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

NCT02204020 | Withdrawn Phase 2 DMC

• 1 other identifier: UPCI 13-165
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)

Keywords

Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); allogeneic; 5-azacytidine (5-aza); hematopoietic; transplantation; transplant; graft-versus-tumor; graft-versus-host disease (GVHD); epigenetic; maintenance; hypomethylation; relapse

Outcome Measures

Primary Outcomes (1)

• Relapse rate at 1 year

  Study will evaluate the relapse rate associated with 5-azacytidine (5-aza) as maintenance therapy after HCT in patients with high-risk AML or MDS.

  3 years

Secondary Outcomes (6)

• Safety of Toxicity Requiring Treatment Discontinuation (TRTD)

  3 years

• Overall survival

  3 years

• Incidence of acute GVHD

  3 years

• Percentage of Toxicity Requiring Treatment Discontinuation (TRTD)

  3 years

• relapse-free survival

  3 years

Other Outcomes (1)

• Effect on the immune system

  3 years

Study Arms (1)

5-azacytidine

EXPERIMENTAL

5-aza SC or IV 32mg/m2 - 75mg/m2 (based on dose escalation)

Drug: 5-azacytidine (5-aza) maintenance therapy after transplant

Interventions

5-azacytidine (5-aza) maintenance therapy after transplant DRUG

The planned initial dose of 5-aza is 32mg/m2 (Level 0) administered either subcutaneously or intravenously for days 1 through 5 of a 28-day cycle, which will be initiated between day+30 and day+100 after HCT. Patients who tolerate this dose based on hematologic parameters and with no SAEs for two consecutive cycles will be eligible for a dose escalation to 50mg/m2 (Level +1). Patients who tolerate this dose based on the same criteria as above for two consecutive cycles will be eligible for a dose escalation to 75mg/m² (Level +2). Patients will continue at dose Level +2 for the remainder of the study provided there are no toxicities that require dose reduction. Patients requiring a dose reduction are not eligible for re-escalation.

Also known as: 5-aza

5-azacytidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 human leukocyte antigen (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
• Fms-like tyrosine kinase 3 (FLT3) mutation
• Disease status ≥ second complete remission (CR2) at time of HCT
• Detectable disease at time of HCT
• Eastern Cooperative Oncology Group (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 (creatinine must be at baseline for subjects with chronic kidney disease)
• 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

You may not qualify if:

• Uncontrolled, life-threatening infection that is not responding to antimicrobial therapy
• Serum creatinine \> 2 x upper limit of normal, unless there is known chronic kidney disease (creatinine must be at baseline for subjects with chronic kidney disease), 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
• Patients will have to meet the following post-transplant eligibility criteria to initiate treatment:
• In complete response (including complete remission with incomplete blood count recovery and marrow complete response) 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 (creatinine must be at baseline for subjects with chronic kidney disease)
• 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

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (1)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Graft vs Host Disease; Recurrence

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Annie Im, MD

  University of Pittsburgh Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 25, 2014
• First Posted: July 30, 2014
• Study Start: April 1, 2015
• Primary Completion: April 1, 2015
• Study Completion: May 4, 2016
• Last Updated: March 30, 2018

Record last verified: 2018-03

Locations

US (1)