Open-label, multicenter, single-arm study of FABLOx (metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin) in patients with metastatic pancreatic cancer: Phase I results
Authors: V. Sahai, W. Saif, A. Kalyan, P. Philip, C. Rocha-Lima, A. Ocean, M. Ondovik, D. Simeone, M. Karnoub, C. Louis, V. Picozzi
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer (PC) is a leading cause of cancer-related deaths globally, with a dismal all-stage 5-year survival rate of 8%. Systemic chemotherapy can prolong survival and palliate symptoms in patients with metastatic PC (MPC). The phase III MPACT trial demonstrated superiority of first-line nab -paclitaxel plus gemcitabine vs gemcitabine monotherapy across all endpoints, including the primary endpoint of overall survival (OS) in patients with MPC. Promising results have been observed with regimens containing nab -paclitaxel and 5-fluorouracil (5-FU); however, toxicity is a major concern with high-dose intermittent therapy. The goal of this study is to determine whether metronomic therapy (continuous, low-dose treatment) with FABLOx can reduce the associated toxicities without affecting efficacy. Methods: Patients (aged 18 - 65 years) with previously untreated, histologically or cytologically confirmed MPC and an ECOG performance status of 0 or 1 were eligible. Patients with preexisting peripheral neuropathy grade > 1 were excluded. Phase I of the study assessed potential dose-limiting toxicities (DLTs) to determine the recommended phase II dose (RP2D); phase II was designed to evaluate efficacy and further assess safety of the RP2D. During the dose-determining phase, a minimum of 6 patients were to be enrolled in each consecutive dosing cohort, and 5-FU, nab -paclitaxel, and oxaliplatin doses were to be de-escalated to the next lower dose if ≥ 2 of 6 patients experienced a DLT in cycle 1 (to a maximum of dose level −2). Patients received 5-FU 180 mg/m 2/day on days 1 to 14; nab -paclitaxel 75 mg/m 2 on days 1, 8, and 15; bevacizumab 5 mg/kg on days 1 and 15; leucovorin 20 mg/m 2 on days 1, 8, and 15; and oxaliplatin 40 mg/m 2 on days 1, 8, and 15 of each 28-day cycle in cohort I (the starting dose level). The primary endpoint of phase I was incidence of DLTs, and the secondary endpoint was safety. Patients were treated until disease progression, unacceptable toxicity, withdrawal of consent, physician decision, or death. Results: Two DLTs were observed in 1 patient (grade 3 anemia requiring a transfusion and grade 3 mucositis unresponsive to medical treatment within 4 days of onset); cohort I was expanded from 6 to 12 patients. The median age was 57.5 (range, 41 - 64) years; 3 women and 9 men were enrolled, and 3 patients continue to be followed up for survival analysis. Patients received a median of 7.0 treatment cycles of nab -paclitaxel, bevacizumab, leucovorin, and 5-FU and 5.5 cycles of oxaliplatin. The evaluation of grade ≥ 3 treatment-emergent adverse events is pending. The objective response rate was 42% (5 partial responses); the median PFS and OS were 5.6 and 11.5 months, respectively. Conclusion: Results from phase I of this study demonstrate that metronomic FABLOx treatment is feasible for patients with MPC. Preliminary data suggest promising antitumor activity with the regimen. NCT02620800.