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EP-4741017-A2 - METHODS OF TREATING SMALL CELL LUNG CANCER WITH LURBINECTEDIN FORMULATIONS

EP4741017A2EP 4741017 A2EP4741017 A2EP 4741017A2EP-4741017-A2

Abstract

Provided are methods for the treatment of SCLC patients by administering therapeutic amounts of lurbinectedin by intravenous infusion. Also provided are methods of treating cancer by administering lurbinectedin in combination with other anticancer drugs, in particular topoisomerase inhibitors. The invention further relates to the administration of lurbinectedin in combination with anti-emetic agents for effective control of symptoms related to nausea and vomiting, reduced lurbinectedin dosages to achieve a safer administration and an increase in the number of treatment cycles. Stable lyophilized formulations of lurbinectedin are also provided

Inventors

  • CALVO, PILAR
  • TOBIO, Maria

Assignees

  • Pharma Mar S.A.

Dates

Publication Date
20260513
Application Date
20200529

Claims (17)

  1. A method of storing a lyophilized lurbinectedin composition comprising: storing a lyophilized composition comprising 4 mg lurbinectedin; a buffer derived from an organic carboxylic acid; and a disaccharide at a temperature of 5° C ± 3° C, 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 wherein after 24 months storage, the amount of deacetylated lurbinectedin present in the composition would not be more than 0.8% wt./wt. of the total lurbinectedin weight.
  2. A pharmaceutical composition comprising: a lyophilized composition comprising 4 mg lurbinectedin, a buffer derived from an organic acid, and a disaccharide, wherein the lurbinectedin and disaccharide are present at a ratio of 1 mol lurbinectedin to 455 to 465 mol disaccharide, 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 wherein the lyophilized composition further comprises a degradation product resulting from deacetylation of lurbinectedin at a value no greater than 0.8% wt./wt. based upon the total weight of lurbinectedin.
  3. A method of reducing lurbinectedin degradation in a lyophilized formulation comprising lurbinectedin, the method comprising adding lactate buffer to a stock solution from which the lyophilized formulation is prepared, wherein the resulting ratio of lurbinectedin to lactate buffer is between 1 mol:44 mol and 1 mol:54mol; wherein the lurbinectedin degradation product from deacetylation does not exceed 0.8% wt./wt. of the total lurbinectedin weight when stored 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.
  4. The pharmaceutical composition of claim 2, wherein the lyophilized composition is packaged in a vial; wherein the lyophilized composition comprises less than about 0.3 % of deacetylated lurbinectedin (wt./wt. based on lurbinectedin) when the composition is packaged, and wherein upon storage at about 5 degrees C for about 24 months or about 36 months or about 48 months the composition would comprise not more than about 0.8% of deacetylated lurbinectedin (wt./wt. based on lurbinectedin); or wherein the lyophilized composition comprises less than about 0.3 % of deacetylated lurbinectedin (wt./wt. based on lurbinectedin) when the composition is packaged, and wherein the composition would comprise substantially the same amount of deacetylated lurbinectedin (wt./wt. based on lurbinectedin) after the packaged composition has been stored at about 25 degrees C and about 60% relative humidity for up to about 1, 2, 3, 6, 9, or 12 months.
  5. The pharmaceutical composition of claim 2 or 4, wherein the composition is prepared by a process comprising: (a) providing a solution of lurbinectedin and an organic acid; (b) providing a solution of a base, an organic acid and a disaccharide; (c) combining the solutions of Step (a) and Step (b); (d) adjusting (if necessary) the pH of the solution of Step (c) to about 3.5 to about 4.5; and (e) lyophilizing the solution of Step (d) to provide the lyophilized composition.
  6. The pharmaceutical composition of claim 5, wherein the solution of step (a) has a pH of 1 to 5, optionally less than 4, less than 3.5, less than 3, or around 3; and/or wherein in step (a) the organic acid has a molarity of 0.1M to 0.5M, optionally 0.2M to 0.4M, 0.3M or 0.31M.
  7. The pharmaceutical composition of claim 2, prepared by: lyophilizing an aqueous stock solution comprising lurbinectedin, an organic carboxylic acid, sodium hydroxide, and a disaccharide to produce a lyophilized powder, wherein the concentration of lurbinectedin in the aqueous stock solution is 0.5 mg/mL; and wherein, after storing the lyophilized powder at 5° C ± 3° C for 30 months to 60 months, the amount of deacetylated lurbinectedin present in the composition is not more than 0.8% wt./wt. of the total lurbinectedin weight.
  8. The method of claim 1 or the pharmaceutical composition of any one of claims 2, 4 or 7, wherein the solution has a pH of about 3.8 to 4.5, 3.5 to 4.1, 3.8 to 4.1, 4.0 to 4.1, 4.0 or 4.1; or the pharmaceutical composition of claim 5 or 6, wherein the solution of step (d) is adjusted (if necessary) to a pH of about 3.8 to 4.5, 3.5 to 4.1, 3.8 to 4.1, 4.0 to 4.1, 4.0 or 4.1.
  9. The method according to any one of claims 1, 3 or 8, or the pharmaceutical composition according to any one of claims 2 or 4 to 8, wherein the disaccharide is a bulking agent and is selected from sucrose, trehalose or lactose, or a combination thereof; preferably sucrose; and optionally wherein the ratio of lurbinectedin to disaccharide is 1 mol lurbinectedin : 455 to 465 mol disaccharide.
  10. The method according to claim 1, or the pharmaceutical composition according to any one of claims 2 or 4 to 9, wherein the organic acid is selected from acetic acid, succinic acid, citric acid and lactic acid; optionally wherein the buffer derived from the organic carboxylic acid is a lactate buffer, most optionally a sodium lactate buffer.
  11. The method according to any one of claims 1, 3 or 10, or the pharmaceutical composition according to any one of claims 2 or 4 to 10; wherein the molar ratio of buffer to lurbinectedin is from 44 to 54:1, 46 to 52:1, 48 to 52:1, 48 to 51:1, 48 to 50:1 or 48:1.
  12. The method according to any one of claims 1, 3 or 11, or the pharmaceutical composition according to any one of claims 2 or 4 to 11; wherein the pharmaceutical composition is formulated such that reconstitution with 8 mL of water will yield a solution having a molarity of 0.03M and/or such that reconstitution with 8 mL of water will yield a solution having a pH of 3.8 to 4.5, 3.5 to 4.1, 3.6 to 4.1, 3.8 to 4.1 4.0 to 4.1, 4.0 or 4.1.
  13. The method according to any one of claims 1, 3 or 12, or the pharmaceutical composition according to any one of claims 2 or 4 to 12; wherein the lyophilized lurbinectedin composition may be stored for 48 months; preferably wherein after 48 months of storage, the amount of deacetylated lurbinectedin present in the lyophilized lurbinectedin composition would not be more than 0.8% wt./wt. of the total lurbinectedin weight.
  14. The method according to any one of claims 1, 3 or 13, or the pharmaceutical composition according to any one of claims 2 or 4 to 13; wherein: after 24 months storage at 5°C ± 3°C, the composition would comprise no more than 0.8% wt/wt of deacetylated lurbinectedin based on the total weight of lurbinectedin in the composition; or wherein after 6 months storage at 25°C 60% relative humidity, the composition would comprise no more than 0.8% wt/wt of deacetylated lurbinectedin based on the total weight of lurbinectedin in the composition; or wherein the amount of deacetylated lurbinectedin in the composition would be substantially unchanged after 24 months storage at 5°C ± 3°C; or wherein the amount of deacetylated lurbinectedin in the composition would be substantially unchanged after 6 months storage at 25°C 60% relative humidity.
  15. The method according to any one of claims 1, 3 or 14, or the pharmaceutical composition according to any one of claims 2 or 4 to 14; wherein the pharmaceutical composition may be stored at 5° C ± 3° C for 30 months or may be stored at 5° C ± 3° C for 60 months.
  16. The method according to any one of claims 1, 3 or 15, or the pharmaceutical composition according to any one of claims 2 or 4 to 15; wherein reference to an amount of deacetylated lurbinectedin of not more than 0.8% wt./wt. of the total lurbinectedin weight, is not more than 0.7%, 0.6%, 0.5%, or 0.4% wt./wt. of the total lurbinectedin weight.
  17. A pharmaceutical composition according to any one of claims 2 or 4 to 16, for use in the treatment of small cell lung cancer (SCLC), optionally SCLC with extensive disease or metastatic SCLC; comprising administering to a patient a reconstituted solution of the lurbinectedin composition as claimed in any one of claims 2 or 4 to 16; wherein lurbinectedin is administered every 21 days by intravenous infusion at a dose of 3.2 mg/m2.

