Clinical trial NCT03502668: Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS
Official title: A Randomized, Open-Label, Phase 1-2 Study of ASTX727 Low Dose (ASTX727 LD) Extended Schedule in Subjects With Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: low risk myelodysplastic syndromes, MDS, ASTX727
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2018-04-19
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Multicenter, open label
Primary purpose: TREATMENT

Brief summary: Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with International Prognostic Scoring System (IPSS) risk category of low-risk or Intermediate-1 MDS. This study will be conducted in two phases. In phase 1 subjects will be randomized into 3 cohorts in a 28-day cycles. Phase 2, 80 new subjects will be randomized in a 1:1 ratio into 2 doses/schedules.

Detailed description: A Phase 1-2, multicenter, open-label study of various ASTX727 LD doses and schedules to assess the safety, pharmacodynamics (PD), pharmacokinetics (PK), and hematologic response in subjects with IPSS risk category of low-risk or Intermediate-1 MDS. The study will be conducted in 2 phases.

Phase 1: In Stage A, subjects will be randomized into 3 cohorts of 6 subjects each testing different doses of oral decitabine with cedazuridine in 28-day cycles. When safety has been established in Phase 1 Stage A, Phase 1 Stage B will open, wherein additional 30 subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 10 subjects.

Phase 2: Using 2 doses/schedules one of which will be selected from Phase 1, 40 additional subjects per dose/schedule will be randomized in a 1:1 ratio. The selected doses/schedules will be evaluated for safety (drug-related AEs), efficacy (including hematologic response), PD (long interspersed nucleotide element-1 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Eligibility criteria: Inclusion Criteria:

1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure.
2. Men or women ≥18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization:

   1. Red blood cell (RBC) transfusion dependence of 2 or more units of RBC transfusions (RBC transfusion administered for hemoglobin (Hb) levels ≤9.0 g/dL are counted).
   2. Hb of \<9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received.
   3. Absolute Neutrophil Count (ANC) of \<0.5 × 10\^9/L in at least 2 blood counts prior to randomization.
   4. Platelet counts of \<50 × 10\^9/L in at least 2 blood counts prior to randomization.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
4. Adequate organ function.
5. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group \[CTFG\]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.
6. Women of child-bearing potential must agree to use contraceptive measures of birth control for 6 months after completing treatment; men must use contraceptive measures and agree not to father a child for at least 3 months after completing treatment.

Exclusion Criteria:

1. Treatment with any investigational drug or therapy within 2 weeks before study treatment.
2. Treatments for MDS must be concluded 1 month prior to study treatment.
3. Prior treatment with azacitidine, decitabine, or guadecitabine.
4. Diagnosis of chronic myelomonocytic leukemia (CMML).
5. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
6. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.
7. Known active infection with human immunodeficiency virus or hepatitis viruses.

Primary outcomes:
measure: Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule
timeFrame: 18-24 months
measure: Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)
timeFrame: 18-24 months
Secondary outcomes:
measure: %LINE-1 methylation change from baseline
timeFrame: 18-24 months
measure: Area under the curve (AUC)
timeFrame: 18-24 months
measure: Maximum plasma concentration (Cmax)
timeFrame: 18-24 months
measure: Time to reach maximum concentration (Tmax)
timeFrame: 18-24 months
measure: Half life (t1/2)
timeFrame: 18-24 months
measure: Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)
timeFrame: 18-24 months
measure: Time to bone marrow blasts >5%
timeFrame: 18-24 months
measure: Leukemia-free survival
timeFrame: 18-24 months
measure: Overall survival
timeFrame: 18-24 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Aurora
country: United States
facility: University of Colorado, Anschutz Cancer Pavilion
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Plantation
country: United States
facility: BRCR Medical Center Inc.
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center Site#507
state: Florida
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Hospital - Simon Cancer Center
state: Indiana
city: Westwood
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Bethesda
country: United States
facility: The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division)
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University Knight Cancer Institute
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Hematology-Oncology
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler
state: Texas
city: Antwerp
country: Belgium
facility: ZNA - Campus Middelheim
city: Brugge
country: Belgium
facility: Az St-Jan Brugge-Oostende A.V.
city: London
country: Canada
facility: London Regional Cancer Center
state: Ontario
city: Edmonton
country: Canada
facility: University of Alberta Hospital - Hematology Research
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg Site#703
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Firenze
country: Italy
facility: Universita degli Studi di Firenze
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d Hebron
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia Badalona Hospital Universitari Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Valencia
country: Spain
facility: Hospital Univeristario y Politecnico La Fe Servicio de Hematologia
Study officials:
References: