A Study of H3B-8800 (RVT-2001) in Participants With Lower Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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A Phase 1, an Open-label, Multicenter Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 (RVT-2001) for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

Detailed Description
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This study 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 (RVT-2001) in subset of participants with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). The study consists of three parts, the dose escalation part (Part 1) exploring multiple once daily (QD) schedules and MDS Expansion part (Part 2) and Dose Optimization part (Part 3) exploring dosing schedules in lower-risk MDS.

Official Title
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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

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic

Intervention / Treatment
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* Drug: H3B-8800 (RVT-2001)


Participation Criteria
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Eligibility Criteria
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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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: H3B-8800 (RVT-2001) Dose Escalation<br>H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia. | Drug: H3B-8800 (RVT-2001)<br>* H3B-8800 (RVT-2001) orally at specified doses and schedules.<br>|
| Experimental: H3B-8800 (RVT-2001) MDS Expansion<br>Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1. | Drug: H3B-8800 (RVT-2001)<br>* H3B-8800 (RVT-2001) orally at specified doses and schedules.<br>|
| Experimental: H3B-8800 (RVT-2001) Dose Optimization<br>Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1, and who have not been exposed to HMA's or lenalidomide in a prior line of therapy. | Drug: H3B-8800 (RVT-2001)<br>* H3B-8800 (RVT-2001) orally at specified doses and schedules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-limiting Toxicities (DLTs) |  | Escalation Cycle 1 (28 days) | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | The type and frequency of AEs and SAEs using CTCAE v4.03, as well as changes in clinical laboratory values, ECG parameters, ophthalmologic examinations, and vital sign measurements. | From the first dose of study drug until 30 days after final dose of study drug (up to approximately 50 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t) | Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed | Up to Cycle 6 Day 15 (each cycle length=28 days) | 
| Maximum Observed Plasma Concentration (Cmax) | Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed | Up to Cycle 6 Day 15 (each cycle length=28 days) | 
| Time of Maximum Observed Plasma Concentration (Tmax) | Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed | Up to Cycle 6 Day 15 (each cycle length=28 days) | 
| Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence |  | Up to approximately 50 months | 
| Number of Participants with Hematologic Improvement |  | Up to approximately 50 months | 
| Objective Response Rate (ORR) | 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. | Up to approximately 50 months | 
| Duration of Response (DOR) | 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. | Up to approximately 50 months | 
| Time to Progression |  | Up to approximately 50 months | 
| Overall Survival (OS) | Overall Survival is defined as the time from first dose date to the date of death from any cause. | Up to approximately 50 months | 
| Mortality Rate at 3 and 6 Months |  | Months 3 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CMML, Myelodysplastic Syndromes, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, H3B-8800 (RVT-2001), Splicing Modulator, AML, MDS