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

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00660400
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 75
• Patients Per Site Per Month: 0.3

Study Details

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)	N/A

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
• 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: Mar 1, 2008
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Jun 1, 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 Names: 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 Names: HCT

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Relapse-free Survival (RFS) [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) [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) [Up to 3 years]

   Proportion of patients enrolled who subsequently proceeded to allogeneic HCT.

3. Percentage of Participants With Overall Survival (OS) [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

Criteria

• Ages Eligible for Study: 18 Years to 68 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT00660400
• Other Study ID Numbers: MCC-15158; 106349
• First Posted: Apr 17, 2008
• Last Update Posted: Sep 22, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Myeloid; Monocytic
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Azacitidine

Study Results

Participant Flow

Recruitment Details	From 05/2008 to 08/2010, 25 patients with Myelodysplastic Syndrome (MDS) were enrolled to the study at Moffitt Cancer Center.
Pre-assignment Detail	Four patients did not proceed to allogeneic HCT.

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Period Title: Overall Study
STARTED	25
COMPLETED	21
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 92%
>=65 years	2 8%
Sex: Female, Male (Count of Participants)
Female	15 60%
Male	10 40%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Relapse-free Survival (RFS)
Description	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.
Time Frame	One year post allogeneic HCT

Outcome Measure Data

Analysis Population Description

Participants who proceeded to allogeneic HCT

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	52 208%

2. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	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.
Time Frame	At the end of up to six (28 day) cycles of 5-azacitidine

Outcome Measure Data

Analysis Population Description

Participants who proceeded to allogeneic HCT

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Measure Participants	21
Partial Response	48 192%
Complete Remission	0 0%
Stable Disease	33 132%
Progressive Disease	19 76%

3. Secondary Outcome

Title	Percentage of Participants Who Proceed to Hematopoietic Cell Transplantation (HCT)
Description	Proportion of patients enrolled who subsequently proceeded to allogeneic HCT.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Measure Participants	25
Number [percentage of participants]	84 336%

4. Secondary Outcome

Title	Percentage of Participants With Overall Survival (OS)
Description	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.
Time Frame	One year

Outcome Measure Data

Analysis Population Description

Participants who proceeded to allogeneic HCT

Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	62 248%

Adverse Events

Time Frame	3 years, 4 months
Adverse Event Reporting Description	This was a standard of care study for Myelodysplastic Syndrome patients, with 5-Azacitidine prior to standard transplant.
Arm/Group Title	Combined Therapy
Arm/Group Description	5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).
All Cause Mortality
	Combined Therapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combined Therapy
	Affected / at Risk (%)	# Events
Total	8/25 (32%)
Gastrointestinal disorders
Diarrhea	1/25 (4%)	3
General disorders
Constitutional symptoms - Other, fatigue	1/25 (4%)	1
Constitutional symptoms - Other, anorexia	1/25 (4%)	1
Infections and infestations
Febrile neutropenia	1/25 (4%)	1
Infection (documented clinically or microbiologically) - skin (cellulitis)	1/25 (4%)	1
Infection with unknown ANC - Lung (pneumonia)	1/25 (4%)	1
Infection - Other, sepsis	1/25 (4%)	1
Metabolism and nutrition disorders
Creatinine - Acute renal failure	1/25 (4%)	1
Nervous system disorders
Neurology - Other, weakness	1/25 (4%)	1
Neurology - Other - numbness, tingling	1/25 (4%)	1
Cerebrovascular accident	1/25 (4%)	1
Renal and urinary disorders
Renal failure	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	1/25 (4%)	1
Pulmonary/Upper Respiratory - Other, pneumonia	1/25 (4%)	1
Vascular disorders
Deep venous thrombosis	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Combined Therapy
	Affected / at Risk (%)	# Events
Total	0/25 (0%)

Limitations/Caveats

Limitation: Small single center pilot study to show the use of pre-treatment 5-Azacitidine and successfully proceeding to transplant.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.