Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR

NCT ID: NCT02497404

Last Updated: 2021-09-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-13
• Study Completion Date: 2021-06-17

Brief Summary

The purpose of this study is to determine whether 5-Azacytidine priming before the conditioning regimen for subjects receiving a hematopoietic stem cell transplant is an effective treatment for high risk myeloid malignancies in complete remission (CR).

Detailed Description

This open label two-step phase II study is designed to determine the safety and efficacy of epigenetic priming with 5-Azacytidine immediately prior to reduced intensity conditioning for an in vivo T-cell depleted hematopoietic stem cell transplantation for high risk myeloid malignancies in complete remission (CR).

Subjects will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine, melphalan and total body irradiation (TBI) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated Human Leukocyte Antigen (HLA) matched donor.

The effect of 5-azacytidine on global gene methylation will be assessed. Evaluations for safety, in particular for graft failure, transplant related mortality and acute graft versus host disease will be made on a weekly basis. Efficacy, as defined by disease free survival, will be evaluated with a bone marrow biopsy at the standard time points, which are one-, three-, six-, and twelve-months after transplant and upon clinical suspicion within regular follow-up visits - weekly for the first 3 months, then biweekly for 3 months, then monthly until one-year post-stem cell transplant. Thereafter, unless otherwise dictated by the clinical scenario, the follow up visits will be every 3 months.

Conditions

Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

5 Azacytidine

Patients will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor.

Group Type: EXPERIMENTAL

5-Azacytidine

Intervention Type: DRUG

Patients will be given a five day course of subcutaneous 5-azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. 5-Azacytidine 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9,

-8 and -7. This will be administered on an outpatient basis if possible.

Fludarabine

Intervention Type: DRUG

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.

Melphalan

Intervention Type: DRUG

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Melphalan will be given at 140 mg/m2 IV on day -3.

Alemtuzumab

Intervention Type: DRUG

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.

Total Body Irradiation

Intervention Type: RADIATION

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Total Body Irradiation (TBI) will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).

Interventions

5-Azacytidine

Patients will be given a five day course of subcutaneous 5-azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. 5-Azacytidine 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9,

-8 and -7. This will be administered on an outpatient basis if possible.

Intervention Type: DRUG

Fludarabine

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.

Intervention Type: DRUG

Melphalan

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Melphalan will be given at 140 mg/m2 IV on day -3.

Intervention Type: DRUG

Alemtuzumab

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.

Intervention Type: DRUG

Total Body Irradiation

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Total Body Irradiation (TBI) will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).

Intervention Type: RADIATION

Other Intervention Names

Vidaza; Fludara; Alkeran; Campath, Lemtrada; TBI

Eligibility Criteria

Inclusion Criteria

• Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as specified below:

1. Acute myeloid leukemia with poor risk cytogenetics in complete morphologic remission. These include: del (5q)/-5, del (7q)/-7, abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (≥ 3 unrelated abnormalities); or

2. Acute myeloid leukemia with either Flt-3, TET-2, p53, DNMT3A, or ASXL1 mutation, mutations of genes involved in the chromatin/spliceosome category (EZH2, SRSF2, U2AF1, ZRSR2), BCOR, and RUNX1, as well as MLL rearrangement, EVI1 overexpression in complete morphologic remission; or

3. Acute myeloid leukemia with a white blood cell count of greater than or equal to 50,000/mcL at presentation in first complete morphologic remission; or

4. Acute myeloid leukemia in first complete morphologic remission, having required more than one course of induction chemotherapy to attain remission status; or

5. Acute myeloid leukemia, all types, excluding M3 (Promyelocytic leukemia) in second or higher complete morphologic remission; or

6. Myelodysplastic syndromes (intermediate-2, high risk and chronic myelomonocytic leukemia (CMML) with bone marrow blasts <5%); or

7. Secondary acute myeloid leukemia on the basis of prior MDS or prior myeloproliferative neoplasm (MPN) in complete morphologic remission

• Life expectancy not severely limited by concomitant disease
• Karnofsky Performance Score greater than or equal to 70%.
• Adequate organ function as defined below:

Serum Bilirubin:<2.0 mg/dL; Alanine Aminotransferase (ALT) (SGPT): <3 x upper limit of normal; Creatinine Clearance:>60 mL/min (eGFR as estimated by the modified Modification of Diet in Renal Disease Study (MDRD) equation)

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• Evidence of chronic active hepatitis or cirrhosis
• HIV infection
• Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown.
• There are no prior therapies or concomitant medications that would render the patients ineligible

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Weill Medical College of Cornell University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sebastian Mayer, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Medical College of Cornell University

Locations

Weill Cornell Medical College

New York, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1306014009

Identifier Type: -

Identifier Source: org_study_id