A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma

M Peeters, A H Strickland, M Lichinitser, A V S Suresh, G Manikhas, J Shapiro, W Rogowski, X Huang, B Wu, D Warner, R Jain, N C Tebbutt, M Peeters, A H Strickland, M Lichinitser, A V S Suresh, G Manikhas, J Shapiro, W Rogowski, X Huang, B Wu, D Warner, R Jain, N C Tebbutt

Abstract

Background: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer.

Methods: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS).

Results: One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ≥3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%).

Conclusion: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.

Trial registration: ClinicalTrials.gov NCT00752570.

Figures

Figure 1
Figure 1
Disposition of study patients. Noncompliance includes patients who did not comply with study drug administration, visit schedule, or other protocol requirement(s). QW=once weekly.
Figure 2
Figure 2
Progression-free survival among patients randomised to trebananib 10 mg kg−1 QW plus FOLFIRI or placebo plus FOLFIRI. QW=once weekly.
Figure 3
Figure 3
(A) Descriptive statistics for the pharmacokinetics of trebananib at week 5 among patients who received trebananib 10 mg kg−1 QW plus FOLFIRI (intensive pharmacokinetic analysis subset). (B) Cmax at week 5 of irinotecan among patients who received trebananib 10 mg kg−1 QW plus FOLFIRI or placebo plus FOLFIRI. (C) Cmax at week 5 of SN-38 among patients who received trebananib 10 mg kg−1 QW plus FOLFIRI or placebo plus FOLFIRI. (D) Baseline 5-FU Css at week 1 among patients who received placebo plus FOLFIRI by patient sex. (E) Css of 5-FU at week 5 among patients who received trebananib 10 mg kg−1 QW plus FOLFIRI or placebo plus FOLFIRI. Cmax=maximum observed concentration; Css=concentration at steady state; CV=coefficient of variation; QW=once weekly.

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