| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndromes (MDS)
Chronic myelomonocytic leukemia (CMML) |
|
| E.1.1.1 | Medical condition in easily understood language |
Myelodysplastic syndromes (MDS)
Chronic myelomonocytic leukemia (CMML) |
|
| 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 | 10028536 |
| E.1.2 | Term | Myelodysplastic syndromes |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009018 |
| E.1.2 | Term | Chronic myelomonocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 MDS or CMML previously treated with a hypomethylating agent (azacitidine or decitabine, or both).
TC options are low dose cytarabine (LDAC), standard intensive chemotherapy (IC) of a 7+3 regimen (cytarabine and an anthracycline given as per institutional standard practice), or best supportive care only (given according to standard and institutional practice).
Best supportive care 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 MDS or CMML previously treated with a hypomethylating agent (azacitidine or decitabine, or both) with respect to the following variables:
- Transfusion independence.
- Marrow complete response (mCR) with transfusion independence.
- Survival rate at 1 year after randomization.
- Leukemia-free survival.
- Number of days alive and out of the hospital (NDAOH).
- Disease response based on IWG 2006 MDS criteria including complete response (CR), partial response (PR), mCR, and hematological improvement (HI; erythroid, platelet, or neutrophil response); and duration of response.
- Number of red blood cell (RBC) and platelet transfusions.
- Health-related quality of life (QOL).
- Safety.
Exploratory:
Assess influence of demographic characteristics, disease characteristics, and molecular biomarkers on treatment outcomes; evaluate pharmacokinetic 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 and comply with study procedures, and provide written informed consent before any study-specific procedure.
2. Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
3. Performance status (Eastern Cooperative Oncology Group [ECOG]) of 0-2.
4. Subjects with previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed, relapsed or was refractory to HMA treatment as follows:
a. Subject received HMA for at least 6 cycles and is transfusion dependent (as defined in 5b below), OR
b. Subject received HMA for at least 2 complete cycles and had disease progression defined as
i. ≥50% increase in bone marrow blasts from pre-HMA-treatment levels or from nadir post-HMA-treatment levels to >5% (fro subjects with pretreatment or nadir blasts ≤5%), or to >10% (for subjects with pretreatment or nadir blasts >5%) and/or
ii. Transfusion dependent and ≥2 g/dL reduction of Hgb from pre-HMA-treatment levels.
In addition to HMAs, other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.
5. Subjects must have either:
a. Bone marrow blasts >5% at randomization, OR
b. Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.
6. Creatinine clearance or glomerular filtration rate ≥30 mL/min 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 childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing 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 and for at least 3 months after completing treatment and (b) while receiving treatment with LDAC or IC and for at least 6 months after completing treatment or for the duration specified in local prescribing information, whichever is longer. |
|
| E.4 | Principal exclusion criteria |
1. Subjects who have been diagnosed as having acute myeloid leukemia (AML) with peripheral blood or bone marrow blasts of ≥20%.
2. Subjects who may still be sensitive to repeated treatment with decitabine or azacitidine such as subjects who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
3. Prior treatment with guadecitabine.
4. Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
5. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
6. Treated with any investigational drug within 2 weeks of the first dose of study treatment.
7. Total serum bilirubin >2.5 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.
8. 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.
9. 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.
10. Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute (LPM) oxygen.
11. Life expectancy of less than one month
12. Subjects with TP53 mutations. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival (OS), defined as the number of days from the day the subject was randomized to the date of death (regardless of cause). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After randomization, visits will occur on every treatment day. In addition, visits will occur on Days 8, 15, and 22 of the first 2 cycles of therapy, and on Days 1 and 15 of Cycles 3-6 (Days 8, 15 and 22 are not required for subjects receiving TC; instead institutional standards should be followed. In Cycles >6, only treatment day visits are required, with study-specified assessments required only on Day 1. Additional visits, based on treatment effect and blood counts, may be done at the investigator’s discretion. Subjects will attend a safety follow-up visit after the last study treatment. Detailed information are provided in the protocol. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
- Transfusion independence for any 8 consecutive weeks based on rolling 8-week assessments [number and rate of subjects who are free of transfusions for 8 consecutive weeks (or more) at any time after start of study treatment and who have Hgb of ≥8 g/dL and platelets ≥20×109/L].
- Marrow CR (mCR) based on IWG 2006 criteria with transfusion independence (as defined above).
- Survival rate at 1 year after randomization.
- Leukemia-free survival defined as the number of days from the day of randomization to the date when BM or peripheral blood (PB) blasts reach ≥20%, or death of any cause.
- Number of days alive and out of the hospital (NDAOH).
- Disease response including CR, mCR, PR, and HI; including HI with erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) response, based on IWG 2006 criteria.
- Duration of response.
- Number of RBC or platelet transfusions (units) over the duration of the study treatment.
- 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 mortality. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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: given according to standard and institutional practice. |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Canada |
| Japan |
| Korea, Democratic People's Republic of |
| 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 316 death events have occurred, or as otherwise noted.
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 | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 27 |
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