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Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Primary Purpose

Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Fludarabine

Fractionated total body irradiation

Busulfan

Cyclophosphamide

Single dose total body irradiation

Melphalan

Granulocyte-colony stimulating factor

Stem cell transplant

Azacitidine

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Washington University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm 1: Azacitidine

Arm 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

Outcomes

Primary Outcome Measures

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.

Maximum tolerated dose of azacitidine (Phase I only)

Grade II-IV acute GvHD rate of azacitidine (Phase II only)

Secondary Outcome Measures

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).

Overall survival (OS)

OS is defined as the time from the date of Day 0 until death from any cause.

Disease-free survival (DFS)

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.

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.

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.

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).

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).

Full Information

NCT ID

NCT02750254

First Posted

April 18, 2016

Last Updated

October 16, 2020

Sponsor

Washington University School of Medicine

1. Study Identification

Unique Protocol Identification Number

NCT02750254

Brief Title

Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Terminated

Why Stopped

Toxicity. Only enrolled patients in phase I portion of trial.

Study Start Date

June 27, 2016 (Actual)

Primary Completion Date

May 24, 2017 (Actual)

Study Completion Date

October 14, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphocytic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1: Azacitidine

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara, 2-Fluoro-ara-A Monophosphate, 2-Fluoro-ara AMP, FAMP

Intervention Type

Radiation

Intervention Name(s)

Fractionated total body irradiation

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Myerlan, Busulphan

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan, CPM, CTX, CYT

Intervention Type

Radiation

Intervention Name(s)

Single dose total body irradiation

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

Alkeran, Phenylalanine mustard

Intervention Type

Drug

Intervention Name(s)

Granulocyte-colony stimulating factor

Other Intervention Name(s)

G-CSF, Plerixafor, Mozobil, Neupogen, Filgrastim

Intervention Type

Procedure

Intervention Name(s)

Stem cell transplant

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Other Intervention Name(s)

Vidaza, Ladakamycin

Primary Outcome Measure Information:

Title

Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events

Description

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.

Time Frame

Up to Day 35

Title

Maximum tolerated dose of azacitidine (Phase I only)

Time Frame

Estimated to be 3-4 months (completion of all Phase I patients through Day 35)

Title

Grade II-IV acute GvHD rate of azacitidine (Phase II only)

Time Frame

Up to Day 100

Secondary Outcome Measure Information:

Title

Event-free survival (EFS)

Description

Time Frame

Up to 48 months

Title

Overall survival (OS)

Description

OS is defined as the time from the date of Day 0 until death from any cause.

Time Frame

Up to 48 months

Title

Disease-free survival (DFS)

Time Frame

Up to 48 months

Title

Non-relapse mortality (NRM)

Description

Time Frame

Up to Day 100

Title

Time to neutrophil engraftment

Description

Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen-induced nadir.

Time Frame

Up to 12 months

Title

Time to platelet engraftment

Description

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.

Time Frame

Up to 12 months

Title

Rate of acute GvHD

Description

Time Frame

Up to Day 100

Title

Rate of chronic GvHD

Description

Time Frame

Day 100 through Day 365

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark Schroeder, M.D.

Organizational Affiliation

Washington University School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://www.siteman.wustl.edu

Description

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

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Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

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