Allogeneic Transplantation For Severe Osteopetrosis

NCT ID: NCT00775931

Last Updated: 2019-07-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-08-31
• Study Completion Date: 2013-06-30

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.

Conditions

Severe Osteopetrosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

marrow graft transplant conditioning

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.

Group Type: ACTIVE_COMPARATOR

Campath-1H

Intervention Type: DRUG

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

Total Lymphoid Irradiation

Intervention Type: RADIATION

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

Busulfan

Intervention Type: DRUG

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.

Fludarabine monophosphate

Intervention Type: DRUG

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.

marrow graft transplantation

Intervention Type: PROCEDURE

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.

cord blood transplant conditioning

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.

Group Type: ACTIVE_COMPARATOR

umbilical cord blood transplantation

Intervention Type: PROCEDURE

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.

Campath-1H

Intervention Type: DRUG

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

Cyclophosphamide

Intervention Type: DRUG

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.

Busulfan

Intervention Type: DRUG

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.

Interventions

umbilical cord blood transplantation

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: PROCEDURE

Campath-1H

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

Intervention Type: DRUG

Total Lymphoid Irradiation

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

Intervention Type: RADIATION

Cyclophosphamide

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

Busulfan

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

Fludarabine monophosphate

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: DRUG

marrow graft transplantation

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.

Intervention Type: PROCEDURE

Other Intervention Names

UCBT; Alemtuzumab; TLI; Cytoxan; Busulfex; Fludara; HSCT

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.

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

• Minimum Eligible Age: 1 Day
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Masonic Cancer Center, University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paul Orchard, MD

Role: PRINCIPAL_INVESTIGATOR

Masonic Cancer Center, University of Minnesota

Locations

University of MInnesota, Fairview

Minneapolis, Minnesota, United States

Countries

United States

Other Identifiers

0808M42261

Identifier Type: OTHER

Identifier Source: secondary_id

MT2008-20

Identifier Type: -

Identifier Source: org_study_id