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HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy (RAFA)

Primary Purpose

Fanconi Anemia, Severe Marrow Failure, Myelodysplastic Syndrome (MDS)

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Busulfan

Cyclophosphamide

Fludarabine

rabbit ATG

G-CSF

Peripheral blood stem cell

About this trial

This is an interventional treatment trial for Fanconi Anemia focused on measuring marrow aplasia, cytopenia, myelodysplasia, AML, bone marrow transplant, cytoreductive regimen, T-cell reduction

Eligibility Criteria

3 Months - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have a diagnosis of Fanconi anemia
Patients must have one of the following hematologic diagnoses:
1. Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:
  1. Platelet count <20 x 109/L or platelet transfusion dependence*
  2. ANC <1000 x 109/L
  3. Hgb <8 gm/dl or red cell transfusion dependence*
2. Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
3. 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:
1. 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%
2. Hepatic: < 5 x upper limit of normal (ULN) alanine transaminase (ALT) and < 2.0 mg/dl total serum bilirubin.
3. Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 50 ml/min/1.73 m2
4. 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

Sites / Locations

Memorial Sloan Kettering Cancer Center
Cincinnati Children's Hospital Medical CenterRecruiting
Fred Hutchinson Cancer Research CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Arm A: Good Risk Patients

Arm B: Intermediate Risk Patients

Arm C: High Risk Patients

Arm Description

Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to > 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients.

Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled in this arm will be 10.

Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10.

Outcomes

Primary Outcome Measures

Graft Failure or Rejection

Primary non-engraftment is diagnosed when the patient fails to achieve an ANC >=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) >=500/mm3, the ANC declines to <500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently.

Secondary Outcome Measures

Post-transplant severe morbidity and mortality

The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system.

Full Information

NCT ID

NCT02143830

First Posted

April 28, 2014

Last Updated

February 22, 2023

Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Center

1. Study Identification

Unique Protocol Identification Number

NCT02143830

Brief Title

HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

Acronym

RAFA

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 2014 (undefined)

Primary Completion Date

July 2024 (Anticipated)

Study Completion Date

July 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Fanconi Anemia, Severe Marrow Failure, Myelodysplastic Syndrome (MDS), Acute Myelogenous Leukemia (AML)

Keywords

marrow aplasia, cytopenia, myelodysplasia, AML, bone marrow transplant, cytoreductive regimen, T-cell reduction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A: Good Risk Patients

Arm Type

Experimental

Arm Description

Arm Title

Arm B: Intermediate Risk Patients

Arm Type

Experimental

Arm Description

Arm Title

Arm C: High Risk Patients

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Myleran, Busulfex IV

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

rabbit ATG

Other Intervention Name(s)

thymoglobulin

Intervention Description

Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.

Intervention Type

Drug

Intervention Name(s)

G-CSF

Other Intervention Name(s)

Granulocyte colony-stimulating factor, filgrastim, neupogen

Intervention Description

All patients will also receive G-CSF post-transplant to foster engraftment.

Intervention Type

Biological

Intervention Name(s)

Peripheral blood stem cell

Intervention Description

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 Measure Information:

Title

Graft Failure or Rejection

Description

Time Frame

5 years

Secondary Outcome Measure Information:

Title

Post-transplant severe morbidity and mortality

Description

Time Frame

2 years post-transplant

Other Pre-specified Outcome Measures:

Title

Graft Versus Host Disease

Description

Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines.

Time Frame

One year

Title

Leukemic Relapse

Description

For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.

Time Frame

5 years

Title

Secondary malignancies

Description

Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy.

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Months

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jamie Wilhelm

Phone

(513)803-1102

Jamie.Wilhelm@cchmc.org

First Name & Middle Initial & Last Name or Official Title & Degree

Sara Loveless, RN

Phone

(513)803-7656

Sara.Loveless@cchmc.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Parinda Mehta, MD

Organizational Affiliation

CCHMC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10174

Country

United States

Individual Site Status

Completed

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Parinda Mehta, MD

Facility Name

Fred Hutchinson Cancer Research Center

City

Seattle

State/Province

Washington

ZIP/Postal Code

98109

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sheri Ballard

Phone

206-667-4222

sballard@fredhutch.org

First Name & Middle Initial & Last Name & Degree

K. Scott Baker, MD

12. IPD Sharing Statement

Learn more about this trial

HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

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