A Phase I Dose Escalation Study of Oral c-MET Inhibitor Tivantinib (ARQ 197) in Combination with Gemcitabine in Patients with Solid Tumors

Mené sur 29 patients atteints d'une tumeur solide de stade métastatique ou avancé, cet essai de phase I avec escalade de dose évalue la dose maximale tolérée du tivantinib en combinaison avec la gemcitabine

Résumé en anglais

Background : Tivantinib (ARQ 197) is an orally available, non-ATP competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase 2 dose (RP2D) of tivantinib and gemcitabine combination.

Patients and methods : Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120 mg - 360 mg capsules) in combination with gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (BID) for 2 weeks, 3 weeks, or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration).

Results : Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg BID (n=4), 240 mg BID (n=6) and 360 mg BID (n=19). No dose limiting toxicities (DLT's) were observed in escalation. The RP2D was 360 mg BID daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54/74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were evaluable for response. Eleven (20%) patients achieved a partial response (PR) and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over four months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine.

Conclusion : The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of anti-tumor activity may warrant further development of this combination in non small cell lung cancer (NSCLC), ovarian, pancreatic and cholangiocarcinoma.ClinicalTrials.gov Identifier. NCT00874042