Osteopetrosis
Conditions
Keywords
osteopetrosis
Brief summary
We believe that hematopoietic stem cell transplantation (HSCT) will help subjects with Osteopetrosis generate functioning osteoclasts, and by so doing assist in the resolution of the abnormal bone architecture, and the anemia and bone marrow failure that is also characteristic of this disease. However, we have found in past studies that approximately 30% of Osteopetrosis patients do not engraft. Therefore, in this study, we plan to use a different combination 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. The purpose of this research is to find 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.
Detailed description
This transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 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, Campath levels just prior to the administration of the graft, and establishment of mesenchymal stem cell lines. In older patients, studies to evaluation osteoclast differentiation and function will also be offered.
Interventions
PROCEDUREStem Cell or Umbilical Cord Blood Transplantation
Stem Cell (unrelated or matched related donor grafts (both peripheral blood and marrow) infusion on Day 0 and 42; Umbilical Cord Blood on Day 0 and 42
DRUGCampath, Busulfan, Clofarabine
* 12 Campath-1H 0.3 mg/kg intravenously (IV) over 2 hours * 11 Campath-1H 0.3 mg/kg intravenously over 2 hours * 10 Campath-1H 0.3 mg/kg intravenously over 2 hours * 9 Busulfan \<12 kg: 2.2 mg/kg/dose IV every 12 hours \>12 kg: 1.6 mg/kg/dose IV every 12 hours * 8 Busulfan \<12 kg: 2.2 mg/kg/dose IV every 12 hours \>12 kg: 1.6 mg/kg/dose IV every 12 hours * 7 Rest * 6 Clofarabine 40 mg/m2 intravenously over 2 hours * 5 Clofarabine 40 mg/m2 intravenously over 2 hours * 4 Clofarabine 40 mg/m2 intravenously over 2 hours * 3 Clofarabine 40 mg/m2 intravenously over 2 hours * 2 Clofarabine 40 mg/m2 intravenously over 2 hours
PROCEDURETotal Lymphoid Irradiation
Dose 500 cGy via anteroposterior (AP) and posteroanterior (PA) fields (250 cGy AP and 250 cGy PA).
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 45 Years
Healthy volunteers
No
Inclusion criteria
* Patients eligible for transplantation under this protocol will be \<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 substantially 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving Donor Cell Engraftment | Day 100 | Number of patients with persistent presence of donor-derived cells at Day 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Transplant Related Death | Day 100 | Number of participants died during study by Day 100 and reason for death was related to transplant. |
| Number of Patients With Transplant Related Toxicity | Day 100 | Number of patients experiencing adverse effects due to transplant categorized by body system using Common Terminology Criteria for Adverse Events coding from the National Cancer Institute, Version 3.0. |
| Differential Imaging and Biologic Evaluations | Day 100, 6 months, 1, 2 and 5 years | These outcome measures were not assessed due to early study termination. |
Countries
United States
Participant flow
Pre-assignment details
This study was terminated early due to stopping rules. The first 3 patients enrolled died by Day 100 of study.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Osteopetrosis Who Received Transplant All patients enrolled with osteopetrosis and received transplant. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Patients With Osteopetrosis Who Received Transplant |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 3 / 3 |
Outcome results
Primary
Number of Patients Achieving Donor Cell Engraftment
Number of patients with persistent presence of donor-derived cells at Day 100
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With Osteopetrosis Who Received Transplant | Number of Patients Achieving Donor Cell Engraftment | 2 Participants |
Secondary
Differential Imaging and Biologic Evaluations
These outcome measures were not assessed due to early study termination.
Time frame: Day 100, 6 months, 1, 2 and 5 years
Secondary
Number of Patients With Transplant Related Death
Number of participants died during study by Day 100 and reason for death was related to transplant.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Death | 3 Participants |
Secondary
Number of Patients With Transplant Related Toxicity
Number of patients experiencing adverse effects due to transplant categorized by body system using Common Terminology Criteria for Adverse Events coding from the National Cancer Institute, Version 3.0.
Time frame: Day 100
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Toxicity | Neurologic | 1 Participants |
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Toxicity | Renal | 1 Participants |
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Toxicity | Pulmonary | 3 Participants |
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Toxicity | Peri-Transplant Mortality (Death by Day 100) | 3 Participants |
| Patients With Osteopetrosis Who Received Transplant | Number of Patients With Transplant Related Toxicity | Vascular | 1 Participants |