E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | 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 evaluate the efficacy of lenalidomide (RevlimidTM) in low/int-1 risk MDS with or without a treatment with Epo (NeoRecormonTM)/G-CSF (NeupogenTM) in terms of hematological improvement (HI) as defined by the modified response criteria of the IWG for MDS. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of lenalidomide (RevlimidTM) in low/int-1 risk MDS with or without Epo (NeoRecormonTM)/G-CSF (NeupogenTM)
- Time-to-HI and duration-of-HI
- The number of given treatment cycles per patient and for arm B the number of patients receiving Epo and/or G-CSF
- The response rate (in terms of CR, PR, including cytogenetic response according to the modified response criteria of the IWG for MDS)
- Progression-Free-Survival (i.e. time from registration to disease progression, including progression to leukemia, or death from any cause)
- Transfusion requirements of red blood cells
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients with MDS classified as
- RA, RARS and RAEB (with <10% myeloid blasts), CMML (with <10% myeloid
blasts), according to FAB or
- RA, RARS, RCMD, RCMD-RS, RAEB-1, MDS-U according to WHO or
- patients with MPD/MDS (CMML-1 according to WHO) with a WBC ≤ 12x109/l
with an IPSS ≤ 1.0
- Hb ≤ 6.2 mmol/l (10.0 g/dl)
or Hb ≤ 7.2 mmol/l and ANC ≤ 1.0x109/l
or red blood cell transfusion dependent
- Age ≥ 18 years
- WHO performance status 0-2
- Patient not previously treated with Epo/G-CSF, or
failure of response or relapse after hematological improvement or disease
progression to maximal RAEB-1 after previous therapy with Epo/G-CSF
- Serum creatinin < 150 µmol/l
- Serum billirubin < 25 µmol/l and ASAT, ALAT and Alkaline phosphatase < 2.5 times
the upper limit of normal, except if related to disease
- The patient must give written informed consent
- Negative pregnancy test within 7 days prior to start of study drug, if applicable.
- Patient (all men, pre-menopausal women) agrees to use adequate contraceptive
methods.
- Serum erythropoietin level
> 200 U/l or
≤ 200 U/l if failure of response or loss of hematological improvement or disease
progression to maximal RAEB-1 after prior standard therapy with Epo/G-CSF;
Epo/G-CSF should be stopped at least 1 month before randomization.
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E.4 | Principal exclusion criteria |
- Severe cardiac, pulmonary, neurologic, metabolic or psychiatric diseases or active malignancies.
- Anemia due to other causes than MDS including iron, B12 and folate deficiencies, auto-immune hemolysis and/or paroxysmal noctural hemoglobinuria (PNH)
- Hypoplastic MDS
- High predictive score (score 0 or 1) to respond on standard treatment with Epo/G-CSF according to guidelines
- Active uncontrolled infection
- Absolute neutrophil count (ANC) < 0.5x109/l
- Patients dependent on platelet transfusions or with platelet counts < 25x109/l or patients with active bleeding
- Patients treated with biological response modifiers (i.e. growth factors, immunosuppressive agents and/or chemotherapy) within 1 month prior to randomization
- Lactating women
- Prior treatment with lenalidomide
- Prior CTCAE ≥ grade 3 allergic reaction/hypersensitivity to thalidomide
- Prior CTCAE ≥ grade 3 rash/blistering while taking thalidomide
- Prior CTCAE ≥ grade 3 allergic/hypersensitivity to Epo and/or G-CSF
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E.5 End points |
E.5.1 | Primary end point(s) |
-Primary endpoint
• Hematological improvement (HI) according to IWG 2006 criteria
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Hematological improvement (HI) will be assessed on day 1 of every cycle starting form day 1 of cycle 2.
HI will be assessed for each cell line. Dependent on the relevant pre-treatment parameter e.g. Hb, platelet count or ANC, HI will be assessed and responses must last at least for 8 weeks.
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E.5.2 | Secondary end point(s) |
Secondary endpoints
• Adverse events of CTCAE ≥ grade 2 (see appendix E)
• Time-to-HI and duration-of-HI (i.e. time from HI to relapse after HI or death from any cause)
• Number of given treatment cycles per patient, and especially for arm B the number of patients receiving Epo and/or G-CSF
• Response rate (in terms of CR, PR, including cytogenetic response according to the modified response criteria of the IWG for MDS [40], appendix C)
• Progression-free-survival, i.e. time from registration to relapse, disease progression (as defined in appendix C) or death from any cause
• Leukemic evolution. The risk of leukemic evolution will be calculated with competing risk death without previous evolution
• Number of transfusions of red blood cells and duration of RBC transfusion independence
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Hematological improvement (HI) will be assessed on day 1 of every cycle starting form day 1 of cycle 2.
Disease and cytogenetic response should be assessed at month 6 and 12 or at any indication (e.g. off treatment or (signs of) progressive disease). |
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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 | 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 |
treatment without epo and/or G-CSF |
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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 | 60 |
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 | No |
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 | 9 |
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 | 9 |
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 |