5×ULN. 44. Lurbinectedin was administered to patients as a 1-hour intravenous infusion to achieve a total plasma C of within 80%–125% of approximately 107 μg / L. max 44. The method according to any one of items 14 to 43, wherein the method achieves an AUC∞ within 80% to 125% of about 551 μg*h / L. 45. A method for storing a lyophilized lurbinectedin composition, comprising: storing the lyophilized composition comprising 4 mg of lurbinectedin; a buffer derived from an organic carboxylic acid; and a disaccharide at a temperature of 5° C.±3° C. for at least 48 months. Including, The lyophilized composition is formulated so that, when reconstituted with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained; After storage for at least 24 months, the amount of impurity D present in the composition is 0.8% wt. / wt. or less of the total mass of lurbinectedin. method. 46. ​​The method according to item 45, wherein the amount of impurity D present in the composition is 0.8% wt. / wt. or less of the total mass of lurbinectedin after storage for at least 48 months. 47. The method of claim 45 or 46, wherein the lyophilized composition comprises 4 mg of lurbinectedin; 22.1 mg of lactic acid; 5.1 mg of sodium hydroxide; and 800 mg of sucrose, or the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium. 48. The method of any one of paragraphs 45 to 47, wherein the lyophilized composition is stored in a 30 mL vial. 49. A vial containing a lyophilized composition consisting of 4 mg lurbinectedin; 22.1 mg lactic acid; 5.1 mg sodium hydroxide; and 800 mg sucrose, or a lyophilized composition consisting of 800 mg sucrose, 0.245 mmol lactate, and 0.128 mmol sodium; Labeling on the vial, including a use-by date that is at least 24 months from the date of manufacture 1. A pharmaceutical product comprising: 50. The pharmaceutical product of paragraph 49, wherein the label affixed to the vial includes an expiration date that is at least 48 months from the date of manufacture. 51. The pharmaceutical product according to paragraph 49 or 50, wherein the vial is a 30 mL vial. 52. The pharmaceutical product of any one of paragraphs 49 to 51, wherein the lyophilized composition contains impurity D at a value of less than or equal to 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt based on the total mass of lurbinectedin. 53. The pharmaceutical product of any one of clauses 49 to 52, wherein the lyophilized composition does not contain a phosphate buffer. 54. A method of treating solid tumors of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer in a patient in need thereof, comprising: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to method. 55. Irinotecan 50mg~75mg / m 2 The method of claim 54, wherein a dose of a topoisomerase inhibitor equivalent to is administered on day 8 of the treatment cycle. 56. The method of paragraph 54 or 55, wherein the treatment cycle is an 18, 19, 20, 21, 22, 23, 24, or 25 day cycle. 57. Lurbinectedin is administered at a dose of 2 mg / m 2 57. The method of any one of clauses 54 to 56, wherein the dose is 58. The topoisomerase inhibitor is irinotecan at 75 mg / m 2 58. The method of any one of clauses 54 to 57, wherein the dose is 59. The method of any one of clauses 54 to 58, wherein the treatment cycle is 21 days. 60. The method of any one of paragraphs 54 to 59, wherein the solid tumor is SCLC, endometrial carcinoma, soft tissue sarcoma, or glioblastoma. 61. The method of any one of paragraphs 54 to 60, wherein the patient is administered G-CSF to manage the myelosuppressive effects of the treatment. 62. The method of any one of clauses 54 to 61, wherein administration of the dose of irinotecan on day 8 of the treatment cycle is omitted if the patient experiences hematological toxicity after dosing on day 1. 63. The method of any one of clauses 54 to 62, further comprising administering one or more antiemetic agents on day 1 of the treatment cycle. 64. The method of any one of clauses 55 to 64, wherein lurbinectedin is administered as an infusion formulation prepared by diluting a reconstituted lyophilized formulation of 4 mg lurbinectedin, 22.1 mg lactic acid or 0.245 mmol lactate, 5.1 mg sodium hydroxide or 0.128 mmol sodium, and 800 mg sucrose, having a pH of 3.5 to 4.5 when reconstituted. 65. The method according to claim 64, wherein the pH is 3.8 to 4.5. 66. The method according to paragraph 64 or 65, wherein the freeze-dried composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted solution. 67. The method according to paragraph 66, wherein the lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 68. The method of any one of paragraphs 64 to 67, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 69. The method according to paragraph 68, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 70. The method of any one of paragraphs 64 to 69, wherein the lyophilized composition is provided in a 30 mL vial. 71. The method of any one of paragraphs 64 to 70, wherein the lyophilized composition contains impurity D at a value of less than or equal to 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt. 72. The method of any one of paragraphs 64 to 71, wherein the reconstituted solution or lurbinectedin infusion solution contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less. 73. A process for lyophilizing an aqueous stock solution comprising lurbinectedin, an organic carboxylic acid, sodium hydroxide, and sucrose to produce a lyophilized powder, comprising: the concentration of lurbinectedin in the aqueous stock solution is 0.5 mg / mL, the ratio of lurbinectedin to sucrose is 1 mol lurbinectedin to 455-465 mol sucrose, and the lyophilized powder is formulated such that upon reconstitution with 8 mL of water, a solution having a pH of 3.5-4.1 is obtained; and storing the lyophilized powder at 5°C ± 3°C for 30 to 60 months to produce a pharmaceutical composition; After storage, the amount of impurity D present in the composition is 0.8% wt. / wt. or less of the total mass of lurbinectedin. A pharmaceutical composition prepared by 74. A method of administering a pharmaceutical composition, comprising: Reconstituting the lyophilized pharmaceutical composition in a vial after storing the composition for 30 to 60 months, A lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution containing 4 mg of lurbinectedin, a buffering agent derived from an organic carboxylic acid, and sucrose; The composition comprises lurbinectedin and a disaccharide in a ratio of lurbinectedin 1 mol:sucrose 455-465 mol; The lyophilized composition is formulated so that upon reconstitution with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained; and Administering the reconstituted solution to a patient. The method includes: 75. The method of claim 74, wherein the pharmaceutical composition comprises an amount of lurbinectedin that is at least 95% of the amount of lurbinectedin on the first day of storage. 76. The method of claim 74 or 75, wherein the vial is a 30 mL vial. 77. A method of treating SCLC in a patient in need thereof, comprising: Lurbinectedin at 2–3.2 mg / m 2 administering to a patient by intravenous infusion at a dose of Including, The patient is administered an immunotherapeutic antibody to treat SCLC prior to beginning a treatment cycle; the duration of response is at least 2, 3, 4, 5, or 6 months, or the overall response rate is at least 40%; method. 78. The method of claim 77, wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 79. The method of paragraph 78, wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 80. The method of paragraph 79, wherein the immunotherapeutic antibody is administered to the patient simultaneously with the chemotherapeutic agent. 81. The method according to paragraph 80, wherein the chemotherapeutic agent is carboplatin or etoposide. 82. The method of paragraph 81, wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic agent is carboplatin or etoposide. 83. The method of any one of clauses 69 to 74, wherein one dose of lurbinectedin is administered per treatment cycle, and the treatment cycle is an 18, 19, 20, 21, 22, 23, 24, or 25 day cycle. 84. The method of any one of clauses 77 to 83, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 85. The method of any one of clauses 77 to 84, wherein the overall response rate is at least 40%, or at least 50%, or at least 60%. 86. The method of any one of paragraphs 77 to 85, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months. 87. The method of any one of paragraphs 77 to 86, wherein the patient has not received an immuno-oncogenic therapeutic antibody at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 88. The method of any one of paragraphs 77 to 87, wherein the patient discontinued responding to immune-oncogenic therapeutic antibodies prior to administration of lurbinectedin. 89. The method of any one of paragraphs 77 to 87, wherein the immuno-oncogenic therapeutic antibody is not administered simultaneously with lurbinectedin. 90. A lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide. Including, lurbinectedin and the disaccharide are present in a ratio of 1 mol of lurbinectedin to 455 to 465 mol of the disaccharide; The lyophilized composition is formulated so that, when reconstituted with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained; The lyophilized composition further comprises degradation products resulting from deacetylation of lurbinectedin at levels of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt. / wt. or less based on the total weight of lurbinectedin. Pharmaceutical compositions. 91. The pharmaceutical composition according to item 90, wherein lurbinectedin and the organic acid are present in a ratio of 1 mol of lurbinectedin to 44 to 54 mol of organic acid. 92. The pharmaceutical composition according to item 90 or 91, wherein the vial is a 30 mL vial. 93. The pharmaceutical composition of any one of paragraphs 90 to 92, wherein the lyophilized composition does not contain a phosphate buffer. 94. A pharmaceutical composition according to any one of paragraphs 90 to 93, wherein the buffer derived from an organic acid is selected from lactate buffer, butyrate buffer, propionate buffer, acetate buffer, succinate buffer, citrate buffer, ascorbic acid buffer, tartaric acid buffer, malic acid buffer, maleic acid buffer, fumaric acid buffer, glutamic acid buffer, aspartic acid buffer, gluconic acid buffer, and α-ketoglutaric acid buffer. 95. A pharmaceutical composition according to any one of paragraphs 90 to 94, wherein the organic acid-derived buffer is lactic acid. 96. A pharmaceutical composition according to any one of paragraphs 90 to 95, comprising 22.1 mg lactic acid; 5.1 mg sodium hydroxide; and 800 mg sucrose, or comprising 800 mg sucrose, 0.245 mmol lactate, and 0.128 mmol sodium. 97. A method for reducing degradation of lurbinectedin in a lyophilized formulation containing lurbinectedin, comprising the step of adding a lactate buffer to a stock solution from which the lyophilized formulation is prepared, wherein the resulting ratio of lurbinectedin to lactate buffer is 1 mol:44 mol to 1 mol:54 mol; and wherein lurbinectedin degradation products derived from deacetylation do not exceed 0.8% wt. / wt. of the total lurbinectedin mass when stored at 5°C ± 3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months. 98. The method of claim 97, comprising the step of adding sucrose to the stock solution from which the lyophilized formulation is prepared, and the resulting ratio of lurbinectedin to lactate buffer is 1 mol:455 mol to 1 mol:465 mol. 99. The method according to claim 97, wherein the freeze-dried composition does not contain a phosphate buffer. 100. A method for treating small cell lung cancer (SCLC) in a patient in need thereof, comprising administering lurbinectedin at a dose of 2 to 3.2 mg / m every 3 weeks. 2 wherein the lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, and sucrose, wherein the ratio of lurbinectedin:lactic acid:sucrose is from 1 mol:46 mol:455 mol to 1 mol:50 mol:465 mol, and the formulation is stable at 5°C ± 3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months, such that lurbinectedin degradation products derived from deacetylation do not exceed 0.8% wt. / wt. of the total lurbinectedin mass. 101. The topoisomerase inhibitor is irinotecan 75mg / m 2 and lurbinectedin was administered at a dose equivalent to 2.0 mg / m 2 The method of claim 100, wherein the dose is 102. A packaged lyophilized composition comprising: Packaged in a vial, containing 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide. Including, Dissolution of the lyophilized composition in about 8 mL of water produces a lurbinectedin solution having a pH of about 3.5 to about 4.1; the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage at about 5° C. for about 24 months, about 36 months, or about 48 months, the composition contains about 0.8% or less impurity D (w / w based on lurbinectedin); Lyophilized composition. 