Azacitidine in Patients Undergoing Matched Unrelated Stem Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this phase I/II study is to define the maximum tolerated dose of 5-AzaC and the effect on grade II-IV GvHD when given after matched unrelated donor transplant (MUD).

Official Title
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Phase I/II Trial of Intravenous Azacitidine in Patients Undergoing Matched Unrelated Stem Cell Transplantation

Conditions
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Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention / Treatment
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* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet the following criteria within 30 days prior to Day 0 unless otherwise noted. Phase I: Diagnosis of any hematological malignancy listed below (excluding myelofibrosis) in remission or with stable minimal residual disease Acute myelogenous leukemia (AML) in 1st or subsequent remission or in relapse after any remission Acute lymphoblastic leukemia (ALL) in 1st or subsequent remission or in relapse after any remission Myelodysplastic syndrome either intermediate 1 or 2, or high risk by the International Prognostic Scoring System Chronic myelogenous leukemia (CML) in accelerated or second chronic phase Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete remission, partial remission, or refractory relapse Chronic lymphocytic leukemia (CLL), Rai Stage 2-4, failing at least 2 prior regimens Multiple myeloma (MM), Stage 2-3 Myeloproliferative disorder or neoplasm Phase II: Diagnosis of AML in remission 1 or 2 or a diagnosis of myelodysplastic syndrome either intermediate 1 or 2, or high risk by the International Prognostic Scoring System. Patients with MDS must be transplant candidates by current clinical standards. Patients who have been treated with hypomethylating agents prior to entering the study are eligible. Must have matched unrelated donor (8 of 8 HLA match at A, B, C, and DR loci) by high resolution DNA typing Must have donor peripheral blood stem cells mobilized by NMDP standards. No bone marrow donors. Must have 2-8 x 10^6 CD34+ cells/kg (recipient weight) infused on Day 0. Must have at least one additional aliquot of >=1 x 10^6 CD34/kg cryopreserved cells stored at the time of transplant. Must receive a myeloablative or reduced intensity conditioning regimen for SCT as defined by the CIBMTR Cyclophosphamide and single dose total body irradiation Fludarabine and busulfan Fractionated TBI and cyclophosphamide Busulfan and cyclophosphamide Must be able to receive GVHD prophylaxis with tacrolimus and methotrexate. Must be ≥ 18 yrs old and ≤ 70 yrs old. Azacitidine is not approved by the FDA for use in children. Must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Must have laboratory results indicating: Total bilirubin < 2.0 mg/dl, unless a diagnosis of Gilbert's disease AST/ALT ≤ 3 X the upper limit of institutional normal Serum creatinine ≤ 2.0 mg/dl Patient must have ability to understand and willingness to provide written informed consent prior to participation in the study and any related procedures being performed. The effects of azacitidine on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because category D agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing age must have a negative serum pregnancy test (ß-human chorionic gonadotropin) within 72 hours prior to initiating the conditioning regimen and be willing to not become pregnant by using effective contraception while undergoing treatment and for at least 3 months after the last dose of azacitidine. Men must be willing not to father a new child while receiving therapy. They must use an effective barrier method of contraception during the study and for 3 months following the last dose. Exclusion Criteria: Must not have myelofibrosis or other disease known to prolong neutrophil engraftment to > 28 days after transplant. Must not be receiving any other investigational agents within 14 days of first dose of azacitidine (Day 7). Must not have myeloablative conditioning as defined below: TBI < or = Gy +/- purine analog Flu + Cy +/- ATG Flu + AraC + Ida Cladribine + AraC Total Lymphoid Irradiation + ATG Must not receive antithymocyte globulin as part of pre-transplant conditioning regimens. Antithymocyte globulin is excluded due to its potential impact on modulating the incidence of GvHD or GvL. Must not have uncontrolled intercurrent illness including ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements. Must not be pregnant or breastfeeding. Pregnant women are excluded from this study because azacitidine is a Category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with azacitidine, breastfeeding should be discontinued if the mother is treated azacitidine. These potential risks may also apply to other agents used in this study. Must not have a known or suspected hypersensitivity to azacitidine, mannitol, or compounds of similar composition to azacitidine.. Must not have an advanced malignant hepatic tumor. Must not be HIV, HBV, or HCV positive.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Conditioning treatment Transplant on Day 0 15 mg/m^2 azacitidine Days 7-11 15 mg/m^2 azacitidine Days 35-39 15 mg/m^2 azacitidine Days 63-67 15 mg/m^2 azacitidine Days 91-95 | Drug: Azacitidine<br> <br> * Other names: 5-AzaC;|
| Experimental: Cohort 2<br>Conditioning treatment Transplant on Day 0 30 mg/m^2 azacitidine Days 7-11 30 mg/m^2 azacitidine Days 35-39 30 mg/m^2 azacitidine Days 63-67 30 mg/m^2 azacitidine Days 91-95 | Drug: Azacitidine<br> <br> * Other names: 5-AzaC;|
| Experimental: Cohort 3<br>Conditioning treatment Transplant on Day 0 37.5 mg/m^2 azacitidine Days 7-11 37.5 mg/m^2 azacitidine Days 35-39 37.5 mg/m^2 azacitidine Days 63-67 37.5 mg/m^2 azacitidine Days 91-95 | Drug: Azacitidine<br> <br> * Other names: 5-AzaC;|
| Experimental: Cohort 4<br>Conditioning treatment Transplant on Day 0 45 mg/m^2 azacitidine Days 7-11 45 mg/m^2 azacitidine Days 35-39 45 mg/m^2 azacitidine Days 63-67 45 mg/m^2 azacitidine Days 91-95 | Drug: Azacitidine<br> <br> * Other names: 5-AzaC;|
| Experimental: Phase II Cohort<br>Conditioning treatment Transplant on Day 0 Dose determined in Phase I - 45 mg/m^2 azacitidine Days 7-11 Dose determined in Phase I - 45 mg/m^2 azacitidine Days 35-39 Dose determined in Phase I - 45 mg/m^2 azacitidine Days 63-67 Dose determined in Phase I - 45 mg/m^2 attitudinize Days 91-95 | Drug: Azacitidine<br> <br> * Other names: 5-AzaC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: to Determine the Maximum Tolerated Dose (MTD) of Azacitidine in Patients Undergoing Matched (8 Out of 8) Unrelated Donor Transplant for Any Hematological Malignancy in Remission or With Stable Disease. | The MTD is defined as the dose level immediately below the dose level at which patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity. | 28 days | 
| Phase II: Number of Participants With Grades II-IV Acute GvHD | GVHD rate and severity will be assessed based on modified Glucksberg criteria. Grade II-IV and III-IV aGVHD in first 180 days after transplant will be assessed. | Day +180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Grades III-IV aGVHD at Day +180. | GVHD rate and severity will be assessed based on modified Glucksberg criteria. | Day +180 | 
| Overall Survival as Measured by Number of Participants Alive at 1 Year After Transplant | Date of transplant to the date of death from any cause. | One year after transplant | 
| Treatment-related Mortality | Death that results from a transplant procedure-related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause. | Day +140 | 
| Number of Participants Who Relapsed Within the First Year of Transplant | Recurrence of the original malignant disease after transplantation. The time to relapse is the time to the first observation of hematologic, radiographic, or cytogenetic changes, which result in characterization as relapse. | Within the first year of transplant | 
| Rate of Chronic GvHD |  | One year after transplant |