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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Vydané v:	Cancer chemotherapy and pharmacology Ročník 89; číslo 2; s. 255 - 265
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2022 Springer Nature B.V
Predmet:	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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0344-5704 1432-0843 1432-0843
DOI:	10.1007/s00280-021-04384-1