Combination of 5-azacitidine and Lenalidomide in Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML) Myelodysplastic Syndromes

Study Overview
=================
Brief Summary
-----------------
The hypothesis of this study is that 5-aza and lenalidomide act synergistically in MDS and AML patients with chromosomal abnormalities involving monosomy 5 or del5q. Therefore, this phase I study will investigate the maximum tolerated dose (MTD) of lenalidomide in combination with a fixed dose of 5-aza in this patient population.

Detailed Description
-----------------
Cytogenetics are the main predictors of outcome in patients with AML. In fact, a monosomy 5 or del (5q) as single aberration are poor prognostic markers. Overall, the complete response rate for conventionally treated patients with newly-diagnosed AML with chromosome 5 abnormalities is about 31% to 37 % and all patients rapidly relapse if not rescued by allogeneic HSCT. The situation is almost similar in patients with high-risk MDS.Vidaza® has been shown in clinical trials to achieve remission rates in about 29% (CR+PR) of the patients while a total of 49% achieve improvement of blood counts.Revlimid® is also able to achieve complete remissions in advanced MDS and even overt leukemia with or without chromosome 5 abnormalities. Nevertheless, response rates are lower compared to low-risk MDS (IPSS Low/INT-1). Therefore, Revlimid® seems to be too weak as a single agent, but a promising compound for a combination therapy.

Official Title
-----------------
A Phase I Study of a Combination of 5-azacitidine Followed by Lenalidomide in High-risk MDS or Relapsed/Refractory AML Patients With Cytogenetic Abnormalities Including -5 or Del(5q)

Conditions
-----------------
Myelodysplastic Syndromes, Acute Myelogenous Leukemia

Intervention / Treatment
-----------------
* Drug: Azacitidine
* Drug: Lenalidomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Understand and voluntarily sign an informed consent form. Age >=18 years at the time of signing the informed consent form. Able to adhere to the study visit schedule and other protocol requirements. Relapsed or refractory AML (>30% blasts, FAB classification)with karyotype abnormalities involving monosomy 5 or del(5q) or MDS and t-MDS INT-2 or HIGH according to IPSS classification with karyotype abnormalities involving monosomy 5 or del(5q) either previously treated or untreated Not eligible for an immediate allogeneic HSCT (due to donor unavailability) All previous MDS or AML specific therapy with exception of corticosteroids not exceeding doses of 10mg/day prednisone must have been discontinued at least 1 week prior to study enrollment. Non-hematological toxicity (except alopecia) resulting from previous treatment must be resolved to WHO CTC Grade ≤ 2. ECOG performance status of < 3 at study entry. Laboratory test results within these ranges:Serum creatinine <= 2.0 mg/dL, Total bilirubin <= 3 x ULN, AST (SGOT) and ALT (SGPT) <= 3 x ULN Females of childbearing potential must agree to use a reliable form of contraception or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while on study). Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Known hypersensitivity to thalidomide, lenalidomide, 5-azacitidine or mannitol. Myocardial infarction within 6 months before study entry, New York Heart Association Class III or IV heart failure, uncontrolled angina or severe uncontrolled ventricular arrhythmias. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. Uncontrolled lung disease. Known positive for HIV or acute infectious hepatitis, type A, B or C. Participation in another clinical study in the 4 weeks prior to enrollment or during this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine and Lenalidomide<br>Azacitidine 75 mg/m² SC days 1-5 every 28 days for a maximum of 8 cycles and Lenalidomide 10 - 25 mg PO days 6-19 every 28 days for a maximum of 8 cycles | Drug: Azacitidine<br>* 75 mg/m² SC days 1-5 every 28 days for a maximum of 8 cycles<br>* Other names: Vidaza;Drug: Lenalidomide<br>* 10 - 25 mg PO days 6-19 every 28 days for a maximum of 8 cycles<br>* Other names: Revlimid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of Revlimid® (lenalidomide)in combination with Vidaza®(5-azacitidine) |  | during first cycle of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical and cytogenetic response |  | during therapy | 
| Safety (type, frequency, severity, and relationship of adverse events to study treatment) |  | during therapy | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
monosomy 5, del5q, lenalidomide, azacitidine