103. The composition according to paragraph 102, which when packaged, contains substantially the same amount of impurity D (w / w based on lurbinectedin) after storage at about 5°C for about 24 months, about 36 months, or about 48 months. 104. The composition according to paragraph 102 or 103, wherein the buffer is a salt of an organic anion selected from the group consisting of acetate, succinate, citrate, and lactate. 105. The composition according to paragraph 104, wherein the salt is a lactate salt. 106. The composition of any one of paragraphs 102 to 105, wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and combinations of two or all three of said disaccharides. 107. The composition according to paragraph 106, wherein the disaccharide is sucrose. 108. The composition of paragraph 107, wherein the w / w ratio of lurbinectedin to sucrose is about 1:200. 109. The composition according to any one of paragraphs 102 to 108, comprising 4 mg of lurbinectedin, 22.1 mg of lactic acid, 5.1 mg of sodium hydroxide, and 800 mg of sucrose, or the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium. 110. The composition of any one of paragraphs 102 to 109, wherein dissolution in about 8 mL of water produces a lurbinectedin solution having a pH of about 4.0. 111. A packaged lyophilized composition comprising: Packaged in a vial, containing 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide. Including, Dissolution of the lyophilized composition in about 8 mL of water produces a lurbinectedin solution having a pH of about 3.8 to about 4.1; the lyophilized composition, when packaged, contains less than about 0.3% impurity D (w / w based on lurbinectedin), and after storage of the packaged composition at about 25° C. and a relative humidity of about 60% for up to about 1, 2, 3, 6, 9, or 12 months, the composition contains substantially the same amount of impurity D (w / w based on lurbinectedin); Lyophilized composition. 112. The composition according to paragraph 11, comprising 4 mg of lurbinectedin, 22.1 mg of lactic acid, 5.1 mg of sodium hydroxide, and 800 mg of sucrose, or the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium. 113. The composition of claim 111 or 112, wherein dissolution in about 8 mL of water produces a lurbinectedin solution having a pH of about 4.0. 114. (a) providing a solution of lurbinectedin and an organic acid; (b) providing a solution of a base, an organic acid, and a disaccharide; (c) combining the solutions of steps (a) and (b); (d) adjusting the pH of the solution of step (c) to about 3.8 to about 4.1; and (e) freeze-drying the solution of step (d) to provide a freeze-dried composition. 114. The composition according to any one of claims 102 to 113, which is prepared by a method comprising: 115. The composition according to item 114, wherein the organic acid is selected from the group consisting of citric acid, succinic acid, lactic acid, and acetic acid. 116. The composition according to paragraph 114, wherein the organic acid is lactic acid. 117. The composition of any one of paragraphs 114 to 116, wherein the base is sodium hydroxide. 118. The composition of any one of paragraphs 114 to 117, wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and combinations of two or all three of said disaccharides. 119. The composition of any one of paragraphs 14 to 117, wherein the organic acid is lactic acid, the base is sodium hydroxide, and the disaccharide is sucrose. 120. A method of treating small cell lung cancer (SCLC) in a patient in need thereof, comprising: 1) dissolving a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.5 to about 4.1; and 2) Approximately 2 to 3.2 mg / m every 3 weeks 2 administering lurbinectedin of formula (I) to patients whose SCLC has progressed after prior platinum-containing therapy by intravenous infusion. Including, the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) upon packaging, and upon storage for about 24 months at about 5° C., the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin); method. 121. Administration 1) dissolving a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.8 to about 4.1; and 2) administering lurbinectedin to a patient in need thereof. Including, the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) upon packaging, and upon storage for about 24 months at about 5° C., the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin); Item 120. The method according to item 120. 122. The method according to paragraph 120 or 121, wherein prior to administration, the lyophilized composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted lurbinectedin solution. 123. The method of paragraph 122, wherein the reconstituted lurbinectedin solution is stored at room temperature or at 5°C ± 3°C for up to 24 hours following reconstitution prior to administration, and wherein the reconstituted lurbinectedin solution after storage contains no more than 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt of lurbinectedin impurity D. 124. The method according to paragraph 122 or 123, wherein the lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 125. The method according to paragraph 124, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 126. The method according to paragraph 124 or 125, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 127. The method of any one of paragraphs 120 to 126, wherein the lurbinectedin infusion solution is stored at room temperature or at 5°C ± 3°C for up to 24 hours following reconstitution of the lyophilized lurbinectedin formulation, and wherein the reconstituted lurbinectedin solution after storage contains less than 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt of impurity D based on the total mass of lurbinectedin. 128. Use of lurbinectedin in the manufacture of a medicament for use in therapy to treat small cell lung cancer (SCLC) in a patient in need thereof, the medicament comprising 2 to 3.2 mg / m 2 of lurbinectedin in combination with a prophylactic dose of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient. 2 and the prophylactic dose is administered on the day and prior to administering lurbinectedin to the patient. 129. The use according to paragraph 128, wherein the corticosteroid is dexamethasone formulated for intravenous administration at a dose of 8 mg of dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 130. Use according to item 128 or 129, wherein the serotonin antagonist is ondansetron formulated for intravenous administration at a dose of 8 mg of ondansetron or at a dose of a serotonin antagonist equivalent to 8 mg of ondansetron administered intravenously. 131. Use according to any one of items 128 to 130, wherein the medicament is administered in combination with one or more antiemetics and is administered within 2, 3, or 4 days after administration of lurbinectedin to the patient. 132. Use according to item 131, wherein one or more antiemetics administered after lurbinectedin administration are selected from corticosteroids, serotonin antagonists, and metoclopramide. 133. Use according to item 132, wherein one or more antiemetics are 4 mg of dexamethasone, 8 mg of ondansetron, or 10 mg of metoclopramide, or a combination thereof. 134. Use according to any one of items 121 to 126, wherein the patient is not treated with doxorubicin in combination with lurbinectedin. 135. Use according to any one of items 128 to 134, wherein the patient is progressing after prior platinum-containing therapy or prior immunotherapy. 136. Use of lurbinectedin in the manufacture of a medicament for use in a therapy for treating small cell lung cancer (SCLC) in a patient in need thereof, wherein the medicament is administered to the patient by intravenous infusion at a first dose of 3.2 mg / m 2 in a first treatment cycle, and the same amount is administered in subsequent treatments unless an adverse reaction is identified in the patient, wherein the adverse reaction is selected from the group consisting of grade 3 (severe) or higher non-hematological toxicity, grade 4 thrombocytopenia (platelet count < 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count < 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count < 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction; After identifying the adverse reaction, the patient's neutrophil count was 1500 cells / mm 3 Larger; platelet count is approximately 100,000 cells / mm 3 after hemoglobin levels rise above approximately 9 g / dL: (i) The identified adverse reaction was grade 4 neutropenia (< 500 cells / mm 3 or if the patient has a neutrophil count less than 100 mg / kg / day, a dose of G-CSF is administered in combination with a dose of lurbinectedin equal to the first dose in a subsequent treatment cycle; or (ii) if the identified adverse reaction is not grade 4 isolated neutropenia, a reduced dose of lurbinectedin compared to the first dose is administered to the patient; The two doses of lurbinectedin are administered at least 21 days apart. use. 137. After the first occurrence of an adverse reaction that is not grade 4 isolated neutropenia, the first reduced dose is 80-85% of the first dose, or after the first occurrence of an adverse reaction that is not grade 4 isolated neutropenia, the first reduced dose is 2.6 mg / m 2 Item 137. The use according to item 136, wherein 138. After a second occurrence of an adverse reaction that is not grade 4 isolated neutropenia, the second reduced dose is 60-65% of the first dose, or after a second occurrence of an adverse reaction that is not grade 4 isolated neutropenia, the second reduced dose is 2.0 mg / m 2 and a second reduced dose is administered to the patient. 139. The use according to paragraph 138, wherein administration of lurbinectedin is discontinued following identification of adverse reactions following administration of a second, reduced dose. 140. The use according to any one of clauses 136 to 139, wherein the medicament is administered as an infusion formulation prepared by diluting a reconstituted lyophilized formulation of lurbinectedin 4 mg, lactic acid 22.1 mg or lactate 0.245 mmol, sodium hydroxide 5.1 mg or sodium 0.128 mmol, and sucrose 800 mg, which has a pH of 3.5 to 4.5 when reconstituted. 141. Use of lurbinectedin in the manufacture of a medicament for use in therapy to treat small cell lung cancer (SCLC) in a patient in need thereof, wherein the medicament is administered in a dose of 3.2 mg / m 2 wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a reconstituted solution at a pH of 3.5 to 4.5. 142. The use according to item 141, wherein the disaccharide is sucrose, and optionally the composition comprises lurbinectedin and sucrose in a ratio of 1 mol lurbinectedin:455-465 mol sucrose. 143. The use according to item 141 or 142, wherein the organic carboxylic acid is lactic acid, and optionally the composition comprises lurbinectedin and lactic acid in a ratio of 1 mol lurbinectedin:44 to 54 mol lactic acid. 144. The use according to any one of paragraphs 141 to 143, wherein the pH is 3.8 to 4.5. 145. The use according to any one of paragraphs 141 to 144, wherein the freeze-dried composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted solution. 146. The use according to paragraph 145, wherein the lurbinectedin injection solution is prepared by diluting the reconstituted solution with an isotonic solution. 147. The use of any one of paragraphs 141 to 146, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare the lurbinectedin infusion solution. 148. The use according to paragraph 146, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 149. A freeze-dried composition comprising: Lactic acid 22.1 mg; 5.1 mg sodium hydroxide; and Sucrose 800mg Including, Or, the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium; 149. The use according to any one of clauses 141 to 148. 150. The use of any one of paragraphs 141 to 149, wherein the lyophilized composition is provided in a 30 mL vial. 151. The use according to any one of paragraphs 141 to 150, wherein the lyophilized composition contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 152. The use according to any one of paragraphs 141 to 151, wherein the lyophilized composition does not contain a phosphate buffer. 