A Study of BH-30236 in Relapsed/ Refractory Acute Myelogenous Leukemia and Higher Risk Myelodysplastic Syndrome

Official title

A Phase 1/1b Open-Label, Dose Escalation, First-in- Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-leukemic Activity of the Orally Available CDC-Like Kinase (CLK) Inhibitor, BH-30236, in Adults With Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML) or Higher-Risk Myelodysplastic Syndrome (HR-MDS)

Overview

Study BH-30236-01 is a first-in-human (FIH), Phase 1/1b, open-label, dose escalation and expansion study in participants with relapsed/refractory acute myelogenous leukemia (R/R AML) or higher-risk myelodysplastic syndrome (HR-MDS). Phase 1, Part 1 Dose Escalation - Monotherapy will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BH-30236 administered orally. Approximately 50 participants may be enrolled in Phase 1, Part 1 Dose Escalation - Monotherapy. Phase 1, Part 2 Dose Escalation - Combination with Venetoclax will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BH-30236 administered as a combination therapy with venetoclax. Approximately 48 participants may be enrolled in Phase 1, Part 2 Dose Escalation - Combination with Venetoclax. Phase 1b (Dose Expansion) will follow Phase 1 to further understand the relationships among dose, exposure, toxicity, tolerability, and clinical activity. Up to 72 participants may be enrolled in Phase 1b of the study as a monotherapy or in combination with venetoclax.

Detailed description

This is a Phase 1/1b, multi-center, open-label, dose escalation, first-in-human study to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of the CLK inhibitor, BH-30236 as a monotherapy or in combination with venetoclax, in adult participants with R/R AML or HR-MDS.

The study consists of three parts: Phase 1, Part 1 Dose Escalation - Monotherapy, Phase 1, Part 2 Dose Escalation - Combination with Venetoclax, and Phase 1b Dose Expansion.

Phase 1, Part 1 Dose Escalation - Monotherapy is anticipated to enroll approximately 50 participants to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of BH-30236, as well as determine the MTD and/or the preliminary recommended dose(s) for expansion (RDEs).

Phase 1, Part 2 Dose Escalation - Combination with Venetoclax is anticipated to enroll approximately 48 participants to evaluate the safety, tolerability, PK, PD, and preliminary anti-leukemic activity of BH-30236, as well as determine the MTD and/or the preliminary recommended dose(s) for expansion (RDEs).

Phase 1 will follow a Bayesian optimal interval (BOIN) design dose escalation, where participants will receive ascending doses of BH-30236 to determine the recommended RDEs.

Phase 1b Dose Expansion will enroll approximately 72 participants to evaluate the safety, tolerability, and preliminary anti-leukemic activity of BH-30236 as a monotherapy or in combination with venetoclax at selected RDEs determined in Phase 1 Dose Escalation.

Interventions

• Drug BH-30236
  BH-30236 will be provided as either a 5 mg, 15 mg or 30 mg tablet. Participants will take BH-30236 tablets orally depending on their dose level assignment.
• Drug Venetoclax
  Venetoclax will be provided as 10 mg, 50 mg or 100 mg tablets. Participants will take venetoclax orally per label instructions.

Primary outcome measures

• Dose Escalation: Frequency of dose limiting toxicities (DLTs) [Time frame: Dose-limiting toxicities are collected during the first treatment cycle (28 days)]
• Dose Escalation and Expansion: Safety evaluation of BH-30236: Number of participants with treatment-related adverse events as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [Time frame: From first dose until 28 days after last dose of BH-30236]
• Dose Expansion: Composite Complete Remission (CR) Rate [Time frame: From first dose of BH-30236 until disease progression (up to approximately 1 year)]

Secondary outcome measures (10)

