Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer

Abstract

Purpose: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castrationresistant prostate cancer.Experimental Design: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex.Results: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/ esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks.Conclusions: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis.

A phase 2, randomized, double‐blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low‐ or intermediate‐1–risk myelodysplastic syndrome

“…The overall safety profile was similar between treatment groups, and no unexpected safety findings were reported during the study. The observed safety profile was consistent with existing siltuximab safety data from previous studies investigating siltuximab for other indications [14,16,17]. Because safety concerns were not observed in the study, it may be feasible to explore a higher dose of siltuximab.…”

“…Siltuximab treatment has been associated with marked improvement in hemoglobin levels in multicentric Castleman's disease [14] and renal cell carcinoma [15], and adverse effects have been uncommon in clinical trials [14,16,17]. Siltuximab has the potential to improve the outcome of patients with MDS through improvement of anemia, reduction in the number of required red blood cell (RBC) transfusions, and modulation of the underlying disease process.…”

A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies

“…18 On the other hand, the increase in total target concentration is often observed postdose due to the stabilization of the target-mAb complex, [26][27][28][29] and it is then easier to measure. Since efficacy is associated with a decrease in free target concentration, it is desirable to establish a relationship between the increase in total target concentration and the decrease in free target concentration.…”

Targeting the inflammatory pathways to enhance chemotherapy of cancer

“…Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis. 127 Besides, in a three-part phase I/II study, siltuximab was able to stabilize disease in more than 50% of patients with progressive metastatic renal cell carcinoma. However, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Rα and gp130, depending on the in vivo environmental circumstances.…”