153. The use according to any one of paragraphs 141 to 152, wherein the reconstituted solution or lurbinectedin infusion solution contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 154. The use of any one of paragraphs 141 to 153, wherein lurbinectedin is administered in combination with prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to a patient, the prophylactic doses being administered on the days and prior to administration of lurbinectedin to the patient. 155. The use according to paragraph 154, wherein the corticosteroid is dexamethasone formulated for intravenous administration at a dose of 8 mg of dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 156. The use according to paragraph 154 or 155, wherein the serotonin antagonist is ondansetron formulated for intravenous administration at a dose of 8 mg of ondansetron, or at a dose of serotonin antagonist equivalent to 8 mg of ondansetron administered intravenously. 157. The use of any one of clauses 154 to 156, wherein the medicament is administered in combination with one or more antiemetic agents and is administered within 2, 3, or 4 days after administration of lurbinectedin to the patient. 158. The use according to paragraph 157, wherein the one or more antiemetic agents are selected from corticosteroids, serotonin antagonists, and metoclopramide. 159. The use of paragraph 158, wherein the one or more antiemetic agents is dexamethasone 4 mg, ondansetron 8 mg, or metoclopramide 10 mg, or a combination thereof. 160. The medicament, in combination with G-CSF, is capable of inducing 500 cells / mm 3 160. The use of any one of clauses 141 to 159, wherein the neutrophil count is administered to a patient identified as having a neutrophil count below the normal range or any value below the normal range and associated with infection / sepsis. 161. The use of any one of clauses 141 to 160, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 162. The use of any one of clauses 141 to 161, wherein the overall response rate is at least 11% or at least 20% for patients with a CTFI interval of less than 90 days, or the overall response rate is at least 30% or at least 40% for patients with a CTFI interval of more than 90 days. 163. The use of any one of paragraphs 141 to 162, wherein the duration of response is at least 2.5 months or at least 4.5 months for patients with a CTFI interval of less than 90 days, or the duration of response is at least 3.5 months, 5 months, or 6 months for patients with a CTFI interval of more than 90 days. 164. The use of any one of paragraphs 141 to 163, wherein the patient has not received platinum-containing therapy at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 165. The use according to any one of clauses 141 to 164, wherein the patient has discontinued platinum-containing therapy prior to administration of lurbinectedin. 166. The use of any one of clauses 141 to 165, wherein the patient has previously been administered immunotherapy. 167. The use according to paragraph 166, wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 168. The use according to paragraph 167, wherein the immunotherapy is atezolizumab or nivolumab. 169. The use of any one of clauses 166 to 168, wherein the patient is progressing after receiving immunotherapy. 170. The use of any one of paragraphs 141 to 169, wherein the patient has an estimated creatinine clearance greater than 30 mL / min, AST or ALT less than 3×ULN, or bilirubin less than 1.5×ULN. 171. Lurbinectedin was administered to patients as a 1-hour intravenous infusion to achieve a plasma total C of within 80%–125% of approximately 107 μg / L. max 171. The method according to any one of clauses 141 to 170, wherein the method achieves an AUC∞ within 80% to 125% of about 551 μg*h / L. 172. Use of lurbinectedin in the manufacture of a medicament for use in therapy to treat endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer in a patient in need thereof, the medicament being administered at a dose of 1 to 2.5 mg / m in combination with a topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. 2 The topoisomerase inhibitor is irinotecan 50-75 mg / m 2 Administered in a dose equivalent to, use. 173. Lurbinectedin is administered at a dose of 2.0 mg / m by intravenous infusion on day 1 of the treatment cycle. 2 and irinotecan was administered at a dose of 75 mg / m 2 173. The use of claim 172, wherein the dose is administered. 174. 75mg / m 2174. The use of paragraph 172 or 173, wherein a subsequent dose of irinotecan at 100 mg / kg is administered on day 8 of the treatment cycle. 175. The use of any one of clauses 172 to 174, wherein the treatment cycle is 21 days. 176. The use of any one of clauses 172 to 175, wherein the medicament is administered in combination with G-CSF during the treatment cycle. 177. The use of any one of paragraphs 172 to 176, wherein if a patient experiences hematological toxicity after dosing on day 1, then subsequent doses of irinotecan are not administered to said patient during the treatment cycle. 178. The use of any one of paragraphs 172 to 177, further comprising administering one or more antiemetic agents on day 1 of the treatment cycle. 179. The use of any one of paragraphs 172 to 178, wherein the patient is being treated for endometrial cancer, SCLC, soft tissue sarcoma, or glioblastoma. 180. Use of a lyophilized pharmaceutical composition for administering the pharmaceutical composition to a patient in need thereof, the lyophilized pharmaceutical composition being reconstituted in a vial and administered to the patient after storing the composition for 30 to 60 months; A lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution containing 4 mg of lurbinectedin, a buffering agent derived from an organic carboxylic acid, and sucrose; The composition comprises lurbinectedin and a disaccharide in a ratio of lurbinectedin 1 mol:sucrose 455-465 mol; The lyophilized composition is formulated so that, upon reconstitution with 8 mL of water, a solution having a pH of 3.5 to 4.5 is obtained. use. 181. The use according to paragraph 180, wherein the pharmaceutical composition comprises an amount of lurbinectedin that is at least 95% of the amount of lurbinectedin on the first day of storage. 182. The use according to paragraph 180 or 181, wherein the vial is a 30 mL vial. 183. Use of lurbinectedin in the manufacture of a medicament for treating SCLC in a patient in need thereof, comprising: Lurbinectedin, 2-3.2 mg / m2 is administered to the patient by intravenous infusion at a dose of; The patient is administered an immunotherapeutic antibody to treat SCLC prior to beginning a treatment cycle; the duration of response is at least 2, 3, 4, 5, or 6 months, or the overall response rate is at least 40%; use. 184. The use of paragraph 183, wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 185. The use according to paragraph 184, wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 186. The use according to paragraph 185, in which the immunotherapeutic antibody is administered to the patient simultaneously with a chemotherapeutic agent. 187. The use according to paragraph 186, wherein the chemotherapeutic agent is carboplatin or etoposide. 188. The use according to paragraph 187, wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic agent is carboplatin or etoposide. 189. The use of any one of clauses 183 to 188, wherein one dose of lurbinectedin is administered per treatment cycle, and the treatment cycle is an 18, 19, 20, 21, 22, 23, 24, or 25 day cycle. 190. The use of any one of paragraphs 183 to 189, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 191. The use of any one of paragraphs 183 to 190, wherein the patient is administered 5 doses of lurbinectedin over 17 weeks, or at least 6 doses of lurbinectedin over 20 weeks, or at least 7 doses of lurbinectedin over 22 weeks. 192. The use of any one of paragraphs 183 to 191, wherein the overall response rate is at least 40%, or at least 50%, or at least 60%. 193. The use of any one of paragraphs 183 to 192, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months. 194. The use of any one of paragraphs 183 to 193, wherein the patient has not received an immuno-oncogenic therapeutic antibody at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 195. The use of any one of paragraphs 183 to 194, wherein the patient discontinued responding to immune-oncogenic therapeutic antibodies prior to administration of lurbinectedin. 196. The use of any one of paragraphs 183 to 195, wherein the immuno-oncogenic therapeutic antibody is not administered simultaneously with lurbinectedin. 197. Use of lurbinectedin in the manufacture of a medicament for use in treating small cell lung cancer (SCLC) in a patient in need thereof, wherein lurbinectedin is administered at a dose of 2 to 3.2 mg / m every 3 weeks. 2 and the medicament is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, and sucrose, wherein the ratio of lurbinectedin:lactic acid:sucrose is from 1 mol:46 mol:455 mol to 1 mol:50 mol:465 mol, and the formulation is stable at 5°C±3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months, such that deacetylation-derived lurbinectedin degradation products do not exceed 0.8% wt. / wt. of the total lurbinectedin mass. 198. The drug is irinotecan 75mg / m 2 and 2.0 mg / m 2 The use according to claim 197, wherein the compound is used in combination with lurbinectedin administered at a dose of 199. Use of lurbinectedin in the manufacture of a medicament for use in treating small cell lung cancer (SCLC) in a patient in need thereof, wherein the medicament is a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide, and is administered at a dose of about 2 to 3.2 mg / m every 3 weeks. 2is dissolved in about 8 mL of water to form a lurbinectedin solution having a pH of about 3.5 to about 4.1 for administration by intravenous infusion to patients whose SCLC has progressed after prior platinum-containing therapy; The lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage at about 5° C. for about 24 months or about 36 months, the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin). use. 200. A pharmaceutical composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide, the composition being dissolved in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.8 to about 4.1 for administration to a patient in need thereof; The lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage at about 5° C. for about 24 months or about 36 months, the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin). 200. The use according to any one of paragraphs 128 to 199. 201. The use of any one of paragraphs 128 to 200, wherein prior to administration, the lyophilized composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted lurbinectedin solution. 202. The use according to paragraph 201, wherein the reconstituted lurbinectedin solution is stored at room temperature or at 5°C ± 3°C for up to 24 hours following reconstitution prior to administration, and the reconstituted lurbinectedin solution after storage contains no more than 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt of impurity D based on the total mass of lurbinectedin. 203. The use according to paragraph 201 or 202, wherein the lurbinectedin injection solution is prepared by diluting the reconstituted solution with an isotonic solution. 204. The use according to paragraph 203, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare a lurbinectedin injection solution. 205. The use according to paragraph 203 or 204, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 206. The use of any one of paragraphs 203 to 205, wherein the lurbinectedin infusion solution is stored at room temperature or at 5°C ± 3°C for up to 24 hours following reconstitution of the lyophilized lurbinectedin formulation, and the reconstituted lurbinectedin solution after storage contains no more than 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt of impurity D based on the total lurbinectedin mass. 207. (1) administering, on the day and prior to administering lurbinectedin to the patient, prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient; and (2) Lurbinectedin at 2 to 3.2 mg / m 2 administering to the patient by intravenous infusion at a dose of 23. A composition for the treatment of small cell lung cancer (SCLC) in a patient in need thereof, comprising: 208. The composition according to paragraph 207, wherein the corticosteroid is dexamethasone administered intravenously at a dose of 8 mg of dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 209. The composition of paragraph 207 or 208, wherein the serotonin antagonist is ondansetron administered intravenously at a dose of 8 mg of ondansetron, or at a dose of serotonin antagonist equivalent to 8 mg of ondansetron administered intravenously. 