Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS

Myelodysplastic Syndromes Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03502668
• Other study ID #: ASTX727-03
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: July 27, 2018
• Est. completion date: December 2024

Study information

• Verified date: May 2024
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
• ASTX727 SD
oral decitabine (SD) + cedazuridine (E7727)

Locations

Country	Name	City	State
Belgium	ZNA - Campus Middelheim	Antwerp
Belgium	Az St-Jan Brugge-Oostende A.V.	Brugge
Canada	University of Alberta Hospital - Hematology Research	Edmonton
Canada	London Regional Cancer Center	London	Ontario
Germany	Universitaetsklinikum Freiburg Site#703	Freiburg
Germany	Universitätsklinikum Halle	Halle
Italy	Universita degli Studi di Firenze	Firenze
Spain	Hospital Universitario Vall d Hebron	Barcelona
Spain	Institut Català d'Oncologia Badalona Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Univeristario y Politecnico La Fe Servicio de Hematologia	Valencia
United States	University of Colorado, Anschutz Cancer Pavilion	Aurora	Colorado
United States	The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division)	Bethesda	Maryland
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	The University of Chicago	Chicago	Illinois
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Indiana University Health Hospital - Simon Cancer Center	Indianapolis	Indiana
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Vanderbilt University Medical Center - Hematology-Oncology	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	BRCR Medical Center Inc.	Plantation	Florida
United States	Oregon Health and Science University Knight Cancer Institute	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Moffitt Cancer Center Site#507	Tampa	Florida
United States	Texas Oncology - Tyler	Tyler	Texas
United States	University of Kansas Clinical Research Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of drug-related Grade =3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule	Phase 1: Safety	18-24 months
Primary	Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)	Phase 2: Efficacy	18-24 months
Secondary	%LINE-1 methylation change from baseline	pharmacodynamics	18-24 months
Secondary	Area under the curve (AUC)	pharmacokinetics parameter	18-24 months
Secondary	Maximum plasma concentration (Cmax)	pharmacokinetics parameter	18-24 months
Secondary	Time to reach maximum concentration (Tmax)	pharmacokinetics parameter	18-24 months
Secondary	Half life (t1/2)	pharmacokinetics parameter	18-24 months
Secondary	Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence)	Phase 1: Efficacy	18-24 months
Secondary	Time to bone marrow blasts >5%	Number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by =50%.	18-24 months
Secondary	Leukemia-free survival	Number of days from the date of randomization to the date when bone marrow or peripheral blood blasts reach =20%, or death from any cause	18-24 months
Secondary	Overall survival	Number of days from the date of randomization to the date of death from any cause	18-24 months