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

Endometrial cancer; Lurbinectedin; Phase 2Càncer d'endometri; Lurbinectedina; Fase 2Cáncer de endometrio; Lurbinectedina; Fase 2Second-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.The study was funded by Pharma Mar S.A, including partial funding by grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study (grant number IDI-20150006). VS is supported by a US National Institutes of Health (NIH) grant (no. R01CA242845 and R01CA273168); MD Anderson Cancer Center Department of Investigational Cancer Therapeutics is supported by the Cancer Prevention and Research Institute of Texas (no. RP1100584), the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (no. 1U01 CA180964), NCATS (Center for Clinical and Translational Sciences) Grant (no. UL1 TR000371), and the MD Anderson Cancer Center Support Grant (no. P30 CA016672)

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

Ewing Sarcoma; LurbinectedinSarcoma de Ewing; LurbinectedinaSarcoma d'Ewing; LurbinectedinaPurpose: 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

Pooled Safety Analysis of Single-Agent Lurbinectedin in Patients With Advanced Solid Tumours

Lurbinectedin; Phase II; Pooled safetyLurbinectedina; Fase II; Seguretat conjuntaLurbinectedina; Fase II; Seguridad conjuntaBackground Lurbinectedin was approved by FDA and other health regulatory agencies for treating adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Safety profile at approved dose (3.2 mg/m2 every 3 weeks) was acceptable and manageable in 105 adult SCLC patients from a phase II basket trial. This study analyses safety data from several solid tumours treated at the lurbinectedin-approved dose. Methods Data were pooled from 554 patients: 335 from all nine tumour-specific cohorts of the phase II basket trial and 219 from a randomised phase III trial (CORAIL) in platinum-resistant ovarian cancer. Events and laboratory abnormalities were graded using NCI-CTCAE v.4. Results Most common tumours were ovarian (n = 219, 40%), SCLC (n = 105, 19%) and endometrial (n = 73, 13%). Transient haematological laboratory abnormalities were the most frequent grade 3 or more events: neutropenia (41%), leukopenia (30%), anaemia (17%) and thrombocytopenia (10%). Most common treatment-emergent non-haematological events (any grade) were transient transaminase increases (alanine aminotransferase [66%], aspartate aminotransferase [53%]), fatigue (63%), nausea (57%), constipation (32%), vomiting (30%) and decreased appetite (25%). Dose reductions were mostly due to haematological toxicities, but most patients (79%) remained on full lurbinectedin dose. Serious events mostly consisted of haematological disorders. Eighteen treatment discontinuations (3%) and seven deaths (1%) were due to treatment-related events. Conclusions This analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.The trials were funded by Pharma Mar SA, including grants from the Centro para el Desarrollo Tecnológico Industrial (CDTI) during the conduct of the study

Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer

RAS mutation; Binimetinib; Colorectal cancerMutació RAS; Binimetinib; Càncer colorectalMutación RAS; Binimetinib; Cáncer colorrectalIntroduction Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. Methods Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. Results No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. Conclusions The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).This study was sponsored by Array Biopharma in collaboration with Novartis. Array Biopharma was acquired by Pfizer in July 2019. Medical writing and editorial assistance were provided by Namiko Abe of Caudex and were funded by Pfizer. Research was supported by the National Institutes of Health Cancer Center Core Grant P30 CA 008748

Joint ITC and DFT Study of the Affinity of Some Lewis Bases to HIFP in Solution

HFIP, i.e. 1,1,1,3,3,3-hexafluoropropan-2-ol, was found to be an exceptional medium,[1] either as solvent or co-solvent, that allows many reactions to occur.[2-5] However, the exact role and mode of action of HFIP in various chemical transformations still remains elusive. Despite many reports dealing with water/HFIP complexes, little has been published on other molecular complexes of HFIP as well as on thermochemistry of the formation of such complexes.[6] Within this study the affinity of a series of eight different Lewis bases (3 sulfoxides, 3 Nsp2 pyridine derivatives, 1 aromatic amine, 1 cyclic aliphatic ether) to HFIP (as Lewis acid) is investigated experimentally by Isothermal Titration Calorimetry (ITC) and theoretically using static DFT-D calculations. Measured ITC association enthalpy values ΔHaITC spanned -9.3 kcal/mol - -14 kcal/mol. Computations including a PCM implicit solvation model produced similar exothermicity of association of all studied systems - ΔHa values ranging -8.5 – -12.7 kcal/mol. In general, most of interaction energy is due to the hydrogen bonding and not due to formation of significantly strong halogen bonds. An additional set of calculations combining implicit and explicit solvation by chlorobenzene of the reactants, pointed out the relatively low interference of the solvent with the HFIPbase complexation, which main effect is to slightly enhance the Gibbs energy of the HFIP-Lewis base association. It is speculated that the interactions of bulk HFIP with Lewis bases therefore may significantly intervene in catalytic processes not only via the dynamic miscrostructuration of the medium but also more explicitly by affecting bonds’ polarization at the Lewis bases

Supplementary data for the article: Milovanović, M. R.; Dherbassy, Q.; Wencel‐Delord, J.; Colobert, F.; Zarić, S. D.; Đukić, J.-P. The Affinity of Some Lewis Bases for Hexafluoroisopropanol as a Reference Lewis Acid: An ITC/DFT Study. ChemPhysChem 2020, 21 (18), 2136–2142. https://doi.org/10.1002/cphc.202000560.

Supplementary material for: [https://doi.org/10.1002/cphc.202000560]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4337]Related to accepted version: [https://cherry.chem.bg.ac.rs/handle/123456789/4339

Safety, tolerability, and potential clinical activity of a glucocorticoid-induced TNF receptor-related protein agonist alone or in combination with nivolumab for patients with advanced solid tumors: a phase 1/2a dose-escalation and cohort-expansion clinical trial

Importance: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. Objective: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. Design, Setting, and Participants: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. Interventions: The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. Main Outcomes and Measures: The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. Results: With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. Conclusions and Relevance: Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. Trial Registration: ClinicalTrials.gov identifier: NCT02598960

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population