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Pharmacokinetic analysis indicated that sorafenib had no impact about the disposition of tivantinib. Among 14 of 18 patients with evaluable responses, a greatest response of SD for 732 weeks was demonstrated. Nearly all patients with SD had renal cell cancer or hepatocellular cancer.

By far the most generally observed adverse effects were thrombocytopenia, anemia, neutropenia, fatigue, nausea, and leukopenia. Therapy related significant adverse effects were observed in three cdk1 inhibitor patients. Among the 27 patients with evaluable responses, five had partial response, and 15 had decline in tumor markers. Two patients with PR and two with SD had failed to respond to prior gemcitabine. On the basis of the favorable safety profile and encouraging signs of antitumor activity, phase II combination studies are being planned in different tumor types. This study is based on the hypothesis that adding tivantinib to irinotecan plus cetuximab may decrease resistance to cetuximab treatment and improve patient outcomes.

Patients with locally advanced or metastatic colorectal cancer who received more than one prior line of chemotherapy, were KRAS wild type and had Eastern Cooperative Cell Cycle inhibitor Oncology Group performance status less than 2 were included in this study. Patients were treated with irinotecan and cetuximab every 2 weeks along with escalating doses of tivantinib twice daily. Preliminary toxicity and efficacy data are available for nine patients. No DLTs were observed and grade 3/4 adverse events included neutropenia, fatigue and one case each of grade 3 leukopenia, acneiform rash, vomiting, diarrhea, anemia and syncope. In nine patients with evaluable responses, best responses included one complete response, 2 PRs, five SD and one progressive disease. The randomized phase II portion of the study continues to accrue data for the recommended phase II dose of 360 mg tivantinib twice daily.

Interestingly, this study also demonstrated the potential antimetastatic activity of tivantinib. For intention to treat patients, median time to new metastatic lesions was increased from 3. 6 months in the erlotinib plus placebo cdk1 inhibitor arm to 7. 3 months in the tivantinib plus erlotinib arm. Patients with nonsquamous histology had an even more pronounced effect, with median time to metastatic disease being increased from 3. 6 to 11. 0 months. Overall, treatment with tivantinib was well tolerated with no significant differences in adverse effects between treatment and control arms. The most frequent adverse effects included grade 1/2 rash, diarrhea, anorexia, anemia and fatigue.

Based on the results of this study, a global phase III randomized, double blind, placebo controlled study of tivantinib plus erlotinib in previously treated patients with metastatic nonsquamous NSCLC is currently ongoing. MetMAb is a monovalent monoclonal Cell Cycle inhibitor antibody directed against c MET, which prevents HGF from binding to the c MET receptor, thereby blocking HGF induced dimerization and receptor activation.