Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Stem cell transplant; Drug: Melphalan; Drug: Busulfan; Drug: Azacitidine; Radiation: Fractionated total body irradiation; Radiation: Single dose total body irradiation; Drug: Granulocyte-colony stimulating factor

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1: Azacitidine; 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: Cyclophosphamide; Other Names: Cytoxan; CPM; CTX; CYT; Drug: Fludarabine; Other Names: Fludara; 2-Fluoro-ara-A Monophosphate; 2-Fluoro-ara AMP; FAMP; Procedure: Stem cell transplant; Drug: Melphalan; Other Names: Phenylalanine mustard; Alkeran; Drug: Busulfan; Other Names: Busulphan; Myerlan; Drug: Azacitidine; Other Names: Ladakamycin; Vidaza; Radiation: Fractionated total body irradiation; Radiation: Single dose total body irradiation; Drug: Granulocyte-colony stimulating factor; Other Names: Filgrastim; G-CSF; Neupogen; Mozobil; Plerixafor

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2016
• Primary Completion (Actual): May 24, 2017
• Study Completion (Actual): October 14, 2020

Study Registration Dates

• First Submitted: April 18, 2016
• First Submitted That Met QC Criteria: April 20, 2016
• First Posted (Estimate): April 25, 2016

Study Record Updates

• Last Update Posted (Actual): October 20, 2020
• Last Update Submitted That Met QC Criteria: October 16, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Myelodysplastic Syndromes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Cyclophosphamide; Lenograstim; Melphalan; Azacitidine; Fludarabine; Fludarabine phosphate; Busulfan; Plerixafor
• Other Study ID Numbers: 201604081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No