Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

NCT02750254 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 201604081
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

• Event-free survival (EFS)

  Up to 48 months

• Overall survival (OS)

  Up to 48 months

• Disease-free survival (DFS)

  Up to 48 months

• Non-relapse mortality (NRM)

  Up to Day 100

• Time to neutrophil engraftment

  Up to 12 months

Study Arms (1)

Arm 1: Azacitidine

EXPERIMENTAL

* 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; 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

Interventions

Fludarabine DRUG

Also known as: Fludara, 2-Fluoro-ara-A Monophosphate, 2-Fluoro-ara AMP, FAMP

Arm 1: Azacitidine

Fractionated total body irradiation RADIATION

Arm 1: Azacitidine

Busulfan DRUG

Also known as: Myerlan, Busulphan

Arm 1: Azacitidine

Cyclophosphamide DRUG

Also known as: Cytoxan, CPM, CTX, CYT

Arm 1: Azacitidine

Single dose total body irradiation RADIATION

Arm 1: Azacitidine

Melphalan DRUG

Also known as: Alkeran, Phenylalanine mustard

Arm 1: Azacitidine

Granulocyte-colony stimulating factor DRUG

Also known as: G-CSF, Plerixafor, Mozobil, Neupogen, Filgrastim

Arm 1: Azacitidine

Stem cell transplant PROCEDURE

Arm 1: Azacitidine

Azacitidine DRUG

Also known as: Vidaza, Ladakamycin

Arm 1: Azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

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

MeSH Terms

Conditions

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

Interventions

fludarabine; fludarabine phosphate; Busulfan; Cyclophosphamide; Whole-Body Irradiation; Melphalan; Granulocyte Colony-Stimulating Factor; plerixafor; Filgrastim; Stem Cell Transplantation; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Proteins; Biological Factors; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Mark Schroeder, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2016
• First Posted: April 25, 2016
• Study Start: June 27, 2016
• Primary Completion: May 24, 2017
• Study Completion: October 14, 2020
• Last Updated: October 20, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)