Pre-Transplant 5-Azacitidine In Patients With High-Risk Myelodysplastic Syndrome Who Are Candidates For Allogeneic Hematopoietic Cell Transplant

• ClinicalTrials.gov Identifier: NCT00660400
• Recruitment Status: Completed
• First Posted: April 17, 2008
• Results First Posted: July 16, 2014
• Last Update Posted: September 22, 2014
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborator: Celgene Corporation
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Study Description

Brief Summary:

The purpose of this study is to find out if treating people who have high-risk myelodysplastic syndrome (MDS) with 5-Azacitidine (Vidaza) prior to their allogeneic hematopoietic cell transplant (HCT) is helpful in preventing their myelodysplastic syndrome from coming back.

In previous research, 5-Azacitidine appeared to help the bone marrow of a patient with MDS begin to function more normally. This means bone marrow cells can grow and do their work the way they were meant to. 5-Azacitidine is approved by the Food and Drug Administration (FDA) for the treatment of MDS. The effect of 5-Azacitidine in patients receiving hematopoietic cell transplants have not been studied.

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: 5-azacitidine; Procedure: Allogeneic Hematopoietic Cell Transplantation (HCT)	Not Applicable

Detailed Description:

RESEARCH PLAN

• This will be a single-center prospective trial
• Patients with high risk MDS that are potentially eligible for HCT will be enrolled.
• A donor search will be initiated, and 5-Azacitidine will be given per standard practice.
• 5-Azacitidine dose is 75 mg/M^2/day subcutaneously by standard practice (generally this is 7 days per monthly cycle, but alterations occur depending on clinical and laboratory parameters).
• Patients where a suitable donor is not found can continue with 5-Azacitidine per standard treatment. These patients will be followed until progression of MDS to acute myelogenous leukemia (AML) or death, for up to one year.
• If a suitable donor is obtained, the patient will proceed to HCT. The HCT conditioning regimen will be dictated by the Blood and Marrow Transplant (BMT) physician. While waiting HCT, additional cycles 5-Azacitidine may be given. Pre-HCT conditioning regimen therapy will begin no more than 8 weeks and no less than 4 weeks after the last administration of 5-Azacitidine.
• As the number of cycles of 5-Azacitidine is not standardized and the retrospective review of our patients noted above indicated a benefit to ANY exposure to 5-Azacitidine, the actual number of cycles of 5-Azacitidine delivered will not be specified. In addition, as high risk MDS patients have an average time to death of 0.4 years, any delay to HCT once it is available is to be avoided.
• A bone marrow biopsy will be performed to reassess disease response to therapy after the last cycle of 5-Azacitidine before transplant, or after the fourth cycle of 5-Azacitidine, whichever comes first. Note that both the biopsy and the timing of the biopsy is a standard evaluation procedure.
• Donor progenitor cell collection will be prescribed by the BMT Attending Physician.

HCT

• The patient will undergo HCT designated per attending BMT physician.
• Supportive care will be based on institutional guidelines, Stem cell collections, processing and laboratory studies

Stem cell collections, processing and laboratory studies

• Graft assessment, processing, and characterization will be done as per institutional guidelines
• Chimerism testing will be obtained to document post-transplant engraftment, per standard practice.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Of Pre-Transplant 5-Azacitidine (Vidaza) In Patients With High-Risk Myelodysplastic Syndrome (MDS) Who Are Candidates For Allogeneic Hematopoietic Cell Transplantation
• Study Start Date: March 2008
• Actual Primary Completion Date: December 2013
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm

Intervention/treatment

Experimental: Combined Therapy; 5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).

Drug: 5-azacitidine; Once enrolled, the patients will receive pre-transplant 5-azacitidine (Vidaza) 75 mg/M^2/day subcutaneously for 5-7 days every 28 days). Adjustments in dose and timing may occur based on clinical and hematological parameters.; Other Name: Vidaza; Procedure: Allogeneic Hematopoietic Cell Transplantation (HCT); Patients will receive transplantation if there is either a suitable sibling or an unrelated donor.; Response will be evaluated by bone marrow biopsy after 4 cycles of 5-azacitidine or prior to HCT whichever comes first. Due to the very high risk of progression to AML or death in this patient population, the HCT will be done as soon as possible.; The patients may have additional cycles of 5-azacitidine per standard hematology practice until scheduled for transplant or until progression of disease.; All patients will be followed until time to progression of MDS, AML or death or a maximum of 1 year. For patients that are transplanted, follow up will be to one year post-transplant.; Other Name: HCT

