Acute Myeloid Leukemia (AML) MedDRA version: 20.0 Level: HLT Classification code 10024291 Term: Leukaemias acute myeloid System Organ Class: 100000004851
Conditions
Sponsors
Astex Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adult subjects =18 years of age who are able to understand study procedures, comply with them, and provide written informed consent before any study-specific procedure. 2. History of cytologically or histologically confirmed diagnosis of AML (except acute promyelocytic leukemia) according to the 2008 World Health Organization (WHO) classification (bone marrow [BM] or peripheral blood [PB] blast counts =20%). 3. Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2. 4. Subjects with AML previously treated with induction therapy using an intensive chemotherapy regimen, defined as a regimen including cytarabine and an anthracycline, and who are refractory to induction (primary refractory) or in relapse after such induction with or without prior HCT. 5. Subjects must have either PB or BM blasts =5% at time of randomization. 6. Creatinine clearance or glomerular filtration rate =30 mL/min as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas, such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration). 7. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; see below* for details) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child (a) while receiving treatment with guadecitabine, decitabine, or azacitidine and for at least 3 months after completing treatment and (b) while receiving treatment with highintensity TC or LDAC and for at least 6 months after completing treatment. Contraceptive measures which may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception(oral, injectable, implantable) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of birth control. * According to recommendations of the CTFG (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf), a woman is considered of childbearing potential (ie, fertile) following menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 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 150 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 150
Exclusion criteria
Exclusion criteria: 1. Known clinically active central nervous system (CNS) or extramedullary AML, except leukemia cutis. 2.Subjects who are in first relapse after initial induction, if they had a response duration of >12 months from date when first response was documented or if they are good candidates for HCT. 3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 4. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy. 5. Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin inhibitor or prednisone more than 5 mg/day. (Note: Prednisone at any dose for other indications is allowed.) 6. Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine or azacitidine. 7. Hypersensitivity to decitabine, guadecitabine, or any of their excipients. 8. Treated with any investigational therapy within 2 weeks of the first dose of study treatment. 9. Total serum bilirubin >2.5 × upper limit of normal (ULN; except for subjects with Gilbert's Syndrome for whom direct bilirubin is 2 liters per minute (LPM) oxygen or any other condition that puts the subject at an imminent risk of death. 13.Subjects with high PB blasts >50% AND poor ECOG PS of 2.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess and compare overall survival (OS) between guadecitabine and treatment choice (TC) in adults with previously treated acute myeloid leukemia (AML). TC options are: • High intensity (intermediate or high dose cytarabine [HiDAC]; mitoxantrone, etoposide, and cytarabine [MEC]; or fludarabine, cytarabine, granulocyte colony stimulating factor [G-CSF], +/- idarubicin [FLAG/FLAG-Ida]) • Low intensity (low dose cytarabine [LDAC], decitabine, or azacitidine) • Best Supportive Care (BSC). BSC will be provided to all subjects as per standard and institutional practice.;Secondary Objective: To assess and compare effects of guadecitabine and TC in adults with previously treated AML with respect to the following variables: Event-free survival (EFS). Long-term survival. Number of days alive and out of the hospital (NDAOH). Transfusion needs. Complete response (CR) and CR with partial hematologic recovery (CRh) rates. Composite CR rate (CRc). CRc = CR + CR with incomplete blood count recovery (CRi) + CR with incomplete platelet recovery (CRp). Bridge to hematopoietic cell transplant (HCT). Health-related quality of life (QOL). Safety. Exploratory Objectives To assess influence of demographics, disease characteristics, and molecular biomarkers on treatment outcomes. To evaluate pharmacokinetic (PK) exposure-response relationships with efficacy and safety parameters.;Primary end point(s): OS, defined as the number of days from date of randomization to date of death.;Timepoint(s) of evaluation of this end point: Treatment cycles to be repeated every 28 days. Visits will occur on treatment days, as necessary. Also, during the first 3 cycles, visits will occur weekly on Days 8, 15, and 22, then on Day 15 in Cycles 4-6. In Cycles >6, visits will only occur on treatment days (if necessary), with study-specified assessments on Day 1. Subjects will attend a safety follow-up visit after the last study treatment. For subjects who discontinue study treatment be | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): EFS defined as the number of days from randomization to the earliest of disease progression, treatment discontinuation, start of alternative anti-leukemia therapy (except HCT), or death. Survival rate at 1 year after randomization. (Subjects will also be followed long term to estimate 2-year survival rate.) NDAOH. Transfusion independence rate, calculated based on the number of subjects without red blood cell (RBC) or platelet transfusion for any period of 8 weeks after treatment. CR and CRh rates based on modified International Working Group (IWG) 2003 AML Response Criteria. CRc (CR+CRi+CRp) rate. HCT rate. (In subjects who undergo HCT, time to stem cell engraftment and 100-day mortality rate post HCT will also be assessed.) Duration of combined CR and CRh, defined as the time from first CR or CRh to time of relapse. Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale [EQ VAS]). Incidence and severity of adverse events (AEs). 30- and 60-day all-cause early mortality.;Timepoint(s) of evaluation of this end point: As for primary endpoint and as specified in protocol. | — |
Countries
Belgium, Canada, Denmark, France, Germany, Hungary, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Sweden, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical trial info. ASTRAL-2
Astex Pharmaceuticals, Inc.
Outcome results
None listed