Azacitidine Plus Deferasirox (ICL670) in Higher Risk Myelodysplastic Syndromes (MDS)

Study Overview
=================
Brief Summary
-----------------
Myelodysplastic syndromes are common blood disorders that can affect as many as one in 1000 Canadians over the age of 65. They are characterized by low blood counts that require frequent blood transfusions. The development of iron overload in these patients is inevitable. The iron deposits in vital organs such as the heart and the liver and can lead to organ dysfunction. Deferasirox is a well-studied drug that helps remove iron from the body. Most people with this disorder die due to progression of their disease to acute leukemia through multiple mechanisms. Iron overload in patients with myelodysplastic syndromes has been shown to be associated with shorter survival, and potentially a higher chance of leukemia. In a certain sub-group of higher risk patients, the drug azacitidine has been shown to decrease the chance of progression to leukemia and death from it. Thus, it is presently the standard of care for these patients. However, 50% of higher risk patients are still unresponsive to this medication, leaving a large group of patients for which other treatment options are emergently needed. Given that a large proportion of higher risk MDS patients fail to respond to azacitidine, and the evidence that iron deposition may lead to increased leukemic transformation, we would like to study whether iron removal from the body with deferasirox potentiates azacitidine in its effects on overall survival, as well as the chance of leukemia transformation. This question needs to be addressed in a randomized controlled trial, and the first step is a preliminary study to determine if the combination of azacitidine and deferasirox has any biologic effect. This study will determine whether this combination leads to blood count improvement over azacitidine alone. If this drug combination ultimately proves more useful than azacitidine alone with respect to survival, this has the potential to impact the care of a large proportion of patients with myelodysplastic syndromes.

Detailed Description
-----------------
Patients with stable disease after 6 cycles of AZA with higher risk MDS will be randomized to either standard of care (continued AZA until progression ) or AZA + defasirox. Primary endpoint is augmented response rate by the addition of deferasirox

Official Title
-----------------
A PHASE II STUDY OF Azacitidine Plus Deferasirox (ICL670) in Higher Risk Myelodysplastic Syndromes (MDS)

Conditions
-----------------
Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Deferasirox + Azacitidine
* Drug: Azacitidine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults >18 yrs of age WHO defined MDS with Higher risk MDS (IPSS int-2/high) Azacitidine X at least 6 cycles with no hematologic improvement/no disease progression as per IWG 2006 criteria Ferritin >500 µg/L If transfusion independent, must have Hb <110 g/L OR Neutrophils < 1,000/mL OR Platelets < 100,000/mL ECOG ≤2 CrCl >40 ml/min Exclusion Criteria: Increased ALT (>300 U/L) Uncontrolled infection HIV+ Pregnant or breast-feeding Previous and concurrent iron chelation Concurrent use of hematopoietic growth factors including erythropoietin, darbepoietin and granulocyte colony stimulating factor Concurrent use of other disease modifying agents including cytotoxic chemotherapy, histone deacetylase inhibitors, other hypomethylating agents or lenalidomide

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox + Azacitidine<br>Azacitidine 75 mg/m2 daily X 7 days every 28 days for 6 cycles + Deferasirox 10-30 mg/kg/d depending on transfusion needs | Drug: Deferasirox + Azacitidine<br>* Deferasirox: 20 mg/kg/d for < 14ml/kg/mo pRBCs (  <4U/mo), 30mg/kg/d for ≥14ml/kg/mo pRBCs(≥4U/mo), 10mg/kg/d for transfusion-independent patients<br>* Other names: Vidaza;Drug: Azacitidine<br>* Azacitidine 75mg/m2 sc daily X 7 days (5-2-2 schedule permitted) on a 28 day cycle for 6 cycles<br>* Other names: Vidaza;|
| Active Comparator: Azacitidine<br>Azacitidine 75 mg/m2 daily X 7 days every 28 days for 6 cycles | Drug: Azacitidine<br>* Azacitidine 75mg/m2 sc daily X 7 days (5-2-2 schedule permitted) on a 28 day cycle for 6 cycles<br>* Other names: Vidaza;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in proportion of patients with hematologic improvement as defined by the IWG criteria30 with the addition of deferasirox to azacitidine compared with azacitidine alone in higher risk non-responding MDS patients after 6 cycles of azacitidine. | improvement in blood counts or remission status | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability (defined by the percentage of patients able to remain on deferasirox for 6 cycles concurrent with azacitidine) and safety (type, using CTCAE version 4.0, frequency, severity, and relationship of adverse events to study therapy) | toxicity as defined by compliance | 6 months | 
| Percentage and absolute change in serum ferritin and labile plasma iron (LPI) between baseline and end of study | Impact of experimental arm on iron parameters | 6 months | 
| Percentage change in CD34 cell intracellular reactive oxygen species (ROS) from baseline to end of study. | Impact of experimental arm on markers of oxidative stress in the bone marrow | 6 months | 
| Percentage change in erythroid colony forming units (BFU-E and CFU-E) from baseline to end of study | Impact of experimental arm on erythropoiesis | 6 months | 
| Percentage change in markers of DNA damage (lipid peroxidation, GSH content, and gH2AX expression), and activity of NFkappaB and Akt signaling pathways between baseline and end of study. | Impact of experimental arm on markers of DNA damage | 6 months |