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 randomized 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/m2 on day 1 and prednisone 5 mg twice daily and were randomized 1:1 to receive either cixutumumab or ramucirumab 6 mg/kg intravenously weekly in a 21-day cycle. Primary endpoint was composite progression-free survival (cPFS). Secondary endpoints included safety, response, radiographic 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% 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-hematologic 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.

Persistent androgen receptor addiction in castration-resistant prostate cancer

“…Ultimately, there was no significant difference in the rate of undetectable PSA at 28 weeks (the primary endpoint) with the addition of cixutumumab. Cixutumumab has also been studied in combination with mitoxantrone in men with CRPC and was also found to have insufficient activity to warrant further development [ 140 ]. Studies evaluating cixutumumab as part of a targeted combination strategy have yet to be reported (clinicaltrials.gov: NCT01026623, NCT00683475).…”

Efficacy and safety of different interventions in castration resistant prostate cancer progressing after docetaxel-based chemotherapy: Bayesian network analysis of randomized controlled trials

“…A flow chart of trial selection was shown in Figure 1 . Eight RCTs of CRPC therapies were excluded because of unclear primary outcome assessment 37 - 41 and comparison of different dosing regimens without a common comparator group 42 - 44 . One study 45 presenting Mitoxantrone plus prednisone was excluded because it did not meet our inclusion criterion for data integration of control arms.…”

Ramucirumab – egy új gyógyszer az onkológiában

“…A nem hematológiai grade 3-4 nemkívánatos események incidenciája <10% volt mindkét karon. Kardiális diszfunkció 7,6%-ban jelentkezett a ramucirumabkaron [25].…”