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WO2021228414A1 - Méthodes de traitement du cancer du poumon à petites cellules avec des formulations de lurbinectédine - Google Patents

Méthodes de traitement du cancer du poumon à petites cellules avec des formulations de lurbinectédine Download PDF

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Publication number
WO2021228414A1
WO2021228414A1 PCT/EP2020/063734 EP2020063734W WO2021228414A1 WO 2021228414 A1 WO2021228414 A1 WO 2021228414A1 EP 2020063734 W EP2020063734 W EP 2020063734W WO 2021228414 A1 WO2021228414 A1 WO 2021228414A1
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Prior art keywords
lurbinectedin
patient
composition
dose
administered
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PCT/EP2020/063734
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Inventor
Pilar Calvo
Carmen KAHATT
Javier Gomez
Antonio NIETO
Herve DHELLOT
José María FERNANDEZ
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Pharmamar SA
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Pharmamar SA
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Priority to PH1/2022/551216A priority Critical patent/PH12022551216A1/en
Priority to CA3158733A priority patent/CA3158733A1/fr
Priority to JP2022529896A priority patent/JP2023503318A/ja
Priority to CN202411258141.3A priority patent/CN118924687A/zh
Priority to US17/777,982 priority patent/US20230027502A1/en
Priority to PE2022000823A priority patent/PE20221338A1/es
Priority to CN202080090766.7A priority patent/CN115151259B/zh
Priority to BR112022009283A priority patent/BR112022009283A2/pt
Priority to EP20729071.9A priority patent/EP4061372A1/fr
Priority to MX2022006208A priority patent/MX2022006208A/es
Priority to AU2020388196A priority patent/AU2020388196B2/en
Priority to CR20220289A priority patent/CR20220289A/es
Priority to CN202411258158.9A priority patent/CN118924689A/zh
Priority to PCT/EP2020/065093 priority patent/WO2021098992A1/fr
Priority to JOP/2022/0118A priority patent/JOP20220118A1/ar
Priority to CN202411258155.5A priority patent/CN118924688A/zh
Priority to KR1020227021161A priority patent/KR20220119618A/ko
Priority to IL293128A priority patent/IL293128A/en
Priority to IL322021A priority patent/IL322021A/en
Publication of WO2021228414A1 publication Critical patent/WO2021228414A1/fr
Priority to SA522432668A priority patent/SA522432668B1/ar
Priority to CL2022001342A priority patent/CL2022001342A1/es
Priority to CONC2022/0008437A priority patent/CO2022008437A2/es
Priority to ECSENADI202249008A priority patent/ECSP22049008A/es
Anticipated expiration legal-status Critical
Priority to US18/448,145 priority patent/US12440490B2/en
Priority to US18/448,144 priority patent/US20230390285A1/en
Priority to US18/448,122 priority patent/US12324806B2/en
Priority to US18/448,097 priority patent/US20240041872A1/en
Priority to US18/448,124 priority patent/US12433890B2/en
Priority to JP2024139008A priority patent/JP2024170325A/ja
Priority to CL2025001170A priority patent/CL2025001170A1/es
Priority to AU2025203941A priority patent/AU2025203941A1/en
Priority to AU2025203954A priority patent/AU2025203954A1/en
Priority to AU2025203950A priority patent/AU2025203950A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • kits for the treatment of SCLC patients by administering therapeutic amounts of lurbinectedin by intravenous infusion are also provided.
  • 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.
  • Lung cancer is the leading cause of cancer death in both men and women in the United States. In 1998, an estimated 171 ,500 new cases were diagnosed, and about 160,100 deaths resulted from this disease. More women die from lung cancer than breast, ovarian, and uterine cancer combined, and 4 times as many men die from lung cancer than from prostate cancer.
  • Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.
  • the two major types of lung cancer are small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non small cell lung cancer
  • SCLC comprises only about 13-15% of all lung cancers at diagnosis; however, SCLC is the more aggressive form of lung cancer.
  • SCLC the cancer cells tend to grow quickly and travel to other parts of the body, or metastasize, more easily. Its incidence is associated with smoking, almost two thirds of patients present with advanced disease, and although response rates to chemotherapy are high, the benefit is short-lived.
  • the median survival of patients with untreated SCLC is two to four months (Clark, 1998; Glisson, 2003; Davies, 2004).
  • Topotecan is the only approved drug for second-line treatment of patients with a chemotherapy-free interval longer than 60 days. Topotecan monotherapy improves survival and quality of life, as well as cancer-related symptoms in the second-line setting.
  • doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control.
  • Amrubicin a novel anthracyline, showed promising activity in refractory and relapsed patients.
  • Phase III trials are ongoing.
  • Other agents with activity include paclitaxel, docetaxel, gemcitabine, bendamustine and vinorelbine.
  • Lurbinectedin (PM01183) is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin- 8(1 H)-one alkaloid analogue with antineoplastic activity. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand break generating 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.
  • Lurbinectedin has demonstrated a highly potent in vitro activity against solid and non-solid tumor cell lines as well as a significant in vivo activity in several xenografted human tumor cell lines in mice, such as those for breast, kidney and ovarian cancer. Preliminary clinical results have shown that lurbinectedin has activity as a second line therapeutic as a single agent in SCLC. There is a need for treatment for SCLC and other solid tumors.
  • Phase 2 clinical trial results demonstrate an at least 30% (35.2%) overall response rate for SCLC patients with lurbinectedin as a second line agent administered as single agent.
  • Results from a phase 1 b-2 trial in solid tumor patients demonstrated activity of a combination of lurbinectedin and irinotecan, particularly in SCLC, endometrial carcinoma, soft tissue sarcoma and glioblastoma.
  • kits for treating SCLC in patients in need thereof especially those 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 to respond adequately to prior treatment, those who may have responded to prior treatment but then experienced progression of the disease, and those who may have had such response followed by progression more than once.
  • methods of treating solid tumors, particularly SCLC, endometrial carcinoma, soft tissue sarcoma, and glioblastoma in patients in need thereof administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan or SN-38.
  • Stable lyophilized formulations are further provided.
  • the methods provided herein involve administering to a patient suffering from SCLC, particularly an SCLC patient who has progressed after prior platinum-containing therapy, an effective amount of lurbinectedin by intravenous infusion.
  • an effective amount of lurbinectedin by intravenous infusion are provided.
  • Lurbinectedin is preferably administered at a dose of 3.2 mg/m 2 every 3 weeks, typically over a period of multiple months, and in most cases until disease progression and death or the patient experiences unacceptable toxicity, depending upon the patient’s response to the administration.
  • treatment effective amounts of lurbinectedin may be administered every 3 weeks to the patient as a 1-hour IV infusion using dosing levels of 3.2 mg/m 2 , to achieve mean total plasma Cmax of about 85.6 ⁇ g/L to 133.75 ⁇ g/L, preferably 107 ⁇ g/L, and mean AUC ⁇ of about 440.8 ⁇ g*h/Lto 688.75 ⁇ g*h/L, preferably 551 ⁇ g*h/L.
  • Overall survival for a median of 9.3 months may be achieved according to the methods disclosed herein.
  • a method of managing hematological adverse events associated with lurbinectedin treatment regimen by dose reduction and/or administration of G-CSF relates to administering to an SCLC patient a lurbinectedin formulation by IV infusion at a dose of 3.2 mg/m 2 ; assessing, after administering the lurbinectedin, whether the patient experiences an adverse reaction associated with the lurbinectedin administration that is a ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions.
  • neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/d, (i) if the adverse reaction consists of an isolated Grade 4 neutropenia, then administering to the patient a dose of G-CSF and a dose of lurbinectedin that is the same as the previous dose, for example, 3.2 mg/m 2 , or (ii) if the adverse reaction is a hematological abnormality that is not solely Grade 4 neutropenia, then administering a dose that is reduced compared to the prior dose, for example is 80 to 85% of the prior dose, for example, 2.6 mg/m 2 if the prior dose is 3.2 mg/m 2 .
  • the dose may be reduced if the adverse reaction is Grade 4 neutropenia.
  • the adverse reaction is Grade 4 neutropenia.
  • a patient experiences an adverse event that is a ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm3), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm3) with bleeding that requires transfusion), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions (but, in certain embodiments, not solely isolated Grade 4 neutropenia), then at the next scheduled dosage, preferably 3 weeks after the prior dose, and once the patient’s neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/d, administering a second reduced dosage to the patient which is 60 to
  • an antiemetic is prophylactically administered prior to administration of lurbinectedin associated (acute and delayed- phase) nausea and/or vomiting comprising administering an antiemetic prophylaxis on the day of and prior to administering a dose of 2 to 3.2 mg/m 2 lurbinectedin to the patient, particularly where the antiemetic agents comprise a corticosteroid and a serotonin antagonist.
  • the corticosteroid is dexamethasone, preferably a dose of 8 mg administered intravenously, or a dose of a corticosteroid that is equivalent to 8 mg dexamethasone intravenously and where the serotonin antagonist is ondansetron, preferably a dose of 8 mg administered intravenously, or a dose of serotonin antagonist that is equivalent to 8 mg ondansetron administered intravenously.
  • antiemetic therapy is administered post-infusion on the day of, or for 2, 3, or 4 days after administration of lurbinectedin, preferably comprising administering a corticosteroid, a serotonin antagonist and metoclopramide.
  • the corticosteroid is dexamethasone administered orally at a dose of 4 mg, or a dose of corticosteroid 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;
  • metoclopramide is administered at a dose of 10 mg either intravenously or orally, or the dose equivalent to oral or intravenous 10 mg metoclopramide, wherein the metoclopramide is administered every 8 hours.
  • One aspect of the invention is a method of treating patients with solid tumors in need thereof by administering lurbinectedin in combination with a topoisomerase inhibitor, particularly irinotecan.
  • the solid tumor patient is treated with a treatment regimen in which lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 on day 1 with a dose of 75 mg/m 2 irinotecan administered on day 1 and day 8 of the treatment cycle, and the irinotecan is administered with G-CSF.
  • the solid cancer is selected from endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, and epithelial ovarian cancer.
  • the solid tumor is endometrial cancer, SCLC, soft tissue sarcoma, or glioblastoma.
  • a stable, lyophilized formulation of lurbinectedin comprising lurbinectedin, a buffer derived from an organic acid (such as lactate buffer) and a disaccharide which has a pH of 3.8 to 4.5 when reconstituted with 8 mL of water.
  • 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 ingredients in this ratio).
  • the composition is preferably packaged in a 30 ml vial and may be reconstituted in 8 mL water, to yield a solution containing 0.5 mg/ml lurbinectedin.
  • the lyophilized formulation may be stored for 24 months or 36 months or more at 5 e C ⁇ 3 e C. After 24 months or 36 months of storage, the amount of Impurity D (lurbinectedin degradation product resulting from deacetylation of lurbinectedin) present in the composition is not more than 0.8% wt./wt. of the total lurbinectedin weight. Also provided are methods of storing the lurbinectedin lyophilized formulation and methods of treating SCLC and solid tumors by administration of a lurbinectedin infusion solution prepared from a stored, stable lyophilized lurbinectedin solution. [0017] The present invention identifies methods of treatment using lurbinectedin alone or in combination with further agents.
  • the present invention also encompasses lurbinectedin and/or said further agents in the manufacture of a medicament for the treatment of cancer and also lurbinectedin and/or said further agents for use in the treatment of cancers as disclosed herein.
  • SCLC small cell lung cancer
  • methods of for the efficacious treatment of small cell lung cancer based on the administration of lurbinectedin as monotherapy.
  • methods of treating solid tumors by administration of a combination of lurbinectedin and irinotecan. Such methods may be carried out by administration of lurbinectedin prepared from stable, lyophilized formulations disclosed herein. Lurbinectedin
  • Lurbinectedin is a synthetic alkaloid and an ecteinascidin analog having the following chemical structure:
  • Lurbinectedin may be prepared according to methods known in the art, for example, the process disclosed in International Application Publication PCT WO 2003/014127, which is incorporated herein by reference. [0020] Any lurbinectedin compound referred to herein is intended to represent hydrates, solvates, amorphous and crystalline or partially crystalline forms, and mixtures thereof when such forms exist in the medium. In addition, lurbinectedin compounds referred to herein may exist in isotopically-labelled forms.
  • cancer it is meant to include tumors, neoplasias, and any other malignant disease having as cause malignant tissue or cells.
  • treating means reversing, alleviating, or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • the methods of “treatment” or “treating” herein may be used for alleviating one or more symptoms of solid tumors, delaying progression of solid tumors, shrinking tumor size in a solid tumor patient, inhibiting solid tumor growth, prolonging overall survival, prolonging progression free survival, preventing or delaying solid tumor metastasis, reducing (such as eradicating) preexisting solid tumor metastasis, reducing incidence or burden of preexisting solid tumor metastasis, or preventing recurrence of solid tumors.
  • immunotherapy means therapy that modulates the immune response, including promoting an immune response or blocking inhibition of an immune response, to cancer cells, for example, but not limited to, antibodies, proteins or other agents that bind to a checkpoint inhibitor, such as, CTLA-4, PD-1 , PD-L1 and others with like activity that promote immune response to cancer cells.
  • a checkpoint inhibitor such as, CTLA-4, PD-1 , PD-L1 and others with like activity that promote immune response to cancer cells.
  • immunotherapies include, but are not limited to, atezolizumab, nivolumab, pembrolizumab, ipilimumab, cemiplimab, durvalumab, avelumab and the like.
  • Embodiments of this invention include methods of treating SCLC in a patient suffering therefrom by administering to the patient a therapeutically effective amount of lurbinectedin according to dosing regimen of one or more treatment cycles using pharmaceutical formulations of lurbinectedin described herein.
  • Lurbinectedin therapy in certain embodiments, is second line therapy, such that patients have previously been administered and disease has progressed in response to, therapies such as platinum- containing therapy and/or immune-oncology therapy.
  • Such treatment regimens are preferably administering to the SCLC patient a dose of 2.0 to 3.2 mg/m 2 lurbinectedin, in preferred embodiments at least for an initial dose, 3.2 mg/m 2 , by intravenous infusion, preferably over 1 hour, every three weeks, provided that dose may be reduced and/or delayed depending upon the occurrence of adverse events, particularly hematological abnormalities as disclosed herein.
  • the SCLC patient is administered 3.2 mg/m 2 by intravenous infusion over 60 minutes repeated every 3 weeks until disease progression or unacceptable toxicity.
  • treatment results in an overall response rate of greater than 30%, including greater than 35% or 35.2%; progression free survival for a median of 3.5 months, including 2.6 to 4.6 months, or 2.6 months (in resistant patient population (CTFI less than 90 days)) to 4.6 months (in sensitive patient populations (CTFI greater than or equal to 90 days)); and overall survival for a median of 9.3 months (resistant patient population (CTFI less than 90 days) of 5.0 months and sensitive patient population (CTFI greater than or equal to 90 days) at 11.9 months).
  • the invention provides methods for treating small cell lung cancer (SCLC) in a patient in need thereof, especially those whose SCLC has progressed after prior therapy such as platinum-containing therapy, immunotherapy, or both, including among others patients who have failed to respond or to respond adequately to prior treatment, those who may have responded to prior treatment but then experienced progression of the disease, and those who may have had such response followed by progression more than once.
  • SCLC small cell lung cancer
  • the lurbinectedin therapy can be second-line therapy wherein the SCLC patient has been previously treated with one or more other chemotherapeutic agents such as carboplatin or cisplatin and etoposide.
  • the treatments are suited for SCLC patients who are relapsing or refractory to previous chemotherapy.
  • the SCLC patient ceased to respond or ceased to respond adequately to prior platinum-containing therapy or had no response to prior platinum-containing therapy.
  • lurbinectedin therapy can be used when a SCLC patient is refractory, resistant, or relapsed/progressive, including in certain embodiments, within 0 to 90 days, or within 91 to 180 days, after cessation of first-line platinum-containing chemotherapy, and optionally radiation treatment.
  • SCLC patients that progress within 0 to 90 days or within the 91 to 180 day period after cessation of the first-line therapy, as well as patients whose SCLC is refractory to treatment and progress, including within 90 days, 180 days or at any time, or whose SCLC responds to initial treatment and then progresses within 90 days, 180 days or at any time of cessation of initial treatment, can advantageously be treated with lurbinectedin so as to increase one or more of their progression-free survival, overall survival, or duration of response.
  • the SCLC patient had a chemotherapy-free interval of at least 90 days, at least 120 days, at least 150 days, or at least 180 days after prior administration of the prior platinum containing therapy.
  • the patient had not received platinum-containing therapy in at least 30 days or at least 60 days or at least 90 days prior to administration of lurbinectedin.
  • the present disclosure provides methods of treating patients with SCLC who have progressed after prior platinum-containing therapy.
  • the lurbinectedin therapy can also be administered following first-line platinum- containing chemotherapy, such as carboplatin or cisplatin and etoposide, in combination with checkpoint inhibitors, such as atezolizumab, pembrolizumab, ipilimumb, durvalumab, or a combination thereof, or following second-line therapy with nivolumab or other immunotherapy, such as atezolizumab, pembrolizumab, ipilimumab or durvalumab.
  • the treatments are suited for SCLC patients who are relapsing or refractory to prior immunotherapy.
  • lurbinectedin treatment are suited for SCLC patients who are relapsing or refractory to prior first-line carboplatin/etoposide/atezolizumab combination therapy or second-line immunotherapy with nivolumab.
  • the SCLC patient ceased to respond or ceased to respond adequately to prior immunotherapy or had no response to prior immunotherapy.
  • lurbinectedin therapy can be used when a SCLC patient is refractory, resistant, sensitive or relapsed/progressive within 91 to 180 days, after cessation of first-line platinum-containing chemotherapy in combination with immunotherapy or second-line nivolumab, and, in certain embodiments, the patient has received radiation treatment.
  • SCLC patients that progress after cessation of the first-line immunotherapy (in combination with platinum-containing therapy) or second-line immunotherapy at any time after therapy (including in certain embodiments within 90 days or within 180 days of treatment), as well as patients whose SCLC is refractory to treatment (has a chemotherapy free interval less than 90 days) and progresses within 180 days, or whose SCLC responds to initial treatment and then progresses within 180 days of cessation of initial treatment, can advantageously be treated with lurbinectedin so as to increase one or more of their progression-free survival, overall survival, or duration of response.
  • the SCLC patient had, with respect to prior treatment, a chemotherapy-free interval, including immunotherapy, of less than 90 days, and in other embodiments, the SCLC had a chemotherapy-free interval of at least 90 days, at least 120 days, at least 150 days, or at least 180 days, but in certain embodiments, no more than 120 days, 150 days or 180 days.
  • the patient had not received first-line immunotherapy (in combination with platinum- containing therapy) or second-line immunotherapy in at least 30 days or at least 60 days or at least 90 days prior to administration of lurbinectedin.
  • 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% for patients with a chemotherapy-free interval of less than 90 days or wherein the overall response rate is at least 30% or at least 40% for patients with a chemotherapy-free interval of at least 90 days.
  • the duration of response is at least 5.3 months or at least 4.7 months for the resistant patient (chemotherapy-free interval of less than 90 days) or wherein the duration of response is at least 6.2 months for the sensitive patient with a chemotherapy-free interval of at least 90 days.
  • the treatment can be a second-line therapy for SCLC with extensive or limited disease that is refractory to initial chemotherapy or progressive within less than 90 days (3 months) of completing first line, platinum-containing therapy.