210. The composition of any one of paragraphs 207 to 209, further comprising administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient. 211. The composition of paragraph 210, wherein the one or more antiemetic agents administered following administration of lurbinectedin are selected from corticosteroids, serotonin antagonists, and metoclopramide. 212. The composition according to item 211, wherein one or more antiemetics are dexamethasone 4 mg, ondansetron 8 mg, or metoclopramide 10 mg, or a combination thereof. 213. The composition according to any one of items 207 to 212, wherein the patient is progressing after prior platinum-containing therapy or prior immunotherapy. 214. A composition for the treatment of small cell lung cancer (SCLC) in a patient in need thereof, (1) administering to the patient by intravenous infusion a first dose of 3.2 mg / m 2 of lurbinectedin; and (2) identifying an adverse reaction in the patient, wherein the adverse reaction is grade 3 (severe) or higher non-hematological toxicity, grade 4 thrombocytopenia (platelet count less than 25,000 cells / mm 3 ), grade 3 thrombocytopenia with bleeding requiring transfusion (platelet count less than 50,000 cells / mm 3 ), grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), or any grade of neutropenia associated with infection / sepsis (neutrophil count < LLN) or any other adverse reaction, the step; (3) after identifying the adverse reaction, when the patient's neutrophil count is greater than 1500 cells / mm 3 ; the platelet count is greater than about 100,000 cells / mm 3 ; and the hemoglobin level is higher than about 9 g / dL: (i) if the identified adverse reaction consists of grade 4 neutropenia (neutrophil count less than 500 cells / mm 3 ), administering to the patient a dose of G-CSF and a dose of lurbinectedin equal to the first dose; or (ii) if the identified adverse reaction is not only grade 4 neutropenia, administering to the patient a reduced dose of lurbinectedin compared to the first dose comprising administering two doses of lurbinectedin at least 21 days apart, the composition. 215. After the first occurrence of an adverse reaction other than grade 4 neutropenia, the first reduced dose is 80-85% of the first dose, or after the first occurrence of an adverse reaction other than grade 4 neutropenia, the first reduced dose is 2.6 mg / m 2 Item 215. The composition according to item 214, wherein 216. After a second occurrence of adverse reactions other than grade 4 neutropenia, the second reduced dose is 60-65% of the first dose, or after a second occurrence of adverse reactions other than grade 4 neutropenia, the second reduced dose is 2.0 mg / m 2 and a second reduced dose is administered to the patient. 217. The composition of paragraph 216, further comprising the step of discontinuing administration of lurbinectedin after identification of an adverse reaction following administration of the second reduced dose. 218. The composition of any one of paragraphs 214 to 217, wherein lurbinectedin is administered as an infusion formulation prepared by diluting a reconstituted lyophilized formulation of 4 mg lurbinectedin, 22.1 mg lactic acid, 5.1 mg sodium hydroxide, and 800 mg sucrose, having a pH of 3.5 to 4.5 when reconstituted. 219. Patient is given lurbinectedin 3.2 mg / m 2 by intravenous infusion of a lurbinectedin infusion solution at a dose of 4 mg of lurbinectedin, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg of reconstituted lurbinectedin, a buffer derived from an organic carboxylic acid, and a disaccharide to form a reconstituted solution at a pH of 3.5 to 4.5. 23. A composition for the treatment of small cell lung cancer (SCLC) in a patient in need thereof, comprising: 220. The composition of paragraph 219, wherein the disaccharide is sucrose, and optionally the composition comprises lurbinectedin and sucrose in a ratio of 1 mol lurbinectedin:455-465 mol sucrose. 221. The composition according to paragraph 219 or 220, wherein the organic carboxylic acid is lactic acid, and optionally the composition comprises lurbinectedin and lactic acid in a ratio of 1 mol lurbinectedin:44 to 54 mol lactic acid. 222. The composition according to any one of paragraphs 219 to 221, having a pH of 3.8 to 4.5. 223. The composition of any one of paragraphs 219 to 222, wherein the lyophilized composition is reconstituted with about 8 mL of an aqueous solution to obtain a reconstituted solution. 224. The composition according to paragraph 223, wherein the lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution. 225. The composition of any one of paragraphs 219 to 224, wherein the reconstituted solution is diluted with at least 100 mL or at least 250 mL of isotonic solution to prepare a lurbinectedin infusion solution. 226. The composition according to paragraph 225, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution. 227. A freeze-dried composition comprising: Lactic acid 22.1 mg; 5.1 mg sodium hydroxide; and Sucrose 800mg 227. The composition of any one of claims 219 to 226, comprising: 228. The composition of any one of paragraphs 219 to 227, wherein the lyophilized composition is provided in a 30 mL vial. 229. The composition of any one of paragraphs 219 to 228, wherein the lyophilized composition contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 230. The composition of any one of paragraphs 219 to 229, wherein the lyophilized composition does not contain a phosphate buffer. 231. The composition of any one of paragraphs 219 to 230, wherein the reconstituted solution or lurbinectedin infusion solution contains impurity D at a value of 0.8%, 0.7%, 0.6%, 0.5%, or 0.4% wt / wt or less based on the total mass of lurbinectedin. 232. The composition of any one of paragraphs 219 to 231, further comprising administering, on the day and prior to administering lurbinectedin to the patient, prophylactic doses of a corticosteroid and a serotonin antagonist effective to reduce nausea associated with administration of lurbinectedin to the patient. 233. The composition according to paragraph 232, wherein the corticosteroid is dexamethasone administered intravenously at a dose of 8 mg of dexamethasone or at a dose of corticosteroid equivalent to 8 mg of dexamethasone administered intravenously. 234. The composition of paragraph 232 or 233, wherein the serotonin antagonist is ondansetron administered intravenously at a dose of 8 mg of ondansetron, or at a dose of serotonin antagonist equivalent to 8 mg of ondansetron administered intravenously. 235. The composition of any one of paragraphs 232 to 234, further comprising administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient. 236. The composition according to paragraph 235, wherein the one or more antiemetic agents are selected from corticosteroids, serotonin antagonists, and metoclopramide. 237. The composition of paragraph 236, wherein the one or more antiemetic agents is dexamethasone 4 mg, ondansetron 8 mg, or metoclopramide 10 mg, or a combination thereof. 238. G-CSF, 500 cells / mm 3 238. The composition of any one of paragraphs 219 to 237, further comprising the step of administering to a patient identified as having a neutrophil count below normal or any value below the normal range and associated with infection / sepsis. 239. The composition of any one of paragraphs 219 to 238, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 240. The composition of any one of clauses 219 to 239, wherein the overall response rate is at least 11% or at least 20% for patients with a CTFI interval of less than 90 days, or the overall response rate is at least 30% or at least 40% for patients with a CTFI interval of more than 90 days. 241. The composition of any one of paragraphs 219 to 240, wherein the duration of response is at least 2.5 months or at least 4.5 months for patients with a CTFI interval of less than 90 days, or the duration of response is at least 3.5 months, 5 months, or 6 months for patients with a CTFI interval of more than 90 days. 242. The composition of any one of paragraphs 219 to 241, wherein the patient has not received platinum-containing therapy at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 243. The composition of any one of paragraphs 219 to 242, wherein the patient has discontinued platinum-containing therapy prior to administration of lurbinectedin. 244. The use of any one of paragraphs 219 to 243, wherein the patient has previously been administered immunotherapy. 245. The composition of paragraph 244, wherein the immunotherapy is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 246. The composition of paragraph 245, wherein the immunotherapy is atezolizumab or nivolumab. 247. The composition of any one of paragraphs 244 to 246, wherein the patient is progressing after receiving immunotherapy. 248. The composition of any one of paragraphs 219 to 247, wherein the patient has an estimated creatinine clearance greater than 30 mL / min, AST or ALT less than 3×ULN, or bilirubin less than 1.5×ULN. 249. Lurbinectedin was administered to patients as a 1-hour intravenous infusion to achieve a plasma total C of within 80%–125% of approximately 107 μg / L. max and achieving an AUC∞ within 80% to 125% of about 551 μg*h / L. 250. A composition for the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal cancer, or epithelial ovarian cancer in a patient in need thereof, comprising: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from SN-38 and irinotecan on day 1 of a treatment cycle. Including, Lurbinectedin, 1 to 2.5 mg / m 2 is administered at a dose of Topoisomerase inhibitor: irinotecan 50-75mg / m 2 Administered at a dose equivalent to composition. 251. Lurbinectedin is administered at a dose of 2.0 mg / m by intravenous infusion on day 1 of the treatment cycle. 2 and irinotecan was administered at a dose of 75 mg / m 2 The composition of claim 250, wherein the composition is administered in a dose of 252. 75mg / m 2 The composition of paragraph 250 or 251, wherein a subsequent dose of irinotecan at 100 mg / kg is administered on day 8 of the treatment cycle. 253. The composition of any one of paragraphs 250 to 252, wherein the treatment cycle is 21 days. 254. The composition of any one of paragraphs 250 to 253, wherein the medicament is administered in combination with G-CSF during the treatment cycle. 255. The composition of any one of paragraphs 250 to 254, wherein if a patient experiences hematological toxicity after dosing on day 1, then no subsequent doses of irinotecan are administered to the patient during the treatment cycle. 256. The composition of any one of paragraphs 250 to 255, further comprising administering one or more antiemetic agents on day 1 of the treatment cycle. 257. The composition of any one of paragraphs 250 to 256, wherein the patient is being treated for endometrial cancer, SCLC, soft tissue sarcoma, or glioblastoma. 258. A composition for the treatment of SCLC in a patient in need thereof, comprising: Lurbinectedin at 2–3.2 mg / m2 administering to a patient by intravenous infusion at a dose of Including, The patient is administered an immunotherapeutic antibody to treat SCLC prior to beginning a treatment cycle; the duration of response is at least 2, 3, 4, 5, or 6 months, or the overall response rate is at least 40%; composition. 259. The composition of paragraph 258, wherein the immunotherapeutic antibody is an anti-CTLA-4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. 260. The composition of paragraph 259, wherein the immunotherapeutic antibody is atezolizumab or nivolumab. 261. The composition of paragraph 260, wherein the immunotherapeutic antibody is administered to the patient simultaneously with a chemotherapeutic agent. 262. The composition according to paragraph 261, wherein the chemotherapeutic agent is carboplatin or etoposide. 263. The composition according to paragraph 262, wherein the immuno-oncogenic therapeutic antibody is atezolizumab and the chemotherapeutic agent is carboplatin or etoposide. 264. The composition of any one of paragraphs 258 to 263, wherein one dose of lurbinectedin is administered per treatment cycle, and the treatment cycle is an 18, 19, 20, 21, 22, 23, 24, or 25 day cycle. 265. The composition of any one of paragraphs 258 to 264, wherein one dose of lurbinectedin is administered per treatment cycle, and the patient receives at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, or 24 treatment cycles. 266. The composition of any one of paragraphs 258 to 264, wherein the overall response rate is at least 40%, or at least 50%, or at least 60%. 267. The composition of any one of paragraphs 258 to 264, wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months, or 6 months. 268. The composition of any one of paragraphs 258 to 264, wherein the patient has not received an immuno-oncogenic therapeutic antibody at least 30 days, or at least 60 days, or at least 90 days prior to administration of lurbinectedin. 