Phase I/Ib study of crenolanib with ramucirumab and paclitaxel as second-line therapy for advanced esophagogastric adenocarcinoma

Purpose Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibit...

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Published in:Cancer chemotherapy and pharmacology Vol. 89; no. 2; pp. 255 - 265
Main Authors: Moy, Ryan H., Greally, Megan, Chou, Joanne F., Li, Jia, Desai, Avni M., Chalasani, Sree B., Won, Elizabeth, Kelsen, David P., Ilson, David H., Janjigian, Yelena Y., Capanu, Marinela, Ku, Geoffrey Y.
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2022
Springer Nature B.V
Subjects:
Adenocarcinoma
Adenocarcinoma - drug therapy
Adenocarcinoma - pathology
Adult
Aged
Antibodies, Monoclonal, Humanized - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Benzimidazoles - administration & dosage
Cancer
Cancer Research
Clinical Trial Report
Dose-Response Relationship, Drug
Esophageal cancer
Esophageal Neoplasms - drug therapy
Esophageal Neoplasms - pathology
Female
Gastric cancer
Humans
Immunotherapy
Leukopenia
Male
Maximum Tolerated Dose
Medicine
Medicine & Public Health
Metastases
Middle Aged
Monoclonal antibodies
Neutropenia
Oncology
Paclitaxel
Paclitaxel - administration & dosage
Patients
Pharmacology/Toxicology
Piperidines - administration & dosage
Platelet-derived growth factor
Progression-Free Survival
Ramucirumab
Stomach Neoplasms - drug therapy
Stomach Neoplasms - pathology
Targeted cancer therapy
VEGFR2
PDGFR
Ramucirumab
Crenolanib
Gastric cancer
Esophageal cancer
ISSN:0344-5704, 1432-0843, 1432-0843
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Summary:Purpose Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab. Methods Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m 2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD. Results We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23–78%] and the objective response rate (ORR) was 42% (95% CI 15–72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor. Conclusions The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID. Clinical trial registration NCT03193918. June 19, 2017.
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ISSN:0344-5704
1432-0843
1432-0843
DOI:10.1007/s00280-021-04384-1