Mahalingam, Devalingam

3583 Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .

Aim Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using ‘3 + 3’ dose escalation. Methods In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non‐small‐cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose‐limiting toxicity, or withdrawal of consent. Results Fifty of 68 enrolled patients received imalumab. The most common treatment‐related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose‐limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). Conclusions Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

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.

Abstract Background: MIF is a pleiotropic cytokine involved in tumor proliferation, invasiveness, angiogenesis, and the proinflammatory microenvironment. oxMIF is the pathogenic form mainly in tumor and its surrounding stroma. Imalumab (BAX69) is a novel recombinant, fully-human, monoclonal antibody that targets oxMIF, inhibiting tumorigenesis. Preclinical data demonstrated that imalumab has antitumor activities and acceptable toxicities. Methods: The primary endpoint of this dose-escalation study (3+3 design) was to assess maximum tolerated dose (MTD). The secondary endpoints were to assess antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts) received intravenous (IV) imalumab [28-d cycles; 2 dose schedules (DS)]: biweekly in all solid tumors (DS1); weekly in metastatic colorectal cancer (mCRC), metastatic ovarian cancer (OvCa) and metastatic non-small cell lung cancer (NSCLC) (DS2). Results: As of July 1 2015, 48 pts were treated in this study. DS1 = 19 pts in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and DS2 = 29 pts in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into mCRC, OvCa and NSCLC. AUC and Cmax increased with dose. Dose escalation was stopped at 50 mg/kg (DS1) and 25mg/kg (DS2). An MTD was not reached for either DS. One pt reported dose-limiting toxicities: hypersensitivity pneumonitis (DS1; 50 mg/kg). There were no other grade 3 and 4 treatment related adverse events (trAEs). Grade 2 trAEs include: fatigue (n = 2), constipation (n = 1), peripheral edema (n = 1), infusion reaction (n = 1), and urticaria (n = 1). Stable disease (SD) ?4 mo was seen in 7 heavily pre-treated pts, including 1 pt with NSCLC who achieved SD for 13.4 mo. In DS2; Pre- and on-therapy tumor biopsies showed satisfactory tissue penetration of imalumab resulting in target saturation in all biopsy evaluable patients in all 3 tumor types. Biopsies revealed regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on clinical PK and PD study, 10mg/kg weekly was considered a biologically active dose and sufficient to reach ?95% target binding by the end of first cycle. Conclusions: Imalumab was well tolerated and showed single agent antitumor activity in heavily pretreated pts. An MTD was not reached. Recommended phase II dose (RP2D) is 10 mg/kg IV weekly. NCT01765790 Citation Format: Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Niels Halama, Ramesh K. Ramanathan, John Sarantopoulos, Xiaochun Liu, Salim Yazji, Dirk Jaeger, Deyaa Adib, Randolf Kerschbaumer, Apostolia Maria Tsimberidou. First-in-human phase 1 study assessing imalumab (BAX69), an anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT046.