A Study of H3B-8800 (RVT-2001) in Participants With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

Sponsor

Hemavant Sciences GmbH (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02841540

Collaborator

(none)

200

Enrollment

Locations

Arms

97.8

Anticipated Duration (Months)

7.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Leukemia, Myelomonocytic, Chronic	Drug: H3B-8800 (RVT-2001)	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Oct 6, 2016

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: H3B-8800 (RVT-2001) Dose Escalation H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.	Drug: H3B-8800 (RVT-2001) H3B-8800 (RVT-2001) orally at specified doses and schedules.
Experimental: H3B-8800 (RVT-2001) MDS Expansion 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) H3B-8800 (RVT-2001) orally at specified doses and schedules.
Experimental: H3B-8800 (RVT-2001) Dose Optimization 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) H3B-8800 (RVT-2001) orally at specified doses and schedules.

Arm

Intervention/Treatment

Experimental: H3B-8800 (RVT-2001) Dose Escalation

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

Drug: H3B-8800 (RVT-2001)

H3B-8800 (RVT-2001) orally at specified doses and schedules.

Experimental: H3B-8800 (RVT-2001) MDS Expansion

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)

H3B-8800 (RVT-2001) orally at specified doses and schedules.

Experimental: H3B-8800 (RVT-2001) Dose Optimization

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)

H3B-8800 (RVT-2001) orally at specified doses and schedules.

Outcome Measures

Primary Outcome Measures

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) [From the first dose of study drug until 30 days after final dose of study drug (up to approximately 50 months)]
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.

Secondary Outcome Measures

Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t) [Up to Cycle 6 Day 15 (each cycle length=28 days)]
Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed
Maximum Observed Plasma Concentration (Cmax) [Up to Cycle 6 Day 15 (each cycle length=28 days)]
Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed
Time of Maximum Observed Plasma Concentration (Tmax) [Up to Cycle 6 Day 15 (each cycle length=28 days)]
Plasma samples for PK analyses will be collected at predetermined timepoint and analyzed
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) [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) [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.
Time to Progression [Up to approximately 50 months]
Overall Survival (OS) [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 [Months 3 and 6]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.
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).

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.
Participants with AML must either refuse or not be considered candidates for intensive induction chemotherapy using consensus criteria for defining such participants.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Center	Stanford	California	United States	94305
2	SCRI - Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
3	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
4	University of Miami	Miami	Florida	United States	33136
5	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
6	University of Chicago	Chicago	Illinois	United States	60637
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
9	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
10	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
11	Mayo Clinic	Rochester	Minnesota	United States	55905
12	Rosewell Park Cancer Center	Buffalo	New York	United States	14263
13	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
14	University of North Carolina Chapel Hill	Chapel Hill	North Carolina	United States	27514
15	Cleveland Clinic	Cleveland	Ohio	United States	21287
16	SCRI - Tennessee Oncology	Nashville	Tennessee	United States	37203
17	MD Anderson Cancer Center	Houston	Texas	United States	77030
18	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
19	Institut Gustave Roussy	Villejuif	Val-de-Marne	France	94805
20	Hôpital Saint Louis	Paris		France	75475
21	Eisai Trial Site 1	Hannover	Lower Saxony	Germany	30625
22	Eisai Trial Site 2	Dresden	Sachsen	Germany	01307
23	Eisai Trial Site 3	Leipzig	Sachsen	Germany	04103
24	Clinica Universidad Navarra	Pamplona	Navarra	Spain	31008
25	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
26	Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain	28040
27	Hospital Universitario HM Sanchinarro - CIOCC	Madrid		Spain	28050