A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer

Autor: David Bing Zhen, Jason E. Savage, Joshua M. Ruch, Kevin Camphausen, Diane M. Simeone, Kent A. Griffith, Mark M. Zalupski, Vaibhav Sahai, Edward J. Kim
Rok vydání: 2016
Předmět:
0301 basic medicine
Oncology
Male
Pyridines
Deoxycytidine
chemistry.chemical_compound
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Clinical endpoint
Pharmacology (medical)
Anilides
6.2 Cellular and gene therapies
Cancer
Tumor
Pharmacology and Pharmaceutical Sciences
Middle Aged
Prognosis
Survival Rate
030220 oncology & carcinogenesis
6.1 Pharmaceuticals
Adenocarcinoma
Female
medicine.drug
Adult
medicine.medical_specialty
Cabozantinib
Maximum Tolerated Dose
Clinical Trials and Supportive Activities
Article
03 medical and health sciences
Pancreatic Cancer
Rare Diseases
Clinical Research
Internal medicine
Pancreatic cancer
Biomarkers
Tumor
medicine
Humans
XL-184
Oncology & Carcinogenesis
Survival rate
Neoplasm Staging
Aged
Pharmacology
Performance status
business.industry
Evaluation of treatments and therapeutic interventions
medicine.disease
Gemcitabine
Surgery
Pancreatic Neoplasms
030104 developmental biology
Orphan Drug
chemistry
business
Digestive Diseases
Biomarkers
Follow-Up Studies
Zdroj: Investigational new drugs, vol 34, iss 6
Invest New Drugs
Popis: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (-)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25% of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25% for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95% CI: 1.4-9.7) and 10.1months (95% CI: 3.6-20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.
Databáze: OpenAIRE
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