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

Stephen V. Liu, Susan G. Groshen, Karen Kelly, Karen L. Reckamp, Chandra Belani, Timothy W. Synold, Amir Goldkorn, Barbara J. Gitlitz, Mihaela C. Cristea, I. Yeh Gong, Thomas J. Semrad, Yucheng Xu, Tong Xu, Marianna Koczywas, David R. Gandara, Edward M. Newman

Research output: Contribution to journalArticle

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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. 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/m2/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. 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. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

Original languageEnglish (US)
Pages (from-to)723-732
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume82
Issue number4
DOIs
StatePublished - Oct 1 2018

Fingerprint

Topotecan
Tumors
Circulating Neoplastic Cells
Neoplasms
Phosphorylation
Pharmacokinetics
Neutropenia
Protein-Tyrosine Kinases
Lung Neoplasms
Type I DNA Topoisomerase
Granulocyte Colony-Stimulating Factor
Therapeutics
Thrombocytopenia
Toxicity
ARQ 197
Cells
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Liu, S. V., Groshen, S. G., Kelly, K., Reckamp, K. L., Belani, C., Synold, T. W., ... Newman, E. M. (2018). A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 82(4), 723-732. https://doi.org/10.1007/s00280-018-3672-y
Liu, Stephen V. ; Groshen, Susan G. ; Kelly, Karen ; Reckamp, Karen L. ; Belani, Chandra ; Synold, Timothy W. ; Goldkorn, Amir ; Gitlitz, Barbara J. ; Cristea, Mihaela C. ; Gong, I. Yeh ; Semrad, Thomas J. ; Xu, Yucheng ; Xu, Tong ; Koczywas, Marianna ; Gandara, David R. ; Newman, Edward M. / A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2018 ; Vol. 82, No. 4. pp. 723-732.
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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. 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/m2/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. 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. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.",
author = "Liu, {Stephen V.} and Groshen, {Susan G.} and Karen Kelly and Reckamp, {Karen L.} and Chandra Belani and Synold, {Timothy W.} and Amir Goldkorn and Gitlitz, {Barbara J.} and Cristea, {Mihaela C.} and Gong, {I. Yeh} and Semrad, {Thomas J.} and Yucheng Xu and Tong Xu and Marianna Koczywas and Gandara, {David R.} and Newman, {Edward M.}",
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Liu, SV, Groshen, SG, Kelly, K, Reckamp, KL, Belani, C, Synold, TW, Goldkorn, A, Gitlitz, BJ, Cristea, MC, Gong, IY, Semrad, TJ, Xu, Y, Xu, T, Koczywas, M, Gandara, DR & Newman, EM 2018, 'A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 82, no. 4, pp. 723-732. https://doi.org/10.1007/s00280-018-3672-y

A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors. / Liu, Stephen V.; Groshen, Susan G.; Kelly, Karen; Reckamp, Karen L.; Belani, Chandra; Synold, Timothy W.; Goldkorn, Amir; Gitlitz, Barbara J.; Cristea, Mihaela C.; Gong, I. Yeh; Semrad, Thomas J.; Xu, Yucheng; Xu, Tong; Koczywas, Marianna; Gandara, David R.; Newman, Edward M.

In: Cancer Chemotherapy and Pharmacology, Vol. 82, No. 4, 01.10.2018, p. 723-732.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors

AU - Liu, Stephen V.

AU - Groshen, Susan G.

AU - Kelly, Karen

AU - Reckamp, Karen L.

AU - Belani, Chandra

AU - Synold, Timothy W.

AU - Goldkorn, Amir

AU - Gitlitz, Barbara J.

AU - Cristea, Mihaela C.

AU - Gong, I. Yeh

AU - Semrad, Thomas J.

AU - Xu, Yucheng

AU - Xu, Tong

AU - Koczywas, Marianna

AU - Gandara, David R.

AU - Newman, Edward M.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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. 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/m2/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. 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. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

AB - 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. 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/m2/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. 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. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

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