Ryan, David P.

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.

325 Background: TH-302 is a hypoxia-targeted drug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G+T to standard dose G as first-line therapy of PAC. Methods: An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1,000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint was a comparison of PFS between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Overall survival (OS) was a secondary endpoint. Results: 214 pts were treated; 163 (76%) Stage IV and 51 (24%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 38% ECOG 0/62% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G+T240; 55% G+T340. Median PFS was 3.6 mo in G vs 5.6 mo in G+T240 (p=0.06) and 6.0 mo in G+T340 (p=0.01). Median OS was 6.9 mo in G vs 8.7 in G+T240 (p=0.83) vs 9.2 mo in G+T340 (p=0.80). 6-mo OS was 57% in G vs 69% in G+T240 (p=0.12) and 73% in G+340 (p=0.04); 12-mo OS was 26% in G vs 37% in G+T240 (p=0.18) and 38% in G+340 (p=0.13). RECIST best response was 10% in G vs 17% in G+T240 and 26% in G+T340. 14 and 12 pts in G crossed over to T240 and T340, respectively. Median post crossover PFS was 1.8 mo in T240 vs 2.9 mo in T340 (p=0.13). Median post crossover OS was 2.6 mo in T240 vs 13.4 mo in T340 (p=0.01). AEs leading to discontinuation were: 16% G, 17% G+T240 and 12% G+T340. Rash (47% in G+T340) and stomatitis (42% in G+T340) were greater in combination, 3 pts Grd 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G+T240 and 63% G+T340 and Grd 3/4 neutropenia were 31% G, 56% G+T240 and 60% G+T340. Conclusions: The combination of G plus TH-302 improved the PFS of G. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. A phase 3 study of TH-302 (340 mg/m2) in combination with G is planned with OS as the primary efficacy endpoint. Clinical trial information: NCT01144455.

Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

Abstract Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50–1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration–time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002–9. ©2014 AACR.

Abstract A hypoxic microenvironment is believed to be a characteristic of solid tumors including pancreatic adenocarcinoma (PAC) and is associated with resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to specifically target the hypoxic microenvironment. Combining G with TH-302 may enable the targeting of both the normoxic and hypoxic regions of PAC. TH-302 was investigated with full-dose G as part of a Phase 1/2 study with a 21% response, median PFS and OS of 5.9 and 8.5 months, respectively, and one-year survival of >40%. Based upon these data, a randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G+T to standard dose G for first-line therapy of PAC. An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1) was initiated in June 2010. G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G arm could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint is a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). 214 pts (69 G: 71 G+T240: 74 G+T340) with advanced PAC including 77% distant metastases, 62% involving liver and 11% with prior adjuvant tx; median age: 65 (range 29-86); 126 M/88 F; 79/128 ECOG 0/1. Median cycles received: G - 4, G+T240 - 5, G+T340 - 6. Median PFS was 3.6 mo in G vs 5.6 mo in G+T arms with HR of 0.61 (95% CI: 0.43 - 0.87) and logrank p-value of 0.005. Median PFS in G + T340 was 6.0 mo. RECIST best response was 12% in G, 17% in G+T 240 and 27% in G+T340. 153 (71%) patients had elevated CA19-9 and follow-up. CA19-9 decreases were significantly greater in the G+T groups and greatest in the G+T340 arm which had 37 of 53 (70%) pts with a greater than 50% CA19-9 decrease. One death (suicide) was considered possibly related to study drug. Adverse events leading to discontinuation were: 16% G, 15% G+T240 and 11% G+T340. Serious adverse events were balanced across the treatment arms. The most common non-laboratory events, fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (38%), were similar across groups. Rash (14% G, 39% G+T240 and 45% G+T340) and stomatitis (6% G, 17% G+T240 and 36% G+T340) were significantly greater with G+T combination but no Grd 4 (4 pts with Grade 3). Grd 3/4 thrombocytopenia (11% G, 39% G+T240 and 59% G+T340) and Grd 3/4 neutropenia (28% G, 56% G+T240 and 59% G+T340) were higher with G+T. G+T combination with full dose G improved the efficacy of G with significantly longer PFS, higher response rate and greater CA19-9 declines. The G+T combination was well tolerated. Skin and mucosal toxicity and myelosuppression were the most common related adverse events with no increase in treatment discontinuation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-121. doi:1538-7445.AM2012-LB-121