Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

NCT00326417 | Completed Phase 1 Results DMC

• 4 other identifiers: BMTCTN0301U01HL0692945U01HL069294-055U24CA076518
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 22

Brief Summary

The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Conditions

Anemia, Aplastic

Keywords

Severe Aplastic Anemia

Outcome Measures

Primary Outcomes (1)

• Disease-free Survival (DFS)

  DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10\^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.

  Day 100

Secondary Outcomes (4)

• Cumulative Incidence of Graft Failure

  Day 365

• Acute Graft vs Host Disease (GVHD)

  Day 100

• Chronic GVHD

  Day 365

• Overall Survival (OS)

  Day 365

Study Arms (4)

Cyclophosphamide 150mg

EXPERIMENTAL

Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)

Drug: Fludarabine; Drug: Cyclophosphamide 150mg

Cyclophosphamide 100mg

EXPERIMENTAL

Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)

Drug: Fludarabine; Drug: Cyclophosphamide 100mg

Cyclophosphamide 50mg

EXPERIMENTAL

Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)

Drug: Fludarabine; Drug: Cyclophosphamide 50mg

Fludarabine

EXPERIMENTAL

Fludarabine only (no Cyclophosphamide administered)

Drug: Fludarabine

Interventions

Fludarabine DRUG

Doses of 30 mg/m\^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)

Also known as: Fludara

Cyclophosphamide 100mg; Cyclophosphamide 150mg; Cyclophosphamide 50mg; Fludarabine

Cyclophosphamide 150mg DRUG

A total dose of 150 mg/kg will be given as 50 mg/kg per day for 3 days (Days -4, -3, -2)

Also known as: Cytoxan®

Cyclophosphamide 150mg

Cyclophosphamide 100mg DRUG

A total dose of 100 mg/kg will be given as 50 mg/kg per day for 2 days (Days -3, -2)

Also known as: Cytoxan®

Cyclophosphamide 100mg

Cyclophosphamide 50mg DRUG

A total dose of 50 mg/kg will be given once at 50 mg/kg per day on Day -2

Also known as: Cytoxan®

Cyclophosphamide 50mg

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:
• Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells
• Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10\^9/L; platelets less than 20 x 10\^9/L; reticulocytes less than 20 x 10\^9/L
• Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1 antigen; typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1; HLA-DQ typing is recommended but will not count in the match
• Patient and/or legal guardian able to provide signed informed consent
• Matched unrelated donor must consent to provide a marrow allograft
• Patients with adequate organ function as measured by:
• Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%
• Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) less than 4x upper limit of normal for age (as per local laboratory)
• Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)
• Pulmonary: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%
• Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

You may not qualify if:

• Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) on marrow examination
• Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital amegakaryocytosis
• Symptomatic or uncontrolled cardiac failure or coronary artery disease
• Karnofsky performance status less than 60% or Lansky less than 40% for patients younger than 16 years old
• Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)
• Seropositive for the human immunodeficiency virus (HIV)
• Pregnant (positive total HCG) or breastfeeding
• Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis
• Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/ tacrolimus
• Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis
• Concomitant enrollment in a Phase I study
• Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C
• Prior allogeneic marrow or stem cell transplantation
• Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• National Cancer Institute (NCI): collaborator
• National Marrow Donor Program: collaborator

Study Sites (22)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Mattel Children's Hospital at UCLA

Los Angeles, California, 90095, United States

Location

Stanford Hospital and Clinics

Stanford, California, 94305, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33624, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

BMT Program at Northside Hospital

Atlanta, Georgia, 30342, United States

Location

DFCI/Brigham & Women's Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239-3098, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

University of Texas, MD Anderson CRC

Houston, Texas, 77030, United States

Location

Texas Transplant Institute

San Antonio, Texas, 78229, United States

Location

Virginia Commonwealth University, MCV Hospital

Richmond, Virginia, 23298, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (3)

• Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P, Calado R, Kojima S, Eapen M, Harris R, Scheinberg P, Savage S, Maciejewski JP, Tiu RV, DiFronzo N, Horowitz MM, Antin JH. Optimization of therapy for severe aplastic anemia based on clinical, biologic, and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the Blood and Marrow Transplant Clinical Trials Network, March 2010. Biol Blood Marrow Transplant. 2011 Mar;17(3):291-9. doi: 10.1016/j.bbmt.2010.10.028. Epub 2010 Oct 27.

  PMID: 21034841 BACKGROUND

• Anderlini P, Wu J, Gersten I, Ewell M, Tolar J, Antin JH, Adams R, Arai S, Eames G, Horwitz ME, McCarty J, Nakamura R, Pulsipher MA, Rowley S, Leifer E, Carter SL, DiFronzo NL, Horowitz MM, Confer D, Deeg HJ, Eapen M. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Lancet Haematol. 2015 Sep;2(9):e367-75. doi: 10.1016/S2352-3026(15)00147-7. Epub 2015 Sep 2.

  PMID: 26685770 RESULT

• Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, Adams RH, Ewell M, Leifer ES, Gersten ID, Carter SL, Horowitz MM, Nakamura R, Pulsipher MA, Difronzo NL, Confer DL, Eapen M, Anderlini P. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transplant. 2012 Jul;18(7):1007-11. doi: 10.1016/j.bbmt.2012.04.014. Epub 2012 Apr 27.

  PMID: 22546497 RESULT

MeSH Terms

Conditions

Anemia, Aplastic

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Adam Mendizabal, PhD
• Organization: The Emmes Corporation

amendizabal@emmes.com

301-251-1161

Study Officials

• Mary Horowitz, MD

  Center for International Blood and Marrow Transplant Research

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2006
• First Posted: May 16, 2006
• Study Start: January 1, 2006
• Primary Completion: September 1, 2015
• Study Completion: January 1, 2016
• Last Updated: October 28, 2021
• Results First Posted: October 4, 2016

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public.

Locations

US (22)