Description

FIELD OF THE INVENTION Provided are methods for the treatment of SCLC patients by administering therapeutic amounts of lurbinectedin by intravenous infusion. Also provided are methods of treating cancer by administering lurbinectedin in combination with other anticancer drugs, in particular topoisomerase inhibitors. The invention further relates to the administration of lurbinectedin in combination with anti-emetic agents for effective control of symptoms related to nausea and vomiting, reduced lurbinectedin dosages to achieve a safer administration and an increase in the number of treatment cycles. Stable lyophilized formulations of lurbinectedin are also provided. BACKGROUND TO THE INVENTION 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 comprises only about 13-15% of all lung cancers at diagnosis; however, SCLC is the more aggressive form of lung cancer. With 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). The most common regimens include cisplatin or carboplatin and etoposide. Unfortunately, despite the 40-90% response rate to first-line chemotherapy, long-term survival is unusual because patients develop resistance to chemotherapy and relapse (Sundstrom, 2005; Jackman, 2005). The overall expected mean survival after disease relapse without treatment is two to four months (Huisman, 1999). Treatment and survival have not changed substantially during the past two decades. Even limited-stage disease is rarely cured with radical local therapy (surgery or radiotherapy) and systemic chemotherapy (platinum plus etoposide) remains a cornerstone of first-line treatment in SCLC. 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. Alternatively, doxorubicin-based combination therapy can be administered with a similar outcome but a slightly lower rate of symptom control. In refractory patients no standard therapy exists. 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. During the past few years, several clinical trials have evaluated the effect of addition of immunotherapy to conventional chemotherapy in patients with extensive SCLC. Checkpoint inhibitors are currently under investigation, especially the CTLA-4 and PD-1/PD-L1 inhibitors. Nivolumab and Pembrolizumab were the first immunotherapeutic agents to be approved by the FDA for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of chemotherapy. Lurbinectedin (PM01183) is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with antineoplastic activity. Lurbinectedin is a selective inhibitor of oncogenic transcription, induces DNA double-strand 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. SUMMARY OF THE INVENTION 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 1b-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. Accordingly, provided he