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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. )

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.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic Drug: H3B-8800 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 6, 2016
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : April 1, 2022


Arm Intervention/treatment
Experimental: H3B-8800 (Dose Escalation and Expansion)
H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.
Drug: H3B-8800
H3B-8800 orally, QD or BID at specified doses.




Primary Outcome Measures :
  1. Number of Participants with Dose-limiting Toxicities (DLTs) [ Time Frame: Escalation Cycle 1 (28 days) ]
  2. 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) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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.

  5. 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.

  6. Number of Participants with Hematologic Improvement [ Time Frame: Up to approximately 50 months ]
  7. Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence [ Time Frame: Up to approximately 50 months ]
  8. Part 2: The Number of Participants who Achieve Red Blood Cells (RBC) Transfusion Independence by Week 24 [ Time Frame: Up to Week 24 ]
  9. Time to Progression [ Time Frame: Up to approximately 50 months ]
  10. 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.

  11. Mortality Rate at 3 and 6 Months [ Time Frame: Months 3 and 6 ]


Information from the National Library of Medicine

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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:

  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.

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): NCT02841540


Contacts
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Contact: Eisai Medical Information 1-888-274-2378 esi_oncmedinfo@eisai.com

Locations
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Sponsors and Collaborators
H3 Biomedicine Inc.
Eisai Inc.
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Responsible Party: H3 Biomedicine Inc.
ClinicalTrials.gov Identifier: NCT02841540    
Other Study ID Numbers: H3B-8800-G000-101
2016-001792-70 ( EudraCT Number )
First Posted: July 22, 2016    Key Record Dates
Last Update Posted: March 16, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc. ( H3 Biomedicine Inc. ):
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
H3B-8800
Splicing Modulator
CMML
AML
MDS
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases