A Study of Combined Deferasirox, Vitamin D and Azacytidine in High Risk MDS
A Study of Combined Deferasirox, Vitamin D and Azacytidine in High Risk MDS
Determinate safety and response rate of the association Deferasirox -Vitamine D - Azacitidine
 in treatment of high risk MDS

 Deferasirox Exjade:

 The dose of Deferasirox will be assigned according to the ferritin level. Dose escalation is
 scheduled during the phase I, with 5 additional patients per group.

 The maximal tolerated dose of Deferasirox will be required for the phase II of the study.

 The first dose will be assigned according to the ferritin level of the patient at time of
 inclusion:

 5 mg/kg/d if the ferritin is >300ng/ml and < 1000ng/ml in Group 1 10 mg/kg/d if the ferritin
 is ≥1000ng/ml) in Group 2

 Group 1 : Ferritin 300 to 1000ng /ml:

 -  cohort 1 : 5 mg/kg/d

 -  cohort 2 : 10mg/kg/d

 -  cohort 3 : 15 mg/kg/d

 Group 2 : Ferritin > 1000ng /ml:

 -  cohort 1 : 10 mg/kg/d

 -  cohort 2 : 15mg/kg/d

 -  cohort 3 : 20 mg/kg/d

 5 patients will be treated by cohort. In absence of toxicity (extra-hematological
 toxicity grade 3 or 4 or hematological grade 4), 5 additional patients will be included
 in the next cohort.

 Deferasirox will be administrated once daily during all the study period. Uvedose will be
 administrated once weekly during all the study period (100.000 UI P.O).

 Azacitidine will be administrated sc at 75 mg/m²/d, during 7 days, J1 to J7 of each
 cycles(One cycle is 28 days)

 During phase I and II, Deferasirox will always be associated with Vitamin D and Azacitidine

 Patients will be received 6 cycles of treatment (except if progression, unacceptable toxicity
 or withdrawn of patients occured) After 3 and 6 cycles, an evaluation will be done to
 evaluate the efficacy of the treatment.

 No dose modification of deferasirox will be done after 3 cycles of treatment except in case
 of progression). After 6 cycles, patients with CR, PR, marrow CR or HI will be treated with
 the same dose of Deferasirox until progression .
Deferasirox will be administrated once daily in the morning on an empty stomach, 30 minutes
 before meal.

 Deferasirox will be stopped if the ferritin level is under 100 ng/ml,and could be restarted
 is the ferritin level increase to 200 ng/ml

 Uvedose dose could be adjusted according to the phosphocalcic metabolism parameters and the
 plasma Vitamin D3 level.
Inclusion Criteria:

 -  High risk MDS, according to OMS classification

 -  High risk CMML (WBC < 13 G/L)

 -  AREBT of the FAB classification with less than 30% of blastes

 -  IPSS>=1.5 (int-2 and high risk)

 -  Age >=18y

 -  Performance status<=2 (ECOG)

 -  Bilirubin and transaminase < 1.5 x ULN

 -  Normal renal function

 -  Patient not eligible for Allogeneic stem cell transplant

 -  Male and female patients must use an effective contraceptive method during the study
 and for a minimum of 3 months after study treatment.

 -  Agree the need for the use of a condom if engaged in sexual activity with a pregnant
 woman or a woman of childbearing potential. during the entire period of treatment,
 even if disruption of treatment and during 3 months after end of treatment

 -  Male patient: 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 one week after end of
 study drug therapy.

 -  Agree to learn about the procedures for preservation of sperm,before starting
 treatment

 -  Patient be able to adhere to the study visit schedule and other protocol requirements

 Exclusion Criteria:

 -  Active infection or uncontrolled disease

 -  Use of cytotoxic chemotherapeutic agents or experimental agents(agents that are not
 commercially available) for the treatment of MDS within 28 days. In case of used of
 cytotoxic chemotherapeutic agents or hypomethylating agent a wash out of 3 mont is
 required.

 -  Active Cancer or Cancer within one year before inclusion

 -  Previous calcic urinary lithiasis

 -  Previous hyperparathyroid primitive disease or uncontrolled

 -  Hypercalcemia, hyperphosphoremia, hypervitaminosis D

 -  Patient already include in another experimental study

 -  Active infection by HIV, hepatite B or C

 -  Pregnant or lactating females

 -  Patient not able (medical/psychiatric) to understand and sign the written consent

 -  Patients with a ferritin level less than 300ng/ml

 -  Patient eligible for an Allogeneic stem cell transplant