Cytoxan, Fludara, and Antithymocyte Globulin Conditioning Followed By Stem Cell Transplant in Treating Fanconi Anemia

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT00630253
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 3
• Actual Duration (Months): 247.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy, such as cyclophosphamide and fludarabine, before a donor stem cell transplant helps to remove the patient's cells to allow for the transplant cells to take and grow. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells can make an immune response against the body's normal cells. Giving antithymocyte globulin and removing the T cells from the donor cells before transplant and giving cyclosporine before and after transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects of cyclophosphamide, fludarabine, and antithymocyte globulin followed by donor stem cell transplant and to see how well it works in treating patients with Fanconi anemia.

Condition or Disease	Intervention/Treatment	Phase
Fanconi Anemia	Biological: Anti-Thymocyte Globulin; Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: Hematopoietic Stem Cell Transplantation; Drug: Methylprednisolone; Drug: Filgrastim; Drug: Cyclosporine; Drug: Mycophenolate Mofetil	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the probability of engraftment in patients with Fanconi anemia treated with cyclophosphamide, fludarabine phosphate, and antithymocyte globulin followed by HLA-genotypically identical sibling donor hematopoietic stem cell transplantation that is T-cell depleted.

Secondary

• To evaluate the incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in patients treated with this regimen.

• To evaluate the incidence of regimen-related toxicity in these patients.

• To evaluate the 1-year survival of patients treated with this regimen.

• To evaluate the incidence of late secondary malignancies (e.g., squamous cell carcinoma of the head and neck or cervix) in patients treated with this regimen.

OUTLINE:

• Preparative cytoreductive therapy: Patients receive cyclophosphamide IV over 2 hours on days -6 to -3 and fludarabine phosphate IV over 30 minutes and anti-thymocyte globulin IV over 4-6 hours on days -6 to -2.

• T-cell depleted donor hematopoietic stem cell transplantation: Patients undergo T-cell depleted donor bone marrow or umbilical cord blood stem cell transplantation on day 0. Patients also receive filgrastim (G-CSF) IV beginning on day 1 and continuing until blood counts recover.

• Graft-versus-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper. Patients will receive Mycophenolate Mofetil (MMF) therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L.

After completion of study therapy, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study of Cyclophosphamide, Fludarabine, and Antithymocyte Globulin Followed by Matched Sibling Donor Hematopoietic Cell Transplantation in Patients With Fanconi Anemia
• Actual Study Start Date: Feb 17, 2000
• Actual Primary Completion Date: Oct 10, 2020
• Actual Study Completion Date: Oct 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Marrow Isolex bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	Biological: Anti-Thymocyte Globulin; 30 mg/kg/day will be administered after MP on days -6, -5, -4, -3 and -2.; Other Names: ATG ; Drug: Cyclophosphamide; 5 mg/kg is to be given as a 2 hour infusion, Days -6 through -3.; Other Names: Cytoxan ; Drug: Fludarabine; 35 mg/m^2 intravenously (IV) on days -6 through -2.; Other Names: Fludara ; Procedure: Hematopoietic Stem Cell Transplantation; Bone marrow or umbilical cord blood infusion on day 0.; Other Names: HSCT ; Drug: Methylprednisolone; Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -6 until day -2 as a premedication for ATG.; Other Names: MP ; Drug: Filgrastim; 5 mcg/kg per day intravenously (IV) continue until Absolute neutrophil count > or = 2.5 x 10^9/L; Other Names: G-CSF ; Drug: Cyclosporine; Cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper.; Other Names: CSA ; Drug: Mycophenolate Mofetil; Day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours PO (to a maximum dose of 1 gram).; Other Names: MMF
Experimental: UCB No processing Notes: sibling donor UCB is used as the stem cell source and co-enroll for unlicensed UCB registry	Biological: Anti-Thymocyte Globulin; 30 mg/kg/day will be administered after MP on days -6, -5, -4, -3 and -2.; Other Names: ATG ; Drug: Cyclophosphamide; 5 mg/kg is to be given as a 2 hour infusion, Days -6 through -3.; Other Names: Cytoxan ; Drug: Fludarabine; 35 mg/m^2 intravenously (IV) on days -6 through -2.; Other Names: Fludara ; Procedure: Hematopoietic Stem Cell Transplantation; Bone marrow or umbilical cord blood infusion on day 0.; Other Names: HSCT ; Drug: Methylprednisolone; Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -6 until day -2 as a premedication for ATG.; Other Names: MP ; Drug: Filgrastim; 5 mcg/kg per day intravenously (IV) continue until Absolute neutrophil count > or = 2.5 x 10^9/L; Other Names: G-CSF ; Drug: Cyclosporine; Cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper.; Other Names: CSA ; Drug: Mycophenolate Mofetil; Day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours PO (to a maximum dose of 1 gram).; Other Names: MMF
Experimental: Marrow Clinimax bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)	Biological: Anti-Thymocyte Globulin; 30 mg/kg/day will be administered after MP on days -6, -5, -4, -3 and -2.; Other Names: ATG ; Drug: Cyclophosphamide; 5 mg/kg is to be given as a 2 hour infusion, Days -6 through -3.; Other Names: Cytoxan ; Drug: Fludarabine; 35 mg/m^2 intravenously (IV) on days -6 through -2.; Other Names: Fludara ; Procedure: Hematopoietic Stem Cell Transplantation; Bone marrow or umbilical cord blood infusion on day 0.; Other Names: HSCT ; Drug: Methylprednisolone; Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -6 until day -2 as a premedication for ATG.; Other Names: MP ; Drug: Filgrastim; 5 mcg/kg per day intravenously (IV) continue until Absolute neutrophil count > or = 2.5 x 10^9/L; Other Names: G-CSF ; Drug: Cyclosporine; Cyclosporine IV over 2 hours or orally every 8-12 hours beginning on day -3 and continuing until day 100, followed by a taper.; Other Names: CSA ; Drug: Mycophenolate Mofetil; Day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute GVHD. Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 x 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours PO (to a maximum dose of 1 gram).; Other Names: MMF

