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Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS

Information source: University of Pittsburgh
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)

Intervention: 5-azacytidine (5-aza) maintenance therapy after HCT (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Annie Im, MD, Principal Investigator, Affiliation: University of Pittsburgh

Overall contact:
Ann Welsh, RN, Phone: 412-623-4897, Email: welshah2@upmc.edu

Summary

Despite improvements in outcomes after Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), the risk of relapse remains high and is the most common cause of mortality after HCT. Moreover, treatment options for relapse after HCT are limited. Strategies to reduce relapse with maintenance therapy in patients who are at high risk are needed to improve survival. 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. Moreover, 5-aza has properties that suggest protection against graft-versus-host disease (GVHD) as well. Preliminary data shows that it is well tolerated and effective in clinical use for the treatment of AML or MDS relapse after HCT, as well as for maintenance therapy. This study will evaluate the use of 5-aza for maintenance after HCT in patients with AML or MDS with risk factors that are associated with a high risk for relapse.

Clinical Details

Official title: Phase II Study of 5-azacytidine Maintenance After Allogeneic Hematopoietic Cell Transplantation for High-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Relapse rate at 1 year

Secondary outcome:

Safety and percentage of Toxicity Requiring Treatment Discontinuation (TRTD)

Impact on survival

Detailed description: Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT) for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that may enhance the graft-versus-leukemia (GVL) effect, including upregulation of tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties that suggest protection against graft-versus-host disease (GVHD). The primary objective is to evaluate relapse rate at one year. Will also look at the incidence of both acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity. Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune system. Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects are consented, screened, then transplanted. Those showing complete response and no active GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are performed for response assessment after transplant as well as every three cycles (28 days) while on treatment. Dosing starts at 32mg/m2 and can be increased by two levels every 2 cycles without a serious adverse event (SAE), or reduced two levels per toxicity for up to 12 cycles.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age≥18 with MDS or high-risk AML, morphologically confirmed and based on World Health

Organization criteria (see below for definition of high-risk AML)*, who are transplant candidates with an available HLA-matched sibling or unrelated donor with at least 8/8 match *Definition of high-risk AML:

- Age≥60 years

- Age<60 years with any of the following:

- Secondary AML

- Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7,

trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype

- FLT3 mutation

- Disease status≥CR2 at time of HCT

- Detectable disease at time of HCT

- ECOG performance status 0-2

- Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,

total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal, unless there is known chronic kidney disease (CKD) (creatinine must be at baseline for subjects with CKD)

- In agreement to use an effective barrier method of birth control to avoid pregnancy

during the study and for a minimum of 30 days after study treatment, for all male and female patients who are fertile Exclusion Criteria:

- Uncontrolled, life-threatening infection that is not responding to antimicrobial

therapy

- Serum creatinine > 2 x upper limit of normal, unless there is known CKD (creatinine

must be at baseline for subjects with CKD), aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin > 2x upper limit of normal

- History of psychiatric disorder which may compromise compliance with the protocol or

which does not allow for appropriate informed consent

- Patient may not be receiving any other antineoplastic agents

- Pregnancy

- Concurrent use of any other investigational agents on a clinical trial

- Prior allogeneic stem cell transplant

- Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is

allowed Post-transplant eligibility and exclusion criteria Patients will have to meet the following post-transplant eligibility criteria to initiate treatment:

- In CR (including CRi and marrow CR) on bone marrow biopsy for response assessment

after HCT (typically day +30)

- Patient is within 30-100 days after HCT

- Absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 20,000/µL

- ECOG performance status 0-2

- Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,

total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal unless there is known chronic kidney disease (CKD) (creatinine must be at baseline for subjects with CKD)

- In agreement to use an effective barrier method of birth control to avoid pregnancy

during the study and for a minimum of 30 days after study treatment, for all male and female patients who are fertile Patients may not have any of the following post-transplant exclusion criteria:

- Active grade II-IV acute GVHD, for example requiring treatment with steroids at a

dose equivalent to prednisone 1mg/kg daily or higher

- Uncontrolled, life-threatening infection that is not responding to antimicrobial

therapy

- Serum creatinine > 2 x upper limit of normal unless there is known CKD (creatinine

must be at baseline for subjects with CKD), aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin > 2x upper limit of normal

- History of psychiatric disorder which may compromise compliance with the protocol or

which does not allow for appropriate informed consent

- Pregnancy

- Concurrent use of any other investigational agents on a clinical trial

- Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is

allowed

Locations and Contacts

Ann Welsh, RN, Phone: 412-623-4897, Email: welshah2@upmc.edu

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15232, United States; Not yet recruiting
Ann Welsh, RN
Additional Information


Last updated: July 28, 2014

Page last updated: August 23, 2015

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