American Association for Cancer Research
10780432ccr210903-sup-262145_2_supp_7150337_qtsk04.pdf (1.96 MB)

Trial Protocol from A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1

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journal contribution
posted on 2023-03-31, 22:42 authored by Sarah A. Weiss, Dijana Djureinovic, Shlomit Jessel, Irina Krykbaeva, Lin Zhang, Lucia Jilaveanu, Amanda Ralabate, Barbara Johnson, Neta Shanwetter Levit, Gail Anderson, Daniel Zelterman, Wei Wei, Amit Mahajan, Ovid Trifan, Marcus Bosenberg, Susan M. Kaech, Curtis J. Perry, William Damsky, Scott Gettinger, Mario Sznol, Michael Hurwitz, Harriet M. Kluger

Trial Protocol


Yale Cancer Center, Bristol Myers Squibb

Bristol Myers Squibb

Yale Calabresi Immuno-oncology Training Program



Wenner-Gren Foundations



PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23–443). Median cycles were 4.5 (range, 2–21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. This first in-human study of patients with anti-PD-1/PD-L1–resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.