Cetuximab in combination with an irinotecan‐containing regimen is a standard treatment

Cetuximab in combination with an irinotecan‐containing regimen is a standard treatment in patients with wild‐type (wild‐type mCRC. including an irinotecan‐based regimen but not an EGFR inhibitor. Adjuvant chemotherapy was allowed to be counted as a line of therapy if disease progression/recurrence had occurred ≤6 months after completing treatment. Patients were required to be ≥18 years of age have measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) version Bay 65-1942 HCl 1.1 adequate organ and bone marrow function resolution of any toxic effects of prior therapy (except alopecia) and Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. All institutional review boards approved the protocol (Clinical Trials.gov identifier “type”:”clinical-trial” attrs :”text”:”NCT01075048″ term_id :”NCT01075048″NCT01075048) and all participants provided written informed consent. Study design and treatment This phase 1/2 study accrued patients from January 2010 to January 2012. The phase 1 portion was an open‐label classic 3?+?3 dose‐escalation study to evaluate the safety of BID tivantinib in combination with CETIRI (biweekly schedule). The recommended phase 2 dose (RP2D) of tivantinib was determined based on protocol‐specified dose‐limiting toxicities (DLT). Dose escalation would occur if none of three treated patients experienced Bay 65-1942 HCl a tivantinib‐related DLT by Day 29. The phase 2 portion was a randomized double‐blinded placebo‐controlled study to assess the efficacy and safety of tivantinib in combination with CETIRI. Patients had been stratified according to best tumor response to first‐line therapy and ECOG performance status and were randomly assigned 1:1 (Interactive Web Response System code generated by independent biostatistician) to receive either CETIRI plus tivantinib or CETIRI plus placebo (Interactive Voice Response System for study drug). Oral BID tivantinib (360 mg Bay 65-1942 HCl Bay 65-1942 HCl capsule formulation) or placebo was taken with meals. Every 14 days of a 28‐day cycle cetuximab (500 mg/m2) was administered intravenously (IV) followed by oral tivantinib or placebo and IV irinotecan (180 mg/m2). Endpoints and assessments The primary efficacy endpoint for the phase 2 study was investigator‐assessed progression‐free survival (PFS). Secondary endpoints included OS best overall response and objective response rate (ORR). Tumor assessments per RECIST CACN2 version 1.1 with computed tomography (CT) of the chest and CT and/or magnetic resonance imaging (MRI) of the abdomen/pelvis were performed every two treatment cycles (every 8 weeks ±3 days) and at the end of the treatment visit (EOT; 30 days after last dose ±7 days). Safety analyses in patients who received at least one dose of study drug included extent of exposure adverse events (AEs) laboratory tests vital signs and physical examination. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.0 and assigned grades based on National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Additional exploratory analyses included health‐related quality of life (HRQOL) pharmacokinetics (PK) and biomarkers. Patients’ HRQOL was assessed using the Functional Assessment of Cancer Therapy‐Colorectal (FACT‐C) questionnaire. Patients finished the questionnaire at testing and Day time 1 of each other cycle in the EOT check out and Bay 65-1942 HCl the adhere to‐up check out. Archival tumor tissue samples refreshing core‐needle good‐needle or biopsy aspirates were gathered at screening for biomarker assessments. Collected formalin‐set paraffin‐embedded samples had been examined for total MET and PTEN manifestation by immunohistochemistry (IHC). Manifestation of MET was examined with a CLIA‐accredited central lab using the CONFIRM? anti‐total MET (SP44) antibody (Ventana; Roche) and adjudicated by three pathologists. MET‐High examples were thought as a ≥2+ rating in ≥50% of tumor cells. Plasma samples had been collected on Day time 1 of every cycle until Routine 12 on 1st documents of response with EOT. Samples had been analyzed with a central lab for adjustments in HGF (Quantikine Human being HGF assay; high amounts were described by median 1 415.9 pg/mL) vascular endothelial growth factor (VEGF; enzyme immunoassay) soluble MET (enzyme immunoassay) and soluble VEGF.