Back to Search
Start Over
A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2018 Oct; Vol. 82 (4), pp. 723-732. Date of Electronic Publication: 2018 Aug 20. - Publication Year :
- 2018
-
Abstract
- Purpose: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.<br />Methods: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m <superscript>2</superscript> /day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation.<br />Results: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy.<br />Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.
- Subjects :
- Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Antineoplastic Combined Chemotherapy Protocols adverse effects
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Drug Monitoring methods
Female
Humans
Male
Middle Aged
Neoplasm Staging
Neoplasms classification
Neoplasms metabolism
Neoplasms pathology
Proto-Oncogene Proteins c-met antagonists & inhibitors
Proto-Oncogene Proteins c-met metabolism
Treatment Failure
Treatment Outcome
Neoplasms drug therapy
Neutropenia chemically induced
Neutropenia diagnosis
Pyrrolidinones administration & dosage
Pyrrolidinones adverse effects
Pyrrolidinones pharmacokinetics
Quinolines administration & dosage
Quinolines adverse effects
Quinolines pharmacokinetics
Thrombocytopenia chemically induced
Thrombocytopenia diagnosis
Topotecan administration & dosage
Topotecan adverse effects
Topotecan pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 82
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30128950
- Full Text :
- https://doi.org/10.1007/s00280-018-3672-y