Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Study Overview
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Brief Summary
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Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL); however, human leukocyte antigen (HLA)-matched donor availability continues to be a major hurdle. Historically, HLA haploidentical donor hematopoietic cell transplantation (haplo-HCT) was associated with high incidences of graft rejection and excessive non-relapse mortality (NRM), but recent advances utilizing post-transplant cyclophosphamide (PT-Cy) have revolutionized haplo-HCT and the outcomes are now comparable to allo-HCT using more traditional HLA matched related and unrelated donors. However, graft-versus-host disease (GvHD) continues to be a problem and is associated with significant morbidity and mortality in allo-HCT patients including those who receive haplo-HCT on PT-Cy platform. The aim of this early phase study is to investigate the safety and overall efficacy of azacitidine in reducing the incidence and severity of GvHD when added to PT-Cy based haplo-HCT platform for patients with AML, ALL, or advanced MDS.

Official Title
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A Phase I/II Study of Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Fludarabine
* Radiation: Fractionated total body irradiation
* Drug: Busulfan
* Drug: Cyclophosphamide
* Radiation: Single dose total body irradiation
* Drug: Melphalan
* Drug: Granulocyte-colony stimulating factor
* Procedure: Stem cell transplant
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute leukemia (AML/ALL) or advanced MDS (INT-2 or high risk) in complete remission (CR/CRc/CRi) documented by bone marrow biopsy done within 30 days prior to the initiation of conditioning regimen. Available HLA-haploidentical donor that meets the following criteria: Immediate family member (sibling, offspring, or parent) At least 18 years of age HLA-haploidentical donor/recipient match by class I serologic typing at the A&B locus. In the treating physician's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC No active hepatitis (B, C), HTLV, and HIV infections Not pregnant Karnofsky performance status ≥ 70 % Adequate organ function as defined below: Total bilirubin ≤ 2.5 mg/dl (unless the patient has a history of Gilbert's syndrome) AST(SGOT) and ALT(SGPT) ≤ 3.0 x IULN Creatinine ≤ 2.0 x IULN OR estimated creatinine clearance ≥ 30 mL/min/1.73 m^2 by Cockcroft-Gault Formula Oxygen saturation ≥ 90% on room air LVEF ≥ 40% FEV1 and FVC ≥ 50% predicted, corrected DLCO ≥ 40% predicted At least 18 years of age at the time of study registration Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable) Exclusion Criteria: Recipients with donor sensitive antibodies (DSA), defined by 2000 or higher MFI against one or more class I or II antigens Known HIV or active Hepatitis B or C infection Underwent a previous related or unrelated allogeneic transplant Known hypersensitivity to one or more of the study agents Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of the conditioning regimen. Pregnant and/or breastfeeding Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmias. Presence of a readily available 6/6 matched sibling donor who is a candidate for donation

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Azacitidine<br>Treating physician must choose from one of these conditioning regimens (will be given per standard of care) fludarabine and fractionated total body irradiation (Flu/FrTBI) fludarabine and busulfan (Flu/Bu4) fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI) fludarabine and melphalan (Flu/Mel) reduced-intensity fludarabine and busulfan (Flu/Bu2) G-CSF from Day -5 through Day -1 per standard of care On Day 0, the allograft will be infused per standard of care. Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days Cyclophosphamide on Days +3 and +4 post-transplant | Drug: Fludarabine<br> <br> * Other names: FAMP;Radiation: Fractionated total body irradiation<br> <br> Drug: Busulfan<br> <br> * Other names: Busulphan;Drug: Cyclophosphamide<br> <br> * Other names: CYT;Radiation: Single dose total body irradiation<br> <br> Drug: Melphalan<br> <br> * Other names: Phenylalanine mustard;Drug: Granulocyte-colony stimulating factor<br> <br> * Other names: Filgrastim;Procedure: Stem cell transplant<br> <br> Drug: Azacitidine<br> <br> * Other names: Ladakamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | Up to Day 35 | 
| Maximum tolerated dose of azacitidine (Phase I only) |  | Estimated to be 3-4 months (completion of all Phase I patients through Day 35) | 
| Grade II-IV acute GvHD rate of azacitidine (Phase II only) |  | Up to Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | EFS is defined as the time from date of first dose of the preparative regimen until failure to engraft, treatment failure, disease progression/relapse, or death from any cause (whichever occurs first). | Up to 48 months | 
| Overall survival (OS) | OS is defined as the time from the date of Day 0 until death from any cause. | Up to 48 months | 
| Disease-free survival (DFS) |  | Up to 48 months | 
| Non-relapse mortality (NRM) | NRM is defined as death that results from a transplant procedure-related complication (e.g. infection, organ failure, hemorrhage, GvHD) rather than from relapse of the underlying disease prior to Day +100 visit. | Up to Day 100 | 
| Time to neutrophil engraftment | Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen-induced nadir. | Up to 12 months | 
| Time to platelet engraftment | Time to platelet engraftment is measured by determining the first of 3 consecutive measurements of platelet count ≥ 20,000/ul without platelet transfusion support for 7 days. | Up to 12 months | 
| Rate of acute GvHD | Incidence and severity of acute GvHD will be assessed based on the modified Glucksberg criteria and Seattle criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). | Up to Day 100 | 
| Rate of chronic GvHD | Incidence and severity of chronic GvHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s). | Day 100 through Day 365 |