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

Hemavant Sciences

Status and phase: Terminated; Phase 1

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

Treatments: Drug: H3B-8800 (RVT-2001)

Study type: Interventional

Funder types: Industry

Identifiers

NCT02841540

2016-001792-70 (EudraCT Number)

H3B-8800-G000-101

Details and patient eligibility

About

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

Full description

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.

Enrollment: 127 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

   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.

2. 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]).

3. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.

4. For MDS expansion and Dose optimization cohorts - absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).

5. For expansion and Dose optimization cohorts- platelet count >50,000/mcL (50*10^9/L).

6. For Dose-optimization cohort: No prior HMA or lenalidomide in participants with lower-risk MDS.

7. Adequate baseline organ function.

Exclusion criteria

1. Diagnosis of a core binding factor leukemia (t(8;21), t(16;16) or inv(16)). Diagnosis of acute promyelocytic leukemia (t(15;17))
2. Participants are deemed candidate for hematopoietic stem cell transplants at the time of enrollment (for AML participants only).
3. Known prior or current retinal or optic nerve disease (example, Retinitis Pigmentosa, diabetic retinopathy, optic neuritis) not stable for at least 6 months.
4. History of clinically significant, uncorrected vitamin B12 or folate deficiency.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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127 participants in 3 patient groups

H3B-8800 (RVT-2001) Dose Escalation

Experimental group

Description:

H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.

Treatment:

Drug: H3B-8800 (RVT-2001)

H3B-8800 (RVT-2001) MDS Expansion

Experimental group

Description:

Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1.

Treatment:

Drug: H3B-8800 (RVT-2001)

H3B-8800 (RVT-2001) Dose Optimization

Experimental group

Description:

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.

Treatment:

Drug: H3B-8800 (RVT-2001)