Reduced Intensity AlloTransplant For Osteopetrosis

Reduced Intensity Allogeneic Transplantation For Severe Osteopetrosis Incorporating A Second Cd34 Selected Graft

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.

Study Overview

• Status: Terminated
• Conditions: Osteopetrosis
• Intervention / Treatment: Procedure: Stem Cell or Umbilical Cord Blood Transplantation; Drug: Campath, Busulfan, Clofarabine; Procedure: Total Lymphoid Irradiation

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of MInnesota, Fairview

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intent-To-Treat; Patients enrolled and received study treatment.

Procedure: Stem 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; Other Names: Bone Marrow Transplant; Drug: Campath, 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; Other Names: Busulfex, Clolar,Alemtuzumab; Procedure: Total Lymphoid Irradiation; Dose 500 cGy via anteroposterior (AP) and posteroanterior (PA) fields (250 cGy AP and 250 cGy PA).; Other Names: Therapuetic radation, radiation therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Achieving Donor Cell Engraftment	Number of patients with persistent presence of donor-derived cells at Day 100	Day 100

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Transplant Related Death	Number of participants died during study by Day 100 and reason for death was related to transplant.	Day 100
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.	Day 100
Differential Imaging and Biologic Evaluations	These outcome measures were not assessed due to early study termination.	Day 100, 6 months, 1, 2 and 5 years

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: March 11, 2008
• First Submitted That Met QC Criteria: March 18, 2008
• First Posted (Estimate): March 19, 2008

Study Record Updates

• Last Update Posted (Actual): December 28, 2017
• Last Update Submitted That Met QC Criteria: December 3, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: osteopetrosis
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Osteosclerosis; Osteopetrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Clofarabine; Busulfan; Alemtuzumab
• Other Study ID Numbers: 0704M06581; MT2007-06 (Other Identifier: Masonic Cancer Center, University of Minnesota)