Entry Detail
| General information | |
| Database: | DB00047 |
| Objective: | BRAF V600 mutations, present in 510% of patients (pts) with metastatic colorectal cancer (mCRC), are poor prognostic markers and are associated with a low response to the combination of cetuximab (C) and irinotecan (I). Vemurafenib (V) demonstrated a 5% response rate in a phase I trial of pts with BRAFmutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, which is further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAFmutated advanced malignancies have not been defined. |
| Authors: | David S. Hong, et al |
| Title: | Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAFmutated metastatic colorectal cancer and advanced cancers |
| Journal: | J Clin Oncol |
| Year: | 2015 |
| PMID: | http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/3516 |
| Trial Design | |
| Clinical Trial Id: | NCT01787500 |
| Agent: | vemurafenib |
| Target: | BRaf protooncogene serine/threonineprotein kinase |
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | BRAFmutated metastatic colorectal cancer and advanced cancers |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | vemurafenib+irinotecan + cetuximab |
| Study Type: | a III+IIIphase I study |
| Key Patients Feature: | patients with BRAFmutated metastatic colorectal cancer and advanced cancers;Median age was 63 yrs (4273yrs). |
| Biomarker: | BRAF mutant |
| Biomark Analysis: | as in the conclusion |
| Control Group Info: | single arm |
| Treatment Info: | received escalating doses of V in combination with C and I over a 14day cycle. Responses were evaluated every 4 cycles by RECIST 1.1. Adverse events (AEs) were assessed by CTCAE 4.0. |
| Primary End Point: | DLT, MDT, PK, PD, RR, PFS, safety |
| Secondary End Point: | NA |
| Patients Number: | 19 |
| Trial Results | |
| DLT_MTD: | 6 at dose level 1(DL) (V 480mg PO BID, C250 mg/m2 weekly and I 180mg/m2 every 14 days), 6 at DL 2 (increased to V720mg PO BID), and 6 at DL3 (V960mg PO BID). One DLT was observed at each DL (arthralgia in 2 pts, diarrhea in 1 pt). The MTD was determined to be DL3 (V960 mg PO BID, C250 mg/m2 weekly, I180mg/m2 every 14 days). |
| Objective Response Rate: | Six of the 17 evaluable mCRC pts achieved a partial response (RR 35%). Median best response was a reduction of 20% (+21% to 100%) |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 7.7 months |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common AEs were fatigue (94%), diarrhea (89%), nausea (83%), and rash (78%). |
| Conclusions: | The combination of V with I and C is well tolerated in pts with BRAFmutated mCRC with the MTD at V960 mg PO BID, C250 mgm2 weekly, I180mgm2 every 14 days. Responses they were seen in 35% of evaluable mCRC pts. A US cooperative group randomizedphase II trial of I and C with or without V in BRAFmutated mCRC |