269. The composition of any one of paragraphs 258 to 264, wherein the patient discontinued responding to immune-oncogenic therapeutic antibodies prior to administration of lurbinectedin. 270. The composition of any one of paragraphs 258 to 269, wherein the immuno-oncogenic therapeutic antibody is not administered simultaneously with lurbinectedin. 271. A composition for the treatment of small cell lung cancer (SCLC) in a patient in need thereof, comprising lurbinectedin at a dose of 2 to 3.2 mg / m every 3 weeks. 2 wherein the lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, a lactic acid derived buffer, and sucrose, wherein the ratio of lurbinectedin:lactic acid:sucrose is from 1 mol:46 mol:455 mol to 1 mol:50 mol:465 mol, and the formulation is stable at 5°C±3°C for at least 24 months, or at least 36 months, or at least 48 months, or at least 60 months, such that deacetylation-derived lurbinectedin degradation products do not exceed 0.8% wt. / wt. of the total lurbinectedin mass. 272. A composition for the treatment of small cell lung cancer (SCLC) in a patient in need thereof, comprising: 1) dissolving a packaged lyophilized composition comprising 4 mg of lurbinectedin, a buffer derived from an organic acid, and a disaccharide in about 8 mL of water to produce a lurbinectedin solution having a pH of about 3.5 to about 4.1; and 2) Approximately 2 to 3.2 mg / m every 3 weeks 2 administering lurbinectedin of formula (I) to patients whose SCLC has progressed after prior platinum-containing therapy by intravenous infusion. Including, the lyophilized composition contains less than about 0.3% impurity D (w / w based on lurbinectedin) when packaged, and upon storage for about 24 months at about 5° C., the composition contains less than about 0.8% impurity D (w / w based on lurbinectedin); composition. 273. The method, composition, or use of any one of paragraphs 1 to 45, 54 to 72, 74 to 89, 100 to 101, and 120 to 272, 93 to 94, and 113 to 120, wherein the patient is an adult patient. 274. The method, composition, or use of any one of paragraphs 1 to 45, 54 to 72, 74 to 89, 100 to 101, and 120 to 273, wherein the cancer is metastatic SCLC. 275. The method, composition, or use of any one of paragraphs 1 to 45, 54 to 72, 74 to 89, 100 to 101, and 120 to 274, wherein the cancer is metastatic SCLC with disease progression following platinum-based chemotherapy. 276. A method for reducing adverse events associated with administration of lurbinectedin for the treatment of cancer in a patient in need thereof, comprising: Lurbinectedin 3.2 mg / m 2 administering to a patient by intravenous infusion at a dose of determining whether the patient experiences an adverse event selected from the group consisting of neutropenia, thrombocytopenia, and hepatotoxicity; and modifying the dose if the patient experiences neutropenia, thrombocytopenia, or hepatotoxicity. Including, 3.2 mg / m 2 is administered every 21 days in the absence of dose modifications (i.e., normal dosing schedule), method. 277. Before treatment, patients should have an absolute neutrophil count (ANC) of at least 1,500 cells / mm 3 and a platelet count of at least 100,000 cells / mm 3 277. The method of claim 276, 278. The method of paragraph 276 or 277, wherein the dose is modified by delaying administration of lurbinectedin compared to the normal administration schedule. 279. The method of any one of paragraphs 276 to 278, wherein the dosage is modified by reducing the amount of lurbinectedin administered compared to the normal dosing schedule. 280. Dose modification was 2.6 mg / m every 21 days. 2 280. The method of claim 279, comprising administering lurbinectedin at a dose of 281. The dose was modified to 2.0 mg / m every 21 days. 2 280. The method of claim 279, comprising administering lurbinectedin at a dose of 282. If a patient experiences grade 4 neutropenia or any grade febrile neutropenia; withhold lurbinectedin treatment until the patient's neutropenia is ≤ Grade 1, at which point administer lurbinectedin at 2.6 mg / m every 21 days. 2 278. The method of claim 276 or 277, wherein the method is modified by administering at a dose of 283. A patient presented with grade 4 isolated neutropenia (500 cells / mm 3 If the patient experiences a neutrophil count of less than 100 mg / mL, lurbinectedin treatment should be withheld until the patient experiences neutropenia of Grade 1 or less, at which point lurbinectedin should be administered at 3.2 mg / m2 every 21 days in combination with G-CSF prophylaxis. 2 278. The method of claim 276 or 277, wherein the method is modified by administering at a dose of 284. If a patient experiences grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding; the dose is not increased beyond the patient's platelet count of at least 100,000 cells / mm 3 Lurbinectedin treatment should be withheld until the patient has a platelet count of at least 100,000 cells / mm 3 and lurbinectedin 2.6 mg / m every 21 days. 2 278. The method of claim 276 or 277, wherein the method is modified by administering at a dose of 285. If a patient experiences grade 2 hepatotoxicity, lurbinectedin treatment should be withheld until the patient's hepatotoxicity is ≤ grade 1, at which point lurbinectedin should be increased to 3.2 mg / m every 21 days. 2 278. The method of claim 276 or 277, wherein the method is modified by administering at a dose of 286. If a patient experiences Grade 3 or greater hepatotoxicity, lurbinectedin treatment should be withheld until the patient's hepatotoxicity is Grade 1 or less, at which point lurbinectedin should be administered at a dose of 2.6 mg / m every 21 days. 2 278. The method of claim 276 or 277, wherein the method is modified by administering at a dose of 287. Determining whether the patient experiences an adverse event selected from the group consisting of neutropenia, thrombocytopenia, and hepatotoxicity at the modified dose; and Further modifying the dose if the patient experiences neutropenia, thrombocytopenia, or hepatotoxicity. 287. The method of any one of clauses 282 to 286, further comprising: 288. If a patient experiences grade 4 neutropenia or any grade febrile neutropenia at the modified dose; withhold lurbinectedin treatment until the patient's neutropenia is ≤ Grade 1, at which point lurbinectedin should be administered at 2.0 mg / m every 21 days. 2 288. The method of claim 287, further modified by administering at a dose of 289. If a patient experiences grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding at the modified dose; if the dose is such that the patient's platelet count is at least 100,000 cells / mm 3 Lurbinectedin treatment should be withheld until the patient has a platelet count of at least 100,000 cells / mm 3 and lurbinectedin 2.0 mg / m every 21 days. 2 288. The method of claim 287, further modified by administering at a dose of 290. If a patient experiences grade 2 hepatotoxicity at the modified dose, withhold lurbinectedin treatment until the patient's hepatotoxicity is grade 1 or less, at which point lurbinectedin should be increased to 3.2 mg / m every 21 days. 2 288. The method of claim 287, further modified by administering at a dose of 291. If a patient experiences Grade 3 or greater hepatotoxicity at the modified dose, withhold lurbinectedin treatment until the patient experiences Grade 1 or less hepatotoxicity, at which point lurbinectedin should be administered at a dose of 2.0 mg / m every 21 days. 2 288. The method of claim 287, further modified by administering at a dose of 292. The method of any one of paragraphs 277 to 291, wherein if lurbinectedin treatment is withheld for more than two weeks, administration is permanently discontinued. 292a. The method of any one of paragraphs 282, 283, and 288, wherein if lurbinectedin treatment is withheld to achieve Grade 1 or less neutropenia for more than two weeks, administration is permanently discontinued. 292b. At least 100,000 cells / mm 3 289. The method of claim 284 or 289, wherein if withholding lurbinectedin treatment to achieve a platelet count of is more than two weeks, administration is permanently discontinued. 292c. The method of any one of paragraphs 285, 286, 290, and 291, wherein administration is permanently discontinued if lurbinectedin treatment is withheld to achieve Grade 1 or less hepatotoxicity for more than two weeks. 293. The patient is receiving 2 mg / m 2 292. The method of any one of clauses 277 to 291, wherein administration is permanently discontinued if the patient is unable to tolerate the dose. 294. The method of any one of 277 to 293, wherein the cancer is metastatic SCLC with disease progression after platinum-based chemotherapy. 295. A method for safely administering lurbinectedin for the treatment of cancer in a patient in need thereof, comprising: determining whether the patient is receiving a CYP3A inhibitor; and If the patient is receiving a moderate or strong CYP3A inhibitor, warning of a potential drug / drug interaction with the combination of a CYP3A inhibitor and lurbinectedin; and administering lurbinectedin at a modified dose compared to the normal dosing schedule if coadministration of lurbinectedin with a moderate CYP3A inhibitor cannot be avoided. The method includes: 296. The method according to paragraph 295, wherein the warning is to avoid coadministration of lurbinectedin with a strong or moderate CYP3A inhibitor. 297. A patient is receiving 2.6 mg / m every 21 days. 2 The method of claim 295, wherein the moderate CYP3A inhibitor and lurbinectedin are co-administered, with lurbinectedin at a dose of 298. A patient is receiving 2.0 mg / m every 21 days. 2 The method of claim 295, wherein the moderate CYP3A inhibitor and lurbinectedin are co-administered at a dose of 299. Lurbinectedin 4 mg, a buffer derived from an organic acid, and a disaccharide Including, contains less than about 0.8% impurity D (w / w based on lurbinectedin) when the composition is stored at about 25° C. and about 60% relative humidity for up to about 1, 2, 3, 6, 9, or 12 months; Lyophilized composition. 300. The lyophilized composition of paragraph 299, comprising less than about 0.5% impurity D (w / w based on lurbinectedin) when the composition is stored at about 25°C and about 60% relative humidity for up to about 1, 2, 3, 6, 9, or 12 months. 301. The lyophilized composition according to paragraph 299, comprising less than about 0.3% impurity D (w / w based on lurbinectedin) when the composition is stored at about 25°C and about 60% relative humidity for up to about 1, 2, 3, 6, 9, or 12 months. 302. The lyophilized composition according to paragraph 299, comprising less than about 0.1% impurity D (w / w based on lurbinectedin) when the composition is stored at about 25°C and about 60% relative humidity for up to about 1, 2, 3, 6, 9, or 12 months. 303. The freeze-dried composition of any one of paragraphs 299 to 302, wherein the organic acid is selected from the group consisting of citric acid, succinic acid, lactic acid, and acetic acid. 304. The freeze-dried composition according to item 303, wherein the organic acid is lactic acid. 305. The freeze-dried composition of any one of paragraphs 299 to 304, wherein the disaccharide is selected from the group consisting of sucrose, trehalose, lactose, and combinations of two or all three of said disaccharides. 306. The freeze-dried composition of any one of paragraphs 299 to 305, wherein the organic acid is lactic acid and the disaccharide is sucrose. 307. The lyophilized composition of any one of paragraphs 299 to 306, wherein the composition comprises 4 mg of lurbinectedin, 22.1 mg of lactic acid, 5.1 mg of sodium hydroxide, and 800 mg of sucrose, or the lyophilized composition comprises 800 mg of sucrose, 0.245 mmol of lactate, and 0.128 mmol of sodium. 308. The lyophilized composition of any one of paragraphs 299 to 307, wherein dissolution of the lyophilized composition in about 8 mL of water produces a lurbinectedin solution having a pH of about 3.8 to about 4.1. 309. The lyophilized composition of any one of paragraphs 299 to 307, wherein dissolution in about 8 mL of water produces a lurbinectedin solution having a pH of about 4.0. 310. The lyophilized composition of any one of paragraphs 299 to 307, which upon dissolution in approximately 8 mL of water produces a lurbinectedin solution containing 0.47 to 0.5 mg / mL lurbinectedin and having a pH of approximately 3.5 to 4.5. 311. The freeze-dried composition of any one of paragraphs 299 to 310, packaged in a vial. 311a. The lyophilized composition of any one of paragraphs 299 to 311, packaged in a 30 mL vial. 312. Formula (I):

