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A Study of H3B-8800 in Participants With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

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ClinicalTrials.gov Identifier: NCT02841540
Recruitment Status : Recruiting
First Posted : July 22, 2016
Last Update Posted : March 16, 2021
Sponsor:
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Eisai Inc. ( H3 Biomedicine Inc. )

Tracking Information
First Submitted Date  ICMJE July 20, 2016
First Posted Date  ICMJE July 22, 2016
Last Update Posted Date March 16, 2021
Actual Study Start Date  ICMJE October 6, 2016
Estimated Primary Completion Date April 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2021)
  • Number of Participants with Dose-limiting Toxicities (DLTs) [ Time Frame: Escalation Cycle 1 (28 days) ]
  • Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From the first dose of study drug until 30 days after final dose of study drug (up to approximately 50 months) ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • Number of Dose-limiting Toxicities (DLTs) as a function of the dose of H3B-8800 for determination of the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) [ Time Frame: Cycle 1 (28 days) ]
  • Number of participants with treatment emergent adverse event (TEAE) and serious adverse event (SAE) [ Time Frame: Continuously throughout the study until 30 days after treatment discontinuation or up to approximately 32 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2021)
  • Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t) [ Time Frame: Part 1: Cycle 1 Days 1, 4,15: 0-24 hours post-dose; Part 2: Cycle 1 Days 1, 8: 0-24 hours post-dose, Cycle 1 Day 15: 0-4 hours post-dose, Cycle 2 Day 1, Cycle 3 Day 15 and Cycle 6 Day 15: 0.5 to 3 hours post dose (each cycle length=28 days) ]
  • Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Part 1: Cycle 1 Days 1, 4,15: 0-24 hours post-dose; Part 2: Cycle 1 Days 1, 8: 0-24 hours post-dose, Cycle 1 Day 15: 0-4 hours post-dose, Cycle 2 Day 1, Cycle 3 Day 15 and Cycle 6 Day 15: 0.5 to 3 hours post dose (each cycle length=28 days) ]
  • Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Part 1: Cycle 1 Days 1, 4,15: 0-24 hours post-dose; Part 2: Cycle 1 Days 1, 8: 0-24 hours post-dose, Cycle 1 Day 15: 0-4 hours post-dose, Cycle 2 Day 1, Cycle 3 Day 15 and Cycle 6 Day 15: 0.5 to 3 hours post dose (each cycle length=28 days) ]
  • Objective Response Rate (ORR) [ Time Frame: Up to approximately 50 months ]
    ORR will be defined as the percentage of participants achieving a best overall response of partial remission (PR) or complete remission (CR) (PR + CR), from first dose date until disease progression/recurrence. CR includes CR with incomplete blood count recovery (CRi) in AML participants and marrow CR in MDS participants and optimal marrow response in CMML participants. Response will be assessed by the Investigator and the independent central review based on 2006 International Working Group (IWG) response criteria for MDS, 2003 IWG criteria for AML, and the international consortium proposal of uniform response criteria for CMML published in 2015.
  • Duration of Response (DOR) [ Time Frame: Up to approximately 50 months ]
    DOR will be defined as the time from the date of first documented CR/PR until the first documentation of confirmed relapse, or death, whichever comes first.
  • Number of Participants with Hematologic Improvement [ Time Frame: Up to approximately 50 months ]
  • Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence [ Time Frame: Up to approximately 50 months ]
  • Part 2: The Number of Participants who Achieve Red Blood Cells (RBC) Transfusion Independence by Week 24 [ Time Frame: Up to Week 24 ]
  • Time to Progression [ Time Frame: Up to approximately 50 months ]
  • Overall Survival (OS) [ Time Frame: Up to approximately 50 months ]
    Overall Survival is defined as the time from first dose date to the date of death from any cause.
  • Mortality Rate at 3 and 6 Months [ Time Frame: Months 3 and 6 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • Mean area under the plasma concentration-time curve from time 0 through the last measurable point (AUC0-t) [ Time Frame: Days 1 and 4 of Cycle 1 at pre-dose (0 hours [h]); 0.5, 1, 2, 4, 6, 8, 10, and 24 h post-dose (Days 2 and 5); and pre-dose and 4 h post-dose on Day 15 of Cycle 1 ]
  • Mean area under the concentration-time curve from time 0 through the 24 h time point (AUC0-24) [ Time Frame: Days 1 and 4 of Cycle 1 at pre-dose (0 h); 0.5, 1, 2, 4, 6, 8, 10, and 24 h post-dose (Days 2 and 5); and pre-dose and 4 h post-dose on Day 15 of Cycle 1 ]
  • Mean maximum observed plasma concentration (Cmax) [ Time Frame: Days 1 and 4 of Cycle 1 at pre-dose (0 h); 0.5, 1, 2, 4, 6, 8, 10, and 24 h post-dose (Days 2 and 5); and pre-dose and 4 h post-dose on Day 15 of Cycle 1 ]
  • Mean time of maximum observed plasma concentration (tmax) [ Time Frame: Days 1 and 4 of Cycle 1 at pre-dose (0 h); 0.5, 1, 2, 4, 6, 8, 10, and 24 h post-dose (Days 2 and 5); and pre-dose and 4 h post-dose on Day 15 of Cycle 1 ]
  • Objective Response Rate (ORR) [ Time Frame: Up to approximately 32 months ]
  • Duration of Response (DOR) [ Time Frame: Up to approximately 32 months ]
  • Number of Participants with Hematologic Improvement [ Time Frame: Up to approximately 32 months ]
  • Percentage of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence [ Time Frame: Up to approximately 32 months ]
  • Time to Progression [ Time Frame: Up to approximately 32 months ]
  • Overall Survival (OS) [ Time Frame: Up to approximately 32 months ]
  • Mortality Rate at 3 and 6 Months [ Time Frame: Months 3 and 6 ]
  • Post-treatment changes from Baseline in splicing and allele burden in blood and tumor tissue as a measure of pharmacodynamics [ Time Frame: Baseline; up to approximately 32 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of H3B-8800 in Participants With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia
Official Title  ICMJE An Open-label, Multicenter Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia
Brief Summary This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of H3B-8800 in subset of participants with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). The study consists of two parts, a dose escalation part (Part 1) exploring a multiple once daily (QD) schedules and an expansion part (Part 2) exploring a twice daily (BID) schedule.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia, Myeloid, Acute
  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
Intervention  ICMJE Drug: H3B-8800
H3B-8800 orally, QD or BID at specified doses.
Study Arms  ICMJE Experimental: H3B-8800 (Dose Escalation and Expansion)
H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.
Intervention: Drug: H3B-8800
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 1, 2018)
200
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2016)
110
Estimated Study Completion Date  ICMJE April 1, 2022
Estimated Primary Completion Date April 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Confirmed diagnosis of MDS, CMML, or AML. For the MDS expansion cohort, participants must be lower-risk MDS, defined as low or intermediate-1 risk categorization per International Prognostic Scoring System (IPSS) criteria that carries a missense SF3B1 mutation at a variant allele frequency of 5 percent (%) or higher.
  2. The participant must meet the following criteria relevant to their specific diagnosis:

