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Updated: Feb 6, 2026

Predictive Immune Modeling of Solid Tumors
08:50

Predictive Immune Modeling of Solid Tumors

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A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors

Stephen V Liu1, Susan G Groshen2, Karen Kelly3

  • 1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. stephen.v.liu@gunet.georgetown.edu.

Cancer Chemotherapy and Pharmacology
|August 22, 2018
PubMed
Abstract

Insights

The combination of topotecan and tivantinib, a MET tyrosine kinase inhibitor (TKI), was not tolerable in patients with advanced solid tumors due to severe toxicity. Further investigation into this combination therapy is not recommended.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Therapeutics

Background:

  • Tyrosine kinase inhibitors (TKIs) targeting MET signaling show promise in various cancers, including lung cancer.
  • Combination strategies aim to enhance the therapeutic index of MET TKIs.
  • Preclinical synergy between MET and topoisomerase I inhibition informed this study.

Purpose of the Study:

  • To evaluate the safety and tolerability of combining topotecan with the MET TKI tivantinib in a Phase I study.
  • To explore the pharmacokinetic profile of tivantinib in combination with topotecan.
  • To assess changes in MET phosphorylation in circulating tumor cells (CTCs).

Main Methods:

  • A Phase I study enrolled patients with advanced solid malignancies.
  • Patients received escalating doses of oral tivantinib (120-360 mg twice daily) with topotecan (1.0-1.5 mg/m²/day for 5 days every 21 days).
  • Pharmacokinetic analyses and serial CTC collection for MET phosphorylation assessment were performed.

Main Results:

  • 17 out of 18 enrolled patients received treatment.
  • The combination therapy was not tolerable due to severe thrombocytopenia and neutropenia, even with G-CSF support.
  • Increased tivantinib exposure correlated with higher toxicity; no anti-cancer responses were observed.
  • MET phosphorylation in CTCs was measurable but unaffected by the therapy.

Conclusions:

  • The combination of topotecan and oral tivantinib demonstrated unacceptable toxicity in this patient population.
  • This combination strategy is not recommended for further clinical development in advanced solid tumors.
Keywords:
ARQ-197Circulating tumor cellsMET phosphorylationTivantinibTopotecan

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