Clinical Trials List
Protocol NumberH3B-8800-G000-101
NCT Number(ClinicalTrials.gov Identfier)NCT02841540
2022-11-01 - 2024-09-30
Phase I
Recruiting5
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
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Trial Applicant
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Sponsor
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Che-Hung Lin 無
- Ching-Chan Lin 無
- Chi-Ching Chen 無
- Ming-Yu Lien 無
- 鄭富銘 無
- Tzu-Ting Chen 無
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Leukemia, Myeloid, Acute
Objectives
Main Objectives
o To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral H3B-8800 in subjects with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML).
o To evaluate the safety and tolerability of H3B-8800 as a single agent administered orally once daily on a repeated dosing schedule of 5 days on/9 days off over a 28-day cycle in subjects with AML, MDS, and CMML.
o To evaluate the safety and tolerability of H3B-8800 as a single agent administered orally once daily on a 21-day on/7-day off dosing schedule in subjects with AML, MDS, and CMML.
o To evaluate the safety and tolerability of H3B-8800 as a single agent administered orally twice daily (BID) on a 28-day cycle with a continuous daily dosing schedule in subjects with lower-risk MDS and SF3B1 mutations.
o Dose optimization, safety, and tolerability of H3B-8800 administered orally as a single agent on a continuous daily dosing schedule in 28-day cycles in subjects with transfusion-dependent, lower-risk, MDS with SF3B1 mutations (very low to intermediate risk as calculated by IPSS-R) who have not received a hypomethylating agent (HMA) or lenalidomide in prior lines of therapy.
o Evaluate preliminary activity of H3B-8800 at an appropriate expansion dose and schedule in subjects with transfusion-dependent lower-risk MDS (defined as transfusion independence per IWG 2006 criteria) who harbor SF3B1 mutations.
Secondary Objectives
o Characterize the plasma pharmacokinetic (PK) properties of H3B-8800 in subjects with AML, MDS, and CMML
o Evaluate preliminary anti-tumor activity of H3B-8800 at an applicable RP2D and schedule in subjects with AML, MDS, and CMML with spliceosomal mutations of interest in SF3B1, SRSF2, U2AF1, and/or ZRSR2.
o Evaluate the preliminary activity of H3B-8800 using an applicable RP2D and schedule in subjects with transfusion-dependent lower-risk MDS (defined as transfusion independence per IWG 2006 criteria) who harbor SF3B1 mutations.
Exploratory goals
o Evaluate the pharmacodynamic (PD) effects of H3B-8800 in blood and bone marrow cells, including but not limited to effects on splicing and variant allele fraction (for mutation-positive AML, MDS, and CMML subjects).
o Evaluate candidate biomarkers that may predict response to H3B-8800, which may include but are not limited to pre-treatment splicing patterns and methylation patterns. This included assessment of basal expression of TMEM14C transcripts, distribution of the ratio of aberrant splicing junction (AJ) to canonical splicing junction (CJ) transcripts, and association with efficacy.
o Evaluate potential mechanisms of resistance to H3B-8800 therapy during treatment.
Test Drug
H3B-8800 (RVT-2001)
Active Ingredient
H3B-8800 (RVT-2001)
H3B-8800 (RVT-2001)
H3B-8800 (RVT-2001)
Dosage Form
Capsules
Dosage
1mg/Capsules
5mg/Capsules
5mg/Capsules
Endpoints
o The incidence of DLTs (with H3B-8800 dose as a parameter) was used to determine the MTD and RP2D.
o Safety/Tolerability: Type and frequency of adverse events (AEs) and serious adverse events (SAEs) defined using CTCAE version 4.03, and changes in clinical laboratory values, ECG parameters, ophthalmologic examinations, and vital sign measurements.
o Efficacy in the dose-optimized cohort: Number and percentage (%) of subjects who achieved RBC transfusion independence (RBC-TI ?56 days) by Week 24.
o Safety/Tolerability: Type and frequency of adverse events (AEs) and serious adverse events (SAEs) defined using CTCAE version 4.03, and changes in clinical laboratory values, ECG parameters, ophthalmologic examinations, and vital sign measurements.
o Efficacy in the dose-optimized cohort: Number and percentage (%) of subjects who achieved RBC transfusion independence (RBC-TI ?56 days) by Week 24.