    A. Participants with higher-risk MDS/CMML must be intolerant of hypomethylating agents (HMAs) or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of an HMA.

    B. For dose escalation portion, participants with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets (as determined by instructional practices or local standard of care). For enrollment MDS expansion cohort, lower risk MDS participants must be RBC transfusion dependent according to IWG 2006 criteria (having received at least 4 units (U) of RBCs within 8 weeks for hemoglobin (Hb) of less than (<) 9 gram per deciliter (g/dL) prior to first dose of H3B-8800). Participants who are RBC transfusion-dependent must also have failed erythropoiesis stimulating agents (ESA) (primary resistance or relapse after a response) or have serum erythropoietin (EPO) levels greater than (>) 500 units per liter (U/L).

    C. Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such participants. Previously treated participants should have evidence of persistent or recurrent AML in the peripheral blood and/or bone marrow that is refractory to, or has relapsed from, their most recent prior line of treatment. For AML, participants must have white blood cells (WBC) < 15*10^9/liter (L).

    D. Participants with CMML must have been treated with at least one prior therapy (hydroxyurea or a hypomethylating agent [HMA]).

  3. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
  4. For expansion cohort- absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).
  5. For expansion cohort- platelet count >50,000/mcL (50*10^9/L).
  6. Adequate baseline organ function.

Exclusion Criteria:

  1. Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)).
  2. Participant is deemed candidate for hematopoietic stem cell transplants at the time of enrollment (for AML participants only).
  3. Family history of Leber Hereditary Optic Neuropathy, Autosomal Dominant Optic Atrophy, Late-Onset Retinal Degeneration, Familial Dysautonomia or other hereditary mitochondrial disease, unless the causative mutation(s) in the family have been determined and the participant has tested negative for the mutation(s).
  4. Known prior or current retinal or optic nerve disease (example, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) based on screening ophthalmology assessment for eligibility.
  5. Corrected vision is worse than 20/40 unless due to cataracts.
  6. Vitamin B12, folate or vitamin A deficiency. Rescreening following repletion therapy is acceptable.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Eisai Medical Information 1-888-274-2378 esi_oncmedinfo@eisai.com
Listed Location Countries  ICMJE France,   Germany,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02841540
Other Study ID Numbers  ICMJE H3B-8800-G000-101
2016-001792-70 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eisai Inc. ( H3 Biomedicine Inc. )
Study Sponsor  ICMJE H3 Biomedicine Inc.
Collaborators  ICMJE Eisai Inc.
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP