Clinical trial NCT02841540: A Study of H3B-8800 (RVT-2001) in Participants With Lower Risk Myelodysplastic Syndromes
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Keywords: Myelodysplastic Syndromes
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
H3B-8800 (RVT-2001)
Splicing Modulator
CMML
AML
MDS
Lead sponsor: Hemavant Sciences GmbH
Sponsor class: INDUSTRY
First posted: 2016-07-22
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants with Dose-limiting Toxicities (DLTs)
timeFrame: Escalation Cycle 1 (28 days)
measure: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose of study drug until 30 days after final dose of study drug (up to approximately 50 months)
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point (AUC0-t)
timeFrame: Up to Cycle 6 Day 15 (each cycle length=28 days)
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Up to Cycle 6 Day 15 (each cycle length=28 days)
measure: Time of Maximum Observed Plasma Concentration (Tmax)
timeFrame: Up to Cycle 6 Day 15 (each cycle length=28 days)
measure: Number of Participants who Achieve Red Blood Cell (RBC) Transfusion Independence
timeFrame: Up to approximately 50 months
measure: Number of Participants with Hematologic Improvement
timeFrame: Up to approximately 50 months
measure: Objective Response Rate (ORR)
timeFrame: Up to approximately 50 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 50 months
measure: Time to Progression
timeFrame: Up to approximately 50 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 50 months
measure: Mortality Rate at 3 and 6 Months
timeFrame: Months 3 and 6
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Irvine
country: United States
facility: City of Hope
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Eugene
country: United States
facility: Oncology Associates of Oregon
state: Oregon
city: Austin
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialist
state: Virginia
city: Brasschaat
country: Belgium
facility: Algemeen Ziekenhuis Klina
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge Oostende AV
city: Gent
country: Belgium
facility: Universiteit Gent
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Val-de-Marne
city: Amiens
country: France
facility: CHU Amiens-Picardie
city: Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers (CHU d'Angers)
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire (CHU) de Bordeaux
city: Le Mans
country: France
facility: Centre Hospitalier - Le Mans
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria di Bologna - Policlinico S. Orsola Malpighi
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Policlinico Maggiore
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Rozzano
country: Italy
facility: IRCCS Istituto Clinico Humanitas Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
state: Goyang-si
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Medical Center
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Hanyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's Hospital
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitario Valle de Hebrón
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe de Valencia
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Chiayi City
country: Taiwan
facility: Chang-Gung Memorial Hospital, Chiayi
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Hemavant Sciences
name: Keisuke Kuida, MD, PhD
role: STUDY_DIRECTOR
References: