Phase 1b safety run-in study followed by Phase 2 study of ficlatuzumab, azacitidine and venetoclax in untreated Acute Myeloid Leukemia patients aged ≥ 60 years old

Abstract

Abstract Background: Hepatocyte growth factor (HGF) is an autocrine produced cytokine that has been identified to be released by acute myeloid leukemia (AML) cells, promoting leukemia expansion and survival through multiple signaling pathways. Higher HGF levels in AML and activation of the MET signaling pathway has been associated with shortened overall survival but fortunately this pathway does not appear to be required for normal hematopoiesis, suggesting that it's an ideal target for inhibition. Ficlatuzumab is a first-in-class anti-hepatocyte growth factor (HGF) antibody that has been previously tested in numerous clinical trials. In a primary induction refractory AML population, ficlatuzumab in combination with high dose cytarabine had a complete response of 53% with minimal toxicities (NCT02109627). Notably, there is minimal or no evidence of ficlatuzumab-related myelosuppression making it an ideal candidate for combination with venetoclax (ven) and azacitidine (aza). Ven/aza has been a practice changing regimen for AML patients who are not candidates for intensive induction therapy. However, this treatment is still not curative and long-term outcomes are poor. We designed a phase 1b/2 study evaluating ficlatuzumab in combination with ven/aza in newly diagnosed older AML patients is as part of Blood Cancer United's Beat AML Master Trial. Study Design and Methods This is a US-based, multicenter, sub-study of the Beat AML Master Trial (NCT03013998) in which newly diagnosed AML patients age ≥ 60 years are assigned to an investigational therapy based on cytogenetic and central genomics. Patients eligible for this sub-study will not be candidates for intensive induction therapy and will have any genetics, ECOG status ≤ 2, and adequate organ function. The study is designed as a phase 1b safety lead-in followed by a phase 2 with two randomized dose levels. The primary objective of phase 1b is to determine the feasibility of giving ficlatuzumab in combination with ven/aza. The primary objective of phase 2 is to determine the complete remission (CR) rate and composite CR rate at the dose identified in phase 1b and a lower dose. Secondary objectives in both phases will evaluate safety, tolerability, survival, duration of remission, pharmacokinetics, and immunogenicity. A comparison of remission rates to a genetically matched control population receiving ven/aza alone will also be performed. The phase 1b portion of the study utilizes a Bayesian optimal interval design with a target toxicity rate of 25% to identify a safe dose of ficlatuzumab. The pre-specified sample size is 12 patients and will include two dose levels of ficlatuzumab (DL1: 20 mg/kg; DL-1: 15 mg/kg) in combination with ven (400 mg/day, dose adjusted based on antifungals) and aza (75 mg/kg). During induction cycles, ficlatuzumab is dosed 2 days per cycle (days 1 & 15), ven for 28 days, and aza for 7 days. Patients who achieve a marrow remission after up to two induction cycles proceed to continuation therapy cycles. Dose-limiting toxicities will be assessed during induction cycle 1. During continuation therapy cycles, ficlatuzumab will be administered 2 days per cycle (days 1 & 15), ven for 14 days, and aza for 7 days. There must be recovery of neutrophils ≥ 500/uL and platelets ≥ 50,000/uL to proceed to any continuation phase cycle. Patients may continue treatment for up to 24 cycles or until relapse. Upon completion of Phase 1b, a phase 2 study will be conducted utilizing a Simon's two-stage design. The null hypothesis that the CR rate is 35%, based on VIALE-A, will be tested against an alternative hypothesis of 55%. The first stage will require 6 of 14 patients achieving CR in order to proceed to the second stage. At the end of the second stage, the primary endpoint would be met if 21 of 44 total patients achieve CR. The phase 2 design will be applied separately to the two arms of the study evaluating the 2 doses of ficlatuzumab: (1) dose identified in phase 1b (15 or 20 mg/kg) and (2) a lower dose of 10 mg/kg. The phase 2 study will be conducted in the same manner as the phase 1b study. Exploratory objectives will assess pharmacodynamic markers of ficlatuzumab (HGF and others) and their correlation with response and toxicities. Potential additional studies will explore biomarkers of response and resistance to ficlatuzumab using multiomic platforms. The study will begin enrollment in fall 2025 at all Beat AML research sites.