A Study of H3B-8800 (RVT-2001) in Participants With Lower Risk Myelodysplastic Syndromes
- Conditions
- Leukemia, Myelomonocytic, ChronicLeukemia, Myeloid, AcuteMyelodysplastic Syndromes
- Interventions
- Registration Number
- NCT02841540
- Lead Sponsor
- Hemavant Sciences GmbH
- 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
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 127
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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.
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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]).
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Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
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For MDS expansion and Dose optimization cohorts - absolute neutrophil count (ANC) greater than or equal to (>=) 500/ microliter (mcL) (0.5*10^9/L).
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For expansion and Dose optimization cohorts- platelet count >50,000/mcL (50*10^9/L).
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For Dose-optimization cohort: No prior HMA or lenalidomide in participants with lower-risk MDS.
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Adequate baseline organ function.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description H3B-8800 (RVT-2001) MDS Expansion H3B-8800 (RVT-2001) Transfusion-dependent, lower-risk MDS subjects (very-low to intermediate risk categorization per IPSS-R) with missense mutations in SF3B1. H3B-8800 (RVT-2001) Dose Optimization H3B-8800 (RVT-2001) 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. H3B-8800 (RVT-2001) Dose Escalation H3B-8800 (RVT-2001) H3B-8800 Acute Myeloid Leukemia or High Risk Myelodysplastic Syndromes/ Low Risk Myelodysplastic Syndromes/ Chronic Myelomonocytic Leukemia.
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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
Trial Locations
- Locations (48)
City of Hope
🇺🇸Irvine, California, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Virginia Cancer Specialist
🇺🇸Fairfax, Virginia, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University Hospitals Leuven
🇧🇪Leuven, Belgium
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
AZ Sint-Jan Brugge Oostende AV
🇧🇪Brugge, Belgium
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Algemeen Ziekenhuis Klina
🇧🇪Brasschaat, Belgium
Fondazione IRCCS Cà Granda Ospedale Policlinico Maggiore
🇮🇹Milano, Italy
Centre Hospitalier - Le Mans
🇫🇷Le Mans, France
Hanyang University Seoul Hospital
🇰🇷Seoul, Korea, Republic of
Changhua Christian Hospital
🇨🇳Changhua, Taiwan
Centre Hospitalier Universitaire d'Angers (CHU d'Angers)
🇫🇷Angers, France
Universiteit Gent
🇧🇪Gent, Belgium
Azienda Ospedaliera Universitaria di Bologna - Policlinico S. Orsola Malpighi
🇮🇹Bologna, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
IRCCS Istituto Clinico Humanitas Cancer Center
🇮🇹Rozzano, Italy
Hospital Universitario Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Hôpital Claude Huriez
🇫🇷Lille, France
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Chang-Gung Memorial Hospital, Chiayi
🇨🇳Chiayi City, Taiwan
Hospital Universitario Valle de Hebrón
🇪🇸Barcelona, Spain
Complejo Asistencial Universitario de Salamanca
🇪🇸Salamanca, Spain
CHU Amiens-Picardie
🇫🇷Amiens, France
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
Institut Gustave Roussy
🇫🇷Villejuif, Val-de-Marne, France
National Cancer Center
🇰🇷Gyeonggi-do, Goyang-si, Korea, Republic of
China Medical University Hospital
🇨🇳Taichung, Taiwan
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of Miami
🇺🇸Miami, Florida, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Centre Hospitalier Universitaire (CHU) de Bordeaux
🇫🇷Bordeaux, France
Hospital Universitario y Politécnico La Fe de Valencia
🇪🇸Valencia, Spain
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
Arizona Oncology Associates
🇺🇸Tucson, Arizona, United States
Oncology Associates of Oregon
🇺🇸Eugene, Oregon, United States
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Bénite, France
Daegu Catholic University Medical Center
🇰🇷Daegu, Korea, Republic of
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Texas Oncology
🇺🇸Austin, Texas, United States
The Catholic University of Korea Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Rocky Mountain Cancer Center
🇺🇸Aurora, Colorado, United States