  • SCLC patients that progress after cessation of the first-line therapy (including within 30 to 90 days of treatment, but may be at anytime), as well as patients whose SCLC is refractory to treatment and progress within 90 days, or whose SCLC responds to initial treatment and then progress within 90 days of cessation of initial treatment, can advantageously be treated with lurbinectedin so as to increase one or more of their progression-free survival, overall survival, or duration of response.
  • the SCLC patient had a chemotherapy-free interval for the prior treatment of less than 90 days, such as less than 30 days, less than 60 days, or less than 90 days.
  • the SCLC patient is first treated with platinum- containing therapy and immunotherapy, wherein the platinum-containing therapy and the immunotherapy were either given concurrently or consecutively, followed by administering to the patient an effective amount of lurbinectedin.
  • a SCLC patient had received prior immunotherapy comprising administering antibodies targeting PD-L1 , CTLA-4, or PD-1 , wherein the antibodies are selected from atezolizumab, nivolumab, pembrolizumab, ipilimumb, durvalumab, or a combination thereof.
  • atezolizumab is administered in combination with platinum-containing therapy and etoposide.
  • the patient has received nivolumab treatment.
  • Administration of the pharmaceutical compositions comprising lurbinectedin is preferably by intravenous infusion. Infusion times of up to 72 hours can be used, but are preferably between 1 and 24 hours, and generally about 1 hour. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. In a preferred embodiment, lurbinectedin is administered by infusion over 1 hour.
  • the administration of lurbinectedin is performed in cycles.
  • an intravenous infusion of lurbinectedin is given to the patients the first day of each cycle and the patients are allowed to recover for the remainder of the cycle.
  • the preferred duration of each cycle is 3 weeks.
  • the treatment cycle can, however, be increased or decreased, for example by 1 to 6 days, one week, or two weeks, depending on patient response to the treatment.
  • Administration of lurbinectedin by intravenous infusion during about 1 hour once every 3 weeks is the most preferred administration schedule, although other protocols can be devised as variations. Multiple cycles can be given as needed.
  • 1 to 24 doses of lurbinectedin can be administered, with 4 to 8 doses being typically administered, at intervals of about 21 days (three weeks). Intervals of up to six weeks, e.g., 3 to 4 weeks, can be employed if, for example, it is necessary to modify the treatment schedule to reduce or manage side-effects (as discussed in detail below).
  • 1 to 24 treatments of lurbinectedin can be administered, with 4 to 8 treatments being typically administered, at intervals of about 21 days (three weeks).
  • one dose of lurbinectedin is administered per treatment cycle and the patient undergoes 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.
  • Bioavailability of a drug is defined as the proportion of a drug or other substance that enters the circulation when introduced into the body and so is able to have an active effect. Measures 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 drug administration.
  • AUC plasma concentration-time curve
  • Cmax concentration maximum
  • the one or more pharmacokinetic parameters is peak concentration (Cmax) or area-under-the-curve (AUC).
  • Cmax peak concentration
  • AUC area-under-the-curve
  • 3.2 mg/m 2 of lurbinectedin is administered to a SCLC patient in need thereof as a 1 -hour infusion, to achieve mean total plasma Cmax within 80% to 125% of about 107 ⁇ g/L and mean AUC ⁇ within 80% to 125% of about 551 ⁇ g*h/L.
  • lurbinectedin is administered to a SCLC patient on a 1 day on and 20 days off cycle (1/20 cycle).
  • the administration cycle is a 1/20 cycle and the target mean AUC ⁇ is about 551 ⁇ g*h/L.
  • the administration cycle is a 1/20 cycle and the target mean AUC 00 is about 551 ⁇ g*h/L ⁇ 5%, about 551 ⁇ g*h/L ⁇ 10%, about 551 ⁇ g*h/L ⁇ 20%, or about 551 ⁇ g*h/L ⁇ 25%.
  • the administration cycle is a 1/20 cycle and the target mean AUC 00 is within 80% to 125% of about 551 ⁇ g*h/L.
  • the administration cycle is a 1/20 cycle and the mean target Cmax is about 107 ⁇ g/L. In one embodiment, the administration cycle is a 1/20 cycle and the mean target Cmax is about 107 ⁇ g/L ⁇ 5%, about 107 ⁇ g/L ⁇ 10%, about 107 ⁇ g/L ⁇ 20%, or about 107 ⁇ g/L ⁇ 25%. In a preferred embodiments, the administration cycle is a 1/20 cycle and the mean target Cmax is within 80% to 125% of about 107 ⁇ g/L.
  • Renal, hepatic, and hematologic impairment need to be ruled out prior to administration lurbinectedin to a patient afflicted with SCLC.
  • a patient afflicted with SCLC determined to have a neutrophil count of at least 1.5 cells/mm 3 , a platelet count of at least 100,000/mm 3 , and hemoglobin levels of at least 9 g/dL (with transfusion if necessary), a first dose of about 3.2 mg/m 2 lurbinectedin is administered.
  • a patient afflicted with SCLC determined to have a calculated hepatic clearance of greater than 30 mL/min and an AST or ALT less than 3xULN or bilirubin less than 1.5xULN, and a calculated creatinine clearance greater than 30 mL/min
  • a first dose of about 3.2 mg/m 2 lurbinectedin is administered.
  • a second dose of 3.2 mg/m 2 lurbinectedin is administered to the patient about 21 days after the first dose, and further dosing at this level is continued if hematological, renal, and hepatic parameters remain stable.
  • lurbinectedin preferably about 3.2 mg/m 2 of lurbinectedin is administered per dose, e.g., per intravenous infusion.
  • Dosing of lurbinectedin can include about 3.2 mg/m 2 lurbinectedin per dose, e.g., per intravenous infusion or a reduced dose thereof as discussed below.
  • Best supportive care for SCLC comprises a number of palliative treatments.
  • best supportive care includes one or more, and preferably all, administration of analgesics to control pain, management of constipation, and treatment of dyspnea and treatment of anemia, e.g., by transfusions, so as to maintain hemoglobin levels (i.e., >9 g/dL).
  • therapies are administered to specifically prevent and treat or manage nausea and/or vomiting associated with lurbinectedin administration, are set forth below.
  • Chemotherapeutics differ in their emetogenicity. In the absence of antiemetic prophylaxis, agents associated with >90% risk of emesis are classified as highly emetogenic chemotherapy and those associated with 30%-90% risk of emesis classified as moderately emetogenic chemotherapy.
  • aspects include methods of prevention and treatment of lurbinectedin-induced (acute and delayed-phase) nausea and/or vomiting, wherein an effective antiemetic amount of a serotonin antagonist or corticosteroid, or a combination thereof, are administered to the patient prior to administration of lurbinectedin, particularly immediately prior to lurbinectedin administration, in order to reduce the side effects of nausea and vomiting that can accompany administration of lurbinectedin.
  • a preferred embodiment is the treatment of SCLC in a patient in need thereof comprising: (1 ) administering one or more antiemetic agents effective to reduce nausea associated with administration of lurbinectedin to the patient on the day of and prior to administration of lurbinectedin to the patient; and (2) administering lurbinectedin at a dose of 2 to 3.2 mg/m 2 to the patient by intravenous infusion.
  • the lurbinectedin is administered as a single agent chemotherapeutic agent and/or is not administered in combination with doxorubicin.
  • antiemetic agents are given intravenously or orally. If the one or more antiemetic agents are given intravenously, the one or more agents are administered between 30 and 90 minutes before administration of lurbinectedin, or at about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, or about 90 minutes, before administration of lurbinectedin, preferably 30 or 60 minutes. If the one or more antiemetic agents are given orally, the one or more agents are administered between 30 to 60 minutes before administration of lurbinectedin, about 3 hours and 9 hours before administration of lurbinectedin, or about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or about 9 hours before administration of lurbinectedin.
  • the antiemetic agents consist of a corticosteroid and a serotonin antagonists, wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, or methylprednisolone and the serotonin antagonist is selected from a group consisting of ondansetron, granisetron, and palonosetron.
  • the dose of the corticosteroid is or is equivalent to about 4 mg to 20 mg of dexamethasone delivered intravenously, preferably 8 mg delivered intravenously.
  • the dose of the serotonin antagonist is or is equivalent to about 8 mg to 16 mg of ondansetron delivered intravenously, preferably 8 mg delivered intravenously.
  • the dose can be increased to a dose equivalent of up to 24 mg of ondansetron.
  • the prophylactic antiemetic agents comprise dexamethasone intravenously administered at 8 mg, ondansetron intravenously administered at 8 mg, or a combination thereof.
  • the method further comprises administering one or more antiemetic agents within 2, 3, or 4 days after administration of lurbinectedin to the patient, for example, administered on the same day after lurbinectedin administration, for example, within 2, 3, 4, 5, 6, 7 or 8 hours of lurbinectedin administration and/or on day 1 , 2, 3, or 4 after lurbinectedin administration.
  • the one or more antiemetic agents administered after lurbinectedin administration are selected from the group consisting of a corticosteroid, wherein the corticosteroid is selected from dexamethasone, hydrocortisone, and methylprednisolone, a serotonin antagonist, wherein the serotonin antagonist is selected from ondansetron, granisetron, and palonosetron, and metoclopramide.
  • the post-infusion antiemetic treatment is 4 mg dexamethasone (oral), 8 mg ondansetron (oral), or 10 mg metoclopramide (oral or as infusion), or a combination thereof.
  • the metoclopramide may be administered at 8 hour intervals.
  • post-infusion antiemetic agents are administered intravenously.
  • the first dose of post-infusion antiemetic agents are given on the evening of, or 1 , 2, 3, 4, 5, 6, 7 or 8 hours after lurbinectedin administration and continued for up to 1 , 2, 3, or 4 days post infusion.
  • a corticosteroid e.g. dexamethasone
  • metoclopramide is administered at a dose of 10 to 20 mg, orally, every 8 hours post chemotherapy for up to 1 , 2, 3, or 4 days.
  • a serotonin antagonist e.g. ondansetron
  • ondansetron is given orally at a dose equivalent to 8 mg or 16 mg of ondansetron every 12 hours or 24 hours, respectively, for up to 1 , 2 or 3 days after lurbinectedin administration.
  • the antiemetic prophylaxis and optionally the post infusion antiemetic treatment is administered to a SCLC patient who is given about 2.0 mg/m 2 , about 2.6 mg/m 2 , or about 3.2 mg/m 2 of lurbinectedin by intravenous infusion.
  • the antiemetic prophylaxis and optionally the post-infusion antiemetic treatment is administered to a solid tumor patient who is administered 1 .0 to 2.0 mg/m 2 lurbinectedin in combination with irinotecan.
  • Additional embodiments of the invention include a dose modification in the event of identifying a ⁇ Grade 2 adverse event (AE) in a SCLC patient upon administration of a first dose of 3.2 mg/m 2 of lurbinectedin to the patient by intravenous infusion which requires frequent or prolonged (>2 weeks) dose delays.
  • AE ⁇ Grade 2 adverse event
  • a lower amount of lurbinectedin is used as compared to the amount generally used for individual therapy.
  • the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of lurbinectedin than the amount generally used for individual therapy.
  • 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.
  • the first dose modification is a dose reduction from about 3.2 mg/m 2 to about 2.6 mg/m 2 of lurbinectedin and the second dose modification is a dose reduction from about 2.6 mg/m 2 to about 2.0 mg/m 2 of lurbinectedin.
  • Adverse events which require frequent or prolonged (>2 weeks) dose delays include, but are not limited to, any hematologic toxicity that is Grade 3 or Grade 4, or any Grade 3 or Grade 4 non-hematologic toxicity. In the event of non-hematologic toxicities of Grade 3 or Grade 4, the following cycle is delayed until non- hematologic parameters have improved to Grade 1 or 0.
  • Administration of two doses of lurbinectedin are always spaced apart by at least 21 days.
  • hematologic toxicities of Grade 3 or Grade 4 the following cycle is delayed until hematologic parameters, such as neutrophil count, platelet count, and hemoglobin level have improved.
  • hematologic parameters such as neutrophil count, platelet count, and hemoglobin level
  • the lurbinectedin dose is reduced from 3.2 mg/m 2 to 2.6 mg/m 2 and the next cycle is delayed until the patient’s neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000/mm 3 ; and hemoglobin levels are greater than about 9 g/dL.
  • the method comprises administration to the patient a dose of G-CSF (“secondary G-CSF prophylaxis”) as prophylaxis to manage the isolated Grade 4 neutropenia and then a dose of lurbinectedin that is equal to the previous dose rather than reducing the lurbinectedin dose.
  • G-CSF secondary G-CSF prophylaxis
  • the method comprises administering to the patient a reduced dose of lurbinectedin.
  • Administration of two doses of lurbinectedin must be spaced apart by at least 21 days regardless of the dose of lurbinectedin.
  • a preferred embodiment is the treatment of small cell lung cancer (SCLC) in a patient in need thereof, comprising: (1) administering a first dose of 3.2 mg/m 2 of lurbinectedin to the patient by intravenous infusion; (2) identifying an adverse reaction in the patient, wherein the adverse reaction is selected from the group consisting of: ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm 3 ), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions; and (3) after the adverse reaction is identified and after the patient’s neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000/mm 3 ; and hemo
  • the first dose reduction is 80 to 85% of the first dose after first occurrence of the adverse reaction that it not solely isolated Grade 4 neutropenia or wherein a first reduced dose is 2.6 mg/m 2 after a first occurrence of the adverse reaction that is not solely isolated Grade 4 neutropenia.
  • a second reduced dose is 60-65% of the first dose after a second occurrence of the adverse reaction that is not solely isolated Grade 4 neutropenia or wherein a second reduced dose is to 2.0 mg/m 2 after a second occurrence of the adverse reaction that is not solely isolated Grade 4 neutropenia, wherein the second reduced is administered to the patient.
  • Administration of lurbinectedin is discontinued after identification of the adverse reaction after administration of the second reduced dose.
  • the invention is directed to the combination of lurbinectedin with a topoisomerase I and/or II inhibitor in the treatment of cancer, and more particularly in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, and epithelial ovarian cancer.
  • the solid tumor is endometrial cancer, SCLC, soft tissue sarcoma or glioblastoma.
  • the method of treating patients with solid tumors comprises administering lurbinectedin at a dose of 1 to 2.5 mg/m 2 in combination with other anticancer agents, such as a topoisomerase inhibitor selected from SN-38 or irinotecan, wherein the lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 and wherein the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg of irinotecan/m 2 .
  • other anticancer agents such as a topoisomerase inhibitor selected from SN-38 or irinotecan
  • 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 with irinotecan in the treatment of cancer, and more particularly in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, and epithelial ovarian cancer.
  • lurbinectedin is administered at a dose of 1 , 1 .5, 2, or 2.4 mg/m 2 and the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg/m 2 of irinotecan. In preferred embodiments, lurbinectedin is administered at a dose of 2 mg/m 2 and irinotecan is administered at a dose of 75 mg/m 2 .
  • G-CSF is administered to the patient with the combination.
  • the topoisomerase inhibitor is administered on day one of a treatment cycle. In some embodiments, the method further comprises administering G-CSF on the same day as the administration of the topoisomerase inhibitor.
  • the topoisomerase inhibitor is further administered to the patient on day 7, 8, 9, or 10 of the treatment cycle.
  • the treatment cycle is a 18, 19, 20, 21 , 22, 23, 24, or 25 day cycle.
  • the method further comprises administering one or more antiemetic agents on day one of a treatment cycle (as described in detail above).
  • compositions of lurbinectedin that can be used include solutions, lyophilized compositions, etc., with suitable excipients for intravenous administration.
  • lurbinectedin may be supplied and stored as a sterile lyophilized product, comprising lurbinectedin, a buffer derived from an organic acid an organic carboxylic acid buffer, for example, a buffer derived from lactic acid, butyric acid, propionic acid, acetic acid, succinic acid, citric acid, ascorbic acid, tartaric acid, malic acid, maleic acid, fumaric acid, and glutamic acid , aspartic acid, gluconic acid, a-ketoglutaric, particularly, lactic acid or succinic acid; a disaccharide, for example, sucrose, trehalose or lactose, or a combination thereof, and a sufficient base to provide an appropriate pH, particularly, when reconstituted, a pH of around 4, including of 3.5 to 4.5 or
  • the lurbinectedin-containing formulations of this invention can be made by freeze-drying a composition of this invention in the form of a buffered bulk solution including lurbinectedin, a buffer derived from an organic acid, such as a lactate buffer or a succinate buffer, and a disaccharide.
  • the disaccharide is preferably sucrose.
  • the bulk solution will be buffered, for example to a pH of about 3.5 to 4.5, more preferably pH 3.8 to 4.1.
  • the preferred buffering agent is a sodium lactate buffer.
  • the lactate buffer comprises lactic acid and a base, preferably an inorganic, pharmaceutically accepted base such as sodium hydroxide.
  • lurbinectedin has limited aqueous solubility. It was found that lurbinectedin solubility is improved in the bulk solution by first forming a concentrated pre-solution of the lurbinectedin in a buffer derived from an organic acid, for example lactic acid, succinic acid, citric acid, or acetic acid which is further diluted with water for injection.
  • a buffer derived from an organic acid for example lactic acid, succinic acid, citric acid, or acetic acid
  • a basic ingredient for example an aqueous sodium hydroxide solution
  • embodiments of this invention provide a fill volume of 10 ml for a vial containing 1 mg lurbinectedin, and 30 ml for a vial containing 4 mg lurbinectedin.
  • the fill volume can optionally be reduced further in other embodiments of this invention by increasing the lurbinectedin concentration.
  • processes useful for improving the solubility of lurbinectedin in the bulking solution that comprise dissolving lurbinectedin in lactic acid, for example 0.31 M lactic acid (25 mg/ml_), and subsequent dilution of the solution with water for injection to yield a lurbinectedin concentrated solution in 0.1 M 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.
  • pH adjustment is accomplished with a lactate buffer.
  • Illustrative embodiments of bulk solution for freeze drying according to the present invention are provided by a solution of lurbinectedin buffered at pH 4 with sodium hydroxide and lactic acid with sucrose as bulking agent.
  • An illustrative embodiment of the methodology according to this invention provides as follows: lurbinectedin is dissolved in 0.31 M lactic acid, pH ⁇ 3 and subsequently diluted with water for injection to yield a lurbinectedin concentrated solution of 8.3 mg/ml_ lurbinectedin in 0.1 M lactic acid, pH ⁇ 3.
  • Sodium lactate buffer salt solution is prepared by mixing 0.31 M lactic acid solution with 0.01 M 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 yield a 0.04M sodium lactate buffer, pH ⁇ 4.2 containing 17% sucrose.
  • Both solutions, 8.3 mg/ml_ lurbinectedin in 0.1 M lactic acid, pH ⁇ 3 and 0.04M sodium lactate buffer, pH ⁇ 4.2 containing 17% sucrose are then mixed. Dissolution is visually checked at all steps before continuing, and dissolution is considered complete when it is so appreciated visually
  • the pH of the solution is checked and adjusted to a value in the range from about 1 to about 5, more preferably in the range from about 2 to about 4.5, even more preferably in the range from about 3 to about 4.5, and most preferably to a pH of about 4.0 by slow addition of a suitable acid or base.
  • a preferred embodiment of such acid is lactic acid, in which case a preferred concentration is about 0.1 M.
  • a suitable base is optionally added for pH control.