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Relapse-free Survival (RFS) [ Time Frame: One year post allogeneic HCT ]
   Relapse-free survival one year after allogeneic HCT in MDS patients receiving at least one complete cycle of 5-azacitidine (Vidaza) in the pre-transplantation setting. Relapsed disease: if with complete remission (CR) - greater than 5% blasts in bone marrow; if with partial response (PR) - greater than 30% increase in blasts in the marrow; if with stable disease (SD) - return to pretreatment peripheral blood levels and transfusion requirements due to disease.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: At the end of up to six (28 day) cycles of 5-azacitidine ]
   Pre-allogeneic HCT responses to 5-azacitidine (Vidaza), based on the International Working Group criteria: Complete Remission (CR); Partial Response (PR); Stable Disease (SD). Point estimates and 95% confidence intervals were calculated for the response rate to 5-azacitidine, evaluated at marrow evaluation after 4 cycles of 5-azacitidine or prior to HCT whichever came first. CR: Bone marrow with 5% myeloblasts and normal maturation of all cell lines. PR: All CR criteria if abnormal before treatment except bone marrow blasts decreased by 50% over pretreatment but still > 5%. SD: Failure to attain CR, PR, relapsed (or progressive) disease.
2. Percentage of Participants Who Proceed to Hematopoietic Cell Transplantation (HCT) [ Time Frame: Up to 3 years ]
   Proportion of patients enrolled who subsequently proceeded to allogeneic HCT.
3. Percentage of Participants With Overall Survival (OS) [ Time Frame: One year ]
   Overall survival for all participants at one year after first dose of 5-azacitidine (Vidaza). Overall survival was calculated by the method of Kaplan-Meier with standard errors computed using Greenwood's formula.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 68 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Potential candidate for HCT.
• Histologically confirmed diagnosis by pathologic review of previous diagnosis of high-risk myelodysplastic syndrome (MDS): International Prognostic Scoring System (IPSS) > 1 or AML-MDS or treatment related MDS.
• Serum bilirubin levels ≤1.5 times the upper limit of the normal (ULN) range for the laboratory. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis; Serum glutamic-oxaloacetic transaminase (SGOT) [aspartate aminotransferase (AST)] or serum glutamic pyruvic transaminase (SGPT) [alanine aminotransferase (ALT)] levels ≤2 x ULN.
• Serum creatinine levels ≤1.5 x ULN
• Karnofsky performance status greater or equal to 70%
• Signed informed consent form in accordance with institutional policies

Exclusion Criteria:

• Known or suspected hypersensitivity to Vidaza or mannitol
• Pregnant or lactating women
• Human immunodeficiency virus (HIV) or seropositive, confirmed by nucleic acid amplification testing (NAT)
• Active central nervous system (CNS) malignancy
• Active infection
• History or presence of primary hepatoma

Contacts and Locations

Locations

United States, Florida

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, United States, 33612

Sponsors and Collaborators

H. Lee Moffitt Cancer Center and Research Institute

Celgene Corporation

Investigators

• Principal Investigator: Teresa Field, M.D., Ph.D.; H. Lee Moffitt Cancer Center and Research Institute
• Principal Investigator: Janelle Perkins, Pharm.D.; H. Lee Moffitt Cancer Center and Research Institute

More Information

Additional Information:

Moffitt Cancer Center Clinical Trials website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nishihori T, Perkins J, Mishra A, Komrokji R, Kim J, Kharfan-Dabaja MA, Perez L, Lancet J, Fernandez H, List A, Anasetti C, Field T. Pretransplantation 5-azacitidine in high-risk myelodysplastic syndrome. Biol Blood Marrow Transplant. 2014 Jun;20(6):776-80. doi: 10.1016/j.bbmt.2014.02.008. Epub 2014 Feb 15.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00660400
• Other Study ID Numbers: MCC-15158; 106349 ( Other Identifier: USF IRB )
• First Posted: April 17, 2008
• Results First Posted: July 16, 2014
• Last Update Posted: September 22, 2014
• Last Verified: September 2014

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:

Myeloid; Monocytic

Additional relevant MeSH terms:

Preleukemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Azacitidine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors