Reduced-Intensity Hematopoietic Stem Cell Transplant for High Risk Lysosomal and Peroxisomal Disorders

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01626092
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 15.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (TRM) in patients with high-risk lysosomal and peroxisomal disorders using a novel conditioning regimen for hematopoietic cell transplantation (HCT). After a reduced-intensity conditioning regimen using volumetric-modulated arc therapy (VMAT)-delivered low-dose total body irradiation (TBI) with highly conformal marrow boosting, patients will be transplanted using either a related or unrelated allograft. The cell source may be marrow, peripheral blood or cord blood based on donor availability.

Condition or Disease	Intervention/Treatment	Phase
Lysosomal Storage Disease; Peroxisomal Disorder	Drug: Campath-1H; Drug: Clofarabine; Drug: Melphalan; Radiation: Total Body Irradiation with Marrow Boosting; Biological: Hematopoietic stem cell transplantation; Drug: Cyclosporine A; Drug: Mycophenolate mofetil	N/A

Detailed Description

The conditioning regimen consists of alemtuzumab (Campath-1H), clofarabine, melphalan, and VMAT-delivered low-dose TBI with boosted marrow irradiation. Additional graft-versus-host disease prophylaxis consists of mycophenolate mofetil and cyclosporine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of High Risk, Inherited Lysosomal and Peroxisomal Disorders by Reduced-Intensity Hematopoietic Cell Transplantation and Low-Dose Total Body Irradiation With Marrow Boosting by Volumetric-Modulated Arc Therapy (VMAT)
• Actual Study Start Date: Jul 11, 2012
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Intent-To-Treat Patients Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor.

Drug: Campath-1H; A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8.; Other Names: alemtuzumab-1H ; Drug: Clofarabine; A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9, -8, -7, -6, and -5.; Other Names: Clolar ; Drug: Melphalan; A single dose of 140 mg/m2 will be given IV on day -4 over 15 minutes.; Other Names: Alkeran ; Radiation: Total Body Irradiation with Marrow Boosting; Dose to total body 200 cGy in single dose Dose to bone marrow of the following bones 800 cGy in 5 divided daily fractions (160 cGy x 5 doses ). Treated with up to 3 abutting VMAT photon arcs from top of head to maximum inferior border.; Other Names: Volumetric-Modulated Arc Therapy (VMAT) ; Biological: Hematopoietic stem cell transplantation; Patients will be transplanted using either a related or unrelated allograft. The cell source may be marrow, peripheral blood or cord blood based on donor availability.; Drug: Cyclosporine A; Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose IV; if the recipient body weight is <40 kg, dosing will be 3 times daily, and if > 40 kg, twice daily. An attempt will be made to maintain a trough cyclosporine level of 200 mg/L to 400 mg/L.; Other Names: CsA ; Drug: Mycophenolate mofetil; Patients will receive mycophenolate mofetil (MMF) therapy beginning on day -3. Dosing of MMF will be 1 gram three times daily (total daily dose 3 grams/day) if the recipient is >50 kg, or 15 mg/kg/dose three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously.; Other Names: MMF

Outcome Measures

Primary Outcome Measures

1. Donor (Allogeneic) Hematopoietic Engraftment [Day 100 Following Hematopoietic Cell Transplant (HCT)]

   Number of patients who achieve hematopoietic engraftment - assessment of nucleated peripheral blood cells for donor (allogeneic) chimerism following this reduced-intensity HCT.

Secondary Outcome Measures

1. Transplant-Related Mortality [Day 100 following HCT]

   Incidence of death due to complications of HCT following this reduced-intensity conditioning regimen.

2. Neurologic Outcomes [Changes from Baseline, Days 30, 60, 100, Year 1, Year 2, Year 3 Following HCT]

   Depending upon underlying primary disease, a combination of evaluative tools (e.g. brain magnetic resonance imaging (MRI), clinical neurologic exam, neuropsychologic testing, electromyography) will be applied for assessment of neurologic function and how it may be affected by this reduced-intensity HCT regimen.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adrenoleukodystrophy (ALD): Patients from 0-55 years of age diagnosed with ALD as determined by very long chain fatty acid testing will be eligible for this protocol if they have evidence of cerebral or cerebellar disease based on MRI testing,

• Metachromatic Leukodystrophy (MLD): Patients from 0-55 years of age diagnosed with MLD as determined by arylsulfatase A activity.

• Globoid Cell Leukodystrophy (GLD): Patients from 0-55 years of age diagnosed with GLD as determined by galactocerebrosidase activity will be eligible for this protocol

• Wolman's disease, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Sandhoff disease or other inherited metabolic diseases including but not limited to I-cell disease (mucolipidosis II): Patients who are determined to be sufficiently advanced or high risk based on the following reasons:

• Symptomatic disease, as based on neurologic examination or evidence of deterioration based on subsequent neuropsychologic evaluations.

• Evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease.

• Other metabolic disorders, including but not limited to I-cell disease, that are deemed to be high-risk for a poor outcome with a standard transplant regimen due to anticipated toxicity based on experience gained at the University of Minnesota or other centers.

• Donor Availability

• Transplantation using sufficiently matched related donors (such as matched siblings) or unrelated donors will be considered. Both granulocyte-colony stimulating factor (G-CSF) stimulated peripheral blood grafts and bone marrow grafts will be considered, although bone marrow will be the priority.

