Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02750254
• Other study ID #: 201604081
• Status: Terminated
• Phase: Phase 1
• Start date: June 27, 2016
• Est. completion date: October 14, 2020

Study information

• Verified date: October 2020
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: October 14, 2020
• Est. primary completion date: May 24, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Fludarabine

Radiation:
• Fractionated total body irradiation

Drug:
• Busulfan

• Cyclophosphamide

Radiation:
• Single dose total body irradiation

Drug:
• Melphalan

• Granulocyte-colony stimulating factor

Procedure:
• Stem cell transplant

Drug:
• Azacitidine

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Maximum tolerated dose of azacitidine (Phase I only)		Estimated to be 3-4 months (completion of all Phase I patients through Day 35)
Primary	Grade II-IV acute GvHD rate of azacitidine (Phase II only)		Up to Day 100
Secondary	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
Secondary	Overall survival (OS)	OS is defined as the time from the date of Day 0 until death from any cause.	Up to 48 months
Secondary	Disease-free survival (DFS)		Up to 48 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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