Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors.

William F Maguire, John C Schmitz, Jonas Scemama, Ken Czambel, Yan Lin, Anthony G Green, Shaoyu Wu, Huang Lin, Shannon Puhalla, John Rhee, Ronald Stoller, Hussein Tawbi, James J Lee, John J Wright, Jan H Beumer, Edward Chu, Leonard J Appleman

Journal: Cancer chemotherapy and pharmacology 2021;88(4):643-654

PMID: 34164713

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Abstract

PURPOSE

We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody.

METHODS

Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin.

RESULTS

Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin.

CONCLUSIONS

The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression.

TRIAL REGISTRATION

NCT01749384 (First posted 12/13/2012).

Address: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; UPMC Hillman Cancer Center Biostatistics Facility, Pittsburgh, PA, USA.; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.; Pitt Biospecimen Core Research Histology Department, Health Sciences Core Research Facilities, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; School of Pharmaceutical Science, Southern Medical University, Guangzhou, China.; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.; Roche Product Development, Roche (China) Holding Ltd., Shanghai, China.; Department of Melanoma and Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.; Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Department of Oncology and Cancer Therapeutics Program, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].; Cancer Therapeutics Program, UPMC Hillman Cancer Center, 5150 Centre Avenue, Pittsburgh, PA, USA. [email protected].; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].

DOI: 10.1007/s00280-021-04317-y

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MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neoplasms, Proto-Oncogene Proteins c-met, Pyrrolidinones, Quinolines, Treatment Outcome, Tubulin