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Graft Failure [From Day 1 to event, assessed up to100 days]

   graft failure = absolute neutrophil count (ANC) <5 x 10^8/L and an acellular bone marrow aspirate/biopsy

Secondary Outcome Measures

1. Number of Participants With Acute Graft-Versus-Host Disease (GVHD) [Day 42]

   Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

2. Number of Participants Experiencing Overall Survival [1 Year]

   The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from enrollment to date of death or censored at the date of last documented contact for patients still alive.

3. Number of Participants With Chronic Graft-Versus-Host Disease (GVHD) [1 Year]

   Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.

4. Number of Participants With Transplant Related Deaths [Day 100]

   In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 59 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be <60 years of age with a diagnosis of Fanconi Anemia (FA).

• Patients must have an HLA-A, B, DRB1 identical sibling donor. Patients and donors will be typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing.

• Patients with FA must have moderately severe aplastic anemia (AA), early myelodysplastic syndrome (MDS) with no excess blasts with or without chromosomal abnormalities.

• In patients <18 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

• platelet count <40 x 10^9/L

• absolute neutrophil count (ANC) <10 x 10^8/L

• Hgb <9 g/dL

• In patients 18-60 years of age, moderately severe aplastic anemia is defined as having at least one of the following:

• platelet count <20 x 10^9/L

• absolute neutrophil count ANC <5 x 10^8/L

• Hgb <8 g/dL

• Early myelodysplastic syndrome, with multilineage dysplasia with < 5% blasts, with or without chromosomal anomalies.

• Adequate major organ function including:

• Cardiac: ejection fraction >45%

• Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites)

• Karnofsky performance status >70% or Lansky >50%

• Women of child bearing age must be using adequate birth control and have a negative pregnancy test.

Exclusion Criteria:

• Active bacterial infection within one week of hematopoietic cell transplant (HCT)

• Active fungal infection at time of HCT.

• Late MDS with greater than 5% blasts in bone marrow.

• Acute myelogenous leukemia (AML) or history of AML

• Malignant solid tumor (e.g. squamous cell carcinoma of the head/neck/cervix) within 2 years of HCT.

• Pregnant or lactating female.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Margaret L. MacMillan, MD, Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 3, 2019

