Dataset Information

A Study of MEK162 and AMG 479 in Patients With Selected Solid Tumors

ABSTRACT: This is a multi-center, open-label, phase Ib/II study. First, the aim of the phase Ib part is to estimate the MTD(s) and/or to identify the recommended phase II dose(s) (RP2D) for the combination of MEK162 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. The dose escalation part of the study will be guided by a Bayesian Logistic Regression Model (BLRM). At least 18 patients are expected to be enrolled in the dose escalation part. Following MTD/ RP2D declaration, patients will be enrolled in three phase II arms to assess efficacy of the combination as well as to better understand the safety, tolerability, PK, antibody concentrations and PD of the combination at MTD/RP2D. Phase II arm 1 will consist of approximately 25 patients with KRAS-mutant colorectal adenocarcinoma. Phase II arm 2 will consist of approximately 20 patients with metastatic pancreatic adenocarcinoma. Phase II arm 3 will consist of approximately 28 patients with mutant BRAFV600 melanoma. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. All patients will be followed up - at minimum patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment.

DISEASE(S): Adenocarcinoma,Colorectal Adenocarcinoma,Pancreatic Adenocarcinoma Metastatic,Melanoma,Colorectal Adenocarcinoma.metastatic Pancreatic Adenocarcinomamelanoma,Braf Mutated Melanoma,Metastatic Pancreatic Adenocarcinoma,Adenocarcinoma Colorrectal Adenocarcinoma Pancreático Metastásicomelanoma

PROVIDER: 2122635 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:This phase I/II neoadjuvant trial determined maximally-tolerated doses (MTD), dose-limiting toxicities (DLT), response-to-therapy, and explored the role of new response biomarkers. The combination regimens were delivered with acceptable toxicity, good clinical response, inducing changes in tumor RNA content and integrity. Pre-treatment gene expressions impacted clinical response, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness. The NCIC Clinical Trials Group MA.22 phase I/II clinical trial (ClinicalTrials.gov identifier NCT00066443) sought to determine the optimal dosing regimens for docetaxel/epirubicin combination chemotherapy in women with locally advanced (over 95% of patients) or inflammatory breast cancer. The protocol was approved by Health Canada and local Ethics Review Boards, and patients provided written, informed consent. Various doses of epirubicin and docetaxel were administered to patients in either a standard q3 weekly (Schedule A) or dose dense q2 weekly (Schedule B) regimen. Doses for Schedule A were 75 mg/m2 IV of docetaxel and 75, 90, 105, or 120 mg/m2 IV of epirubicin (with 6 mg of pegfilgrastim per cycle on day 2 to prevent neutropenia). Doses for both docetaxel and epirubicin in Schedule B were 50, 60, and 70 mg/m2 IV (with identical pegfilgrastim support). For each schedule, phase I was dose finding for phase II. Patients were allocated to the various phases and dosing regimens of the trial without randomization. None of the patients received trastuzumab in the initial years of the study and HER2+ patients were not enrolled on study, once trastuzumab funding became available. Six tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 cores for pathologic assessment; 3 cores for microarray studies. Total RNA was isolated from these cores and RNA integrity was assessed using Agilent Bioanalyzer. One of the RNA samples with the best quality was used for microarray study. One colour microarray of Agilent whole human genome nucleotide arrays was conducted with one array per patient. The current data set represents pre-treatment set. MA.22 clinical trial accrued T3N0, any N2 or N3, and T4 breast cancer patients (according to the classification described at; http://emedicine.medscape.com/article/2007112-overview). However, since the current study does not focus on the tumor grade/stage, the information was not provided in the current records.

Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

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A Study of MEK162 and AMG 479 in Patients With Selected Solid Tumors

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