Study design and patients
DLTs, hematologic adverse, toxicities, non-hematologic, Tumors, tumour, RCC
DISEASE PROGRESSION, DISEASE, TUMORS, TUMOUR, ONCOLOGY, RCC
This was an open-label phase 1b/2 multicenter study (ClinicalTrials.gov; NCT02599324) conducted between December 2015 and March 2020, to determine the recommended phase 2 dose (RP2D) of ibrutinib combined with everolimus in RCC, docetaxel in GC, and cetuximab in CRC for previously treated patients. The data cutoff date for this analysis was 19 April 2021.The phase 1b study followed a 3 + 3 + 3 design in each cohort to evaluate dose-limiting toxicities (DLTs) and determine the RP2D. The DLT observation period was 21 days following the initiation of combination therapy at the start of Cycle 1. A DLT was defined as any grade 3 or higher non-hematologic or grade 4 hematologic adverse event (AE) possibly related to either ibrutinib and/or drug combination that occurred during the DLT-observation period. DLTs were assessed in the first three evaluable patients at each dose level by a safety review committee and expanded to 6 or 9 patients if 1 of 3 or 2 of 6 patients experienced a DLT, respectively. The subsequent phase 2 portion of the study utilised a Simon’s 2-stage design in the GC and CRC cohorts. All patients were ≥ 18 years old with adequate hematologic, hepatic, and renal function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (patients with RCC or CRC with an ECOG performance score of 2 were potentially acceptable after a discussion with the medical monitor). Patients had advanced (locally recurrent and/or metastatic) disease with histologically confirmed clear cell RCC, gastric or gastro-esophageal junctional adenocarcinoma or K-Ras and N-Ras wildtype (EGFR-expressing) CRC, with one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Patients were assessed by investigator to be a suitable candidate for the treatment partner (everolimus, docetaxel, or cetuximab) and ibrutinib as per their tumour type. To be eligible for the RCC cohort, patients had received between one and four prior lines of therapy in the advanced setting, including a VEGF-tyrosine kinase inhibitor. For the GC cohort, patients had received between one and three prior lines of therapy in the advanced setting, including a fluoropyrimidine regimen. For the CRC cohort, patients had received at least two and no more than four prior regimens in the advanced setting, which must have included both an irinotecan and oxaliplatin-based regimen unless unable to tolerate irinotecan chemotherapy. Key exclusion criteria included prior anti-cancer therapy within 28 days of the first dose of study drug (including neoadjuvant or adjuvant therapy if disease progression occurred at ≥ 12 months of treatment completion) and prior treatment with everolimus or temsirolimus (RCC cohort), any taxane (GC cohort), or cetuximab or panitumumab (CRC cohort).All patients provided written informed consent for participation in this study as approved by the Institutional Review Board/Research Ethics Board/Independent Ethics Committee before any study-specific screening procedures were performed.