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)

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

Sponsors

Lead sponsor: Astex Pharmaceuticals, Inc.

Source Astex Pharmaceuticals, Inc.
Brief Summary

Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with 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 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.

Overall Status Recruiting
Start Date July 27, 2018
Completion Date December 2020
Primary Completion Date December 2020
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule 18-24 months
Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) 18-24 months
Secondary Outcome
Measure Time Frame
%LINE-1 methylation change from baseline 18-24 months
Area under the curve (AUC) 18-24 months
Maximum plasma concentration (Cmax) 18-24 months
Time to reach maximum concentration (Tmax) 18-24 months
Half life (t1/2) 18-24 months
Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) 18-24 months
Time to bone marrow blasts >5% 18-24 months
Leukemia-free survival 18-24 months
Overall survival 18-24 months
Enrollment 160
Condition
Intervention

Intervention type: Drug

Intervention name: ASTX727 LD

Description: oral decitabine (LD) + cedazuridine (E7727)

Other name: oral decitabine (LD) + cedazuridine (E7727)

Intervention type: Drug

Intervention name: ASTX727 SD

Description: oral decitabine (SD) + cedazuridine (E7727)

Arm group label: Phase 2

Other name: oral decitabine (SD) + cedazuridine (E7727)

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 RBCs or Hb of <8.5 g/dL in at least 2 blood counts prior to randomization.

2. ANC of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.

3. 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. Diagnosis of chronic myelomonocytic leukemia (CMML).

4. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.

5. 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.

6. Known active infection with human immunodeficiency virus or hepatitis viruses.

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Yuri Sano, MD, PhD Study Director Astex Pharmaceuticals, Inc.
Overall Contact

Last name: Yuri Sano, MD, PhD

Phone: 925-560-2844

Email: [email protected]

Location
facility status contact investigator
The University of Alabama at Birmingham | Birmingham, Alabama, 35233, United States Recruiting Nandika S Nagodawithana, MBBS, MSc, MD, MSHI 205-934-6624 [email protected] Kimo Bachiashvili, MD Principal Investigator
University of Colorado, Anschutz Cancer Pavilion | Aurora, Colorado, 80045, United States Recruiting Derek Schatz, BS, CCRP 720-848-0628 [email protected] Daniel Pollyea, MD Principal Investigator
BRCR Medical Center Inc. | Plantation, Florida, 33324, United States Recruiting Ana Losada 561-447-0614 106 [email protected] Harshad Amin, MD Principal Investigator
Moffitt Cancer Center | Tampa, Florida, 33612, United States Recruiting William Prada, MD 813-745-2071 [email protected] David A Sallman, MD Principal Investigator
Indiana University Health Hospital - Simon Cancer Center | Indianapolis, Indiana, 46202, United States Recruiting Jill Weisenbach, RN 317-278-0597 [email protected] Larry Cripe, MD Principal Investigator
University of Kansas Clinical Research Center | Westwood, Kansas, 66205, United States Recruiting Jeanette Firth-Braun, RN, BSN [email protected] Abdulraheem Yacoub, MD Principal Investigator
The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division) | Bethesda, Maryland, 20817, United States Recruiting Natalie Bongiorno, RN, MSHS 301-571-2016 [email protected] Victor Priego, MD Principal Investigator
University of Nebraska Medical Center | Omaha, Nebraska, 68198, United States Recruiting Amberley Proctor, RN, BSN 402-836-9171 [email protected] Lori Maness, MD Principal Investigator
Roswell Park Comprehensive Cancer Center | Buffalo, New York, 14263, United States Recruiting Krista Belko, PhD 716-845-3373 [email protected] Elizabeth Griffiths, MD Principal Investigator
Sarah Cannon Research Institute | Nashville, Tennessee, 37203, United States Recruiting Nurse 844-482-4812 [email protected] William Donnellan, MD Principal Investigator
Texas Oncology - Ft. Worth | Fort Worth, Texas, 76104, United States Recruiting Cindi Schoenfeldt, RN 817-413-1645 [email protected] Stephen Richey, MD Principal Investigator
The University of Texas MD Anderson Cancer Center | Houston, Texas, 77030, United States Recruiting Jennifer Frazer, RN, BSN 713-745-5468 [email protected] Guillermo Garcia-Manero, MD Principal Investigator
Texas Oncology - San Antonio | San Antonio, Texas, 78240, United States Recruiting Debbie Ponce, RN 210-595-5692 [email protected] Roger Lyons, MD Principal Investigator
Texas Oncology - Tyler | Tyler, Texas, 75702, United States Recruiting Karen Poe 903-579-9800 [email protected] Habte Yimer, MD Principal Investigator
Virginia Oncology Associates | Norfolk, Virginia, 23502, United States Recruiting Karen McClain, RN, BSN, OCN 757-213-5658 [email protected] Paul Conkling, MD Principal Investigator
Location Countries

United States

Verification Date

November 2019

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Arm group label: Phase 1 Stage A

Arm group type: Experimental

Description: 3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD

Arm group label: Phase 1 Stage B

Arm group type: Experimental

Description: 3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD

Arm group label: Phase 2

Arm group type: Experimental

Description: 80 additional subjects randomized in a 1:1 ratio studying two different doses

Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Sequential Assignment

Intervention model description: Multicenter, open label

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov