Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer

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Abstract

Purpose

This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy.

Methods

Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m2 every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ⩾3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression.

Results

Siltuximab plus M/P was well tolerated in Part 1 (n = 9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P = 0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P = 0.0003).

Conclusion

While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated.

Introduction

Prostate cancer is the most common cancer diagnosed and a leading cause of cancer death among men in the United States and the European Union.1, 2 Current treatments include surgery, radiation, anti-androgen therapies and chemotherapy. While anti-androgen therapy may temporarily control prostate tumours, they inevitably develop into castration-resistant prostate cancer (CRPC).3 Mitoxantrone combined with prednisone has been a reference cytotoxic treatment for metastatic CRPC despite the absence of survival improvement. Results from two phase III trials changed this treatment paradigm4, 5; docetaxel combined with prednisone is now considered the first-line treatment of choice for metastatic CRPC. Future treatment strategies for CRPC may involve a combination of cytotoxic agents and targeted therapies with complementary mechanisms of action and non-overlapping toxicities.

Overproduction of interleukin-6 (IL-6) may contribute to the pathogenesis of solid tumours, including prostate cancer.6, 7 Elevated IL-6 in patients with prostate cancer is strongly associated with disease stage, presence of metastases, and poor prognosis.8, 9, 10 Moreover, IL-6 may act as a growth factor and protect cancer cells from certain chemotherapeutic agents, including doxorubicin, etoposide and cisplatin.11, 12

Siltuximab (CNTO 328) is an anti-IL-6 chimeric monoclonal antibody that has been shown to markedly reduce expression of IL-6 and has demonstrated inhibition of androgen resistance and androgen-independent prostate tumour growth in xenograft models.13 In a phase 1 study of siltuximab as monotherapy prior to radical prostatectomy, analysis of gene expression patterns indicated inhibition of the IL-6- and androgen-signalling pathways.14 In a mouse model of prostate cancer, siltuximab enhanced the antitumour activity of cytotoxic agents, including mitoxantrone. This phase II study was conducted to evaluate the safety and efficacy of siltuximab plus mitoxantrone/prednisone compared with mitoxantrone/prednisone alone in patients with metastatic CRPC. This trial was registered at www.clinicaltrials.gov as #NCT00385827.

Section snippets

Eligibility criteria

Enrolled patients were men aged 18 years or older with histologically or cytologically confirmed prostate adenocarcinoma; radiologically documented metastatic disease; at least 6 weeks of treatment with one prior docetaxel-based chemotherapy for metastatic CRPC; and disease progression during or within 6 months of cessation of prior docetaxel-based chemotherapy, determined by serum prostate-specific antigen (PSA; PSA ⩾5.0 ng/mL at screening) or radiologic evidence (bone scan). Additional

Study conduct

The study was conducted in 31 sites from October 2006 to February 2008. Nine patients were treated in Part 1, and 97 patients were treated in Part 2. Study treatment was suspended for a planned safety review, and enrolment was prematurely stopped by the IDMC after their review showed an imbalance in the patient characteristics (favoring the mitoxantrone/prednisone arm) that made it very unlikely, in their view, that the study could achieve its primary efficacy end-point. The IDMC review did not

Discussion

Despite evidence of an additive effect in a preclinical study, the combination of siltuximab and mitoxantrone/prednisone did not demonstrate improvement in clinical outcomes over mitoxantrone/prednisone alone in metastatic CRPC. There are several possible explanations. First, the PFS observed with mitoxantrone/prednisone alone markedly exceeded historical expectations,15, 16, 17, 18, 19, 20, 21 likely because of the novel and invalidated definition of progression used. This definition of

Role of the funding source

As authors of the manuscript, employees of the study sponsor participated with the external authors in the study conception and design; collection, analysis, and interpretation of data; writing and editing of the manuscript and the decision to submit the manuscript for publication.

Conflict of interest statement

K. Fizazi has served as a non-compensated consultant/advisor for Centocor, Inc. J.S. De Bono has served as a consultant/advisor and received honoraria from Johnson & Johnson. A. Heidenreich has served as a consultant/advisor for Amgen, Novartis, and Sanofi-Aventis. Ming Qi, R. Bandekar, J. Vermeulen, and M. Cornfeld are employees and stockowners of Johnson & Johnson. A. Flechon, E. Voog, N.B. Davis, and G.R. Hudes have no conflicts of interest to disclose.

Acknowledgements

The authors would like to thank all of the investigators and members of the Independent Data Monitoring Committee for their participation in the study. Funding for this study was provided by Centocor, Inc. Editorial support for the writing of this manuscript was provided by Nancy Bella, PharmD, of MedErgy and was funded by Centocor, Inc.

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