| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia (AML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute Myeloid Leukemia (AML) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10024291 |
| E.1.2 | Term | Leukaemias acute myeloid |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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 <2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.
10. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
11. 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.
12. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or non-AML associated pulmonary disease requiring >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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| OS, defined as the number of days from date of randomization to date of death. |
|
| E.5.1.1 | 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 before Cycle 6, long term follow-up visits will occur monthly until 6 months after the start of study treatment, then every 3 months . For subjects who discontinue study treatment after Cycle 6, long-term follow-up will be every 3 months.
Survival will be monitored and documented throughout the study. |
|
| E.5.2 | 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 rate 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As for primary endpoint and as specified in protocol. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Best Supportive Care only; allowed in all study arms |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The primary efficacy endpoint is overall survival (OS), which will be assessed after at least 315 death events have occurred.
The duration of individual subject participation will vary. Subjects may continue to receive treatment for as long as they continue to benefit.
The final study end will be when the last randomized patient has either died, withdrawn from the study, or stopped study treatment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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