A randomized, placebo-controlled, phase 1/2 study of tivantinib (ARQ 197) in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with wild-type KRAS who have received first-line systemic therapy.

Cetuximab in combination with an irinotecan-containing regimen is a standard treatment in patients with KRAS wild-type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti-EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open-label 3 + 3, dose-escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double-blinded, placebo-controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression-free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m(2) twice daily) with biweekly cetuximab (500 mg/m(2)) and irinotecan (180 mg/m(2)). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55-1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET-High tumors by immunohistochemistry, PTEN-Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib-treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.

Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorectal cancer who are receiving fluorouracil-based chemotherapy.

PURPOSE: This study evaluated the safety and efficacy of recombinant human intestinal trefoil factor (rhITF) administered as topical oral spray for prevention and treatment of chemotherapy-induced oral mucositis (OM). PATIENTS AND METHODS: Ninety-nine patients with colorectal cancer who had moderate to severe OM (WHO grade >or= 2) in the first cycle of chemotherapy were randomly assigned to receive either placebo, rhITF 10 mg/mL (ie, low dose), or rhITF 80 mg/mL (ie, high dose) by oral spray (300 microL, eight times each day) for 14 consecutive days in the second chemotherapy cycle. Patients were assessed on days 1, 3, 5, 7, 10, 12, 14, and 21 (+/- 2 days for the last assessment) for safety and for OM incidence and severity. RESULTS: Treatment of patients at high risk for developing OM with low- or high-dose rhITF significantly reduced the amount of incidence (75% to 81%; low-dose rhITF P < .001; high-dose rhITF P = .002). Frequencies of WHO grade >or= 2 OM in the placebo, low-dose rhITF, and high-dose rhITF groups were 48.5%, 9.1%, and 12.1%, respectively. Assessment of the area under the curve revealed statistically significant reductions in OM severity in the rhITF-treated groups versus placebo. Only a minority of patients (6.1%) reported treatment-emergent adverse events (TEAEs), all of which were mild to moderate in intensity and resolved without sequelae. The incidence of TEAEs was not significantly different among treatment groups. CONCLUSION: rhITF oral spray formulation was safe and effective when used for the reduction of chemotherapy-associated OM in patients with colorectal cancer. Patients exhibited high compliance in dosing administration. Future clinical study is planned to develop this drug for use in OM management in patients with cancer.