A Study of BTX-A51 in People With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Official title

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

Overview

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).

Interventions

• Drug BTX-A51
  Orally administered capsules available in strengths of 0.5 mg, 1.0 mg, 2.0 mg and 7 mg.
• Drug Azacitidine
  Azacitidine will be administered IV or SC 75 mg/m2 QD on Days 1-7 of each 28-day cycle.

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with non-serious AEs and serious AEs (SAEs) [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with laboratory abnormalities and/or AEs [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/or AEs [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with echocardiogram (ECHO) abnormalities and/or AEs [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with vital sign abnormalities and/or AEs [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Number of participants with physical examination abnormalities and/or AEs [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Maximum tolerated dose (MTD) [Time frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1a]
• Recommended Phase 2 dose (RP2D) [Time frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1b]

Secondary outcome measures (12)

• Complete remission (CR) for participants with acute myeloid leukemia (AML) [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Complete remission with incomplete blood count recovery (CRi) for participants with AML [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Morphologic leukemia-free state (MLFS) for participants with AML [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Partial remission (PR) for participants with AML [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Complete remission (CR) for participants with high-risk myelodysplastic syndrome (MDS) [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Partial remission (PR) for participants with high-risk MDS [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Hematologic improvement (HI) for participants with high-risk MDS [Time frame: Up to a total of eight 28-day cycles (approximately 224 days)]
• Overall survival and event-free survival in participants with AML or high-risk MDS [Time frame: Up to 2 years after participant's last dose of BTX-A51 or upon death, whichever occurs first]
• PK parameter: Maximum observed plasma concentration (Cmax) [Time frame: During Cycle 1 for each dosing cohort in Phase 1a on Days 1, 3, and 5 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose); Days 2, 4, 6, 7, 8; and Day 15 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose)]
• PK parameter: Time of maximum plasma concentration (Tmax) [Time frame: During Cycle 1 for each dosing cohort in Phase 1a on Days 1, 3, and 5 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose); Days 2, 4, 6, 7, 8; and Day 15 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose)]
• PK parameter: Plasma CmaxD5 [Time frame: During Cycle 1 for each dosing cohort in Phase 1a on Days 1, 3, and 5 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose); Days 2, 4, 6, 7, 8; and Day 15 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose)]
• PK parameter: Plasma TmaxD5 [Time frame: During Cycle 1 for each dosing cohort in Phase 1a on Days 1, 3, and 5 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose); Days 2, 4, 6, 7, 8; and Day 15 (pre-dose and approximately 1, 2, 3, 5, 8, and 12 hours post-dose)]

Eligibility criteria

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

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

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• City of Hope National Medical Center — Duarte
• Memorial Sloan-Kettering Cancer Center — New York
• The University of Texas MD Anderson Cancer Center — Houston

Identifiers

NCT: NCT04243785 · BTX-A51-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