  • a preferred embodiment of such base is sodium hydroxide, preferably in solution, in which case a preferred concentration is about 0.1 M.
  • the volume is finally adjusted by addition of a suitable, biocompatible fluid, preferably water for injection.
  • the bulk solution is then filled in vials according to the desired dose.
  • 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.
  • the weight ratio in the lyophilized composition is between 0.4% and 0.6% (w/w) of active compound, 96% to 98% (w/w) of sucrose, 2% to 3% (w/w) of lactic acid, and 0.5% to 0.7% (w/w) sodium hydroxide.
  • the weight ratio in the lyophilized composition is 0.5% (w/w) active compound, 96.2% (w/w) sucrose, 2.7% (w/w) lactic acid, and 0.6% (w/w) sodium hydroxide.
  • the lyophilized formulation contains about 0.25 mmol of lactate ion for 4 mg of lurbinectedin.
  • the resulting solution is 0.5 mg/ml lurbinectedin, 0.03M sodium lactate buffer, 10% w/v sucrose at about pH 4.0 (range of pH 3.5 to 4.5, preferably 3.8 to 4.5).
  • the lyophilized material is usually present in a vial which contains a specified amount of lurbinectedin.
  • the lyophilized composition of lurbinectedin is provided in a 30 ml. vial.
  • the specified amount of lurbinectedin in a lyophilized composition can be from between 0.2 to 5 mg, or about 1 mg, about 2 mg, about 3 mg, or about 4 mg.
  • the specified amount of lurbinectedin in a lyophilized composition is preferably 4 mg.
  • the composition contains between 0.4% and 0.6% by weight of lurbinectedin, preferably it is 0.5%.
  • Embodiments of this invention also provide a method of storing a lyophilized lurbinectedin composition.
  • the lurbinectedin lyophilized formulations are storage stable such that after prolonged storage at the lurbinectedin retains its therapeutic activity and exhibits minimal degradation.
  • the amount of a lurbinectedin degradation product resulting from deacetylation of lurbinectedin (“Impurity D”) (having a relative retention time of 0.87 to 0.88 by commercial HPLC assay) is minimized, for example being less than 0.3%, 0.4%, 0.5%, 0.6%, 0.7% or 0.5% wt/wt of the weight of lurbinectedin in the formulation.
  • Impurity D has the following structure:
  • the method of storing a lyophilized lurbinectedin composition comprises storing a lyophilized composition comprising 4 mg lurbinectedin; lactate buffer; and a disaccharide at a temperature of for at least 24 months, wherein the lyophilized composition is formulated such that reconstitution with 8 ml. of water will yield a solution having a pH of 3.5 to 4.5 and a lurbinectedin concentration of 0.5 mg/ml and wherein after the at least 24 months storage, the amount of Impurity D present in the composition is not more than 0.8% wt./wt. of the total lurbinectedin weight.
  • the lyophilized lurbinectedin composition is stored at a temperature of C for, or for at least, 24 months, 30 months, 36 months, 42 months, 48 months or 60 months, wherein after 24 months, 30 months, 36 months, 42 months, 48 months or 60 months of storage, the amount of a lurbinectedin degradation product Impurity D present in the composition is not more than 0.8% wt./wt. of the total lurbinectedin weight.
  • the amount of Impurity D present in the composition after storage at about for 60 months is not more than 0.8% wt./wt, or is 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. of the total lurbinectedin weight. In one embodiment, the amount of lurbinectedin degradation product Impurity D present in the composition is not more than 0.8% wt./wt. of the total lurbinectedin weight after at least 36 months of storage.
  • the total % impurities and degradation products (as % area) after storage at about for 24 months, 30 months or 36 months is not more than 0.6 %, 0.7%, 0.8% 0.9% or 1 .0% (% area).
  • the initial amount of Impurity D present in the composition i.e., one day of lyophilization
  • the initial amount of Impurity D present in the composition is less than 0.4% wt./wt. of the total lurbinectedin weight.
  • the initial amount of Impurity D present in the composition is at least 0.5 % wt./wt. or at least 0.1% wt./wt. of the total lurbinectedin weight.
  • the stable, lyophilized, lurbinectedin formulation shows negligible degradation of lurbinectedin, for example within 1 .0%, 0.5% or 0.2% decrease in the amount of lurbinectedin as compared to the amount of lurbinectedin present in the bulk solution from which the formulation is made.
  • stable, lyophilized lurbinectedin formulations comprising an a buffer derived from an organic acid, for example, succinate, citrate, acetate or lactate buffer at a molar ratio of buffer to lurbinectedin of about 48, including the molar ratio 52 to 46, 54 to 44, 50 to 48, 52 to 58, or the molar ratio 51 to 48, and sucrose as a bulking agent, which, when reconstituted in 8 mL of water has a pH of about 4.0, including pH 3.5-4.5 or pH 3.8-4.1 , which comprises Impurity D at no more than 0.8% wt/wt, or is 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 of the total weight of lurbinectedin and, preferably, the Impurity D does not increase to more than 0.8% wt
  • the lurbinectedin is 95 to 105%, or 97 to 103% of 4 mg lurbinectedin or of the amount of lurbinectedin by assay at day 1 .
  • a buffer derived from an organic acid preferably a lactate or
  • Other impurities or degradation products that may be minimized in the storage of the stable, lyophilized lurbinectedin formulation may be the degradation products with the following relative retention time on the commercial HPLC method: rrt 0.68, rrt 0.80, rrt 1.11 (Impurity G), and rrt 1.12.
  • the method of treating SCLC in a patient in need therefore comprises: (1 ) administering to the patient lurbinectedin at a dose of 3.2 mg/m 2 by intravenous infusion of a lurbinectedin infusion solution, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg lurbinectedin, a lactate buffer, and a disaccharide reconstituted to form a reconstituted solution at a pH of 3.8 to 4.5.
  • the disaccharide is sucrose.
  • the lyophilized composition comprises 4 mg lurbinectedin, a lactate buffer (preferably resulting from a solution comprising 22.1 mg lactic acid and 5.1 mg sodium hydroxide, including 0.25 mmol of lactate), and a disaccharide (preferably sucrose, particularly 800 mg sucrose), wherein reconstitution of the lyophilized composition in about 8 ml. of an aqueous solution provides a lurbinectedin solution at 0.5 mg/ml_ lurbinectedin having a pH of about 3.8 to about 4.5.
  • a lactate buffer preferably resulting from a solution comprising 22.1 mg lactic acid and 5.1 mg sodium hydroxide, including 0.25 mmol of lactate
  • a disaccharide preferably sucrose, particularly 800 mg sucrose
  • a lurbinectedin infusion solution is prepared by diluting the reconstituted solution with an isotonic solution, wherein the isotonic solution is a 0.9% sodium chloride solution or a 5% dextrose solution.
  • the reconstituted solution is diluted with at least 100 ml. or at least 250 ml. of the isotonic solution to prepare a lurbinectedin infusion solution.
  • the solution can be stored for up to 24 hours following reconstitution, including infusion time, at either room temperature (i.e., about 23°C)/light or under refrigerated (5°C ⁇ 3°C) conditions.
  • the % wt/wt of Impurity D relative to lurbinectedin does not increase by more than 0.1%, 0.2% or 0.3% wt/wt upon storage of the reconstituted or diluted solution for 24, 48 or 72 hours at either room temperature (i.e., about 23°C)/light or under refrigerated (5°C ⁇ 3°C) conditions.
  • Some embodiments provide a method of administering a pharmaceutical composition to a patient in need thereof, for example, a patient suffering from SCLC refractory to first line treatment, comprising (1) reconstituting a lyophilized pharmaceutical composition in a vial after the composition has been stored for 30 to 36 months, wherein the lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution comprising lurbinectedin, lactic acid, sodium hydroxide, and sucrose at a ratio of 4 mg lurbinectedin: 22.1 mg lactic acid: 5.1 mg sodium hydroxide: 800 mg sucrose: 8 ml.
  • the reconstituted solution may be diluted with an isotonic solution, such as a 0.9% sodium chloride solution or a 5% dextrose solution, from 100 ml to 250 ml volume for administration to the patient as an infusion solution.
  • an isotonic solution such as a 0.9% sodium chloride solution or a 5% dextrose solution
  • Embodiments of this invention further provide a pharmaceutical product comprising a vial containing a lyophilized lurbinectedin composition.
  • 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, including, 0.25 mmol lactate); and 800 mg sucrose; a label affixed to the vial comprising an expiration date that is at least 48 months from the date of manufacture.
  • the label affixed to the vial comprises an expiration 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.
  • 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 present invention identifies a number of methods of treatment using lurbinectedin alone or in combination with further agents. Where reference is made to a method of treatment the present invention also encompasses lurbinectedin and/or said further agents in the manufacture of a medicament for the treatment of cancer and also lurbinectedin and/or said further agents for use in the treatment of cancer.
  • SCLC small cell lung cancer
  • corticosteroid in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises:
  • a serotonin antagonist in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises:
  • SCLC small cell lung cancer
  • the adverse reaction is selected from the group consisting of: ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm 3 ), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions;
  • neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/dL:
  • G-CSF in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said method comprises:
  • the adverse reaction is selected from the group consisting of: ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm 3 ), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions;
  • neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/dL:
  • lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said method comprises: administering to the patient lurbinectedin at a dose of 3.2 mg/m 2 by intravenous infusion of a lurbinectedin infusion solution, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg lurbinectedin, an organic carboxylic acid, and a disaccharide reconstituted to form a reconstituted solution at a pH of 3.5 to 4.5.
  • SCLC small cell lung cancer
  • lurbinectedin in the manufacture of a medicament for the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, or epithelial ovarian cancer, wherein said treatment comprises: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from
  • SN-38 and irinotecan on day one of a treatment cycle; wherein the lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 and wherein the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg of irinotecan/m 2 .
