Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by a Donor Stem Cell Transplant in Treating Patients With Immunodeficiency or Other Nonmalignant Inherited Disorders

NCT00553098 | Completed Phase 2 Results DMC

• 4 other identifiers: 2007.00NCI-2009-015502007P30CA015704
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 6

Brief Summary

This phase II trial studies fludarabine phosphate and total-body irradiation with or without alemtuzumab followed by donor stem cell transplant to see how well it works in treating patients with immunodeficiency or other nonmalignant inherited disorders. Giving chemotherapy, such as fludarabine phosphate, a monoclonal antibody such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells.

Conditions

Immunodeficiency Syndrome; Non-Cancer Diagnosis

Outcome Measures

Primary Outcomes (1)

• Number of Patients Who Achieve Greater Than 50% Donor T-cell Chimerism

  The study will be considered a success and the protocol worthy of further study if there is sufficient evidence that this rate is greater than the 50% rate observed in the most recently transplanted patients with nonmalignant disorders. Analyses will be carried out separately for the alemtuzumab recipients and the TBI recipients. We will be 80% confidence of success if a one-sided 80% confidence interval for the proportion of patients with successful chimerism exceeds 50%. Cumulative incidence will be used to evaluate the probability of chimerism.

  At 1 year post transplant

Secondary Outcomes (10)

• Overall Survival

  1 year

• Immune Reconstitution by 1 Year Post Transplant

  1 year

• Disease Response by 1 Year Post Transplant

  1 year

• Greater Than 50% CD33+ Donor Chimerisms at 1 Year Post Transplant

  1 year

• Greater Than 50% CD19+ Donor Chimerisms at 1 Year Post Transplant

  1 year

Study Arms (1)

Treatment (chemotherapy, low dose radiation)

EXPERIMENTAL

CONDITIONING REGIMEN: \*Patients with no life-threatening viral or fungal infections within 1 month before the planned HCT receive alemtuzumab IV over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with HLH, IPEX syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0. HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV or PO 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96.

Biological: Alemtuzumab; Procedure: Allogeneic Bone Marrow Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Radiation: Total-Body Irradiation

Interventions

Alemtuzumab BIOLOGICAL

Given IV

Also known as: Anti-CD52 Monoclonal Antibody, Campath, Campath-1H, LDP-03, MabCampath, Monoclonal Antibody Campath-1H

Treatment (chemotherapy, low dose radiation)

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo HCT

Also known as: Allo BMT, Allogeneic BMT

Treatment (chemotherapy, low dose radiation)

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo HCT

Also known as: allogeneic stem cell transplantation, HSC, HSCT

Treatment (chemotherapy, low dose radiation)

Cyclosporine DRUG

Given PO or IV

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Treatment (chemotherapy, low dose radiation)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment (chemotherapy, low dose radiation)

Laboratory Biomarker Analysis OTHER

Correlative study

Treatment (chemotherapy, low dose radiation)

Mycophenolate Mofetil DRUG

Given PO or IV

Also known as: Cellcept, MMF

Treatment (chemotherapy, low dose radiation)

Total-Body Irradiation RADIATION

Undergo low dose TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Treatment (chemotherapy, low dose radiation)

Eligibility Criteria

• Age: Up to 54 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Primary immunodeficiency disorder or other nonmalignant inherited disease (except aplastic anemia and Fanconi anemia) treatable by allogeneic HCT
• Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for a conventional myeloablative HCT
• Donors: Related donor who is human leukocyte antigen (HLA) genotypically identical at least at one haplotype and may be genotypically or phenotypically identical for serological typing for HLA-A, B, -C, and at the allele level for -DRB1 and -DQB1; related donors must be a match or a single allele mismatch at HLA-A, B, and C (at highest resolution available at the time of donor selection) and matched at DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing
• Donors: Unrelated donors who are prospectively:
• Matched for HLA-A, B, C, DRB1 and DQB1 by DNA typing at the highest resolution routinely available at the time of donor selection
• Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing (no mismatching for DRB1 or DQB1 is allowed)

You may not qualify if:

• Patients with Aplastic anemia and Fanconi anemia
• Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score \< 70
• Cardiac ejection fraction \< 30% or, if unable to obtain ejection fraction, shortening fraction of \< 26%) on multi-gated acquisition (MUGA) scan or cardiac echo, symptomatic coronary artery disease, other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction \< 26% may be enrolled if approved by a cardiologist
• Poorly controlled hypertension despite anti-hypertensive medications
• Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3mg/dl, or symptomatic biliary disease (Patients will be allowed on to the protocol with liver problems if gastroenterology approves the patient for HCT)
• Patients who are positive for human immunodeficiency virus (HIV)
• Females who are pregnant or breast-feeding
• Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment
• Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B)
• Donors: Identical twin
• Donors: Pregnancy
• Donors: HIV positive
• Donors: If a patient is homozygous at a particular loci, mismatching at that loci is not allowed due to an isolated graft rejection vector, i.e., patient A\*0101 and the donor is A\*0101, A\*0201; such a mismatch may increase the risk of graft rejection; if patient and donor pairs are both homozygous at a mismatched loci, they are considered a two-HLA antigen mismatch, i.e., the patient is A\*0101 and the donor is A\*0201, and this type of mismatch is not allowed
• Donor: Donor \< 6 months old, \> 75 years old

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (6)

Children's Hospital and Research Center at Oakland

Oakland, California, 94609-1809, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53201, United States

Location

MeSH Terms

Conditions

Immunologic Deficiency Syndromes

Interventions

Alemtuzumab; Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Radiotherapy; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Dr. Lauri Burroughs
• Organization: Fred Hutch Cancer Research

lburroug@fredhutch.org

206-667-2396

Study Officials

• Lauri Burroughs

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

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: November 2, 2007
• First Posted: November 5, 2007
• Study Start: June 1, 2006
• Primary Completion: March 1, 2015
• Last Updated: February 17, 2020
• Results First Posted: May 19, 2017

Record last verified: 2020-02

Locations

US (6)