Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Phase 1 Stage A 3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD |
Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
|
Experimental: Phase 1 Stage B 3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD |
Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
|
Experimental: Phase 2 80 additional subjects randomized in a 1:1 ratio studying two different doses |
Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Names:
Drug: ASTX727 SD
oral decitabine (SD) + cedazuridine (E7727)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule [18-24 months]
Phase 1: Safety
- Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) [18-24 months]
Phase 2: Efficacy
Secondary Outcome Measures
- %LINE-1 methylation change from baseline [18-24 months]
pharmacodynamics
- Area under the curve (AUC) [18-24 months]
pharmacokinetics parameter
- Maximum plasma concentration (Cmax) [18-24 months]
pharmacokinetics parameter
- Time to reach maximum concentration (Tmax) [18-24 months]
pharmacokinetics parameter
- Half life (t1/2) [18-24 months]
pharmacokinetics parameter
- 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]
Phase 1: Efficacy
- Time to bone marrow blasts >5% [18-24 months]
Number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by ≥50%.
- Leukemia-free survival [18-24 months]
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
- Overall survival [18-24 months]
Number of days from the date of randomization to the date of death from any cause
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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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:
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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).
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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.
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Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.
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Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
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Adequate organ function.
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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.
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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:
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Treatment with any investigational drug or therapy within 2 weeks before study treatment.
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Treatments for MDS must be concluded 1 month prior to study treatment.
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Prior treatment with azacitidine, decitabine, or guadecitabine.
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Diagnosis of chronic myelomonocytic leukemia (CMML).
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Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
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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.
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Known active infection with human immunodeficiency virus or hepatitis viruses.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Pinnacle Research Group, LLC | Anniston | Alabama | United States | 36207 |
2 | The University of Alabama at Birmingham | Birmingham | Alabama | United States | 35233 |
3 | City of Hope National Medical Center | Duarte | California | United States | 91010 |
4 | University of Colorado, Anschutz Cancer Pavilion | Aurora | Colorado | United States | 80045 |
5 | Yale Cancer Center | New Haven | Connecticut | United States | 06510 |
6 | Mayo Clinic Florida | Jacksonville | Florida | United States | 32224 |
7 | BRCR Medical Center Inc. | Plantation | Florida | United States | 33324 |
8 | Moffitt Cancer Center | Tampa | Florida | United States | 33612 |
9 | The University of Chicago | Chicago | Illinois | United States | 60637 |
10 | Indiana University Health Hospital - Simon Cancer Center | Indianapolis | Indiana | United States | 46202 |
11 | University of Kansas Clinical Research Center | Westwood | Kansas | United States | 66205 |
12 | The Center for Cancer and Blood Disorders (RCCA MD LLC - Maryland Division) | Bethesda | Maryland | United States | 20817 |
13 | University of Michigan | Ann Arbor | Michigan | United States | 48109-5271 |
14 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
15 | University of Nebraska Medical Center | Omaha | Nebraska | United States | 68198 |
16 | Roswell Park Comprehensive Cancer Center | Buffalo | New York | United States | 14263 |
17 | Oregon Health and Science University Knight Cancer Institute | Portland | Oregon | United States | 97239 |
18 | Charleston Oncology | Charleston | South Carolina | United States | 29414 |
19 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
20 | Vanderbilt University Medical Center - Hematology-Oncology | Nashville | Tennessee | United States | 37232 |
21 | Texas Oncology - Ft. Worth | Fort Worth | Texas | United States | 76104 |
22 | The University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
23 | Texas Oncology - San Antonio | San Antonio | Texas | United States | 78240 |
24 | Texas Oncology - Tyler | Tyler | Texas | United States | 75702 |
25 | Virginia Oncology Associates | Norfolk | Virginia | United States | 23502 |
26 | Fred Hutchinson Cancer Research Center | Seattle | Washington | United States | 98109 |
27 | ZNA - Campus Middelheim | Antwerp | Belgium | ||
28 | Az St-Jan Brugge-Oostende A.V. | Brugge | Belgium | ||
29 | Hospital De Jolimont | Haine-Saint-Paul | Belgium | ||
30 | UZ Leuven - Campus Gasthuisberg | Leuven | Belgium | 3000 | |
31 | London Regional Cancer Center | London | Ontario | Canada | N6A 5W9 |
32 | University of Alberta Hospital - Hematology Research | Edmonton | Canada | T6G 2B7 | |
33 | Sir Mortimer B Davis/Jewish General Hospital | Québec | Canada | ||
34 | Staedtisches Klinikum Braunschweig gGmbH | Braunschweig | Germany | ||
35 | Universitaetsklinikum Freiburg | Freiburg | Germany | 79106 | |
36 | Universitätsklinikum Halle | Halle | Germany | 06120 | |
37 | Universita degli Studi di Firenze | Firenze | Italy | ||
38 | Hospital de La Santa Creu i Sant Pau | Barcelona | Spain | ||
39 | Hospital Universitario Vall d Hebron | Barcelona | Spain | ||
40 | Institut Català d'Oncologia Badalona Hospital Universitari Germans Trias i Pujol | Barcelona | Spain | ||
41 | H. San Pedro de Alcántara | Cáceres | Spain | ||
42 | Hospital General Universitario Gregorio Marañón | Madrid | Spain | ||
43 | Hospital Univeristario y Politecnico La Fe Servicio de Hematologia | Valencia | Spain | 46026 |
Sponsors and Collaborators
- Astex Pharmaceuticals, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ASTX727-03