• Dose Escalation and Expansion: Maximum observed blood concentration (Cmax) of BH-30236. [Time frame: Evaluation performed in Cycle 1 (cycle duration is 28 days).]
• Dose Escalation: Area under the blood concentration time curve (AUC) of BH-30236. [Time frame: Evaluation performed in Cycle 1 (cycle duration is 28 days).]
• Dose Escalation and Expansion: Concentration before dose at steady state (Ctrough). [Time frame: Evaluation performed in all treatment cycles up to one year (cycle duration is 28 days).]
• Dose Escalation and Expansion: Objective Response Rate (ORR) [Time frame: From first dose of BH-30236 until disease progression (up to approximately 1 year)]
• Dose Escalation and Expansion: Duration of Response (DoR) [Time frame: Time from first documented response until disease progression or death (approximately 1 year).]
• Dose Escalation and Expansion: Time to remission (TTR) [Time frame: From first dose of BH-30236 until complete remission, disease progression or death (approximately 1 year).]
• Dose Escalation and Expansion: Relapse-free Survival (RFS) [Time frame: From first dose of BH-30236 until disease progression, death, or initiation of a new anti-leukemic therapy (approximately 1 year).]
• Dose Escalation and Expansion: Measurable Residual Disease (MRD) [Time frame: From time of first dose until discontinuation of BH-30236 (approximately 1 year).]
• Dose Escalation and Expansion: Measurement of the change in RNA alternative splicing markers on BH-30236 treatment [Time frame: From time of first dose until discontinuation of BH-30236 (approximately 1 year).]
• Dose Escalation and Expansion: Complete remission (CR) / complete remission with partial hematologic recovery (CRh) rate for AML and complete remission/partial remission (CR/PR) rate for HR-MDS [Time frame: Time from first documented response until disease progression or death (approximately 1 year)]

Eligibility criteria

Inclusion criteria

• ≥18 years.
• Diagnosis of relapsed/refractory acute myelogenous leukemia (R/R) AML or higher-risk myelodysplastic syndrome (HR-MDS) with ≥5% bone marrow blast at time of inclusion.
• Prior treatment history must include 1-5 prior lines of therapy.
• ECOG performance status ≤2.
• Adequate organ function evidenced by the following laboratory values:
• Hepatic: Transaminase levels aspartate aminotransferase \[AST\]/ alanine transaminase \[ALT\] ≤ 2.5 × upper limit of normal (ULN). In cases of liver involvement by AML or MDS, AST and ALT < 5.0 × ULN is acceptable. Total bilirubin ≤ 1.5 × ULN in the absence of documented Gilbert's disease.
• Renal: Measured or calculated creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula)

The above are a summary, other inclusion criteria details may apply.

Exclusion criteria

• Diagnosis of acute promyelocytic leukemia or chronic myeloid leukemia with blast crisis.
• Prior allogeneic HSCT within 3 months or donor lymphocyte infusion within 30 days of start of therapy;
• Active and uncontrolled infections.
• Unresolved AEs greater than Grade from prior therapies.
• History of other active malignancy (with certain exceptions)
• Prior treatment with a CLK inhibitor.
• Any acute or chronic graft versus host disease requiring systemic therapy within 4 weeks prior to study drug administration with the exception of topical steroids or the equivalent of 20 mg of prednisone or less.

The above is a summary, other exclusion criteria details may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• City of Hope Medical Center — Duarte
• University of California Los Angeles — Los Angeles
• Stanford Cancer Center — Palo Alto
• Sylvester Comprehensive Cancer Center — Miami
• Moffitt Cancer Center — Tampa
• Northwestern Medicine - Northwestern Memorial Hospital Galter Pavilion — Chicago
• Roswell Park Cancer Institute — Buffalo
• Memorial Sloan Kettering Cancer Center — New York
• … and 5 more centers

Publications

• Maron MI, Abdel-Wahab O. Outstanding Questions to Understand and Target Splicing Factor-Mutant Blood Cancers. Blood Cancer Discov. 2026 May 5;7(3):348-352. doi: 10.1158/2643-3230.BCD-26-0047. PMID 42013378

Identifiers

NCT: NCT06501196 · BH-30236-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