[0325] [ka]

[0326] Form B of lurbinectedin, exhibiting an X-ray powder diffraction pattern including four or more peaks at 2 theta angles selected from the group consisting of 6.2±0.2°, 7.6±0.2°, 9.0±0.2°, 10.9±0.2°, 14.9±0.2°, and 15.3±0.2°. Lurbinectedin form B. 313. The lurbinectedin according to paragraph 312, wherein the X-ray powder diffraction pattern comprises 5 or more peaks at 2 theta angles selected from the group consisting of 6.2±0.2°, 7.6±0.2°, 9.0±0.2°, 10.9±0.2°, 14.9±0.2°, and 15.3±0.2°. 314. Lurbinectedin according to paragraph 312, having an X-ray powder diffraction pattern comprising peaks at 2-theta angles of 6.2±0.2°, 7.6±0.2°, 9.0±0.2°, 10.9±0.2°, 14.9±0.2°, and 15.3±0.2°. 315. The lurbinectedin of any one of paragraphs 312 to 314, further comprising peaks at 2-theta angles of 12.4±0.2°, 19.2±0.2°, and 26.5±0.2°. 316. The lurbinectedin of any one of paragraphs 312 to 315, further comprising peaks at 2-theta angles of 18.4±0.2°, 20.7±0.2°, and 24.9±0.2°. 317. The following:

