Abstract Background and significance: Venetoclax (VEN)-based lower-intensity therapies are the current standard for older/unfit patients (pts) with newly diagnosed acute myeloid leukemia (AML) and are being investigated in younger pts. However, 30-50% pts do not respond to such regimens, and among responders, more than 40% experience relapse, leading to 4-year overall survival (OS) of 15%. Outcomes after failure of frontline VEN-based regimens are dismal with CR rates of 5% and median OS of 2 to 3 months. Furthermore, pts with TP53 mutations or complex karyotypes (CK) are frequently resistant to VEN. Consequently, novel therapies are needed to abrogate emergence of resistance, for relapsed/refractory (R/R), and adverse risk AML. HC-7366 is a novel, oral, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of the integrated stress response (ISR). Physiologically, GCN2 is activated by amino acid deprivation, leading to phosphorylation of eIF2α and inhibition of bulk translation. Activation of ISR initially promotes survival in the face of nutrient scarcity, but prolonged or hyper-activation of ISR induces apoptosis in a p53 independent manner. Activation of GCN2 by HC-7366 is designed to exploit endogenous tumor cell stress signaling, triggering cell death. Importantly, leukemic stem cells have high basal levels of ISR signaling (van Galen et al Cell Rep, 2018) and may be markedly sensitive to GCN2 hyperactivation. Indeed, HC-7366 is efficacious as a monotherapy in minimally differentiated AML xenograft models. VEN-based therapies are limited by development of resistance via tumor suppressor and signaling mutations, suppression of proapoptotic proteins NOXA/PUMA, upregulation of MCL-1, or increased oxidative phosphorylation. Preclinical studies using xenograft models demonstrated efficacy for HC-7366 in combination with VEN/AZA in TP53 mutant AML models, as well as opposition to these multiple VEN resistance mechanisms as a single agent or in combination with azacitidine (AZA) and VEN. Based on promising preclinical data, HC-7366 recently received FDA Fast Track designation for treatment of R/R AML. Study Design and Methods: This is an open-label, investigator-initiated phase 1b study evaluating the safety and tolerability of HC-7366 as monotherapy and in combination with AZA and VEN, in patients with R/R AML or MDS/AML. Trial Design: The study includes two parallel treatment arms: HC-7366 monotherapy and HC-7366 in combination with AZA and VEN. Dose escalation follows a Bayesian Optimal Interval (BOIN) design. Monotherapy will enroll up to 31 patients across five dose levels (20, 30, 40, 50 and 60 mg). The triplet combination arm will enroll up to 24 patients at three dose levels (20, 40 and 60 mg) of HC-7366, with standard-dose AZA and VEN. A staggered escalation approach allows the triplet combination arm to proceed in parallel with monotherapy, pending safety review. Eligibility: Adults (≥18 years) with R/R AML or MDS/AML, ECOG PS 0-2, no available standard treatment options. Key exclusions are APL, poor end-organ function, immunosuppression, chronic GI condition (e.g., colitis, IBD), uncontrolled infections or CNS leukemia. Objectives: The primary objective is to assess safety and determine dose-limiting toxicities. Secondary objectives include overall response rate, complete responses (CR/CRh/CRi) within 4 cycles, minimal residual disease (MRD) negativity, overall and relapse-free survival. Exploratory endpoints include pharmacokinetic and pharmacodynamic analyses of HC-7366 as a monotherapy and in combination with AZA and VEN, duration of response, time to blood count recovery, time to first response and time to MRD negativity. Status: Trial is currently enrolling. Monotherapy dose escalation of 20, 30 and 40 mg, has been completed. Initiation of triplet dose escalation is planned for Q3 2025. (NCT06285890) Funding: MDACC NCI Cancer Center Support Grant, HiberCell, Inc.
Daver et al. (Mon,) studied this question.