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 language | English (US) |
|---|---|
| Pages (from-to) | 723-732 |
| Number of pages | 10 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 82 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 1 2018 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85051767669&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051767669&partnerID=8YFLogxK
U2 - 10.1007/s00280-018-3672-y
DO - 10.1007/s00280-018-3672-y
M3 - Article
C2 - 30128950
AN - SCOPUS:85051767669
VL - 82
SP - 723
EP - 732
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 4
ER -