A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer

作者：Wainberg Zev A^*; Messersmith Wells A; Peddi Parvin F; Kapp Amy V; Ashkenazi Avi; Royer Joo Stephanie; Portera Chia C; Kozloff Mark F

来源：Clinical Colorectal Cancer, 2013, 12(4): 248-254.

DOI：10.1016/j.clcc.2013.06.002

• Apoptosis
• Apo2L/TRAIL
• Death receptor
• Dulanermin
• FOLFOX
• Metastatic colorectal cancer

Dulanermin, a human recombinant form of Apo2 ligand/tumor necrosis factor related apoptosis-inducing ligand with proapoptotic activity in cancer cells, was tested in this phase 1B study in combination with FOLFOX and bevacizumab in the first-line treatment of patients with advanced colorectal cancer. The combination was found to be well tolerated in the 23 patients treated with no dose-limiting toxicity and with evidence of efficacy.
Objectives: The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. Patients and Methods: A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. Results: In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). Conclusions: Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.

• 出版日期2013-12