A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)
- Conditions
- Acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML)MedDRA version: 21.1Level: PTClassification code 10000880Term: Acute myeloid leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: PTClassification code 10028533Term: Myelodysplastic syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: PTClassification code 10009018Term: Chronic myelomonocytic leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-003395-12-AT
- Lead Sponsor
- Astex Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 208
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 legally effective 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.
c) In Canada: Subjects with de novo or secondary AML, as defined by WHO criteria, who in the judgment of their physician are not deemed candidates for standard induction chemotherapy for AML and for whom there is no available approved standard therapy in Canada.
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 =2 × upper limit of normal (ULN); AST/SGOT and ALT/SGPT =2.5 × 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
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 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.Hypersensitivity to decitabine, cedazuridine, or any of the excipients in ASTX727 tablets or IV decitabine.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: • To establish decitabine AUC equivalence of 5-day dosing between<br>ASTX727 and IV decitabine.;Secondary Objective: To assess the following:<br>• Long-term safety and efficacy (response rate) of ASTX727<br>• Long interspersed nucleotide elements-1 (LINE-1) demethylation<br>• Additional pharmacokinetics (PK) parameters.;Primary end point(s): Primary Endpoint<br>Comparison between ASTX727 and IV decitabine:<br>• 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 Outcome Measures
Name Time Method