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

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

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

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic
• Intervention / Treatment: Drug: H3B-8800 (RVT-2001)

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 Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Hemavant Sciences Clinical Contact; Phone Number: (213) 549-2979; Email: hemavant@patientwing.com

Study Locations

• Belgium
  • Brasschaat, Belgium
    • Algemeen Ziekenhuis Klina
  • Brugge, Belgium
    • AZ Sint-Jan Brugge Oostende AV
  • Gent, Belgium
    • Universiteit Gent
  • Leuven, Belgium
    • University Hospitals Leuven
• France
  • Amiens, France
    • CHU Amiens-Picardie
  • Angers, France
    • Centre Hospitalier Universitaire d'Angers (CHU d'Angers)
  • Bordeaux, France
    • Centre Hospitalier Universitaire (CHU) de Bordeaux
  • Le Mans, France
    • Centre Hospitalier - Le Mans
  • Lille, France
    • Hopital Claude Huriez
  • Pierre-Bénite, France
    • Centre Hospitalier Lyon Sud
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94805
      • Institut Gustave Roussy
• Italy
  • Bologna, Italy
    • Azienda Ospedaliera Universitaria di Bologna - Policlinico S. Orsola Malpighi
  • Milano, Italy
    • Fondazione IRCCS Cà Granda Ospedale Policlinico Maggiore
  • Pavia, Italy
    • Fondazione IRCCS Policlinico San Matteo
  • Rozzano, Italy
    • IRCCS Istituto Clinico Humanitas Cancer Center
• Korea, Republic of
  • Daegu, Korea, Republic of
    • Daegu Catholic University Medical Center
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • The Catholic University of Korea Seoul St. Mary'S Hospital
  • Seoul, Korea, Republic of
    • Hanyang University Seoul Hospital
  • Goyang-si
    • Gyeonggi-do, Goyang-si, Korea, Republic of
      • National Cancer Center
• Spain
  • Barcelona, Spain
    • Hospital Universitario Valle de Hebrón
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
  • Salamanca, Spain
    • Complejo Asistencial Universitario de Salamanca
  • Valencia, Spain
    • Hospital Universitario y Politécnico La Fe de Valencia
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
• Taiwan
  • Changhua, Taiwan
    • Changhua Christian Hospital
  • Chiayi City, Taiwan
    • Chang-Gung Memorial Hospital, Chiayi
  • Taichung, Taiwan
    • China Medical University Hospital
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85711
      • Arizona Oncology Associates
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Irvine, California, United States, 96218
      • City of Hope
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oncology Associates of Oregon
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22301
      • Virginia Cancer Specialist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hemavant Sciences GmbH
• Investigators: Study Director: Keisuke Kuida, MD, PhD, Hemavant Sciences

Publications and helpful links

Helpful Links

• For more information and to see if you may qualify, click here.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2016
• Primary Completion (Actual): February 13, 2024
• Study Completion (Actual): February 13, 2024

Study Registration Dates

• First Submitted: July 20, 2016
• First Submitted That Met QC Criteria: July 20, 2016
• First Posted (Estimated): July 22, 2016

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; MDS; Myelodysplastic Syndromes; CMML; Chronic Myelomonocytic Leukemia; H3B-8800 (RVT-2001); Splicing Modulator
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic
• Other Study ID Numbers: H3B-8800-G000-101; 2016-001792-70 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No