HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

Official title

A Phase II Trial of HSCT for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Risk-Adjusted Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine

Overview

The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.

Detailed description

The trial proposed is a three arm phase II treatment protocol designed to investigate the safety and efficacy of risk-adjusted chemotherapy-based cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. Candidates for this trial will include patients with Fanconi anemia presenting with severe marrow failure (transfusion dependent) or myelodysplastic syndrome, or acute myelogenous leukemia for whom an allogeneic stem cell transplant is indicated.

Interventions

• Drug Busulfan
  A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control. A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.
• Drug Cyclophosphamide
  Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.
• Drug Fludarabine
  Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.
• Drug rabbit ATG
  Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
• Drug G-CSF
  All patients will also receive G-CSF post-transplant to foster engraftment.
• Biological Peripheral blood stem cell
  The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

Primary outcome measures

• Graft Failure or Rejection [Time frame: 5 years]

Secondary outcome measures (1)

• Post-transplant severe morbidity and mortality [Time frame: 2 years post-transplant]

Eligibility criteria

Inclusion criteria

• Patients must have a diagnosis of Fanconi anemia
• Patients must have one of the following hematologic diagnoses:

• Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:

• Platelet count <20 x 109/L or platelet transfusion dependence\*
• ANC <1000 x 109/L
• Hgb <8 gm/dl or red cell transfusion dependence\*
• Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
• Acute Myelogenous Leukemia (untreated, in remission or with refractory or relapsed disease)
• Donors will be either human leukocyte antigen (HLA) compatible unrelated or HLA-genotypically matched related donors (no fully matched sibling donor).
• Patients and donors may be of either gender or any ethnic background.
• Patients must have a Karnofsky adult, or Lansky pediatric performance scale status > 70%.
• Patients must have adequate physical function measured by:

• Cardiac: asymptomatic or if symptomatic then 1) left ventricular ejection fraction (LVEF) at rest must be > 50% and must improve with exercise or 2) Shortening Fraction > 29%
• Hepatic: < 5 x upper limit of normal (ULN) alanine transaminase (ALT) and < 2.0 mg/dl total serum bilirubin.
• Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 50 ml/min/1.73 m2
• Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted
• Each patient must be willing to participate as a research subject and must sign an informed consent form.
• Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant while on study.

Exclusion criteria

• Active CNS leukemia
• Female patients who are pregnant (positive serum or urine HCG) or breast-feeding.
• Active uncontrolled viral, bacterial or fungal infection
• Patient seropositive for HIV-I/II; HTLV -I/II

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Memorial Sloan Kettering Cancer Center — New York
• Cincinnati Children's Hospital Medical Center — Cincinnati
• Fred Hutchinson Cancer Research Center — Seattle

Identifiers

NCT: NCT02143830 · 2013-7501

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