Inclution Criteria
Inclusion Criteria:
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.
For the Dose Optimization cohort, participants must be transfusion-dependent, lower-risk MDS, defined as very-low to intermediate risk categorization per IPSS-R criteria that carries a missense SF3B1 mutation.
Participants 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 the Dose Escalation portion, participants with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets.
For the MDS expansion cohort, lower risk MDS participants must be RBC transfusion dependent according to IWG 2006 criteria and must also have failed erythropoiesis stimulating agents (ESA) or have serum erythropoietin (EPO) levels greater than (>) 500 units per liter (U/L).
C. For the Dose Optimization cohort, lower-risk MDS participants must be RBC transfusion-dependent at baseline defined as ≥3 RBC units (concentrates) in 16-weeks in at least 2 transfusion episodes prior to the first dose of H3B-8800 (RVT-2001) and must also have failed ESA or have serum EPO levels > 500 U/L. Any ESA use should be discontinued ≥6 weeks prior to enrollment.
D. Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such participants.
E. Participants with CMML must have been treated with at least one prior therapy (hydroxyurea or a hypomethylating agent [HMA]).
Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
For MDS expansion and Dose optimization cohorts - absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).
For expansion and Dose optimization cohorts- platelet count >50,000/mcL (50*10^9/L).
For Dose-optimization cohort: No prior HMA or lenalidomide in participants with lower-risk MDS.
Adequate baseline organ function.
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.
For the Dose Optimization cohort, participants must be transfusion-dependent, lower-risk MDS, defined as very-low to intermediate risk categorization per IPSS-R criteria that carries a missense SF3B1 mutation.
Participants 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 the Dose Escalation portion, participants with lower-risk MDS/CMML must be transfusion-dependent for red blood cells or platelets.
For the MDS expansion cohort, lower risk MDS participants must be RBC transfusion dependent according to IWG 2006 criteria and must also have failed erythropoiesis stimulating agents (ESA) or have serum erythropoietin (EPO) levels greater than (>) 500 units per liter (U/L).
C. For the Dose Optimization cohort, lower-risk MDS participants must be RBC transfusion-dependent at baseline defined as ≥3 RBC units (concentrates) in 16-weeks in at least 2 transfusion episodes prior to the first dose of H3B-8800 (RVT-2001) and must also have failed ESA or have serum EPO levels > 500 U/L. Any ESA use should be discontinued ≥6 weeks prior to enrollment.
D. Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such participants.
E. Participants with CMML must have been treated with at least one prior therapy (hydroxyurea or a hypomethylating agent [HMA]).
Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
For MDS expansion and Dose optimization cohorts - absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).
For expansion and Dose optimization cohorts- platelet count >50,000/mcL (50*10^9/L).
For Dose-optimization cohort: No prior HMA or lenalidomide in participants with lower-risk MDS.
Adequate baseline organ function.
Exclusion Criteria
Exclusion Criteria:
Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)). Diagnosis of acute promyelocytic leukemia (t(15;17))
Participants are deemed candidate for hematopoietic stem cell transplants at the time of enrollment (for AML participants only).
Known prior or current retinal or optic nerve disease (example, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) not stable for at least 6 months.
History of clinically significant, uncorrected vitamin B12 or folate deficiency.
Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)). Diagnosis of acute promyelocytic leukemia (t(15;17))
Participants are deemed candidate for hematopoietic stem cell transplants at the time of enrollment (for AML participants only).
Known prior or current retinal or optic nerve disease (example, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) not stable for at least 6 months.
History of clinically significant, uncorrected vitamin B12 or folate deficiency.
The Estimated Number of Participants
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Taiwan
10 participants
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Global
64 participants
