A Phase II Study of the Efficacy and Safety of Lenalidomide Combined to Azacitidine in Intermediate-2 or High Risk MDS With Del 5q
A Phase II Study of the Efficacy and Safety of Lenalidomide Combined to Azacitidine in Intermediate-2 or High Risk MDS With Del 5q
Higher risk MDS with del(5q) carry very poor prognosis, but show some response to azacitidine and Lenalidomide as single agents . The combination of Lenalidomide and Azacytidine is currently tested in non del 5q MDS patients. Preliminary results have been recently presented at ASH meeting (Sekeres et al, 2007).
Overall, the combination of Lenalidomide and Azacitidine is well-tolerated and early results suggest some efficacy in advanced MDS without del 5q.
In this trial, we will combine Lenalidomide to Azacytidine in higher risk MDS with del (5q).
Patients will receive azacitidine( 75mg/m2/day for 5 days every 28 days) combined to escalating doses of lenalidomide (starting at relatively low dose).
For patients in hematological CR, PR, HI or marrow CR after cycle 2 or 4, it is mandatory to continue on Azacitidine + Lenalidomide as long as there is no unacceptable toxicity or overt progression, with the schedule that yielded response.
In patient still responding after 52 weeks, the drug will continue to be supplied, and follow up until death will be continued in all patients.
Inclusion Criteria:
age > ou = 18 years and < 75 years.
must understand and voluntarily sign an informed consent form.
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.
must be able to adhere to the study visit schedule and other protocol requirements.
prior thalidomide allowed.
documented diagnosis of MDS (according to FAB definition, ie. with marrow blasts up to 30%, or CMML with WBC < 13000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease.
with an associated del 5q[31](the deleted chromosomal region must include 5q[31]), with or without additional cytogenetic abnormalities.
female subjects of childbearing potential must:
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 amenorrhea this applies unless the subject commits to absolute and continuous abstinence confirmed on a monthly basis, to avoid pregnancy for the duration of study.
the following are effective methods of contraception:
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.
Male patients must :
All subjects must :
Signed informed consent prior to start of any study-specific procedures,
Ability to participate to a clinical trial and adhere to study procedures.
A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria: