Evaluating the Safety and Effectiveness of Mozobil Mobilization in Adults With Beta-Thalassemia Major

Beta-Thalassemia Clinical Trial

Official title:

A Pilot Study to Assess the Safety and Efficacy of Mozobil ± G-CSF in Mobilizing Hematopoietic Stem Cells (CD34+ Cells) in Adults With Beta-thalassemia Major

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01206075
• Other study ID #: 36078-B
• Secondary ID: P01HL0537502P01H
• Status: Completed
• Phase: N/A
• First received: September 20, 2010
• Last updated: December 27, 2014
• Start date: October 2010
• Est. completion date: December 2014

Study information

• Verified date: December 2014
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review BoardGreece: Institutional Ethics CommitteeGreece: National Ethics CommitteeGreece: Ministry of Health and WelfareGreece: National Organization of Medicines
• Study type: Interventional

Clinical Trial Summary

Thalassemia is considered the most common genetic disorder worldwide, occurring with high frequency in Mediterranean areas, the Middle East, Southeast Asia, and the Pacific Islands. Currently, the only cure for thalassemia is bone marrow transplantation from a related, compatible donor. Gene transfer, achieved by transplantation of the patient's own blood stem cells that have been genetically-modified with the corrected gene, could potentially cure thalassemia.

The first step in developing gene transfer for treatment of thalassemia is to develop a safe and effective method to obtain blood stem cells from thalassemia patients. Eventually, high numbers of genetically modified cells will need to be infused into the patient for clinical gene transfer to be effective. The blood stem cells are obtained by giving a "mobilization" agent to the patients. This causes the stem cells to leave the bone marrow and go into the blood. The purpose of this study is to test the safety and effectiveness of the new mobilization agent, Mozobil, in causing mobilization of blood stem cells for patients with beta-thalassemia major.

Description:

The purpose of this study is to optimize blood stem cell mobilization in adults with beta thalassemia major. We seek a method of mobilization that will be safe, with minimum side effects, and that will yield high numbers of blood stem cells. For successful gene therapy of thalassemia, high numbers of genetically modified stem cells will need to be introduced into the patient. Participants will include beta-thalassemia patients who failed to mobilize sufficiently with G-CSF (in our previous protocol) and new patients. In this study we will focus on the safety and effectiveness of mobilization with Mozobil or with Mozobil plus G-CSF. Following mobilization, blood stem cells will be recovered using leukapheresis, a procedure similar to a blood donation, in which mobilized white blood cells are collected from the blood of the patient.

During drug administration and leukapheresis, patients will be hospitalized at George Papanicolaou Hospital in Thessaloniki, Greece. Patients who failed to mobilize in the previous protocol will receive Mozobil and G-CSF and will be hospitalized for 5-8 days for the duration of drug administration and leukapheresis. They will receive G-CSF for several days; Mozobil will be added on the last few days of G-CSF. New patients will receive Mozobil only and will be hospitalized for 2-3 days for drug administration and leukapheresis. Mozobil is administered at 240µg/kg, under the skin. Participants will undergo two or three leukapheresis procedures in a row if low numbers of blood stem cells were recovered in the first (and possibly second) leukapheresis. Participants will be discharged from the hospital the day following the last leukapheresis procedure. Weekly follow-up visits will occur for the next month, either at G. Papanicolaou Hospital, or at the participant's local doctor's office. The total period of study participation is approximately 5 weeks. In the event that Mozobil alone does not cause mobilization of high levels of blood cells, patients will be invited to repeat the protocol three months later, receiving Mozobil and G-CSF.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: December 2014
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• ?eta- thalassemia major

• Age >18<50

• Karnofsky performance status ³80%

• Splenectomized patients or patients with spleen volume <800cm3 (only for the non splenectomized patients who will receive Mozobil + G-CSF)

• Compliant with regular transfusions and regular chelation

• Liver iron by MRI <280µmol/gr or ³1.7msec by T2*MRI

• Heart iron by MRI >2.8 (SI/SD) or ³9msec by T2*MRI

• Hepatitis B or C virus load negative by PCR (polymerase chain reaction)

• Left ventricular ejection fraction (LVEF) >45% by echocardiogram

• Adequate respiratory function with DLCO >50%

• Negative pregnancy test, if female

• Ability to give informed consent and willingness to meet all the expected requirements of the protocol for the duration of the study

Exclusion Criteria:

• History of thrombosis or known thrombophilia

• Symptomatic viral, bacterial or fungal infection within 6 weeks prior eligibility evaluation

• Pregnancy or lactation

• HIV positivity

• History of malignancy, other than local skin cancer

• Other systematic disease non thalassemia-associated

• Splenectomized patients with platelet count >900,000 (only for the splenectomized patients who will receive low dose G-CSF+ Mozobil)

• Additional risk factors for thrombosis, including Factor V Leiden; antiphospholipid antibodies and less than 50% of the lowest normal value for the following procoagulants: antithrombin 3, protein C, or protein S.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Beta-Thalassemia
• Thalassemia

Intervention

Drug:
• Mozobil
Previously mobilized splenectomized patients who failed to yield sufficient numbers of cells with Mozobil alone will receive low doses G-CSF subcutaneously (starting at 2.5µg/kg/day and adjusted to the degree of leukocytosis), and Mozobil at 240µg/kg starting on the 4th or 5th day of G-CSF, followed by one to three leukaphereses. Previously non-splenectomized patients who failed to yield sufficient numbers of cells with Mozobil alone will receive G-CSF at 10µg/kg/day subcutaneously for 4-7 days, and Mozobil at 240µg/kg starting on the 4th or 5th day of G-CSF, followed by one to three leukaphereses.
• Mozobil
Previously mobilized splenectomized patients who failed to yield sufficient numbers of cells with G-CSF in the previous study will receive low doses G-CSF subcutaneously (starting at 2.5µg/kg/day and adjusted to the degree of leukocytosis), and Mozobil at 240µg/kg starting on the 4th or 5th day of G-CSF, followed by one to three leukaphereses. Previously non-splenectomized patients who failed to yield sufficient numbers of cells with G-CSF in the previous study will receive G-CSF at 10µg/kg/day subcutaneously for 4-7 days, and Mozobil at 240µg/kg starting on the 4th or 5th day of G-CSF, followed by one to three leukaphereses.
• Mozobil
Up to sixteen patients (splenectomized and non-splenectomized) who were not previously mobilized will receive Mozobil at 240µg/kg for one to three days, followed by one to three leukaphereses.

Locations

Country	Name	City	State
Greece	George Papanicolaou Hospital	Thessaloniki

Sponsors (4)

Lead Sponsor	Collaborator
University of Washington	Genzyme, a Sanofi Company, George Papanicolaou Hospital, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

Greece, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and effectiveness of Mozobil for mobilization of patients with beta thalassemia major	i) To determine the safety of peripheral blood stem cell (PBSC) mobilization with Mozobil alone or with Mozobil + G-CSF in adults with b-thalassemia major ii) To collect with Mozobil or Mozobil+G-CSF a total of at least 6 X 10e6 CD34+ cells/kg for a subsequent clinical beta-globin gene transfer trial.	Five weeks	Yes
Secondary	Clonogenic capacity, transducibility, and engraftment potential (in a mouse model) of genetically modified cells	Secondary: i)To determine the clonogenic capacity of cells mobilized by Mozobil alone, or by Mozobil + G-CSF, ii) To determine the cells' ability to be transduced with a recombinant lentivirus vector for beta-globin, iii) To determine the transduced cells' potential to engraft in a xenograft model.	Six months	Yes