[0327] [Table 37]

[0328] Item 313. The lurbinectedin of item 312, further comprising the peaks and relative intensities of: 318. The following:

[0329] [Table 38]

[0330] Item 313. The lurbinectedin of item 312, further comprising the peaks and relative intensities of: 319. The following:

[0331] [Table 39]

[0332] Item 313. The lurbinectedin of item 312, further comprising the peaks and relative intensities of: 320. Lurbinectedin according to any one of paragraphs 312 to 319, exhibiting an X-ray powder diffraction pattern substantially the same as any one of the X-ray powder diffraction patterns shown in Figure 2a or Figure 2b. 321. 2928, 1755, 1626, 1485, 1456, 1370, 1197, 1150, 1088, 1003, 959, 916, and 587 wavelengths (cm -1 321. The lurbinectedin of any one of paragraphs 312 to 320, further characterized by an IR spectrum comprising a peak at 100 nm to 150 nm. 322. Lurbinectedin according to any one of paragraphs 312 to 321, further characterized by TG-FTIR decomposition above 150°C; and / or characterized by a TG-FTIR mass change up to 150°C with loss of water of less than about 5%, less than about 4%, or less than about 3%; and / or characterized by a TG-FTIR showing loss of water, preferably of approximately 2-3% water, more preferably 2.6% water. 323. Lurbinectedin according to any one of paragraphs 312 to 322, further characterized by DSC, where decomposition begins above 130° C. 324. The lurbinectedin of any one of paragraphs 312 to 323, further characterized by an average charge density of about 30 nC / g or less, about 20 nC / g or less, about 10 nC / g or less, about 6 nC / g or less, about 5 nC / g or less, about 5±2 nC / g, about 4±2 nC / g, about 4-5 nC / g, about 5 nC / g, or about 4 nC / g. 325. The lurbinectedin of any one of paragraphs 312 to 324, further characterized by a charge density distribution of less than 4.8 nC / g, between about 0.7 nC / g and less than 4.8 nC / g, or 2.4±2 nC / g. 326. Lurbinectedin according to any one of paragraphs 312 to 325, characterized by a water content of more than 1.6% w / w or between 1.7 and 5% w / w. 327. Lurbinectedin according to any one of paragraphs 312 to 326, further characterized by less than 1%, 0.5%, 0.1%, or substantially no detectable residual solvent. 328. Partially crystalline lurbinectedin. 329. The partially crystalline lurbinectedin according to paragraph 328, comprising form B of lurbinectedin according to any one of paragraphs 312 to 327. 330. At least a detectable amount of crystalline lurbinectedin, up to 1% crystalline lurbinectedin, up to 5% crystalline lurbinectedin, up to 10% crystalline lurbinectedin, up to 20% crystalline lurbinectedin, up to 30% crystalline lurbinectedin, up to 40% crystalline lurbinectedin, up to 50% crystalline lurbinectedin, up to 60 % crystalline lurbinectedin, up to 70% crystalline lurbinectedin, up to 80% crystalline lurbinectedin, up to 90% crystalline lurbinectedin, up to 95% crystalline lurbinectedin, up to 98% crystalline lurbinectedin, or substantially pure crystalline lurbinectedin. 331. The partially crystalline lurbinectedin according to any one of paragraphs 328 to 330, comprising at least a detectable amount of form B, up to 1% w / w of form B, up to 5% w / w of form B, up to 10% w / w of form B, up to 20% w / w of form B, up to 30% w / w of form B, up to 40% w / w of form B, up to 50% w / w of form B, up to 60% w / w of form B, up to 70% w / w of form B, up to 80% w / w of form B, up to 90% w / w of form B, up to 95% w / w of form B, up to 98% w / w of form B, or substantially pure form B. 332. At least a detectable amount of amorphous lurbinectedin, up to 1% w / w amorphous lurbinectedin, up to 5% w / w amorphous lurbinectedin, up to 10% w / w amorphous lurbinectedin, up to 20% w / w amorphous lurbinectedin, up to 30% w / w amorphous lurbinectedin, up to 40% w / w amorphous lurbinectedin, up to 50% w / w amorphous lurbinectedin 332. The partially crystalline lurbinectedin of any one of paragraphs 328 to 331, comprising up to 60% amorphous lurbinectedin, up to 70% amorphous lurbinectedin, up to 80% amorphous lurbinectedin, up to 90% amorphous lurbinectedin, up to 95% amorphous lurbinectedin, or up to 98% amorphous lurbinectedin. 333. A pharmaceutical composition or pharmaceutical intermediate comprising the partially crystalline lurbinectedin according to any one of items 328 to 332. 334. A pharmaceutical composition made by the method comprising partially crystalline lurbinectedin according to any one of paragraphs 328 to 332. 335. The composition of claim 333 or 334 having a total water content of 3% or less; and / or 1%, 0.5%, 0.1% or less or substantially no detectable residual solvents; and / or 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, or 1.3% or less total impurities; and / or 0.8% or less impurity D; and / or 0.3% or less of any unspecified impurity; and / or 2.0% or less total related substances and (maximum) 0.7% or less of any unspecified substances. 336. A pharmaceutical composition according to any one of paragraphs 333 to 335, which is a lyophilized composition. 337. A process for the preparation of lurbinectedin form B according to any one of paragraphs 312 to 327, comprising: a) preparing an acidic aqueous solution containing lurbinectedin or a protonated form thereof; and b) basifying the resulting acidic aqueous solution with a base or buffer to precipitate lurbinectedin form B. The method includes: 338. The method of paragraph 337, wherein the acidic aqueous solution containing lurbinectedin is prepared by dissolving any form of lurbinectedin in acidic water. 339. The method of claim 337, wherein the acidic water is preferably an aqueous solution of 0.1 M HCl. 340. The method of any one of paragraphs 337 to 339, in which the resulting acidic aqueous solution is basified with a buffer. 341. The method of claim 340, wherein the buffer is NH4Cl / NH4OH. 342. The method of any one of paragraphs 337 to 341, further comprising a washing step between step a) and step b), in which the acidic aqueous solution is washed one or more times with a pharma- ceutically acceptable, water-immiscible polar solvent and one or more times with a pharma- ceutically acceptable, water-immiscible non-polar solvent, preferably a C5-C7 alkane. 343. The method of claim 342, in which the acidic aqueous solution is washed one or more times with dichloromethane and one or more times with n-pentane. 344. The method of any one of paragraphs 337 to 343, wherein lurbinectedin form B is collected by filtration. 345. The method of any one of paragraphs 337 to 344, wherein lurbinectedin form B is dried under vacuum. 346. The method of any one of paragraphs 337 to 345, wherein form B of lurbinectedin is converted into a different physical form. 347. The method of claim 346, wherein the distinct physical form is amorphous. 348. A pharmaceutical composition comprising lurbinectedin according to any one of paragraphs 312 to 327 and a pharma- ceutically acceptable carrier. 349. A pharmaceutical composition comprising lurbinectedin and a pharma- ceutically acceptable carrier, wherein the pharmaceutical composition is produced via the lurbinectedin described in any one of items 312 to 327. 350. The pharmaceutical composition of paragraph 348 or 349, comprising lurbinectedin and a disaccharide. 351. A method for the preparation of a lurbinectedin composition, preferably utilizing lurbinectedin according to any one of paragraphs 312 to 327 or partially crystalline lurbinectedin according to any one of paragraphs 328 to 332 as a starting material. 352. The method of claim 351, comprising predissolving lurbinectedin in an organic acid. 353. The method of claim 352, wherein the organic acid has a pH of less than 4, preferably less than 3.5, more preferably less than 3 or approximately 3. 354. The method of paragraph 352 or 353, wherein the organic acid has a molar concentration of approximately 0.1M to 0.5M, preferably approximately 0.2M to 0.4M, more preferably approximately 0.3M or 0.31M. 355. The method of any one of paragraphs 352 to 354, wherein the organic acid has a molar concentration of approximately 0.1M to 0.5M, preferably approximately 0.2M to 0.4M, more preferably approximately 0.3M or 0.31M. 356. The method of any one of paragraphs 352 to 354, wherein the pre-dissolving step lasts for at least 30 minutes, at least 60 minutes, or at least 90 minutes, 30 to 90 minutes, 60 to 90 minutes, 60 to 70 minutes, or approximately 60 minutes. 357. The method of any one of clauses 352 to 356, wherein the solution is diluted with water for injection (WFI) to form a target concentration; the target concentration is optionally 8.3 mg / mL in 0.1 M organic acid. 358. The method of any one of paragraphs 352 to 357, wherein the organic acid is a carboxylic acid such as succinic acid, citric acid, acetic acid, or lactic acid, preferably lactic acid. 359. The method of any one of paragraphs 351 to 358, in which a solution containing an organic acid buffer and a bulking agent (e.g., a disaccharide) is prepared to form a buffer solution. 360. The method according to item 359, wherein the buffer has a pH of about 5.6 or less, preferably about 4 to about 5.6, or about 4.2 to about 5.6. 361. The method of paragraph 359 or 360, wherein the buffer is derived from an organic acid, preferably an organic carboxylic acid, such as an organic carboxylic acid buffer, such as lactate buffer, butyrate buffer, propionate buffer, acetate buffer, succinate buffer, citrate buffer, ascorbic acid buffer, tartaric acid buffer, malic acid buffer, maleic acid buffer, fumaric acid buffer, glutamic acid buffer, aspartic acid buffer, gluconate buffer, and alpha-ketoglutaric acid buffer. 362. The method of any one of paragraphs 359 to 361, wherein the bulking agent is a disaccharide, preferably sucrose. 363. The method of any one of clauses 352 to 362, wherein the dissolved lurbinectedin solution of any one of clauses 352 to 358 is mixed with a buffer solution of any one of clauses 359 to 362 to form a final bulk solution. 364. The method of paragraph 363, in which the final bulk solution is adjusted with WFI to achieve the final target mass. 365. The method of any one of paragraphs 352 to 364, wherein the final target composition comprises 0.5 mg / mL lurbinectedin in 0.03 M sodium lactate buffer at pH=4 and 10% (w / v) sucrose. 366. The method of any one of paragraphs 352 to 365, wherein the bulk solution of any one of paragraphs 363 to 365 is subjected to sterile filtration prior to filling into vials. 367. The method of any one of paragraphs 351 to 366, wherein the composition is lyophilized to form a lyophilized formulation. 368. The method of paragraph 367, wherein the lyophilized composition is labeled for use. 369. The method of paragraph 367 or 368, in which the lyophilized composition is reconstituted for use. 370. The method according to paragraph 369, in which the composition is reconstituted with 8 mL of water to obtain a solution having a pH of 3.5 to 4.5 and a lurbinectedin concentration of 0.5 mg / ml. 371. The method of paragraph 369 or 370, wherein the reconstituted solution is optionally diluted with 0.9% sodium chloride solution or 5% dextrose solution to form an infusion solution; and optionally, the reconstituted solution is further diluted to at least 100 mL or at least 250 mL to prepare the lurbinectedin infusion solution. 372. A lurbinectedin infusion solution made according to the method of any one of paragraphs 351 to 371. 373. A reconstituted solution made according to the method of any one of paragraphs 351 to 370. 374. A lyophilized composition produced according to the method of any one of paragraphs 351 to 368. 375. A bulk composition made according to the method of any one of paragraphs 351 to 366. 376. Lurbinectedin according to any one of paragraphs 312 to 327 or partially crystalline lurbinectedin according to any one of paragraphs 328 to 332 for use as a medicine. 377. Lurbinectedin according to any one of paragraphs 312 to 327, or partially crystalline lurbinectedin according to any one of paragraphs 328 to 332, for use in the manufacture of a medicament. 378. Lurbinectedin according to any one of paragraphs 312 to 327, or partially crystalline lurbinectedin according to any one of paragraphs 328 to 332, for use in the manufacture of a medicament for the treatment of cancer. 379. A method of treating an individual affected by cancer, comprising administering to the affected individual a therapeutically effective amount of lurbinectedin according to any one of paragraphs 312 to 327, or partially crystalline lurbinectedin according to any one of paragraphs 328 to 332. 380. A method of treating an individual affected by cancer, comprising administering to the affected individual a therapeutically effective amount of a lurbinectedin composition prepared using lurbinectedin described in any one of paragraphs 312 to 327, or partially crystalline lurbinectedin described in any one of paragraphs 328 to 332. 381. The composition, method, use, or method of any one of paragraphs 1 to 380, wherein the reference to reconstitution of lurbinectedin 4 mg in 8 mL with a concentration of 0.5 mg / mL is a reference to a calculated concentration of 0.47 mg / mL in 8.55 mL. 382. Lurbinectedin, substantially as described above with reference to the Examples, except for the Comparative Examples. 383. A lurbinectedin composition substantially as described above with reference to the Examples, except for the Comparative Examples.

Claims

1. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy comprising lurbinectedin, said treatment comprising lurbinectedin at a dose of 3.2 mg / m 2 Within 35 days of receiving lurbinectedin at a dose of 2.6 mg / m2 as monotherapy by intravenous infusion 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 2.6 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) metastatic SCLC with disease progression following platinum-based chemotherapy; (b) At least 100,000 / mm 3 Platelet count, (c) at least 1,500 cells / mm 3 Absolute neutrophil count having The patient previously received the 3.2 mg / m 2 experienced grade 4 neutropenia or any grade febrile neutropenia after receiving lurbinectedin at a dose of The patient previously received the 3.2 mg / m 2 have experienced grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding after receiving lurbinectedin at a dose of The patient is administered the 2.6 mg / m 2 (d) have Grade 1 or less hepatotoxicity upon administration of lurbinectedin at a dose of 3.2 mg / m 2 have experienced grade 3 or greater hepatotoxicity after receiving lurbinectedin at a dose of Pharmaceutical compositions.

2. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy comprising lurbinectedin, said treatment comprising lurbinectedin at a dose of 3.2 mg / m 2 Within 35 days of receiving lurbinectedin at a dose of 2.6 mg / m2 as monotherapy by intravenous infusion 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 2.6 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) metastatic SCLC with disease progression following platinum-based chemotherapy; (b) At least 100,000 / mm 3 Platelet count, (c) at least 1,500 cells / mm 3 absolute neutrophil count, and (d) Grade 1 or less hepatotoxicity having The patient previously received the 3.2 mg / m 2 have experienced grade 3 or greater hepatotoxicity after receiving lurbinectedin at a dose of Pharmaceutical compositions.

3. 1. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy, comprising lurbinectedin, said treatment comprising: (a) 3.2 mg / m as monotherapy 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 3.2 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (i) metastatic SCLC with disease progression following platinum-based chemotherapy; (ii) at least 1,500 cells / mm 3 Absolute neutrophil count, (iii) At least 100,000 / mm 3 platelet count, and (iv) Grade 1 or less hepatotoxicity having The patient is administered the 3.2 mg / m 2 and have experienced Grade 3 or greater hepatotoxicity following administration of lurbinectedin at a dose of 3.2 mg / m 2 have resolved to Grade 1 or less hepatotoxicity within 35 days of receiving lurbinectedin at a dose of (b) The patient has resolved to Grade 1 or less hepatotoxicity and has hepatocellular carcinoma (HCC) of at least 100,000 / mm 3 and a platelet count of at least 1500 cells / mm 3 2.6 mg / m2 as monotherapy after achieving an absolute neutrophil count of 2 administering to said patient by intravenous infusion a dose of lurbinectedin of Pharmaceutical compositions.

4. 2.6 mg / m as monotherapy 2 Within 35 days of receiving lurbinectedin at a dose of 2.0 mg / m2 as monotherapy by intravenous infusion 2 and administering to said patient via intravenous infusion a dose of lurbinectedin of 2.0 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) At least 100,000 / mm 3 Platelet count, (b) at least 1,500 cells / mm 3 absolute neutrophil count, and (c) Grade 1 or less hepatotoxicity having The patient previously received the 2.6 mg / m 2 have experienced grade 3 or greater hepatotoxicity after receiving lurbinectedin at a dose of A pharmaceutical composition according to any one of claims 1 to 3.

5. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy comprising lurbinectedin, said treatment comprising lurbinectedin at a dose of 3.2 mg / m 2 Within 35 days of receiving lurbinectedin at a dose of 2.6 mg / m2 as monotherapy by intravenous infusion 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 2.6 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) metastatic SCLC with disease progression following platinum-based chemotherapy; (b) At least 100,000 / mm 3 platelet count, and (c) at least 1,500 cells / mm 3 Absolute neutrophil count having The patient previously received the 3.2 mg / m 2 experienced grade 4 neutropenia or any grade febrile neutropenia after receiving lurbinectedin at a dose of Pharmaceutical compositions.

6. 1. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy, comprising lurbinectedin, said treatment comprising: (a) 3.2 mg / m as monotherapy 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 3.2 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (i) metastatic SCLC with disease progression following platinum-based chemotherapy; (ii) at least 1,500 cells / mm 3 absolute neutrophil count, and (iii) At least 100,000 / mm 3 Platelet count, having The patient is administered the 3.2 mg / m 2 (c) experiencing grade 4 neutropenia or any grade of febrile neutropenia after administration of lurbinectedin at a dose of 3.2 mg / m 2 At least 1500 cells / mm within 35 days of receiving a dose of lurbinectedin 3 Absolute neutrophil count has recovered to ; (b) an absolute neutrophil count of at least 1500 cells / mm 3 and the patient has a cell count of at least 100,000 / mm 3 2.6 mg / m2 as monotherapy for patients with a platelet count of 2 administering to said patient by intravenous infusion a dose of lurbinectedin of Pharmaceutical compositions.

7. 2.6 mg / m as monotherapy 2 Within 35 days of receiving lurbinectedin at a dose of 2.0 mg / m2 as monotherapy by intravenous infusion 2 and administering to said patient via intravenous infusion a dose of lurbinectedin of 2.0 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) At least 100,000 / mm 3 platelet count, and (b) at least 1,500 cells / mm 3 Absolute neutrophil count It has The patient previously received the 2.6 mg / m 2 have experienced grade 4 neutropenia or any grade febrile neutropenia after receiving lurbinectedin at a dose of 7. A pharmaceutical composition according to any one of claims 1, 5 or 6.

8. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy comprising lurbinectedin, said treatment comprising lurbinectedin at a dose of 3.2 mg / m 2 Within 35 days of receiving lurbinectedin at a dose of 2.6 mg / m2 as monotherapy by intravenous infusion 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 2.6 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) metastatic SCLC with disease progression following platinum-based chemotherapy; (b) At least 100,000 / mm 3 platelet count, and (c) at least 1,500 cells / mm 3 Absolute neutrophil count having The patient previously received 3.2 mg / m 2 have experienced grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding after receiving lurbinectedin at a dose of Pharmaceutical compositions.

9. 1. A pharmaceutical composition for the treatment of metastatic small cell lung cancer (SCLC) in patients with disease progression following platinum-based chemotherapy, comprising lurbinectedin, said treatment comprising: (a) 3.2 mg / m as monotherapy 2 administering to the patient via intravenous infusion a dose of lurbinectedin of 3.2 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (i) metastatic SCLC with disease progression following platinum-based chemotherapy; (ii) at least 1,500 cells / mm 3 absolute neutrophil count, and (iii) At least 100,000 / mm 3 Platelet count, having The patient is administered the 3.2 mg / m 2 and after experiencing grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia following administration of lurbinectedin at a dose of 3.2 mg / m 2 At least 100,000 / mm within 35 days of receiving lurbinectedin at a dose of 3 The platelet count has returned to ; (b) Absolute neutrophil count of at least 100,000 / mm 3 and said patient has a platelet count of at least 1500 cells / mm 3 2.6 mg / m2 as monotherapy for patients with absolute neutrophil counts of 2 administering to said patient by intravenous infusion a dose of lurbinectedin of Pharmaceutical compositions.

10. 2.6 mg / m as monotherapy 2 Within 35 days of receiving lurbinectedin at a dose of 2.0 mg / m2 as monotherapy by intravenous infusion 2 and administering to said patient via intravenous infusion a dose of lurbinectedin of 2.0 mg / m 2 wherein upon administration of lurbinectedin at a dose of: (a) At least 100,000 / mm 3 platelet count, and (b) at least 1,500 cells / mm 3 Absolute neutrophil count It has The patient previously received the 2.6 mg / m 2 have experienced grade 3 thrombocytopenia or grade 4 thrombocytopenia with bleeding after receiving lurbinectedin at a dose of 10. A pharmaceutical composition according to any one of claims 1, 8 or 9.

11. 10. The pharmaceutical composition of any one of claims 1 to 3, 5, 6, 8, or 9, wherein one dose of lurbinectedin is administered per treatment cycle, wherein one treatment cycle is for 21 to 35 days, and wherein the patient is administered lurbinectedin for 2 to 24 cycles.

12. 12. The pharmaceutical composition of claim 11, wherein at least one of the 2 to 24 treatment cycles is for 22 to 35 days.

13. 12. The pharmaceutical composition of claim 11, wherein at least one treatment cycle of the 2 to 24 treatment cycles is 21 days long.

14. 10. The pharmaceutical composition of any one of claims 1 to 3, 5, 6, 8, or 9, wherein one dose of lurbinectedin is administered per treatment cycle, each treatment cycle being for 21 to 35 days, and the patient is administered lurbinectedin for 3 to 24 cycles.

15. 15. The pharmaceutical composition of claim 14, wherein at least one of the 3 to 24 treatment cycles is for 22 to 35 days.

16. 15. The pharmaceutical composition of claim 14, wherein at least one treatment cycle of the 3 to 24 treatment cycles is 21 days long.

17. 10. The pharmaceutical composition of any one of claims 1 to 3, 5, 6, 8, or 9, wherein one dose of lurbinectedin is administered per treatment cycle, wherein one treatment cycle is for 21 to 35 days, and wherein the patient is administered lurbinectedin for 4 to 24 cycles.

18. 18. The pharmaceutical composition of claim 17, wherein at least one treatment cycle of the 4 to 24 treatment cycles is 21 days long.

19. Initial 3.2 mg / m after at least 90 days of chemotherapy-free interval following platinum-based chemotherapy 2 and the patient receives the initial dose of 3.2 mg / m 2 10. The pharmaceutical composition of any one of claims 1 to 3, 5, 6, 8, or 9, having a response duration of at least 6.2 months from administration of a dose of

20. Initial 3.2 mg / m after a chemotherapy-free period of ≤90 days following platinum-based chemotherapy 2 and the patient receives an initial dose of 3.2 mg / m 2 10. The pharmaceutical composition of any one of claims 1 to 3, 5, 6, 8, or 9, having a response duration of at least 4.7 months from administration of a dose of

21. The patient receives 2.6 mg / m 2 10. The pharmaceutical composition of claim 1, wherein the lurbinectedin is administered at a dose of

22. The patient receives 2.6 mg / m 2 10. The pharmaceutical composition of claim 1, wherein the lurbinectedin is administered at a dose of

23. The patient receives 2.6 mg / m 2 10. The pharmaceutical composition of claim 1, wherein the lurbinectedin is administered at a dose of

24. The patient receives 2.0 mg / m 2 The pharmaceutical composition of claim 4, wherein the lurbinectedin is administered at a dose of

25. The patient receives 2.0 mg / m 2 The pharmaceutical composition of claim 7, wherein the lurbinectedin is administered at a dose of

26. The patient receives 2.0 mg / m 2 The pharmaceutical composition of claim 10, wherein the lurbinectedin is administered at a dose of

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