Phase I/II, two-part, open-label, multiple-dose, dose-escalation study of siltuximab in patients with solid tumors.

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2583 Background: Siltuximab (S) is a chimeric mAb with high affinity for soluble IL-6. This Ph 1/2 study evaluated safety, efficacy and PK of escalating, multiple IV doses of S from a new cell line in patients (pts) with advanced refractory solid tumors. Methods: In Ph 1, S was given to 20 pts with advanced solid tumors at escalating dose levels (2.8 or 5.5 mg/kg q2w or 11 or 15 mg/kg q3w) and to 24 pts with taxane and platinum resistant ovarian cancer (OVC) or KRAS mutant (KRASmt) tumors at 15 mg/kg q3w. In Ph 2, 17 OVC pts and 23 KRASmt pts received the Ph 1 selected dose of 15 mg/kg q3w. The Ph 2 primary efficacy endpoint was clinical benefit rate (CBR: CR + PR + SD of > 6 wk). Results: In Ph 1-2, 84 pts (35 colorectal, 29 OVC, 9 pancreatic, 11 other) pretreated with a median of 4 prior tx regimens received a median of 3 (range 1, 45) cycles. 1 DLT occurred at 5.5 mg/kg; MTD was not reached. 62% pts had AEs gr ≥ 3 in Ph 1-2, most common were hepatic function abnormalities (15%), PS deterioration (12%), fatigue (11%). 10% pts had possibly S-related AEs gr ≥ 3; only neutropenia (4%) was reported in >1 pt. 42% pts had SAEs, most were related to underlying disease, 2% were possibly S-related. 18 deaths occurred on study, 17 due to PD, 1 due to AE. No pt had antibodies to S. The PK profile was bi-exponential with a t1/2 ranging 15 − 20 d. PK profile of S from the new Chinese hamster ovary cell line appears similar to the previous murine Sp2/0 myeloma cell line. CBR in Ph 2 was 5%. ORR by RECIST was 26% SD in Ph 1, 9% SD in Ph 2. 1 OVC pt had CA 125 response. In Ph 2 the median PFS was ~ 2 mo in both cohorts; the median OS was 4.2 mo in KRAMSmt and 11 mo in OVC. Hb increased by a max of ≥10 g/L in 73% pts given 15 mg/kg in Ph 2, with 94% showing a median decrease of 68% at d 8 after dose 1 in hepcidin, a regulator of iron homeostasis. CRP was suppressed in all pts during tx, with median decrease 93% at 11 mg/kg and 88 − 93% at 15 mg/kg as early as d 8 after dose 1. Other biomarkers will be presented. Conclusions: S appears to be well tolerated; doses of 11 − 15 mg/kg q3-4w can be used in future studies. No CR/PR was observed, although some pts with advanced solid tumors had durable SD and CRP suppression. Improvement in Hb was observed in a large proportion of pts, indicating a role of IL-6 in anemia that needs to be further explored.