Lurbinectedin in patients with pretreated endometrial cancer: results from a phase 2 basket clinical trial and exploratory translational study.

Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972.

Phase I study of lurbinectedin in combination with weekly paclitaxel with or without bevacizumab in patients with advanced solid tumors.

Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m2) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.

Lurbinectedin in patients with pretreated neuroendocrine tumours: Results from a phase II basket study.

BACKGROUND: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. PATIENTS AND METHODS: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). CONCLUSIONS: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population. TRIAL REGISTRATION NUMBER: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42. CLINICALTRIALS: gov reference: NCT02454972.

Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study.

PURPOSE: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. PATIENTS AND METHODS: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. RESULTS: ORR was 14.3% [95% confidence interval (CI), 4.0%-32.7%], with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. CONCLUSIONS: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study.

OBJECTIVE: Second-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer. METHODS: Thirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0-5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4. RESULTS: Median age (range) was 65 (51-78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort. CONCLUSIONS: In patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.

Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment.

INTRODUCTION: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days. MATERIAL AND METHODS: Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1. RESULTS: ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported. CONCLUSION: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge.

Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome.

Trabectedin is an FDA-approved DNA minor groove binder that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors.

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Phase II clinical trial of PM00104 (Zalypsis(®)) in urothelial carcinoma patients progressing after first-line platinum-based regimen.

PURPOSE: This exploratory phase II clinical trial evaluated the antitumor activity, safety profile and pharmacokinetics of PM00104 (Zalypsis(®)) 3 mg/m(2) 1 h every 3-week intravenous infusion in patients with advanced and/or metastatic urothelial carcinoma progressing after first-line platinum-based chemotherapy. METHODS: The primary efficacy end point was the disease control rate (DCR), defined as the percentage of patients with confirmed objective response or progression-free at 3 months, according to the response evaluation criteria in solid tumors. RESULTS: In a first stage (n = 19 patients evaluable for efficacy), only one patient achieved DCR (stable disease as best response and progression-free survival of 3.1 months). According to the 2-stage design used, the primary efficacy objective was unmet, and therefore, the trial was finalized without opening the second stage. The most common adverse events related to PM00104 were fatigue, anorexia, nausea, troponin I increase and neutropenia, which were transient and manageable with dose modifications or administration delays. Mean PK results (Cmax = 48.57 µg/l and area under the curve (AUC) = 154.97 h µg/l) were similar to those observed in a previous phase I trial evaluating the same dose and schedule. Few troponin I concentrations were higher than 0.10 ng/ml, and none of them were related to parameters of PM00104 exposure such as AUC or Cmax. CONCLUSIONS: No recommendation is given for further evaluation of PM00104 as single-agent treatment of patients with pretreated advanced and/or metastatic urothelial carcinoma. No new safety signals were observed.

First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors.

PURPOSE: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). EXPERIMENTAL DESIGN: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. RESULTS: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m(2). Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m(2), with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. CONCLUSION: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.

Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors.

This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n = 6) or mildly pretreated (n = 14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m(2) was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56-67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33-38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/bevacizumab. Three patients with colorectal cancer, head and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research.

A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors.

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors.

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.