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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Orally administered capsules available in strengths of 0.5 mg, 1.0 mg, 2.0 mg and 7 mg.
Azacitidine will be administered IV or SC 75 mg/m2 QD on Days 1-7 of each 28-day cycle.
City of Hope National Medical Center
Duarte, California, United States
RECRUITINGMemorial Sloan-Kettering Cancer Center
New York, New York, United States
RECRUITINGThe University of Texas MD Anderson Cancer Center
Houston, Texas, United States
RECRUITINGIncidence of dose-limiting toxicities (DLTs)
A DLT is defined as a severe or clinically significant adverse event (AE) or abnormal laboratory value (Grade 3 or greater, unless otherwise specified) starting with the first dose on Cycle 1 Day 1, unless it is clearly related to disease progression, intercurrent illness, preexisting condition, or concomitant medications. DLTs are based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
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)
The severity/intensity of AEs will be graded based upon the participant's symptoms according to the NCI CTCAE Version 5.0
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Number of participants with laboratory abnormalities and/or AEs
Number of participants with potentially clinically significant laboratory values; toxicity will be graded and reported according to the NCI CTCAE Version 5.0
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
Number of participants with potentially clinically significant 12-lead ECG findings; toxicity will be graded and reported according to the NCI CTCAE Version 5.0
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Number of participants with echocardiogram (ECHO) abnormalities and/or AEs
Number of participants with potentially clinically significant ECHO abnormalities and/or AEs, such as elevated or abnormal left ventricular ejection fraction (LVEF) or abnormal Global Longitudinal Strain (GLS)
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Number of participants with vital sign abnormalities and/or AEs
Number of participants with potentially clinically significant vital sign values; toxicity will be graded and reported according to the NCI CTCAE Version 5.0
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Number of participants with physical examination abnormalities and/or AEs
Number of participants with potentially clinically significant physical examination findings; toxicity will be graded and reported according to the NCI CTCAE Version 5.0
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Maximum tolerated dose (MTD)
The DLTs are to be evaluated for determination of the MTD. The MTD will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. If there are ties, the higher dose level when the isotonic estimate is lower than the target toxicity rate will be identified and the lower dose level selected when the isotonic estimate is greater than or equal to the target toxicity rate.
Time frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1a
Recommended Phase 2 dose (RP2D)
The DLTs are to be evaluated based on cumulative safety/PK data in participants treated in Phase 1b for determination of the RP2D (which may or may not differ from the MTD)
Time frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1b
Complete remission (CR) for participants with acute myeloid leukemia (AML)
CR is defined as free of all symptoms related to leukemia and with an absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L (1000/µL), platelet count ≥ 100 × 10\^9/L (100,000/µL), and normal bone marrow (BM) with \< 5 percent blasts; absence of circulating blasts and blasts with Auer rods
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
CRi is defined as all CR criteria except for residual neutropenia (ANC \< 1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (platelet count \< 100 × 10\^9/L \[100,000/µL\])
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Morphologic leukemia-free state (MLFS) for participants with AML
MLFS is defined as BM blasts \< 5 percent; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required. Marrow should not barely be "aplastic;" at least 200 cells should be enumerated or cellularity should be at least 10 percent.
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Partial remission (PR) for participants with AML
PR is defined as all hematologic criteria of CR; decrease of BM blast percentage to 5 - 25 percent; and decrease of pretreatment BM blast percentage by at least 50 percent
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)
CR is defined as free of all symptoms related to leukemia and with an ANC ≥ 1.0 × 10\^9/L, platelet count ≥ 100 × 10\^9/L, BM ≤ 5 percent myeloblasts, with normal maturation of all cell lines, hemoglobin ≥ 11 g/dL, and no blasts in peripheral blood (PB)
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Partial remission (PR) for participants with high-risk MDS
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PR is defined as all CR criteria with ≥ 50 percent decrease in BM blasts over pre-treatment (but still \> 5 percent)
Time frame: Up to a total of eight 28-day cycles (approximately 224 days)
Hematologic improvement (HI) for participants with high-risk MDS
The International Working Group criteria for HI defining specific responses of cytopenias in the three hematopoietic lineages: erythroid (HI-E), platelet (HI-P), and neutrophil (HI-N)
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
Follow-up will occur by telephone contact once every 3 months for assessment of survival status and bone marrow transplant (BMT) conditioning or other new antineoplastic therapies since discontinuation of study drug; the cause of death will be documented. Disease assessment will be collected for participants who discontinue study medication due to any reason other than progression or death. If a participant has not progressed or died, progression-free survival is censored at the date of last follow up. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier.
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)
Maximum observed plasma drug concentration after the first dose
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 to reach 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: Plasma CmaxD5
Maximum observed plasma drug concentration after the dose on Day 5
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 to reach 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: C0
Pre-dose concentrations in PK blood samples on dosing days
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: AUC0-24
Area under the curve from time 0 to 24 hours after the first dose
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: AUC0-24D5
AUC from time 0 to 24 hours after the dose on Day 5
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: Terminal elimination rate constant (Kel)
Calculated by linear least-squares regression analysis from a semi-log plot of the plasma concentration versus time curve after the Day 5 dose
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: Terminal elimination phase half-life (t1/2)
Estimated after the Day 5 dose, calculated as 0.693/Kel
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)