Clinical Trials /

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

NCT04243785

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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 Capsules in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: BTX-A51-001
  • NCT ID: NCT04243785

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
BTX-A51Continued Treatment Phase

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Phase 1a (Dose Escalation Phase)ExperimentalDosing 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.
  • BTX-A51
Phase 1b (Cohort Expansion Phase)ExperimentalDosing 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.
  • BTX-A51
Continued Treatment PhaseExperimentalParticipants 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).
  • BTX-A51

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicities (DLTs)
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete remission (CR) for participants with acute myeloid leukemia (AML)
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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])
Measure:Morphologic leukemia-free state (MLFS) for participants with AML
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description: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.
Measure:Partial remission (PR) for participants with AML
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description: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
Measure: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)
Safety Issue:
Description: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)
Measure:Partial remission (PR) for participants with high-risk MDS
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description:PR is defined as all CR criteria with ≥ 50 percent decrease in BM blasts over pre-treatment (but still > 5 percent)
Measure:Hematologic improvement (HI) for participants with high-risk MDS
Time Frame:Up to a total of eight 28-day cycles (approximately 224 days)
Safety Issue:
Description: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)
Measure: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
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:Maximum observed plasma drug concentration after the first dose
Measure: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)
Safety Issue:
Description:Time to reach Cmax
Measure: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)
Safety Issue:
Description:Maximum observed plasma drug concentration after the dose on Day 5
Measure: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)
Safety Issue:
Description:Time to reach CmaxD5
Measure: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)
Safety Issue:
Description:Pre-dose concentrations in PK blood samples on dosing days
Measure: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)
Safety Issue:
Description:Area under the curve from time 0 to 24 hours after the first dose
Measure: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)
Safety Issue:
Description:AUC from time 0 to 24 hours after the dose on Day 5
Measure: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)
Safety Issue:
Description:Calculated by linear least-squares regression analysis from a semi-log plot of the plasma concentration versus time curve after the Day 5 dose
Measure: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)
Safety Issue:
Description:Estimated after the Day 5 dose, calculated as 0.693/Kel

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BioTheryX, Inc.

Last Updated

January 24, 2020