Tsimberidou, Apostolia M.

Abstract Purpose: Intratumoral injection of Clostridium novyi-nontoxic (C. novyi-NT), lacking alpha-toxin, germinates and subsequently replicates in the tumor hypoxic regions, causing cell lysis and inflammation. This phase Ib study investigated the safety and synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors. Patients and Methods: Patients with injectable solid tumors received one intratumoral C. novyi-NT injection (day 8) across four dose cohorts (3 × 104 to 100 × 104 spores) with pembrolizumab (200 mg intravenously every 3 weeks, day 0–24 months). Sixteen patients were enrolled with a median age of 62.5 years, and the most common tumor types were breast cancer and melanoma. Results: The combination therapy demonstrated a manageable safety profile, with one grade 3 dose-limiting toxicity of abscess formation and the remainder of treatment-related adverse events in ≥10% of patients being grade 1 or 2 injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%), and anemia (13%). The maximum tolerated dose was determined to be pembrolizumab intravenously at 200 mg every 3 weeks and a single dose of 100 × 104C.novyi-NT spores intratumorally on day 8. The confirmed overall objective response rate of 25% was observed among four patients with nonkeratinizing undifferentiated nasopharyngeal squamous carcinoma, human papilloma virus–positive squamous cell carcinoma of the base of the tongue, vulvar melanoma, and chordoma. Among these patients, we obtained three partial responses and one complete response. The median duration of the response was 10.93 months, and stable disease was observed in 69% of patients. Conclusions: This study highlights the potential of the C. novyi-NT and pembrolizumab combination as a promising therapeutic strategy for treatment-refractory solid tumors.

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.

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.