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Allogeneic Transplantation For Severe Osteopetrosis

Primary Purpose

Severe Osteopetrosis

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

umbilical cord blood transplantation

Campath-1H

Total Lymphoid Irradiation

Cyclophosphamide

Busulfan

Fludarabine monophosphate

marrow graft transplantation

About this trial

This is an interventional treatment trial for Severe Osteopetrosis focused on measuring osteopetrosis

Eligibility Criteria

1 Day - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients eligible for transplantation under this protocol will be < or = 45 years of age, and will be diagnosed with severe osteopetrosis. This will be defined as having the following manifestations of the disease.
1. Bones that are uniformly markedly dense based on skeletal survey
2. No history that would suggest autosomal dominant inheritance
3. Evidence of hematologic changes that are attributed to the underlying disease, including
the need for ongoing transfusions, OR
the presence of progressive anemia or thrombocytopenia, OR
a white blood cell differential with a predominance of immature forms and evidence of extramedullary hematopoiesis, OR
persistence of serious infectious complications that are thought to be due to the abnormal architecture of the bone that are resistant to surgical and medical interventions.

Exclusion Criteria:

Patients >45 years of age
Evidence of hepatic failure
Pulmonary dysfunction sufficient to significantly increase the risk of transplant.
Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted.
Cardiac compromise sufficient to substantially increase the risk of transplantation
Severe, stable neurologic impairment.
Human immunodeficiency virus (HIV) positivity.
Pregnant or lactating females

Sites / Locations

University of MInnesota, Fairview

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

marrow graft transplant conditioning

cord blood transplant conditioning

Arm Description

Pre-transplant conditioning using Campath-1H, Busulfan, Fludarabine monophosphate, and total lymphoid irradiation followed by unrelated or matched related donor marrow graft transplantation (both peripheral blood and marrow) and a second CD34 cell infusion on Day 42.

Pre-transplant conditioning using Campath-1H, Busulfan and Cyclophosphamide followed by unrelated umbilical cord blood transplantation and a second smaller portion cord blood graft infusion on Day 42.

Outcomes

Primary Outcome Measures

Number of Patients Who Achieved Donor Cell Engraftment

Secondary Outcome Measures

Transplant Related Mortality at 100 Days

Transplant Related Toxicity

Incidence of Grade II - IV Acute Graft-versus-host Disease

Full Information

NCT ID

NCT00775931

First Posted

October 16, 2008

Last Updated

July 10, 2019

Sponsor

Masonic Cancer Center, University of Minnesota

1. Study Identification

Unique Protocol Identification Number

NCT00775931

Brief Title

Allogeneic Transplantation For Severe Osteopetrosis

Official Title

Allogeneic Hematopoietic Stem Cell Transplantation For Severe Osteopetrosis

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

August 2008 (undefined)

Primary Completion Date

June 2013 (Actual)

Study Completion Date

June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this research is to explore what we believe may be a safer and more effective means of performing stem cell transplantation in patients with Osteopetrosis, using chemotherapy and radiation designed to bring about engraftment and lessen transplant mortality. Prior multi-institutional data in past studies found that approximately 30% of Osteopetrosis patients do not engraft. Therefore, in this study, we utilize a reduced intensity design of pre-transplant drugs to try to make transplants safer for this disease, as well as to provide a second infusion of stem cells in patients with matched related or unrelated donors.

Detailed Description

This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol and a second infusion of stem cells on day 42, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include microarray analysis, and evaluation of blood parameters and genes that may be important in the disease process. In older patients, studies to evaluation osteoclast differentiation and function will also be offered.

6. Conditions and Keywords

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

Severe Osteopetrosis

Keywords

osteopetrosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

marrow graft transplant conditioning

Arm Type

Active Comparator

Arm Description

Arm Title

cord blood transplant conditioning

Arm Type

Active Comparator

Arm Description

Intervention Type

Procedure

Intervention Name(s)

umbilical cord blood transplantation

Other Intervention Name(s)

UCBT

Intervention Description

Umbilical cord blood will be collected, processed and shipped according to existing protocols. 2 cord blood units will be utilized if available. The choice of units will be based on the HLA typing standards of the University of Minnesota Blood and Marrow Program. If 2 units are not available, a single unit may be used. If a single unit is used, the unit should provide at least 10 x 107 nucleated cells/kg recipient body weight.

Intervention Type

Drug

Intervention Name(s)

Campath-1H

Other Intervention Name(s)

Alemtuzumab

Intervention Description

Campath-1H will be administered 0.3 mg/kg subcutaneously per day for three days starting on Day -21 through Day -19.

Intervention Type

Radiation

Intervention Name(s)

Total Lymphoid Irradiation

Other Intervention Name(s)

TLI

Intervention Description

Dose 500 cGy via anteroposterior (AP) and posteroanterior(PA) fields (250 cGy AP and 250 cGy PA).

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

Cyclophosphamide (50 mg/kg/dose) will be given IV on day -4, -3, -2 and -1 over 2 hours. The total dose to be given over 4 days is 200 mg/kg for cord blood grafts-receiving patients only.

Intervention Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Busulfex

Intervention Description

patients<12 kg: 1.1 mg/kg/dose IV every 6 hours for 8 doses total; patients >12 kg: 0.8 mg/kg/dose IV every 6 hours for 8 doses. on Day -8 to -7 for donor grafts-receiving patients, and on Day -9 to -6 for cord blood grafts-receiving patients.

Intervention Type

Drug

Intervention Name(s)

Fludarabine monophosphate

Other Intervention Name(s)

Fludara

Intervention Description

Fludarabine (35 mg/m2 daily for 5 days, 175 mg/m2 total) will be administered IV over 30 minutes on days -6, -5, -4, -3, and -2 for donor grafts-receiving patients only.

Intervention Type

Procedure

Intervention Name(s)

marrow graft transplantation

Other Intervention Name(s)

HSCT

Intervention Description

Related donor marrow will be collected, processed and shipped according to existing protocols of the National Marrow Donor Program or other URD registry, with the goal of achieving a cell dose of ≥ 6.0 x 108 nucleated cells/kg. The proportion of cells that are CD34+ will be determined prior to the administration of the graft. This will allow a portion of the graft (2 x 106 CD34+ cells) to be frozen for a subsequent infusion on day +42.

Primary Outcome Measure Information:

Title

Number of Patients Who Achieved Donor Cell Engraftment

Time Frame

Day 100

Secondary Outcome Measure Information:

Title

Transplant Related Mortality at 100 Days

Time Frame

day 100

Title

Transplant Related Toxicity

Time Frame

Day 100 post transplant

Title

Incidence of Grade II - IV Acute Graft-versus-host Disease

Time Frame

by Day 100 after transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Day

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients eligible for transplantation under this protocol will be < or = 45 years of age, and will be diagnosed with severe osteopetrosis. This will be defined as having the following manifestations of the disease. Bones that are uniformly markedly dense based on skeletal survey No history that would suggest autosomal dominant inheritance Evidence of hematologic changes that are attributed to the underlying disease, including the need for ongoing transfusions, OR the presence of progressive anemia or thrombocytopenia, OR a white blood cell differential with a predominance of immature forms and evidence of extramedullary hematopoiesis, OR persistence of serious infectious complications that are thought to be due to the abnormal architecture of the bone that are resistant to surgical and medical interventions. Exclusion Criteria: Patients >45 years of age Evidence of hepatic failure Pulmonary dysfunction sufficient to significantly increase the risk of transplant. Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted. Cardiac compromise sufficient to substantially increase the risk of transplantation Severe, stable neurologic impairment. Human immunodeficiency virus (HIV) positivity. Pregnant or lactating females

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paul Orchard, MD

Organizational Affiliation

Masonic Cancer Center, University of Minnesota

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of MInnesota, Fairview

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

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Allogeneic Transplantation For Severe Osteopetrosis

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