Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m 2 ) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 mg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 mg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 mg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168-78. Ó2013 AACR.

BACKGROUND: E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids). METHODS: In a phase 1 study, E7974 was given intravenously over a 2-to 5-minute infusion on day 1 of every 21-day cycle. Adult patients with advanced refractory solid tumors who had adequate organ function and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible for this study. A modified Fibonacci schema was used. The maximal tolerated dose (MTD) was the dose where <2 of 6 patients developed a dose-limiting toxicity (DLT). RESULTS: Twentyeight patients (19 men and 9 women; median age, 64 years) treated at different cohort dose levels (0.18 mg/m 2 , 0.27 mg/m 2 , 0.36 mg/m 2 , 0.45 mg/m 2 , and 0.56 mg/m 2 ) received a total of 66 courses of E7974. The MTD was established at 0.45 mg/m 2 , where 1 of 6 patients experienced DLT (grade 4 febrile neutropenia). Of the 17 refractory colon cancer patients with a median of 3 prior treatments, stable disease was seen in 7 patients (41%). There were no tumor responses. Median progression-free survival was 1.2 months, and median overall survival was 6.7 months. In pharmacokinetic analysis, E7974 was characterized by a fast and moderately large distribution (37.95-147.93 L), slow clearance (2.23-7.15 L/h), and moderate to slow elimination (time to half-life, 10.4-30.5 hours). CONCLUSIONS: This study shows that E7974 once every 21-day cycle shows antitumor activity in patients with refractory solid tumors. The recommended phase 2 dose is 0.45 mg/m 2 .

In this multicenter phase Ib study, drozitumab was given in combination with the mFOLFOX6 regimen and bevacizumab in patients with previously untreated, locally advanced recurrent or metastatic colorectal cancer on day 1 of every 14-day cycle. Nine patients were treated at 2 different cohort dose levels of drozitumab. No dose-limiting toxicities occurred at either dose level and the maximum tolerated dose was not reached. Two patients had a partial response of 4.93 and 4.96 months duration. Cohort 2 dose level is the recommended starting dose level for future trials.

GOC is a feasible combination with an acceptable toxicity profile. However, GOC did not significantly extend PFS in the overall patient population to consider it for further development.

Purpose To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every three weeks in combination with daily sunitinib in patients with advanced solid tumors. Experimental Design Eligible patients received either weekly (Schedule A) or every 3 weeks (schedule B) Ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2;; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLTs) were assessed during cycle 1. Results The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3–4 hematological and non-hematological adverse events (AEs) were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response (PR), while 13 patients had stable disease (SD). Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Co-administration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks Ixabepilone led to a significant decrease in PAA post-baseline. Conclusion Co-administration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer.

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5065 Background: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. IL-18 has been shown to increase the anti-tumor activity of doxorubicin in other cancer mouse models. Methods: This multi-center study enrolled 16 patients (pts), and evaluated four cycles (28 days each) of standard pegylated liposomal doxorubicin (PLD) (40 mg/m2 day 1) in combination with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle with a 1 yr follow-up to further evaluate safety and efficacy. Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) did not because of disease progression (5 pts) and PLD hypersensitivity (1 pt). Thirteen (82%) were platinum resistant/refractory having received a median of > 3 prior lines of therapy. SB-485232 up to 100 mg/kg in combination with PLD had an acceptable safety profile. All 16 pts experienced at least 1 AE including chills (81%), nausea (75%), anemia (63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and cytokine release syndrome. Maximal SB-485232 biological activity, assessed by peripheral blood NK and T cell markers, was observed at 10mg/kg-100mg/kg. This drug combination resulted in a 6% partial response rate (RR) and a 38% stable disease rate using RECIST 1.0. Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) months. Conclusions: The SB-485232/PLD combination was tolerable with minimal toxicity. These preliminary efficacy data are comparable to the historical RR and PFS observed with PLD monotherapy in platinum-resistant ovarian cancer. However, given the small sample size, this combination warrants further investigation.

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