Acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) MedDRA version: 21.1 Level: PT Classification code 10000880 Term: Acute myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA versi
Conditions
Sponsors
Astex Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Approximately 200 total subjects (with at least 118 evaluable for the primary PK endpoint analysis) will be enrolled in this study at approximately 70 study centers in North America and Europe. Subjects must fulfill all of the following 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; specifically able to comply with the PK assessment schedule during the first 2 treatment cycles. 2. Men or women =18 years who are candidates to receive IV decitabine according to FDA or EMA approved indications: a) In North America: Subjects with MDS previously treated or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS. b) In Europe: Subjects with de novo or secondary AML, as defined by World Health Organization (WHO) criteria, who are not candidates for standard induction chemotherapy. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 4. Adequate organ function defined as follows: a) Hepatic: Total or direct bilirubin =1.5 × upper limit of normal (ULN); AST/SGOT and ALT/SGPT =2.0 × ULN. b) Renal: serum creatinine =1.5 × ULN or calculated creatinine clearance or glomerular filtration rate >50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. 5. No major surgery within 30 days of first study treatment. 6. Life expectancy of at least 3 months. 7. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to become pregnant for 6 months after completing treatment; men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to father a child while receiving treatment with ASTX727 and for at least 3 months after completing treatment. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 158
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria will be excluded from the study: 1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts. 2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection in the 30 days before screening. 3. Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events (AEs) from previous treatment. 4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment. 5. Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment.) 6. Poor medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the patient at risk of not being able to complete at least 2 cycles of treatment. 7. Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol. 8. Rapidly progressive or highly proliferative disease (total white blood cell count of >15 × 109/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months. 9. Life-threatening illness, a diagnosis of interstitial lung disease (including pulmonary infiltrates, organizing pneumonia, and pulmonary fibrosis), or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ASTX727, or compromise completion of the study or integrity of the study outcomes. 10. 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 2 years. 11: Diagnosis of a chronic viral infection requiring daily anti-viral therapy with drugs that are substrates for cytidine deaminase
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To establish decitabine AUC equivalence of 5-day dosing between ASTX727 and IV decitabine.;Secondary Objective: To assess the following: • Long-term safety and efficacy (response rate) of ASTX727 • Long interspersed nucleotide elements-1 (LINE-1) demethylation • Additional pharmacokinetics (PK) parameters.;Primary end point(s): Primary Endpoint Comparison between ASTX727 and IV decitabine: • Total 5-day AUC exposures of decitabine after treatment with ASTX727 versus IV decitabine.;Timepoint(s) of evaluation of this end point: Study evaluation visits will occur on Days 1-5, then weekly, in Cycles 1 and 2. | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: • For maximum %LINE-1 demethylation, weekly evaluation in the first 2 cycles • For all other secondary endpoints, 28 days evaluation;Secondary end point(s): Secondary Endpoints • Safety as assessed by AEs, concomitant medications, physical examination, clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital signs, ECOG performance status, and electrocardiogram (ECG). • Maximum %LINE-1 demethylation. • Additional secondary PK parameters. • MDS/CMML subjects: Clinical response (complete response [CR], marrow complete response [mCR], partial response (PR), and hematologic improvement [HI]) based on International Working Group (IWG) 2006 MDS response criteria. • AML subjects: CR, CR with incomplete platelet recovery (CRp), and CR with incomplete blood count recovery (CRi) based on IWG 2003 AML response criteria. • Red blood cell (RBC) or platelet transfusion independence (TI). • Leukemia-free survival (MDS/CMML subjects), defined as the 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 (OS), defined as the number of days from the date of randomization to the date of death from any cause. | — |
Countries
Austria, Canada, Czech Republic, France, Germany, Hungary, Italy, Spain, United Kingdom, United States
Contacts
Public ContactCharlotte Gott
Astex Pharmaceuticals, Inc.
Outcome results
None listed