  • a topoisomerase inhibitor selected from SN-38 and irinotecan in the manufacture of a medicament for the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, or epithelial ovarian cancer, wherein said treatment comprises: administering to the patient lurbinectedin and said topoisomerase inhibitor selected from
  • SN-38 and irinotecan on day one of a treatment cycle; wherein the lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 and wherein the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg of irinotecan/m 2 .
  • lurbinectedin in the manufacture of a medicament for the treatment of cancer, the treatment comprising reconstituting a lyophilized pharmaceutical composition in a vial after the composition has been stored for 30 to 60 months, wherein the lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution comprising 4 mg of lurbinectedin, organic carboxylic acid, and sucrose, wherein the composition comprises lurbinectedin and disaccharide at a ratio of 1 mol lurbinectedin: 455 to 465 mol sucrose, wherein the lyophilized composition is formulated such that reconstitution with 8 ml. of water will yield a solution having a pH of 3.5 to 4.5; and administering the reconstituted solution to a patient.
  • lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: administering lurbinectedin at a dose of 2 to 3.2 mg/m 2 to the patient by intravenous infusion; wherein the patient was administered an immunotherapeutic antibody for treating SCLC prior to beginning the treatment cycle and wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months or 6 months or wherein the overall response rate is at least 40%.
  • SCLC small cell lung cancer
  • lurbinectedin in the manufacture of a medicament for the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: administering lurbinectedin at a dose of 2 to 3.2 mg/m2 to a patient by intravenous infusion every 3 weeks, wherein the lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, sucrose, wherein the ratio of lurbinectedin :lactic acid:sucrose is between 1 mol:46 mol:455 mol and 1 mol:50 mol:465 mol , wherein the formulation is stable at 5 degree C +- 3 degree C for at least 24 months or at least 36 months or at least 48 months or at least 60 months such that the lurbinectedin degradation product from deactylation does not exceed 0.8% wt./wt. of the total lurbinectedin weight.
  • SCLC small cell lung cancer
  • SCLC small cell lung cancer
  • a packaged, lyophilized composition comprising 4 mg lurbinectedin, a buffer derived from an organic acid and disaccharide in about 8 ml. of water to provide a lurbinectedin solution having a pH of about 3.5 to about 4.1 , and
  • the lyophilized composition comprises less than about 0.3 % of Impurity D (w/w based on lurbinectedin) when the composition is packaged, and wherein upon storage at about 5 degrees C for about 24 months the composition comprises less than about 0.8% of Impurity D (w/w based on lurbinectedin).
  • SCLC small cell lung cancer
  • a corticosteroid for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises:
  • SCLC small cell lung cancer
  • the adverse reaction is selected from the group consisting of: ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm 3 ), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions;
  • neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/dL:
  • G-CSF for use in the treatment of small cell lung cancer (SCLC), wherein said method comprises:
  • the adverse reaction is selected from the group consisting of: ⁇ Grade 3 (severe) non hematological toxicity, Grade 4 thrombocytopenia (Platelet count less than 25,000 cells/mm 3 ), Grade 3 thrombocytopenia (Platelet count less than 50,000 cells/mm 3 ) with bleeding that requires transfusion, Grade 4 neutropenia (Neutrophil count less than 500 cells/mm 3 ), or any grade neutropenia (Neutrophil count ⁇ LLN) that is associated with infection/sepsis or any other of the adverse reactions; (3) after the adverse reaction is identified and after the patient’s neutrophil count is greater than 1500 cells/mm 3 ; platelet count is greater than about 100,000 mm 3 ; and hemoglobin levels are greater than about 9 g/dL:
  • lurbinectedin for use in the treatment of small cell lung cancer (SCLC), wherein said method comprises: administering to the patient lurbinectedin at a dose of 3.2 mg/m 2 by intravenous infusion of a lurbinectedin infusion solution, wherein the lurbinectedin infusion solution administered to the patient is prepared from a lyophilized composition comprising 4 mg lurbinectedin, an organic carboxylic acid, and a disaccharide reconstituted to form a reconstituted solution at a pH of 3.5 to 4.5.
  • SCLC small cell lung cancer
  • lurbinectedin for use in the treatment of endometrial cancer, SCLC, soft tissue sarcoma, glioblastoma, pancreatic adenocarcinoma, mesothelioma, colorectal carcinoma, or epithelial ovarian cancer, wherein said treatment comprises: administering to the patient lurbinectedin and a topoisomerase inhibitor selected from
  • SN-38 and irinotecan on day one of a treatment cycle; wherein the lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 and wherein the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg of irinotecan/m 2 .
  • 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 carcinoma, or epithelial ovarian cancer, wherein said treatment comprises: administering to the patient lurbinectedin and said topoisomerase inhibitor selected from SN-38 and irinotecan on day one of a treatment cycle; wherein the lurbinectedin is administered at a dose of 1 to 2.5 mg/m 2 and wherein the topoisomerase inhibitor is administered at a dose equivalent to 50 to 75 mg of irinotecan/m 2 .
  • lurbinectedin for use in the treatment of cancer, the treatment comprising reconstituting a lyophilized pharmaceutical composition in a vial after the composition has been stored for 30 to 60 months, wherein the lyophilized pharmaceutical composition was prepared by lyophilizing a stock solution comprising 4 mg of lurbinectedin, organic carboxylic acid, and sucrose, wherein the composition comprises lurbinectedin and disaccharide at a ratio of 1 mol lurbinectedin: 455 to 465 mol sucrose, wherein the lyophilized composition is formulated such that reconstitution with 8 ml. of water will yield a solution having a pH of 3.5 to 4.5; and administering the reconstituted solution to a patient.
  • lurbinectedin for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: administering lurbinectedin at a dose of 2 to 3.2 mg/m 2 to the patient by intravenous infusion; wherein the patient was administered an immunotherapeutic antibody for treating SCLC prior to beginning the treatment cycle and wherein the duration of response is at least 2 months, 3 months, 4 months, 5 months or 6 months or wherein the overall response rate is at least 40%.
  • SCLC small cell lung cancer
  • lurbinectedin for use in the treatment of small cell lung cancer (SCLC), wherein said treatment comprises: administering lurbinectedin at a dose of 2 to 3.2 mg/m2 to a patient by intravenous infusion every 3 weeks, wherein the lurbinectedin is provided in a lyophilized formulation comprising lurbinectedin, lactic acid, sucrose, wherein the ratio of lurbinectedin :lactic acid:sucrose is between 1 mol:46 mol:455 mol and 1 mol:50 mol:465 mol , wherein the formulation is stable at 5 degree C +- 3 degree C for at least 24 months or at least 36 months or at least 48 months or at least 60 months such that the lurbinectedin degradation product from deactylation does not exceed 0.8% wt./wt. of the total lurbinectedin weight.
  • SCLC small cell lung cancer
  • SCLC small cell lung cancer
  • a packaged, lyophilized composition comprising 4 mg lurbinectedin, a buffer derived from an organic acid and disaccharide in about 8 mL of water to provide a lurbinectedin solution having a pH of about 3.5 to about 4.1 , and 2) administering about 2 to 3.2 mg/m 2 of lurbinectedin to a patient whose SCLC has progressed after prior platinum-containing therapy by intravenous infusion every 3 weeks and wherein the lyophilized composition comprises less than about 0.3 % of Impurity D (w/w based on lurbinectedin) when the composition is packaged, and wherein upon storage at about 5 degrees C for about 24 months the composition comprises less than about 0.8% of Impurity D (w/w based on lurbinectedin).
  • a bulk lurbinectedin solution containing 0.5 mg/mL of was prepared in an acetate, citrate, lactate, and succinate buffered solution with the buffer concentrations of 0.02 to 0.05 M buffered to pH 3, 4, and 5 with sodium hydroxide.
  • Table 1 Composition of lurbinectedin 4 mg reconstituted solution.
  • Table 3 Solubility and degradation products profile of lurbinectedin in different organic carboxylic buffers in the pH range 3 to 5.
  • Table 4 Effect of pH on the solubility and stability (25 e C / 60% RH 14 days) of lurbinectedin in different 0.02M-0.05M organic carboxylic buffers in the pH range 3 to 5.
  • Lurbinectedin assay decreased significantly (between 11% and 17%) with respect to the initial content for the three compositions being the % degradation products the major differences observed.
  • the vials formulated in sodium lactate buffer or monopotassium phosphate buffer showed very similar behavior, however sodium citrate buffer promoted larger degradation after storage for 1 month at 50°C.
  • the main degradation product was an impurity eluting at rrt 0.49-0.50 (HPLC Development method), being significantly higher in the lyophilized vial formulated in the sodium citrate buffer.
  • Other degradation products that also appeared 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.
  • Example 5 Effect of Bulk Solution pH on Lyophilized Product Stability
  • the stability of 4 mg of lyophilized product produced from various 0.03M sodium lactate buffer lurbinectedin bulk solutions was studied.
  • the bulk solutions had a concentration of 0.5 mg lurbinectedin / ml. at pH 3.6, pH 4.0 and pH 4.5, using 10% sucrose (w/v) as bulking agent (8 ml. filling in 30 ml. glass vials).
  • the stability of these batches was evaluated under 25°C / 60% RH to determine if small variations in pH could have a significant effect on the stability of the product.
  • the stability results of lyophilized vials after 6 months at 25°C are shown in Table 6. All the batches showed similar behavior. Quality attributes such as the appearance of the lyophilized, appearance, color and pH of the reconstituted solution, water content (%) and assay were kept constant. Total degradation products did not undergo significant changes,
  • Example 6 Bulking Agent Concentration
  • Table 8 below shows the stability results of lyophilized batches with the different bulking agents after 3 months stored at 40 ° C/75% RH.
  • the batch formulated with 5% sucrose was stable, since it did not undergo changes in the appearance of the freeze-dried cake nor in the reconstituted solution, maintained the lurbinectedin assay, and only showed a slight increase in degradation products, being impurity D the main degradation product observed (rrt 0.88 HPLC commercial method).
  • Table 9 Stress stability of lurbinectedin freeze-dried vials formulated in 0.03M lactate buffer pH 4 with sucrose as bulking agent at different concentrations.
  • sucrose showed a protective effect to prevent lurbinectedin degradation during storage at high temperature. Based on these results, sucrose was selected as the most appropriate bulking agent being the concentration of 10% (w/v) an optimal quantity for a suitable and stable lurbinectedin presentation.
  • Example 7 Stabilitv of Lurbinectedin at Lona-term Storaae Conditions [0115] The stability of lyophilized lurbinectedin composition (4 mg) at the conditions proposed for long-term storage (5°C ⁇ 3°C) was evaluated during 36 months. A batch with high residual water content was chosen as it is considered as a worst case.
  • Example 8 Clinical Study - Treatment of SCLC Patients with Lurbinectedin [0117] A clinical study of lurbinectedin monotherapy for patients collectively afflicted with
  • SCLC who have refractory or resistant disease, as defined herein, was carried out.
  • a cohort of 105 patients, who had measurable disease including patients whose SCLC was unresponsive to first- line platinum-containing chemotherapy (cisplatin, carboplatin or oxaliplatin) (refractory) and patients whose SCLC recurred within or equal to 90 days after cessation of first-line therapy (resistant), were treated with lurbinectedin at a dosage of 3.2 mg/m 2 given intravenously over a period of 1 hour every 21 days.
  • Lurbinectedin was provided as a sterile isotonic aqueous solution for IV infusion as described below.
  • the minimum interval between any previous treatment and study commencement had to be 3 weeks for chemotherapy, 4 weeks for immunotherapy or radiotherapy, and 2 weeks for any investigational or palliative therapy. Only patients with grade 1 or lower toxicities from any previous therapies were included, except for cases with alopecia and peripheral sensory neuropathy (both grade 2), which were also allowed. Women of child-bearing age had to receive adequate contraception during the study and for at least 3 months after study conclusion.
  • Patients were excluded if they have: previously received lurbinectedin or trabectedin; previous or concurrent malignant disease unless in complete remission for than 5 years; known CNS involvement (screening of CNS metastasis at baseline are mandatory); concomitant unstable or serious medical condition within the past year (history or presence of unstable angina, myocardial infarction, congestive heart failure, valvular heart disease, arrhythmia, severe dyspnoea, or active infection, such as hepatitis or HIV); impending need for radiotherapy; or inability or restricted ability to comply with the study protocol. More details on inclusion and exclusion criteria can be found in Table 11.
  • Lurbinectedin was presented as lyophilized powder for concentration for solution for infusion in 4mg vials. Before use, the 4mg vials were reconstituted with 8 mL of water for injection to give a solution containing 0.5 mg/mL of lurbinectedin. For administration to patients as an i.v. infusion, reconstituted vials were diluted with glucose 50 mg/mL (5%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. The full composition and the reconstituted solution per mL was as shown in Table 12.
  • Lurbinectedin was administered over a minimum total volume of 100 ml. of solution for infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or over a minimum total volume of 250 ml. if administered through a peripheral line, always over one hour at a fixed infusion rate.
  • Starting dose was 3.2 mg/m 2 .
  • Dose was capped at body surface area of 2.0 mg/m 2 (e.g. dose not allowed to exceed 6.4 mg).
  • Patients received lurbinectedin i.v. as a one-hour infusion on Day 1 every three weeks until disease progression or unacceptable toxicity. Three weeks was defined as one treatment cycle.
  • AE(s), adverse event(s); ANC absolute neutrophil count
  • AP alkaline phosphatase
  • AST/ALT aspartate aminotransferase/alanine aminotransferase
  • CPK creatinine phosphokinase
  • ECOG Eastern Cooperative Oncology Group
  • GGT gamma- glutamyltransferase
  • PS performance status
  • ULN upper limit of normal.
  • ORR overall response rate
  • DOR duration of response
  • Radiological tumor assessment (CT scan or MRI) was performed at baseline, and every 6 weeks from the onset of the study treatment until cycle 6 or evidence of PD, and every 9 weeks thereafter. If an objective response was observed, according to RECIST v1 .1 ., it had to be confirmed by the same method at least four weeks after the date of the first documentation of response.
  • 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 a subsequent therapy or end of patients follow-up according to RECIST v1.1.
  • DOR was calculated from the date of first documented PD, recurrence, or death due to any cause in the responder patients.
  • the IRC determined the patient’s best response and assigned the date of first documentation of response and progression/censoring according to RECIST v1.1.
  • PK analysis of plasma-concentration-time data of lurbinectedin was performed using non-linear mixed-effects modeling and/or non-compartment analysis.
  • ORR Overall Response Rate
  • Duration of Response (DR) DR is defined as the time between the date when the response criteria (PR or CR, whichever one is first reached) are fulfilled to the first date when PD, recurrence or death is documented.
  • Clinical Benefit Clinical Benefit is defined as ORR or stable disease lasting over four months (SD > 4 months)
  • PSF Progression-free Survival
  • PFS4/PFS6 is defined as the Kaplan-Meier estimates of the probability of being free from progression and death after the first infusion at these time points (4 and 6 months).
  • OS6/OS12 OS6/OS12 is defined as the Kaplan-Meier estimates of the probability of being alive after the first infusion at these time points (6 and 12 months)
  • PK Plasma Pharmacokinetics
  • NCA Non-compartmental PK parameters: area under the curve (AUC), cmax, clearance (CL) and half-life (t1/2).
  • AUC area under the curve
  • CCA clearance
  • t1/2 half-life
  • Patients were evaluated at scheduled visits within three study periods: (1) Pre- treatment: from signature of IC to the first infusion of the study treatment; (2) Treatment: from the first infusion of the study treatment to the 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 start of new anti-tumor therapy. Patients were followed up for at least 1 year after their first lurbinectedin infusion. Patients who finished treatment without PD were followed every 2 months during the first six months and every 3 months thereafter until PD, start of a new antitumor therapy, death, or until end of study date.
  • 105 SCLC patients were enrolled into 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 old). Two of the 105 treated patients (1.9%) had previously undergone surgery (curative resection in one patient). Prior radiotherapy had been administered to 75 patients (71.4%). The patients had received a median of one prior line of chemotherapy for advanced disease (range, 1-2 lines). The chemotherapy-free interval was less than 30 days in 21 (21%) patients, less than 90 days in 45 (43%) patients, and 90 days or longer in 60 (57%) patients.
  • Progression-Free Survival was 3.5 months (95% Cl 2.6-4.3) in the overall population: 4.6 months in patients with a chemotherapy-free interval of 90 days or longer and 2.6 months in patients with chemotherapy-free interval of less than 90 days. Eight (9%) of 94 patients who discontinued lurbinectedin treatment had disease progression with new lesions in the CNS. No increased incidence of CNS metastases was therefore observed.
  • Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse.
  • Example 8 Clinical Study - Treatment of Solid Cancer Patients with Lurbinectedin and Irinotecan
  • HIV human immunodeficiency virus
  • HCV hormonal therapy virus
  • HCV hepatitis C virus
  • immunotherapy such as nivolumab
  • Glioblastoma Soft-tissue sarcoma effusion rapidly increasing and/or [excluding gastrointestinal stromal tumors necessitating prompt local treatment within seven days. (GIST)]; Endometrial carcinoma; Epithelial Any other major illness that, in the Investigator's judgment, will substantially ovarian carcinoma (including primary increase the risk associated with the peritoneal disease and/or fallopian tube patient's participation in this study.
  • trabectedin carcinomas and/or endometrial Yondelis®
  • topoisomerase I inhibitors irinotecan, topotecan, etc.
  • Prior adenocarcinomas regardless of platinum topoisomerase inhibitors (e.g., irinotecan) sensitivity; Mesothelioma; are only allowed in patients with colorectal carcinoma.
  • GEP-NET Gastroenteropancreatic neuroendocrine Prior bone marrow or stem cell transplantation, or radiation therapy in more tumors
  • SCLC Pancreatic adenocarcinoma; Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions Gastric carcinoma; Colorectal carcinoma (primary or locally advanced) are eligible.
  • CRC brain metastases or
  • Tumor-specific eligible provided they are radiologically stable, i.e. without evidence of progression cohort(s) at the RD: for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of Measurable disease according to already being tapered within two weeks prior to screening are allowed).
  • Brain CT-scan or Response Evaluation Criteria in Solid MRI results must be provided at baseline.
  • At least three weeks since the last anticancer therapy (excluding immunotherapy that must be at least two weeks, provided that is not combined with chemotherapy), including investigational drugs and radiotherapy, and at least six weeks since nitrosoureas and mitomycin C (systemic).
  • the patient has a new lesion outside of the radiotherapy field, or
  • the patient has undergone brain surgery to remove the tumor before study entry, and progressive disease has been confirmed histologically.
  • Adequate bone marrow, renal, hepatic, and metabolic function (assessed ⁇ 7 days before inclusion in the study): Platelet counts 100 x 10 ⁇ 9/L, hemoglobin ⁇ 9.0 g/dL and absolute neutrophil count (ANC) ⁇ 2.0 x 10 ⁇ 9/L.
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • Alkaline phosphatase ⁇ 2.5 x ULN ( ⁇ 5 x ULN if disease-related/in the case of liver metastases).
