E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelodysplastic Syndrome(MDS) / Acute Myeloid Leukemia(AML) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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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 |
Main objective of the trial:
The goal will be to identify the “safe most successful dose” (sMSD) that is the dose level where the probabilities of success is maximized across the dose levels and the toxicity rate is kept within acceptable boundaries. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of the trial:
Response rate (according to IWG 2006 criteria for MDS and Cheson criteria for AML) to the combination of lenalidomide and azacitidine in adult high and int 2 MDS (IPSS) or AML with del 5q[31] . Safety (particularly hematological toxicity) of the combination of Lenalidomide and azacitidine in int-2 and high risk MDS or AML with del 5q [31]. •Duration of response, •Progression to AML, •And overall survival.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria
1.Age ≥ 18 years 2.Must understand and voluntarily sign an informed consent form 3.Must Especially in the case of AML: Patient considered ineligible for intensive chemotherapy due to age, cardiac contraindication to anthracyclines, comorbidities, previous failure of intensive chemotherapy, or patient willing to avoid intensive chemotherapy 4.Must be able to adhere to the study visit schedule and other protocol requirements 5.Prior Thalidomid allowed 6.Documented diagnosis of MDS, or CMML with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease, or AML 7.with an associated del 5q[31] (the deleted chromosomal region must include 5q[31]), with or without additional cytogenetic abnormalities 8.Female subjects of chilbearing potential* must : - Understand the study drug is expected to have a teratogenic risk. - - Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml on the day of the study visit or in the 3 days prior to the study visit once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. The test should ensure the subject is not pregnant when she starts treatment. - Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. These pregnancy tests should be performed on the day of the study visit or in the 3 days prior to the study visit. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. - Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy even if she has amenorrhoea. This applies unless the subject commits to absolute and continuous abstinence confirmed on a monthly basis, to avoid pregnancy for the duration of study.
If not established on effective contraception, the female subject must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated. Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a female subject is currently using combined oral contraception, the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia . Copper-releasing intrauterine devices are generally not recommended due to the potential risks of infection at the time of insertion and menstrual blood loss which may compromise patients with neutropenia or thrombocytopenia. - Understand that even if she has amenorrhea, she must follow all the advice on effective contraception. - She understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy 9.Male patients must: -Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential. during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment -Agree not to conceive during treatment and study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy -Agree not to donate semen during study drug therapy and for 3 months after end of study drug therapy. -Agree to learn about the procedures for preservation of sperm., before starting treatment 10.All subjects must : - Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy. - Agree not to share study medication with another person and to return all unused study drug to the investigator. - Well understand the expected teratogenic risk to the unborn child. 11.Signed informed consent prior to start of any study-specific procedures, 12.Ability to participate to a clinical trial and adhere to study procedures.
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E.4 | Principal exclusion criteria |
Exclusion criteria
1.Pregnant or lactating females. 2.Proliferative (WBC ≥ 13,000/mL) Chronic Myelomonocytic Leukaemia(CMML) 3.Prior ≥ grade-2 NCI CTCAE (v 3.0) allergic reaction to thalidomide. 4.Prior desquamating (blistering) rash while taking thalidomide. 5.Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years. 6.Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days, with the exception of hydroxyurea in case of high WBC counts 7.Less than 6 months since prior allogeneic bone marrow transplantation. 8.Less than 3 months since prior autologous bone marrow or stem cell transplantation. 9.Recombinant human erythropoietin (rHuEPO) therapy received within 28 days. 10.Known HIV-1 positivity. 11.Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study. 12.Any of the following laboratory abnormalities: •Creatinine Clearance < 50 mL/min •Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 3.0 x up-per limit of normal •Serum total bilirubin > 2 ULN except unconjugated hyperbilirubinemia related toMDS. 13.ubjects with ≥ grade-2 neuropathy |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point:
In this trial, we will test the combination of escalating doses of Lenalidomide (starting at relatively low dose) and azacitidine in intermediate-2-or high risk MDS and AML with del 5 q31.
It is hoped that this combined therapy will increase response rate in intermediate-2-or high risk MDS and AML with del 5 q31 without major toxicity, by comparison with historical results obtained with Lenalidomide alone in the same subset of patients in a phase II study recently conducted by the GFM, and results obtained with Azacitidine alone (AZA 001 Phase III study).
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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 | Yes |
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 | Yes |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | No |
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 | 15 |
E.8.5 | The trial involves multiple Member States | No |
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 | Information not present in EudraCT |
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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |