E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic syndrome and acute myeloid leukemia with a deletion of 5q |
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E.1.1.1 | Medical condition in easily understood language |
Malignant tumor diseases which have their origin in bone marrow or blood cells and have a specific chromosomal defect |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067096 |
E.1.2 | Term | 5q minus myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To study the efficacy of azacitidine with or without the addition of lenalidomide in high-risk MDS (IPSS Int-2 or high) and AML (multilineage dysplasia and 20-30% marrow blasts) with a karyotype oncluding del(5q) |
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E.2.2 | Secondary objectives of the trial |
To study the safety of the combination of lenalidomide and azacitidine in high-risk MDS (IPSS Int-2 or high) and AML (multilineage dysplasia and 20-30% marrow blasts) with a karyotype oncluding del(5q) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Subjects must satisfy the following criteria to be enrolled in the study (del(5q) confirmed by FISH in all cases):
•18 years of age or older at the time of signing the informed consent form.
•MDS with IPSS Int-2 or High with a karyotype including del(5q).
•Acute myeloid leukaemia (AML) with multilineage dysplasia and 20-30 % blasts (former RAEB-t) with a karyotype including del(5q).
•Subject has signed the informed consent form.
•Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test prior to starting lenalidomide. In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, patches, or implantable hormonal contraceptive methods; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasecomized partner) while on lenalidomide. WCBP must agree to have pregnancy tests every 4 weeks while on lenalidomide.
•Males (including those who have had a vasectomy) must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with WCBP while on lenalidomide, when temporarily stopping lenalidomide and 28 days after the last dose of lenalidomide.
Note: Refractory and relapsed patients can be included as long as they fulfil the inclusion criteria. |
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E.4 | Principal exclusion criteria |
•Eligible for upfront allogeneic SCT without prior induction chemotherapy or azacitidine
•Pregnant or lactating females.
•Prior therapy with azacitidine
•Prior therapy with lenalidomide
•Expected survival less than two months.
•Acute promyelocytic leukemia (APL)
•Central nervous system leukemia
•Serum biochemical values as follows
1.Serum creatinine >2.0 mg/dL (177 mmol/L)
2.Serum aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transferase (ALT)/serum glutamate pyruvate transaminase (SGPT) >3.0 x upper limit of normal (ULN)
3.Serum total bilirubin >1.5 mg/dL
•Prior allergic reaction to thalidomide
•Uncontrolled systemic infection
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E.5 End points |
E.5.1 | Primary end point(s) |
Response according to IWG criteria for MDS and AML |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 cycles of azacitidine or azacitidine+lenalidomide treatment, or at end of study if this occurs at an earlier time point |
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E.5.2 | Secondary end point(s) |
Cytogenetic response (FISH and karyotype)
Safety in azacitidine vs azacitidine + lenalidomide groups
Azacitidine cycle interval between groups
Survival in azacitidine vs azacitidine + lenalidomide groups
Relapse in azacitidine vs azacitidine + lenalidomide groups
Analysis of a broad spectrum of molecular and cellular events which previously have been identified as related to MDS with del(5q). These events will be used to a) identify potential biomarkers for response and b) to evaluate the effect of treatment on stem cells with specific biological patterns, e.g “quality of response”. Biological analyses encompass screening for candidate gene mutations, gene, miRNA and protein expression, methylation and histone acetylation patterns, stem cell biology and telomere status (21, 22, 23).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cytogenetic response after 3 cycles (FISH using the LSI EGR1/D5S23,D5S721 FISH probe) and 6 cycles (karyotype) of azacitidine or azacitidine+lenalidomide treatment, or at end of study (karyotype) if this occurs at an earlier time point.
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
azacitidine with and without lenalidomide |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |