Abstract CT172: A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors
Authors: Falchook Gerald , Patel Manish , McKean Meredith , Philipovskiy Alexander , Chiaverelli Rachel , Sun William , Fossler Michael , Novotny William , Kurman Michael , Rowe Sarah , Hunter Deborah , Milhem Mohammed 
Published: April 2023

Abstract
Introduction: PRT1419, a selective inhibitor of MCL-1, has demonstrated preclinical activity in solid tumors and hematologic malignancies. We report the results of a phase 1, open-label, multicenter, dose-escalation study of PRT1419 in pts with advanced/metastatic solid tumors (NCT04837677).
Methods: Adults with select advanced/metastatic solid tumors were enrolled. Key inclusion criteria were absolute neutrophil count &gt;1.0, platelets &gt;75, hemoglobin &gt;9, and left ventricular ejection fraction ≥50%. Key exclusion criteria were active central nervous system malignancy, significant cardiac disease, and concurrent strong CYP2C8 inhibitors. The study employed a 3+3 dose escalation design. PRT1419 was administered as a once-weekly (QW) infusion. Primary outcome measures were to evaluate dose-limiting toxicities (DLT) and establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary outcome measures included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity.
Results: Pts with melanoma (n=8), sarcoma (n=5), esophageal (n=4), cervical (n=3), head and neck (n=3), non-small cell lung, small cell lung, and triple-negative breast cancer (all n=1) were enrolled. Median age was 59.5 (range, 32-78) years, 61.5% pts were female, and median prior lines of systemic therapy was 3 (range, 1-8). Overall, 26 pts received ≥1 dose of PRT1419 (20 mg/m2 [n=4], 40 mg/m2 [n=4], 80 mg/m2 [n=15], and 120 mg/m2 [n=3]). Most pts (84.6%) discontinued treatment (primary reason: progressive disease, 72.7%). No DLTs, adverse events (AEs) of increased troponin or heart failure, or grade 5 (fatal) AEs were observed. Any grade treatment-related AEs (TRAE) occurred in 80.8% pts; the most common were nausea (50.0%), diarrhea (46.2%), and vomiting (46.2%). Grade 3/4 TRAEs occurred in 11.5% pts; the most common was neutropenia (11.5%), which was dose related. Due to neutropenia observed at doses &gt;80 mg/m2, further dose escalation was not investigated. BAX and caspase 3 activation in peripheral blood monocytes was observed at 80 mg/m2 and 120 mg/m2. Stable disease was the best response observed. Tumor shrinkage was seen in 1 pt with melanoma (10% reduction) and 1 pt with lung cancer (4% reduction) but did not meet the criteria for partial response. At Week 3, mean clearance was 12.6 L/hr and mean half-life was 2.5 hrs; no PRT1419 accumulation was seen with QW dosing.
Conclusions: PRT1419 demonstrated acceptable safety and tolerability in pts with advanced/metastatic solid tumors, with primary TRAEs of neutropenia, nausea, diarrhea, and vomiting. No cardiac toxicity was observed. BAX and caspase 3 activation was observed, suggesting potentially successful MCL-1 inhibition. Investigation of PRT1419 in pts with hematologic malignancy in a separate study is ongoing (NCT05107856).
Citation Format: Gerald Falchook, Manish Patel, Meredith McKean, Alexander Philipovskiy, Rachel Chiaverelli, William Sun, Michael Fossler, William Novotny, Michael Kurman, Sarah Rowe, Deborah Hunter, Mohammed Milhem. A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT172.