Phase II Study to Evaluate Overall Response in Patients With Higher Risk Myelodysplastic Syndromes (MDS) Treated With Azacitidine With or Without Deferasirox.

Study Overview
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Brief Summary
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The primary objective of the study is to compare the overall response rate (inclusive of complete response, partial response and hematologic improvement) per IWG 2006 criteria in patients with higher risk MDS treated with azacitidine with or without deferasirox achieved over the course of one year. Hematologic improvement must be maintained for at least 8 weeks.

Official Title
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A 2-year, Multi-center, Phase II, Open-label, Fixed-dose, Randomized Comparative Trial of Azacitidine, With or Without Deferasirox in Patients With Higher Risk Myelodysplastic Syndromes

Conditions
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High Risk MDS

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Azacitidine plus Deferasirox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female, age ≥ 18 years Patients with higher risk MDS with a blast count < 20% at the time of screening IPSS Int-2 or High Risk Serum Ferritin ≥ 300 ng/mL at screening. Sexually active women must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or oophorectomy, or tubal ligation or be postmenopausal (defined as amenorrhea for at least 12 months) Exclusion Criteria: Patients currently receiving any therapy other than AZA for MDS (a ≥ 4 week washout period for any agent (excluding AZA) used to treat MDS prior to first dose of study treatment is required). Patients who have received > 2 cycles of AZA or decitabine at the time of randomization. Patients who have received iron chelation therapy within 1 month of screening. Patients who have received growth factors within 1 month of screening. Patients who have received Revlimid within 1 month of screening. Patients who have undergone hematopoietic stem cell transplant. ECOG Performance Status > 2 Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study treatment Patients with uncontrolled systemic hypertension Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease not controlled by standard medical therapy Patients with a diagnosis of or history of clinically relevant ocular toxicity related to iron chelation Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by liver biopsy or central ultrasound reading) Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive and ALT above the normal range). History of HIV positive test result (ELISA or Western blot) Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug Patients with an active malignancy (currently or within the past two years) with the exception of basal cell skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ. History of drug or alcohol abuse within the 12 months prior to enrollment. History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative. Patients with a known hypersensitivity to azacitidine, mannitol, or deferasirox. Calculated creatinine clearance <40mL/min Serum creatinine greater than 1.5x ULN at screening Urine protein/creatinine ratio> 1 AST or ALT greater than 3x ULN at screening Direct Bilirubin greater than 1.5x ULN at screening. Patients who received treatment with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days or are planning to receive other investigational drugs while participating in the study Patients participating in another therapeutic clinical trial Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after stopping AZA and should not father a child in this period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azacitidine<br>75mg/m2 7days/28 day cycle | Drug: Azacitidine<br>* SC or IV AZA at 75mg/m2 7 days/28 day cycle<br>|
| Experimental: Azacitidine and Deferasirox<br>azacitidine 75mg/m2 7 days/28 day cycle deferasirox 10 mg/kg/day | Drug: Azacitidine plus Deferasirox<br>* SC or IV AZA at 75mg/m2 7 days/28 day cycle DFX 10mg/kg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Per IWG 2006 Criteria | ORR (inclusive of CR, PR and HI) per IWG 2006 criteria including erythroid response, platelet response and neutrophil response over the course of one year. Hematologic improvement must be maintained for at least 8 weeks in order to count as HI. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response | Time to response is defined as time from the date of the first dose of study treatment to the date of the first documented hematologic improvement. | up to 24 months | 
| Duration of Response | Duration of response is defined as time from the date of the first observed hematologic improvement to the date of the first subsequent documented disease progression or relapse per IWG 2006 criteria. | up to 24 months | 
| Progression Free Survival | Progression free survival is defined as time from the date of the first dose of study treatment to the date of the first documented disease progression or relapse per IWG 2006 criteria. | Up to 24 months | 
| Overall Survival | Overall survival is defined as time from the date of the first dose of study treatment to the date of death from any cause. | up to 24 months | 
| Time to AML Transformation | Time to AML transformation is defined as time from the date of the first dose of study treatment to the date of the first documented bone marrow blast count ≥ 20% per WHO classification 1999. | Up to 24 months | 
| Change in Serum Ferritin | Change in Serum Ferritin | up to 24 months | 
| Incidence of Adverse Events | Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs). | up to 24 months | 
| Rate of Infection | Median number of infections (positive bacterial, viral or fungal culture, or infection requiring IV antimicrobial, or infection resulting in hospitalization or death) in patients treated with azacitidine alone vs. azacitidine + deferasirox | up to 24 months | 
| Prevalence of MDS/AML Related Gene Mutations | Prevalence of the following mutations in the study population (TP53, EZH2, ETV6, RUNX1, ASXL1, other mutation that is present in ≥ 5% of patients) | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Int-2 MDS