Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

The Washington University

Status and phase

Terminated

Phase 1

Conditions

Acute Lymphocytic Leukemia

Myelodysplastic Syndrome

Acute Myeloid Leukemia

Treatments

Radiation: Fractionated total body irradiation

Drug: Azacitidine

Drug: Fludarabine

Drug: Granulocyte-colony stimulating factor

Radiation: Single dose total body irradiation

Drug: Busulfan

Procedure: Stem cell transplant

Drug: Cyclophosphamide

Drug: Melphalan

Study type

Interventional

Funder types

Other

Identifiers

NCT02750254

201604081

Details and patient eligibility

About

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.

Enrollment

5 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

5 participants in 1 patient group

Arm 1: Azacitidine

Experimental group

Description:

* 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

Treatment: