Pilot Study of Tigatuzumab (CS-1008) in Combination with Folfiri in Patients with Metastatic Colorectal Cancer (CRC)

ABSTRACT Background Tigatuzumab (T) is a humanized monoclonal antibody that acts as a death receptor 5 (DR5) agonist. Preclinical studies have shown that T monotherapy induces apoptosis in DR5-positive CRC cell lines and significantly inhibits growth in CRC xenograft models. T combined with FOLFIRI (folinic acid, 5-fluorouracil (5-FU), irinotecan) has demonstrated enhancement of preclinical antitumor activity. This pilot study assessed efficacy and safety of this combination therapy in patients (pts) with metastatic CRC. Methods This was an open-label, single-arm, multicenter study of T plus FOLFIRI in pts with histologically-confirmed metastatic CRC, an ECOG (Eastern Cooperative Oncology Group) score ≤ 2, and adequate organ and bone marrow function. Pts were non-homozygous for UGT1A1*28 allele. T was initially administered intravenously (IV) at 6 mg/kg and thereafter at 2 mg/kg weekly with one treatment cycle = 4 weeks (wks). FOLFIRI was administered IV at wks 1 and 3: irinotecan 180mg/m2, folinic acid (leucovorin) 400mg/m2 and 5-FU 400mg/m2 bolus followed by 2400 mg/m2 over 46-48 hours. Radiographic assessments were performed every 8 wks. Results Treated pts (n = 21) had a median of 3 prior therapies; 10 (48%) had prior FOLFIRI. All pts experienced ≥1 treatment-emergent adverse event (TEAE); the most common T-related TEAEs were fatigue (12 pts; 57%) and nausea (8 pts; 38%). 17 pts (81%) experienced a ≥ grade 3 TEAE; the most common was neutropenia (9 pts; 43%) which was partly attributed to T in 5 pts (24%). Serious AEs (SAEs) occurred in 15 pts (71%). The most common SAE was anemia (3 pts; 14%), all unrelated to T. There was 1 SAE of neutropenia related to T. Median progression-free survival (PFS) was 3.7 months. 2 pts had unconfirmed partial response; 9 pts had stable disease. The trial is ongoing. Conclusions T displays acceptable safety and tolerability when combined with FOLFIRI. The observed median PFS compares favorably with historical results in 3rd/4th line treated pts, but study size and single arm design preclude formal conclusions. The SAEs reported were comparable to those reported for T in combination with other chemotherapies. Disclosure J. Greenberg: Full-time employee of and stockholder in Daiichi Sankyo Pharmaceutical Development. P. McCroskery: Full-time employee of and stockholder in Daiichi Sankyo Pharmaceutical Development. Stockholder in Johnson & Johnson Corporation. R. Beckman: Full-time employee of and stockholder in Daiichi Sankyo Pharmaceutical Development. Stockholder in Johnson & Johnson Corporation. A. Grothey: Contracted researcher for Daiichi Sankyo Pharmaceutical Development. All other authors have declared no conflicts of interest.