  • Lurbinectedin was presented as lyophilized powder for concentration for solution for infusion in 4mg vials. Before use, the 4mg vials were reconstituted with 8 mL of water for injection to give a solution containing 0.5 mg/mL of lurbinectedin. For administration to patients as an i.v. infusion, reconstituted vials were diluted with glucose 50 mg/mL (5%) solution for infusion or sodium chloride 9 mg/mL (0.9%) solution for infusion. The full composition and the reconstituted solution per mL was as shown in Table 12 supra. [0154] Irinotecan was presented as lyophilized powder for concentration for solution for infusion in 40 mg, 100 mg, or 300 mg vials.
  • Lurbinectedin was administered over a minimum total volume of 100 ml. of solution for infusion (either on 5% glucose or 0.9% sodium chloride), through a central catheter, or over a minimum total volume of 250 mL if administered through a peripheral line, always over one hour at a fixed infusion rate.
  • Dose levels in patients at the escalation phase were as shown in Table 21. Patients received lurbinectedin i.v. as a one-hour infusion on Day 1 and irinotecan, i.v. as a 90-minute infusion at days 1 and 8 every three weeks. Three weeks was defined as one treatment cycle.
  • MTD maximum tolerated dose
  • RD recommended dose
  • Secondary outcome measures included safety evaluation, peak plasma concentration (Cmax), area-under-the plasma concentration versus time curve (AUC), volume of distribution based on the terminal half-life (Vz), volume of distribution at steady state (Vss), clearance (CL), half-life (t1/2), evaluation of antitumor response (RECIST v1 .1 , start of treatment until PD, other antitumor therapy, death or until 12 months after the inclusion of the last evaluable patient in the study (end of study), whichever occurs first), progression-free survival (from the date of first infusion of study treatment to the date of progression or death or until 12 months after end of study, whichever occurs first), and overall survival (from the date of first infusion to study treatment to the date or death or until 12 months after end of study, whichever occurs first).
  • RD recommended dose
  • RD was defined as lurbinectedin 2.0 mg/m 2 on D1 + irinotecan 75 mg/m 2 on D1 and D8 q3w + G-CSF.
  • Dose limiting toxicities in Cycle 1 were observed in 2/3 evaluable patients at the maximum tolerated dose (MTD) and in 3/13 evaluable patients at the RD.
  • G1/2 toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy;
  • G3/4 hematological abnormalities comprised neutropenia (33%), but no thrombocytopenia.
  • Concentration-time data of lurbinectedin, irinotecan, and SN-38 are available from 39 patients. Mean ( ⁇ SD) of main PK parameters are provided in the Table below, along with those reported elsewhere for lurbinectedin single agent, and irinotecan and SN-38 (Camptosar Label).
  • Encouraging activity has been observed in patients with SCLC, including some cases as third line treatment. Signals of activity were also observed in endometrial carcinoma and soft tissue sarcoma (STS) and glioblastoma (GBM). Consequently, a Phase II expansion at the RD to further explore efficacy and safety in SCLC, GBM, STS, and endometrial carcinoma.
  • STS soft tissue sarcoma
  • GBM glioblastoma
  • the RD is lurbinectedin 2.0 mg/m 2 on day 1 and irinotecan 75 mg/m 2 on day 1 and day 8 q3wk, with GCS-F, in solid tumors.
  • DLTs are mostly day 8 irinotecan omissions in cycle 1 due to hematological toxicity. Main toxicities observed were myelosuppression, gastrointestinal and fatigue. Gastrointestinal and myelosuppression were predictable and manageable.
  • Promising activity has been observed in SCLC. Notable activity has been observed in endometrial carcinoma, and hints of activity have been found in STS (especially Ewing and synovial sarcoma). Modest activity has been observed in glioblastoma patients._Expansion cohorts in SCLC, endometrial carcinoma and STS patients are still ongoing, to enroll a total of 20 patients in each indication.

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Abstract

L'invention concerne des méthodes de traitement de patients atteints de cancer du poumon à petites cellules par administration de quantités thérapeutiques de lurbinectédine par perfusion intraveineuse. L'invention concerne également des méthodes de traitement du cancer par administration de lurbinectédine en association avec d'autres médicaments anticancéreux, en particulier des inhibiteurs de la topoisomérase. L'invention concerne en outre l'administration de lurbinectédine en association avec des agents anti-émétiques pour lutter efficacement contre les symptômes liés à la nausée et aux vomissements, des doses de lurbinectedine réduites pour obtenir une administration plus sûre et une augmentation du nombre de cycles de traitement. L'invention concerne également des formulations lyophilisées stables de lurbinectédine.
PCT/EP2020/063734 2019-11-21 2020-05-15 Méthodes de traitement du cancer du poumon à petites cellules avec des formulations de lurbinectédine Ceased WO2021228414A1 (fr)

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KR1020227021161A KR20220119618A (ko) 2019-11-21 2020-05-29 루비넥테딘 제형으로 소세포폐암을 치료하는 방법
CA3158733A CA3158733A1 (fr) 2019-11-21 2020-05-29 Procedes de traitement du cancer du poumon a petites cellules avec des formulations de lurbinectedine
JP2022529896A JP2023503318A (ja) 2019-11-21 2020-05-29 ルルビネクテジン製剤で小細胞肺がんを処置する方法
CN202411258141.3A CN118924687A (zh) 2019-11-21 2020-05-29 用鲁比卡丁制剂治疗小细胞肺癌的方法
US17/777,982 US20230027502A1 (en) 2019-11-21 2020-05-29 Methods of treating small cell lung cancer with lurbinectedin formulations
PE2022000823A PE20221338A1 (es) 2019-11-21 2020-05-29 Metodos de tratamiento del cancer de pulmon de celulas pequenas con formulaciones de lurbinectedina
CN202080090766.7A CN115151259B (zh) 2019-11-21 2020-05-29 用鲁比卡丁制剂治疗小细胞肺癌的方法
BR112022009283A BR112022009283A2 (pt) 2019-11-21 2020-05-29 Métodos de tratamento do câncer do pulmão de células pequenas com formulações de lurbinectedina
EP20729071.9A EP4061372A1 (fr) 2019-11-21 2020-05-29 Procédés de traitement du cancer du poumon à petites cellules avec des formulations de lurbinectédine
MX2022006208A MX2022006208A (es) 2019-11-21 2020-05-29 Metodos de tratamiento del cancer de pulmon de celulas peque?as con formulaciones de lurbinectedina.
AU2020388196A AU2020388196B2 (en) 2019-11-21 2020-05-29 Methods of treating small cell lung cancer with lurbinectedin formulations
CR20220289A CR20220289A (es) 2019-11-21 2020-05-29 Métodos de tratamiento del cáncer de pulmón de células pequeñas con formulaciones de lurbinectedina
CN202411258158.9A CN118924689A (zh) 2019-11-21 2020-05-29 用鲁比卡丁制剂治疗小细胞肺癌的方法
PCT/EP2020/065093 WO2021098992A1 (fr) 2019-11-21 2020-05-29 Procédés de traitement du cancer du poumon à petites cellules avec des formulations de lurbinectédine
JOP/2022/0118A JOP20220118A1 (ar) 2019-11-21 2020-05-29 طرق لعلاج سرطان الرئة للخلايا الصغيرة بصيغ من لوربينيكتيدين
CN202411258155.5A CN118924688A (zh) 2019-11-21 2020-05-29 用鲁比卡丁制剂治疗小细胞肺癌的方法
IL293128A IL293128A (en) 2019-11-21 2020-05-29 Methods for the treatment of small cell lung cancer using lorbinactadine formulations
PH1/2022/551216A PH12022551216A1 (en) 2019-11-21 2020-05-29 Methods of treating small cell lung cancer with lurbinectedin formulations
IL322021A IL322021A (en) 2019-11-21 2020-05-29 Methods for treating small cell lung cancer using lorbinectadine formulations
SA522432668A SA522432668B1 (ar) 2019-11-21 2022-05-19 طرق لعلاج سرطان الرئة للخلايا الصغيرة بصيغ من لوربينيكتيدين
CL2022001342A CL2022001342A1 (es) 2019-11-21 2022-05-20 Métodos de tratamiento del cáncer de pulmón de células pequeñas con formulaciones de lurbinectedina
CONC2022/0008437A CO2022008437A2 (es) 2019-11-21 2022-06-16 Métodos de tratamiento del cáncer de pulmón de cé-lulas pequeñas con formulaciones de lurbinectedina
ECSENADI202249008A ECSP22049008A (es) 2019-11-21 2022-06-20 M?todos de tratamiento del c?ncer de pulm?n de c?lulas peque?as con formulaciones de lurbinectedina
US18/448,145 US12440490B2 (en) 2019-11-21 2023-08-10 Method of treating SCLC and managing thrombocytopenia
US18/448,144 US20230390285A1 (en) 2019-11-21 2023-08-10 Lurbinectedin Composition and Methods Making the Same
US18/448,122 US12324806B2 (en) 2019-11-21 2023-08-10 Method of treating SCLC and managing hepatotoxicity
US18/448,097 US20240041872A1 (en) 2019-11-21 2023-08-10 Stable lurbinectedin composition
US18/448,124 US12433890B2 (en) 2019-11-21 2023-08-10 Method of treating SCLC and managing neutropenia
JP2024139008A JP2024170325A (ja) 2019-11-21 2024-08-20 ルルビネクテジン製剤で小細胞肺がんを処置する方法
CL2025001170A CL2025001170A1 (es) 2019-11-21 2025-04-17 Métodos de tratamiento del cáncer de pulmón de células pequeñas con formulaciones de lurbinectedina
AU2025203950A AU2025203950A1 (en) 2019-11-21 2025-05-27 Methods Of Treating Small Cell Lung Cancer With Lurbinectedin Formulations
AU2025203941A AU2025203941A1 (en) 2019-11-21 2025-05-27 Methods Of Treating Small Cell Lung Cancer With Lurbinectedin Formulations
AU2025203954A AU2025203954A1 (en) 2019-11-21 2025-05-27 Methods Of Treating Small Cell Lung Cancer With Lurbinectedin Formulations

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