Clinical trial NCT02497404: Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR
Official title: Epigenetic Priming With 5-Azacytidine Prior to in Vivo T-cell Depleted Allogeneic Stem Cell Transplantation for Patients With High Risk Myeloid Malignancies in Morphologic Remission
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Erythroblastic, Acute
Myelodysplastic Syndromes
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
First posted: 2015-07-14
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Disease Free Survival at 1 Year Post-transplant
timeFrame: 1 year post-transplant
Secondary outcomes:
measure: Disease Free Survival at 6 Months Post-transplant
timeFrame: 6 months post-transplant
measure: Disease Free Survival at 2 Years Post-transplant
timeFrame: 2 years post-transplant
measure: Overall Survival at 6 Months Post-transplant
timeFrame: 6 months post-transplant
measure: Overall Survival at 1 Year Post-Transplant
timeFrame: 1 year post-transplant
measure: Overall Survival at 2 Years Post-Transplant
timeFrame: 2 years post-transplant
measure: Graft Failure
timeFrame: 21 days post-transplant
measure: Acute Graft-versus-Host Disease (GVHD)
timeFrame: 2 years post-transplant
measure: High-Risk Extensive Chronic Graft-versus-Host-Disease
timeFrame: 2 years post-transplant
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Sebastian Mayer, MD
role: PRINCIPAL_INVESTIGATOR
References: