First-in-Human Study of Elvn-001, a Highly Selective BCR::ABL1 Tyrosine Kinase Inhibitor, in Patients with Chronic Myeloid Leukemia Who Failed Previous Tyrosine Kinase Inhibitor Therapies

Background: Despite the benefits BCR::ABL1 tyrosine kinase inhibitors (TKIs) have provided altering the natural history of chronic myeloid leukemia (CML), resistance/lack of response and intolerability occurs. ELVN-001 is a highly selective small molecule active site inhibitor of ABL1 that does not significantly inhibit the receptor tyrosine kinases PDGFR, KIT, VEGFR2 or the Src-family (eg SRC, LCK, LYN, FYN). In vitro data also supports ELVN-001 targeting the most common CML mutation, T315I and not being a substrate for drug efflux transporters such as BCRP, which may contribute to resistance or sensitivity to other TKIs.

Non-clinical data suggests ELVN-001 has a favorable absorption, distribution, metabolism, elimination and a pharmacokinetic (PK) profile supporting once daily (QD) dosing, low risk of QTc prolongation, and potential to avoid drug-drug interactions, particularly CYP-mediated. This first-in-human (FIH) study will evaluate the safety, tolerability, PK and preliminary anti-CML activity of ELVN-001 in patients (pts) with chronic (CP) or accelerated phase CML with and without T315I mutations.

Objectives: The primary objectives are to determine the recommended doses for expansion (RDE) and to evaluate the safety and tolerability of ELVN-001. Secondary objectives are to assess the PK profile and preliminary efficacy.

Design: A phase 1 open-label, multi-center, dose escalation and expansion study. Eligible pts are adults with CP and AP CML who are intolerant or have failed (as per ELN 2020 Recommendations) available TKIs known to be active for treatment of their CML. Other key eligibility criteria are Eastern Cooperative Oncology Group performance status 0–2, adequate bone marrow, renal and liver function, and resolved adverse effects of prior therapy. Prior marrow transplant is allowed. CML with point mutations E255, Y253, G250, F317 or Q252 are excluded.

Successive cohorts will receive escalating doses of ELVN-001 starting at 10 mg QD. Dosing will be continuous in 28-day cycles until treatment failure, disease progression or unacceptable toxicity.

A standard 3+3 dose escalation will be used, with PK/pharmacodynamic modeling to identify the RDEs, assuming toxicity is not dose limiting. Safety and efficacy of ELVN-001 will be further explored in CP-CML without T315I mutations and a cohort of T315I mutated CP-CML. Mutational analyses by Sanger and NGS will be conducted at baseline and end of treatment.

Main Outcomes: Primary endpoints are dose limiting toxicities, adverse events, laboratory and ECG abnormalities. Secondary endpoints are PK parameters, response based on BCR-ABL transcript levels by quantitative PCR and hematology.

Conclusions: This FIH study will evaluate dosing, safety, tolerability, PK profile and preliminary efficacy of ELVN-001 in CP-CML with and without T315I mutation.

Study sponsor: Enliven Therapeutics. NCT05304377

ELVN-001-101 Schema: