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

Myelodysplastic Syndromes Clinical Trial

— Encore-MDS  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02841540
• Other study ID #: H3B-8800-G000-101
• Secondary ID: 2016-001792-70
• Status: Terminated
• Phase: Phase 1
• Start date: October 6, 2016
• Est. completion date: February 13, 2024

Study information

• Verified date: February 2024
• Source: Hemavant Sciences GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 127
• Est. completion date: February 13, 2024
• Est. primary completion date: February 13, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Belgium	Algemeen Ziekenhuis Klina	Brasschaat
Belgium	AZ Sint-Jan Brugge Oostende AV	Brugge
Belgium	Universiteit Gent	Gent
Belgium	University Hospitals Leuven	Leuven
France	CHU Amiens-Picardie	Amiens
France	Centre Hospitalier Universitaire d'Angers (CHU d'Angers)	Angers
France	Centre Hospitalier Universitaire (CHU) de Bordeaux	Bordeaux
France	Centre Hospitalier - Le Mans	Le Mans
France	Hôpital Claude Huriez	Lille
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Institut Gustave Roussy	Villejuif	Val-de-Marne
Italy	Azienda Ospedaliera Universitaria di Bologna - Policlinico S. Orsola Malpighi	Bologna
Italy	Fondazione IRCCS Cà Granda Ospedale Policlinico Maggiore	Milano
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	IRCCS Istituto Clinico Humanitas Cancer Center	Rozzano
Korea, Republic of	Daegu Catholic University Medical Center	Daegu
Korea, Republic of	National Cancer Center	Gyeonggi-do	Goyang-si
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Hanyang University Seoul Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Spain	Hospital Universitario Valle de Hebrón	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Clinica Universidad de Navarra	Pamplona	Navarra
Spain	Complejo Asistencial Universitario de Salamanca	Salamanca
Spain	Hospital Universitario y Politécnico La Fe de Valencia	Valencia
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Chang-Gung Memorial Hospital, Chiayi	Chiayi City
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
United States	Rocky Mountain Cancer Center	Aurora	Colorado
United States	Texas Oncology	Austin	Texas
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	Oncology Associates of Oregon	Eugene	Oregon
United States	Virginia Cancer Specialist	Fairfax	Virginia
United States	MD Anderson Cancer Center	Houston	Texas
United States	City of Hope	Irvine	California
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of Miami	Miami	Florida
United States	Mayo Clinic	Rochester	Minnesota
United States	Arizona Oncology Associates	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Hemavant Sciences GmbH

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Korea, Republic of,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Dose-limiting Toxicities (DLTs)		Escalation Cycle 1 (28 days)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence		Up to approximately 50 months
Secondary	Number of Participants with Hematologic Improvement		Up to approximately 50 months
Secondary	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
Secondary	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
Secondary	Time to Progression		Up to approximately 50 months
Secondary	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
Secondary	Mortality Rate at 3 and 6 Months		Months 3 and 6