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00630253
• Other Study ID Numbers: MT2000-09; 0001M34441
• First Posted: Mar 6, 2008
• Last Update Posted: Oct 12, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Masonic Cancer Center, University of Minnesota: Fanconi anemia
• Additional relevant MeSH terms: Fanconi Syndrome; Anemia; Fanconi Anemia; Cyclosporine; Mycophenolic Acid; Methylprednisolone; Cyclophosphamide; Fludarabine; Cyclosporins; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Marrow Isolex	Umbilical Cord Blood (UCB) Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Period Title: Overall Study
STARTED	16	9	6
COMPLETED	16	9	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax	Total
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)	Total of all reporting groups
Overall Participants	16	9	6	31
Age (Count of Participants)
<=18 years	13 81.3%	9 100%	4 66.7%	26 83.9%
Between 18 and 65 years	3 18.8%	0 0%	2 33.3%	5 16.1%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	9 56.3%	4 44.4%	5 83.3%	18 58.1%
Male	7 43.8%	5 55.6%	1 16.7%	13 41.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 11.1%	0 0%	1 3.2%
Not Hispanic or Latino	16 100%	8 88.9%	6 100%	30 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 6.3%	0 0%	0 0%	1 3.2%
Asian	2 12.5%	2 22.2%	0 0%	4 12.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	2 33.3%	2 6.5%
White	12 75%	7 77.8%	3 50%	22 71%
More than one race	1 6.3%	0 0%	0 0%	1 3.2%
Unknown or Not Reported	0 0%	0 0%	1 16.7%	1 3.2%
Region of Enrollment (participants) [Number]
United States	16 100%	9 100%	6 100%	31 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Graft Failure
Description	graft failure = absolute neutrophil count (ANC) <5 x 10^8/L and an acellular bone marrow aspirate/biopsy
Time Frame	From Day 1 to event, assessed up to100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Measure Participants	16	9	6
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Number of Participants With Acute Graft-Versus-Host Disease (GVHD)
Description	Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time Frame	Day 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Measure Participants	16	9	6
Count of Participants [Participants]	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants Experiencing Overall Survival
Description	The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from enrollment to date of death or censored at the date of last documented contact for patients still alive.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Measure Participants	16	9	6
Count of Participants [Participants]	15 93.8%	8 88.9%	5 83.3%

4. Secondary Outcome

Title	Number of Participants With Chronic Graft-Versus-Host Disease (GVHD)
Description	Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Measure Participants	16	9	6
Count of Participants [Participants]	2 12.5%	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With Transplant Related Deaths
Description	In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Marrow Isolex	UCB Arm	Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)	No processing	bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
Measure Participants	16	9	6
Count of Participants [Participants]	1 6.3%	0 0%	1 16.7%

Adverse Events

Time Frame	1 year
Arm/Group Title	Marrow Isolex		UCB Arm		Marrow Clinimax
Arm/Group Description	bone marrow processed using Isolex 300i (for patients enrolled through April 2010)		No processing		bone marrow processed using CliniMACS (for patients enrolled beginning with the August 2010 protocol version)
All Cause Mortality
	Marrow Isolex		UCB Arm		Marrow Clinimax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/16 (6.3%)		1/9 (11.1%)		1/6 (16.7%)
Serious Adverse Events
	Marrow Isolex		UCB Arm		Marrow Clinimax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/9 (0%)		1/6 (16.7%)
Gastrointestinal disorders
Hemorrhage	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Marrow Isolex		UCB Arm		Marrow Clinimax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/16 (56.3%)		6/9 (66.7%)		5/6 (83.3%)
Blood and lymphatic system disorders
Hemolysis	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Cardiac disorders
Cardiac arrect	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Cardiopumonary shock	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Pericardial effusion	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Ear and labyrinth disorders
Ototoxicity	0/16 (0%)	0	1/9 (11.1%)	1	0/6 (0%)	0
Gastrointestinal disorders
GI bleeding	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
General disorders
Graft failure	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Hepatobiliary disorders
Liver Ischemia	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Infections and infestations
Cystitis	2/16 (12.5%)	2	1/9 (11.1%)	1	0/6 (0%)	0
Hepatitis	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Infection	7/16 (43.8%)	27	5/9 (55.6%)	13	4/6 (66.7%)	10
Pneumonia	0/16 (0%)	0	1/9 (11.1%)	1	2/6 (33.3%)	2
Pneumonitis	0/16 (0%)	0	1/9 (11.1%)	1	0/6 (0%)	0
Investigations
Elevaed ALT	2/16 (12.5%)	2	1/9 (11.1%)	1	0/6 (0%)	0
Elevaed bilirubin	1/16 (6.3%)	1	1/9 (11.1%)	1	0/6 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	0/16 (0%)	0	1/9 (11.1%)	1	0/6 (0%)	0
Nervous system disorders
Brain Infarction	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Hypoxic ischemic encephalopathy	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Neurotoxicity	1/16 (6.3%)	1	0/9 (0%)	0	0/6 (0%)	0
Renal and urinary disorders
Hematuria	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Intubation	0/16 (0%)	0	1/9 (11.1%)	1	1/6 (16.7%)	1
Pulmonary hemorrhage	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Respiratory acidosis	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Respiratory failure	0/16 (0%)	0	0/9 (0%)	0	1/6 (16.7%)	1
Vascular disorders
Hypertension	1/16 (6.3%)	1	2/9 (22.2%)	2	3/6 (50%)	3

Limitations/Caveats

[Not Specified]

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.