A phase 1/2 study of metronomic 5-fluorouracil (5-FU) plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with metastatic pancreatic cancer

Abstract

Introduction: nab-Paclitaxel plus gemcitabine is a preferred treatment for patients with metastatic pancreatic cancer and good performance status. An early, single-center study of patients with advanced pancreatic cancer treated with the FABLOx regimen demonstrated an overall response rate of 50% and a median overall survival of approximately 17 months, albeit with considerable toxicity (Isacoff, ASCO 2012). This multicenter phase 1/2 study will evaluate the safety and efficacy of a novel FABLOx regimen in metastatic pancreatic cancer. Methods: To be enrolled in this open-label, multicenter, single-arm study, patients must be 18-65 years of age, have an Eastern Cooperative Oncology Group performance status of≥1, and have adequate hematologic and organ function. In addition, patients must have had no prior treatment for pancreatic cancer (including adjuvant or neoadjuvant therapy), no prior peripheral neuropathy grade > 1. The recommended phase 2 dose (RP2D) determined in phase 1 will be administered to patients in phase 2 (Figure), who will be monitored for a clinically meaningful improvement over historical controls in 1-year survival. The phase 1 primary endpoint is the incidence of dose-limiting toxicities, and the sec-ondary endpoint is safety. Dose-limiting toxicity is defined as any toxicity with onset during the first 28 days and requiring ≤14 days of treatment interruption and includes neutropenia (grade 3/4), anemia (grade 3), hematologic toxicity (grade 4), thrombocytopenia (grade 4) or thrombocytopenia associated with clinically significant bleeding (grade 3/4), pneumonitis or interstitial lung disease (grade ≤2), or hyperbilirubinemia (grade ≤3) not due principally to unconjugated bilirubin. Approximately 12-24 patients in cohorts of≤6 patients will be enrolled; additional patients may be enrolled at investigator discretion. If≤2 patients experience a dose-limiting toxicity in cycle 1, the dose will be de-escalated to the next lower dose (Figure). If≤2 of 6 patients experience a dose-limiting toxicity at the lowest dose, the study will be terminated. For any dose level, if additional patients are enrolled, evaluation will occur at a 1:3 ratio (ie≤2 of 6 or≤4 of 12 patients). In phase 2, approximately 60 patients will receive treatment at the RP2D. The phase 2 primary endpoint is 1-year survival rate. A 1-year survival rate of 62.4% will be considered clinically meaningful; this represents a≤30% improvement (≤ 14.4% difference) over the historical control of a 1-year survival rate of 48%. The phase 2 secondary endpoints are safety, objective response rate, progression-free survival, overall survival, and patient-reported outcomes of cancer symptoms. The trial is ongoing, and currently 6 patients have been enrolled. ClinicalTrials.gov: NCT02620800. Results: Conclusion:.