A First-In-Human, Open-Label, Escalating Multiple-Dose Study to Evaluate the Safety, Toxicity, and Pharmacokinetics of BTX-A51 Capsules Alone and in Combination With Azacitidine in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome BTX-A51

What's the purpose of this trial?

This is an open-label, dose escalation study to evaluate the safety, toxicity, and pharmacokinetics (PK) as well as preliminary efficacy of BTX-A51 capsules in participants with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).

The study will be done in three parts. Part 1a (Monotherapy Dose Escalation) of this study is designed to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally administered BTX-A51 in up to 35 participants who are evaluable for toxicity. Once the MTD is determined, it is planned that an additional 15 participants will be enrolled in Part 1b (Monotherapy Cohort Expansion) of this study for additional experience with safety and efficacy, and to determine the recommended Phase 2 dose (RP2D) which may or may not be different from the MTD. After determination of MTD and RP2D from Part 1a, Part 1c (Azacitidine Combination Dose Escalation) will enroll up to 30 participants.

Continued treatment will be available under this study protocol for up to eight 28-day cycles (Continued Treatment Phase) if the Investigator judges the benefit outweighs the risk.

Once BTX-A51 treatment has completed, participants will be contacted by telephone every 3 months for up to 2 years after their last treatment for survival status and anticancer therapy (Overall Survival Follow-up).

This trial is currently open and accepting patients.

What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

Inclusion Criteria:

* Demonstration of understanding and voluntarily signing of an informed consent form
* Age ≥ 18 years
* Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) according to the World Health Organization classification and, with respect to MDS, that is high risk; participants must have refractory or relapsed disease and be ineligible for or have exhausted standard therapeutic options that would otherwise be likely to provide clinical benefit
* Eastern Cooperative Oncology Group performance status ≤ 2 and life expectancy of ≥ 6 weeks
* Adequate organ function (Grade 1 serum creatinine; Grade 1 total bilirubin; aspartate aminotransferase and/or alanine transaminase ≤ 2 × ULN)
* Females of childbearing age must not be pregnant at time of Screening/beginning of treatment and agree to either abstain from sexual intercourse or use highly effective methods of contraception (for up to 3 months after last dose of study drug)
* Males sexually active with a woman of childbearing age must agree to use barrier method of birth control during and after the study (up to 3 months after last dose of study drug)

Exclusion Criteria:

* Diagnosis of acute promyelocytic leukemia
* White blood cell count \> 20 x 10\^9/L
* Receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug
* In participants who have undergone autologous or allogeneic stem cell transplantation: transplantation within the 3 months prior to Screening; active graft-versus-host disease requiring anything other than topical corticosteroids and budesonide; treatment with systemic immunosuppressive medications including high-dose steroids (≥ 20 mg prednisolone or equivalent per day), or calcineurin inhibitors (e.g., cyclosporine, tacrolimus) for at least 1 week prior to Screening, and sirolimus, mycophenylate mofetil, azathioprine, or ruxolitinib for at least 2 weeks prior to Screening
* Immediate life-threatening severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
* Persistent toxicities from prior treatment of Grade 2 or higher
* Active uncontrolled systemic fungal, bacterial, mycobacterial, or viral infection
* Clinically significant cardiac disease
* Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
* Any other concurrent medical condition or disease that is likely to interfere with study procedures or results, or that, in the opinion of the Investigator, would constitute a hazard for participating in this study
* If female, pregnant or breastfeeding

Additional Trial Information

Phase 1

Enrollment: 80 patients (estimated)

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Published Results

Safety and efficacy of casein kinase 1α and cyclin dependent kinase 7/9 inhibition in patients with relapsed or refractory AML: A first-in-human study of BTX-A51

June 02, 2022

As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42 mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were hypokalemia, nausea, vomiting, diarrhea, and hypotension. The most common Grade 3 or higher TEAEs were anemia, febrile neutropenia, platelet count decreased, and hypokalemia. DLTs included grade 3 hepatic failure at the 42 mg dose in 1 pt and grade 3 alkaline phosphatase elevation in 1 pt at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction > 50% occurred in 4 patients including the 3 responders, all at the 11 and 21 mg dose levels. All 4 pts with > 50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Conclusions: In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction.

Trial Locations

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City of Hope Comprehensive Cancer Center Beckman Research Institute

Duarte, CA

Open and Accepting

New York

Memorial Sloan Kettering Cancer Center

New York, NY

Open and Accepting


MD Anderson Cancer Center The University of Texas

Houston, TX

Open and Accepting
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