Data from A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies Article Swipe
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· 2023
· Open Access
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· DOI: https://doi.org/10.1158/1078-0432.c.6530310
· OA: W4361947190
<div>AbstractPurpose:<p>As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically “cold” cancers, which are intrinsically insensitive to immunotherapy, as well as in “hot/warm” metastatic cancers that are, atypical of such cancers, resistant to immunotherapy.</p>Patients and Methods:<p>In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400–640 mg/m<sup>2</sup>) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1–2, while the latter was administered on day 8 of cycles 1–4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression.</p>Results:<p>Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer (<i>n</i> = 11), pancreatic cancer (<i>n</i> = 7), immunotherapy-resistant melanoma (<i>n</i> = 2), and human papillomavirus–negative head and neck cancer (<i>n</i> = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m<sup>2</sup> evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia.</p>Conclusions:<p>No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.</p></div>
