A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer

Abstract

Background: Cixutumumab, a human monoclonal antibody (HuMAb), targets the insulin-like growth factor receptor. Ramucirumab is a recombinant HuMAb that binds to vascular endothelial growth factor receptor-2. A non-comparative randomised phase II study evaluated cixutumumab or ramucirumab plus mitoxantrone and prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC).

Patients and methods: Men with progressive mCRPC during or after docetaxel therapy received mitoxantrone 12 mg/m(2) on day 1 and prednisone 5mg twice daily and were randomised 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary end-point was composite progression-free survival (cPFS). Secondary end-points included safety, response, radiographic progression-free survival (PFS) and overall survival (OS). Sample size was based on a 50% increase in median cPFS from 2.6 (MP) to 3.9 months (either combination).

Results: 132 men were treated (66 per arm). Median cPFS was 4.1 months (95% confidence interval (CI), 2.2-5.6) for cixutumumab and 6.7 months (95% CI, 4.5-8.3) for ramucirumab. Median time to radiographic progression was 7.5 months for cixutumumab and 10.2 months for ramucirumab, with a median OS of 10.8 and 13.0 months, respectively. Fatigue was the most frequent adverse event (AE). Incidence of most non-haematologic grade 3-4 AEs was <10% on both arms. Grade 3 cardiac dysfunction occurred in 7.6% of patients on ramucirumab.

Conclusion: Combinations of cixutumumab or ramucirumab plus MP were feasible and associated with moderate toxicities in docetaxel-pretreated men with mCRPC. Of the two regimens, the ramucirumab regimen is worthy of further testing based on the observed cPFS relative to the historical control.

Trial registration: ClinicalTrials.gov NCT00683475.

Keywords: Cixutumumab; Mitoxantrone; Prednisone; Prostate cancer; Ramucirumab.

Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

CONSORT diagram.

Figure 2

Kaplan-Meier plots of (a) composite progression-free survival; (b) time to radiographically evident disease progression, and; (c) overall survival.

Figure 2

Kaplan-Meier plots of (a) composite progression-free survival; (b) time to radiographically evident disease progression, and; (c) overall survival.

Figure 2

Kaplan-Meier plots of (a) composite progression-free survival; (b) time to radiographically evident disease progression, and; (c) overall survival.

Figure 3

Waterfall plot for best percent change in PSA from baseline. Response defined as ≥50% PSA decrease from baseline and progression defined as 25% PSA increase. CIX, cixutumumab; M, mitoxantrone; P, prednisone; RAM, ramucirumab. (*Truncated at 200%)