• Cord blood grafts, both related and unrelated, are also eligible. As this protocol will use a reduced intensity regimen, this protocol will use the current recommendations of the University of Minnesota for choosing cord blood grafts. If a single cord blood unit cell dose is insufficient, double cord transplantation should be considered if sufficiently matched cord blood units are available. The priority of choosing cord blood donors is based on the current institutional recommendations.

• Exclusion of Metabolic Disorder Carrier Status from related donor and unrelated cord blood grafts as appropriate for primary disease.

• Adequate Organ Function - Measured within 30 days of study enrollment

• Signed consent

Exclusion Criteria:

• Inability to receive total body irradiation (TBI) with marrow boosting per protocol guidelines as determined by the Radiation Oncologist

• Pregnant - Menstruating females must have a negative serum pregnancy test within 14 days of treatment start.

• Advanced Disease Exclusion: Following evaluation, if a consensus of the members of the Inherited Metabolic and Storage Disease Program is that a patient is too advanced to benefit in a measurable and meaningful way from transplant, this will be communicated to the family, and transplant will not be offered.

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: Weston Miller, MD, Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT01626092
• Other Study ID Numbers: 2011LS147; MT2011-24
• First Posted: Jun 22, 2012
• Last Update Posted: Dec 5, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: bone marrow transplantation; reduced intensity conditioning; Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Wolman's disease; GM1 gangliosidosis; Tay Sachs disease; Sanfilippo syndrome; Sandhoff disease; inherited metabolic; I-cell disease; mucolipidosis II
• Additional relevant MeSH terms: Lysosomal Storage Diseases; Peroxisomal Disorders; Cyclosporine; Mycophenolic Acid; Melphalan; Alemtuzumab; Clofarabine; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8. Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9,
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8 Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9
Overall Participants	3
Age (Count of Participants)
<=18 years	3 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Donor (Allogeneic) Hematopoietic Engraftment
Description	Number of patients who achieve hematopoietic engraftment - assessment of nucleated peripheral blood cells for donor (allogeneic) chimerism following this reduced-intensity HCT.
Time Frame	Day 100 Following Hematopoietic Cell Transplant (HCT)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8. Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9,
Measure Participants	3
Number [participants]	1 33.3%

2. Secondary Outcome

Title	Transplant-Related Mortality
Description	Incidence of death due to complications of HCT following this reduced-intensity conditioning regimen.
Time Frame	Day 100 following HCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8. Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9,
Measure Participants	3
Number [participants]	0 0%

3. Secondary Outcome

Title	Neurologic Outcomes
Description	Depending upon underlying primary disease, a combination of evaluative tools (e.g. brain magnetic resonance imaging (MRI), clinical neurologic exam, neuropsychologic testing, electromyography) will be applied for assessment of neurologic function and how it may be affected by this reduced-intensity HCT regimen.
Time Frame	Changes from Baseline, Days 30, 60, 100, Year 1, Year 2, Year 3 Following HCT

Outcome Measure Data

Analysis Population Description

None of the 3 patients enrolled in the study were evaluable for this outcome. Two had a repeat transplant and one was lost to follow-up.

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8. Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9,
Measure Participants	0

Adverse Events

Arm/Group Title	Intent-To-Treat Patients
Arm/Group Description	Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m^2 IV on days -9 through -5, melphalan 140 mg/m^2 IV on day -4 and Total Body Irradiation with Marrow Boosting [ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure] by Volumetric-Modulated Arc Therapy [VMAT] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor. Campath-1H: A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8 Clofarabine: A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9
All Cause Mortality
	Intent-To-Treat Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Intent-To-Treat Patients
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Intent-To-Treat Patients
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Ear and labyrinth disorders
Hearing loss	1/3 (33.3%)
Eye disorders
Decreased vision	2/3 (66.7%)
Gastrointestinal disorders
Abdominal pain	1/3 (33.3%)
Nausea	3/3 (100%)
Vomiting	2/3 (66.7%)
Mucositis	3/3 (100%)
Acid reflux	1/3 (33.3%)
Loose stools	1/3 (33.3%)
General disorders
Fever	2/3 (66.7%)
Infections and infestations
Positive blood culture - Staphylococcus aureus	1/3 (33.3%)
Positive blood culture - Escherichia coli	1/3 (33.3%)
Fever	1/3 (33.3%)
BK viruria	1/3 (33.3%)
Adenoviremia	1/3 (33.3%)
Injury, poisoning and procedural complications
Acute radiation syndrome	1/3 (33.3%)
Graft failure	3/3 (100%)
Investigations
Elevated lipase	1/3 (33.3%)
Serum amylase increased	2/3 (66.7%)
Hypogammaglobulinemia	1/3 (33.3%)
Elevated ALT	1/3 (33.3%)
Elevated AST	1/3 (33.3%)
Metabolism and nutrition disorders
Anorexia	2/3 (66.7%)
Nervous system disorders
Dizziness	1/3 (33.3%)
Muscle spasms	1/3 (33.3%)
Headache	1/3 (33.3%)
Psychiatric disorders
Anxiety	2/3 (66.7%)
Agitation	1/3 (33.3%)
Renal and urinary disorders
Dysuria	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Decreased oxygen saturation	1/3 (33.3%)
Skin and subcutaneous tissue disorders
Rash	1/3 (33.3%)
Vascular disorders
Hypertension	3/3 (100%)
Hypotension	1/3 (33.3%)

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.