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Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in Patients with Advanced Biliary Cancers.

ABSTRACT: PURPOSE:Mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in biliary tract cancer (BTC). Binimetinib, a selective inhibitor of MEK1/2, has single-agent activity. Preclinical data support binimetinib combination with chemotherapy, when given in an interrupted dosing schedule.Patients and Methods: A phase I/II trial evaluated binimetinib in combination with gemcitabine and cisplatin in patients with untreated advanced BTC. The primary endpoints were to determine the MTD (phase I), and PFS 6 and RR (phase II). Tumor tissue for targeted gene sequencing and blood samples for peripheral blood pERK expression were evaluated. Patients received oral binimetinib twice daily with gemcitabine and cisplatin on day 8 and 15 of a 21-day cycle. Binimetinib was held for 2 days prior to and on day of each chemotherapy treatment. RESULTS:Twelve patients enrolled in the phase I showed the MTD of binimetinib at 45 mg orally twice daily with gemcitabine 800 and cisplatin 20 mg/m2. Twenty-nine patients were treated in the phase II. Six patients treated at MTD in phase I were evaluable as part of phase II. PFS 6 months was 54% and RR was 36%. Median overall survival was 13.3 months (95% CI, 9.8-16.5). MSK-IMPACT 410-gene panel showed aberrations in the RAS-RAF-MEK-ERK pathway and mutations in PIK3CA, AKT2, PIK3CG, BRAF, and MAP3K1 in responding patients. CONCLUSIONS:Binimetinib with gemcitabine and cisplatin did not show an improvement in PFS 6 and RR. Molecular profiling may help select patients who may benefit from this triplet therapy, which is not planned at this time.

SUBMITTER: Lowery MA

PROVIDER: S-EPMC6615467 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Project description:ImportanceAdministration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed.ObjectiveTo evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer.Design, setting, and participantsThis open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017.InterventionsPatients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients.Main outcomes and measuresThe primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population.ResultsOf 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment.Conclusions and relevanceTreatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial.Trial registrationClinicalTrials.gov identifier: NCT02392637.

Project description:PurposeDual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST.MethodsIn this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity.ResultsBetween September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).ConclusionThe study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

Project description:BackgroundBiliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC.MethodsPatients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed.ResultsOverall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3-100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50-100) for cisplatin and 100% (IQR 75-100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0-33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8-62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts.ConclusionAdjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients.Trial registrationThe study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

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Binimetinib plus Gemcitabine and Cisplatin Phase I/II Trial in Patients with Advanced Biliary Cancers.

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