Clinical Trial 23254

• Overview

  Study 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)

  Summary:

  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, in adult subjects with R/R AML or HR-MDS.

  Objective:

  Primary Objectives: Dose Escalation: To evaluate the safety and tolerability of BH-30236 in adult subjects with R/R AML or HR-MDS and to determine the maximum tolerated dose (MTD). To identify the recommended doses for expansion (RDEs). Dose Expansion: To evaluate the safety, tolerability, and preliminary anti-leukemic activity of BH-30236 at selected RDEs to determine the recommended Phase 2 dose (RP2D). Secondary Objectives: To characterize the pharmacokinetic (PK) properties of BH-30236. To characterize the preliminary anti-leukemic activity of BH-30236 in terms of objective response rate (ORR), CR/CRh rate for AML and CR/PR rate in HR-MDS.

• Treatments

  Therapies:

  BCL-2 inhibitor; Hypomethylating agent (HMA); Inhibitor of CDC-like kinase 1/2/4 (CLK1/2/4); Therapy (NOS)

  Medications:

  Azacitidine (); BH-30236 (); GDC-0199 (Venetoclax); Venetoclax ()

• Inclusion Criteria

  Inclusion Criteria:
  • 18 years of age or older.
  • Diagnosis of relapsed/refractory acute myelogenous leukemia (R/R) AML or higher-risk myelodysplastic syndrome (HR-MDS) with 5% or greater bone marrow blast at time of inclusion.
  • Prior treatment history must include 1-5 prior lines of therapy.
  • ECOG performance status 2 or less.
  • Adequate organ function as outlined in protocol
  • Has a life expectancy of >/= 3 months.
  • Ability to swallow oral medications.
  • Amenable to serial bone marrow biopsies/aspirates and peripheral blood sampling during the study. The disease and clinical activity assessment of R/R AML or R/R HR-MDS can be made by bone marrow aspiration when a core biopsy is unobtainable and/or is not a part of the SOC. A bone marrow biopsy is required in case of dry tap or failure (mainly dilution) with the aspiration. For R/R MF, if a core biopsy for histopathologic and/or fibrosis-based assessment cannot be obtained, aspirate-based assessments may still be performed, but biopsy-dependent disease assessment components may be considered not evaluable.
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the start of study treatment and must not intending to become pregnant during study participation. Participants with reproductive potential are defined as one who is biologically capable of becoming pregnant unless they have undergone permanent sterilization or have premature menopause. WOCBP as well as fertile men and their partners, must agree to abstain from sexual intercourse or use an effective form of contraception during the study and for 90 days (females and males) following the last dose of study drug. Participants must also agree not to donate eggs or sperm until at least 90 days after the last dose of study drug. Highly effective contraceptive methods are described in Appendix 1.
  • Agrees not to participate in another interventional study while on treatment.
  • Other criteria apply

• Exclusion Criteria

  Exclusion Criteria:
  • Diagnosis of acute promyelocytic leukemia or chronic myeloid leukemia with blast crisis.
  • History of any concurrent malignancy within the previous 2 years with exception of adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other localized malignancies at low risk of recurrence treated with curative intent (may be allowed in discussion with the Sponsor’s Medical Monitor), or other adequately treated cancers in complete remission for ≥ 2 years at Screening
  • Clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS disease development.
  • For AML and HR-MDS: WBC counts ≥ 25 × 109/L prior to study drug administration. For AML and HR-MDS, hydroxyurea and/or leukapheresis are permitted prior to study drug administration to meet this criterion.
  • Any active bleeding diathesis, clinically significant coagulopathy such as disseminated intravascular coagulation, or history of major bleed within 3 months of protocol specified therapy. For MF, no thrombotic events within 3 months of protocol specified therapy.
  • Allogeneic hematopoietic stem cell transplantation (HSCT) within 3 months prior to the start of protocol specified therapy or donor lymphocyte infusion within 30 days of protocol specified therapy
  • 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.
  • Any clinically significant cardiovascular event within 6 months prior to study entry
  • Failure to recover from effects of prior anti-cancer therapy to baseline or Grade 1 severity (except for alopecia) per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
  • Active and uncontrolled infections.
  • Has known human immunodeficiency virus or active hepatitis B or C infection.
  • 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.
  • Other exclusions apply

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