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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04243785
Recruitment Status : Recruiting
First Posted : January 28, 2020
Last Update Posted : January 28, 2020
Sponsor:
Information provided by (Responsible Party):
BioTheryX, Inc.

Brief Summary:

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 two phases. Phase 1a 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 Phase 1b 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.

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).


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Drug: BTX-A51 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A First-In-Human, Open-Label, Escalating Multiple-Dose Study to Evaluate the Safety, Toxicity, and Pharmacokinetics of BTX-A51 Capsules in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
Actual Study Start Date : January 6, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2025


Arm Intervention/treatment
Experimental: Phase 1a (Dose Escalation Phase)
Dosing in this phase of the study consists of the first cycle of therapy (i.e., 28 days consisting of 3 weeks of treatment followed by 1 week with no study drug). The BTX-A51 starting dose for Cohort 1 is 1 mg, to be given 5 days per week (maximum weekly dose of 5 mg). Beginning with Cohort 2, doses are intended to be administered 3 days per week. Barring dose-limiting toxicity (DLT), sequential dose escalation of BTX-A51 is planned with up to a total of eight dose levels to a maximum of 20 mg (60 mg/week); on the basis of these an MTD will be identified. The numbers of participants and actual doses administered will be determined using a Bayesian optimal interval (BOIN) design to determine the DLTs and MTD of BTX-A51.
Drug: BTX-A51
Orally administered capsules available in strengths of 0.5 mg, 1.0 mg, and 2.0 mg.

Experimental: Phase 1b (Cohort Expansion Phase)
Dosing in this phase of the study consists of the first cycle of therapy (i.e., 28 days consisting of 3 weeks of treatment followed by 1 week with no study drug). Phase 1b will continue at the MTD or the highest dose achieved in Phase 1a.
Drug: BTX-A51
Orally administered capsules available in strengths of 0.5 mg, 1.0 mg, and 2.0 mg.

Experimental: Continued Treatment Phase
Participants who complete one cycle of BTX-A51 treatment in either Phase 1a or Phase 1b will be offered continued access to treatment for up to eight 28-day cycles if the Investigator determines that the benefit outweighs the risk. Dosing will continue at the assigned dose or may be increased (not to exceed a level already tolerated by at least one participant if Phase 1a is ongoing or the MTD/recommended Phase 2 dose if already established).
Drug: BTX-A51
Orally administered capsules available in strengths of 0.5 mg, 1.0 mg, and 2.0 mg.




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    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.

  2. 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) ]
    The severity/intensity of AEs will be graded based upon the participant's symptoms according to the NCI CTCAE Version 5.0

  3. 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 potentially clinically significant laboratory values; toxicity will be graded and reported according to the NCI CTCAE Version 5.0

  4. 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 potentially clinically significant 12-lead ECG findings; toxicity will be graded and reported according to the NCI CTCAE Version 5.0

  5. 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 potentially clinically significant ECHO abnormalities and/or AEs, such as elevated or abnormal left ventricular ejection fraction (LVEF) or abnormal Global Longitudinal Strain (GLS)

  6. 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 potentially clinically significant vital sign values; toxicity will be graded and reported according to the NCI CTCAE Version 5.0

  7. Number of participants with physical examination abnormalities and/or AEs [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    Number of participants with potentially clinically significant physical examination findings; toxicity will be graded and reported according to the NCI CTCAE Version 5.0

  8. Maximum tolerated dose (MTD) [ Time Frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1a ]
    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.

  9. Recommended Phase 2 dose (RP2D) [ Time Frame: Up to 28 days (one cycle) for each dosing cohort in Phase 1b ]
    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)


Secondary Outcome Measures :
  1. Complete remission (CR) for participants with acute myeloid leukemia (AML) [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    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

  2. 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) ]
    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])

  3. Morphologic leukemia-free state (MLFS) for participants with AML [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    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.

  4. Partial remission (PR) for participants with AML [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    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

  5. 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) ]
    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)

  6. Partial remission (PR) for participants with high-risk MDS [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    PR is defined as all CR criteria with ≥ 50 percent decrease in BM blasts over pre-treatment (but still > 5 percent)

  7. Hematologic improvement (HI) for participants with high-risk MDS [ Time Frame: Up to a total of eight 28-day cycles (approximately 224 days) ]
    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)

  8. 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 ]
    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.

  9. 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) ]
    Maximum observed plasma drug concentration after the first dose

  10. 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) ]
    Time to reach Cmax

  11. 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) ]
    Maximum observed plasma drug concentration after the dose on Day 5

  12. 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) ]
    Time to reach CmaxD5

  13. PK parameter: C0 [ 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) ]
    Pre-dose concentrations in PK blood samples on dosing days

  14. PK parameter: AUC0-24 [ 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) ]
    Area under the curve from time 0 to 24 hours after the first dose

  15. PK parameter: AUC0-24D5 [ 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) ]
    AUC from time 0 to 24 hours after the dose on Day 5

  16. PK parameter: Terminal elimination rate constant (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) ]
    Calculated by linear least-squares regression analysis from a semi-log plot of the plasma concentration versus time curve after the Day 5 dose

  17. PK parameter: Terminal elimination phase half-life (t1/2) [ 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) ]
    Estimated after the Day 5 dose, calculated as 0.693/Kel



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04243785


Locations
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United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Eytan Stein, MD    646-608-3749    SteinE@mskcc.org   
Sponsors and Collaborators
BioTheryX, Inc.

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Responsible Party: BioTheryX, Inc.
ClinicalTrials.gov Identifier: NCT04243785    
Other Study ID Numbers: BTX-A51-001
First Posted: January 28, 2020    Key Record Dates
Last Update Posted: January 28, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Botulinum Toxins, Type A
abobotulinumtoxinA
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents