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Stem Cell Gene Therapy for Sickle Cell Disease

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2017 by Donald B. Kohn, M.D., University of California, Los Angeles
Sponsor:
Collaborators:
California Institute for Regenerative Medicine
University of Southern California
Information provided by (Responsible Party):
Donald B. Kohn, M.D., University of California, Los Angeles
ClinicalTrials.gov Identifier:
NCT02247843
First received: September 20, 2014
Last updated: January 5, 2017
Last verified: January 2017
  Purpose
This Phase I clinical trial will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector modified bone marrow for adults with severe sickle cell disease.

Condition Intervention Phase
Sickle Cell Disease Genetic: βAS3-FB vector transduced BM CD34+ cells Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Clinical Research Study of Autologous Bone Marrow Transplantation for Sickle Cell Disease (SCD) Using Bone Marrow CD34+ Cells Modified With the Lenti/βAS3-FB Lentiviral Vector

Resource links provided by NLM:


Further study details as provided by Donald B. Kohn, M.D., University of California, Los Angeles:

Primary Outcome Measures:
  • Evaluation of Safety [ Time Frame: up to 24 months ]
    1. Clinical toxicity: Absence of grade 3-4 SAEs
    2. Absence of replication-competent lentivirus (RCL):
    3. Absence of monoclonal expansion or leukoproliferative disorder from vector insertional effects: To monitor for monoclonal expansion or leukoproliferative complications, LAM-PCR will be performed.
    4. Event-free survival. Event-free survival will be determined for each subject over the 24 months after gene therapy. An event is defined as death or performance of an allogeneic HSCT.
    5. Absence of humoral immune response to novel epitopes of βAS3-globin protein


Estimated Enrollment: 6
Study Start Date: July 2014
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: βAS3-FB vector transduced BM CD34+ cells
This is a single arm study without randomization. All subjects will receive the intervention of BetaAS3 lentiviral vector-modified autologous bone marrow stem cell transplant.
Genetic: βAS3-FB vector transduced BM CD34+ cells
BM CD34+ from SCD patients are transduced ex-vivo with the Lenti/βAS3-FB lentiviral vector. The transduced cells are then infused into the patient.
Other Name: Lenti/βAS3-FB

Detailed Description:

Sickle cell disease (SCD) affects ~90,000 people in the U.S. who suffer significant neurological, lung, and kidney damage, as well as severe chronic pain episodes that adversely impact on quality of life. While current medical therapies for SCD can reduce short-term morbidity, the inevitable progressive deterioration in organ function results in a significant decrease in quality of health with early mortality. Allogeneic hematopoietic stem cell transplant (HSCT) can benefit patients with SCD, by providing a source for life-long production of normal red blood cells. However, allogeneic HSCT is limited by the availability of well-matched donors and immunological complications, especially for the more than 80% of patients who lack an HLA-identical sibling donor. Autologous HSCT using a patient's own bone marrow stem cells that have been corrected by transfer of a modified human beta-globin gene that inhibits polymerization of the HbS (stem cell gene therapy) may provide a better therapeutic alternative, as it would avoid the immunologic complications and donor limitations of allogeneic HSCT.

Up to 6 subjects with SCD lacking matched sibling donors and meeting eligibility criteria for disease severity and adequacy of organ function will be enrolled. Following informed consent, enrolled subjects will be screened to confirm full eligibility for participation. Eligible subjects will undergo bone marrow harvest (with a portion cryopreserved as "back-up") with the remaining portion of marrow used to prepare the gene-modified Final Cellular Product: autologous bone marrow CD34+ cells transduced ex vivo by the Lenti/βAS3-FB lentiviral vector to express an anti-sickling (βAS3) gene. The subject will receive marrow cytoreduction with busulfan prior to infusion of the gene-modified cells. The follow-up period will include an initial 2 years of active end-point evaluations, where the subjects will be seen at intervals of no more than 3 months, followed by offer for enrollment into a long-term follow-up study during years 3-15.

The primary objectives of the Phase I study are to assess safety and feasibility, with secondary objectives to assess efficacy (engraftment, βAS3-globin gene expression, and effects on RBC function and clinical hematologic and disease parameters).

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥18 by time of enrollment
  • Diagnosis of SCD documented by phenotype (Hb electrophoresis) or genetic analysis (S/S, S/β-thalassemia-zero)
  • Must not have medically eligible and available HLA-identical sibling donor or 10/10 allele-matched unrelated donor
  • Inadequate clinical response to hydroxyurea (HU), defined as any one of the following outcomes, while on HU for at least 3 months:

    • 2 or more acute sickle pain crises requiring hospitalization
    • no rise in Hb >1.5 gm/dl from pre-HU baseline or requires transfusion to maintain Hb > 6.0 gm/dL
    • Has an episode of acute chest syndrome despite adequate supportive care measures.
    • Or medical decision for other therapy (e.g. chronic transfusion program), or subject refusal to take HU.
  • The patient must be off HU for at least 90 days (+/- 5 days) before enrolling in the trial.
  • Must have one or more of the following clinical complications demonstrating disease severity:

    • Clinically-significant neurologic event: stroke or any central nervous system deficit lasting >24 hours.
    • Abnormal head CT or brain MRI demonstrating previous stroke
    • Administration of regular RBC transfusions for equal or longer than 1 year to prevent vaso-occlusive crises or other sickle cell disease complications or to maintain Hb >6.
    • Pulmonary arterial hypertension with tricuspid regurgitant jet velocity > 2.5 m/sec.
    • At least one episode of acute chest syndrome that required hospitalization, intubation, and mechanical ventilation support within the 2 years prior to enrollment
    • At least 2 acute sickle pain crises requiring hospitalization within the 2 years prior to enrollment
    • Osteonecrosis requiring joint replacement
    • History of acute dactylitis during childhood
    • Recurrent priapism (2 or more episodes)
  • Karnofsky performance score ≥60%

Exclusion Criteria:

  • Patient has a medically eligible and available HLA-identical sibling donor or 10/10 allele-matched unrelated donor (after at least 3 months search)
  • Cardiac evaluation: left ventricular ejection fraction (LVEF) < 40% or LV shortening fraction < 26% by cardiac echocardiogram or by MUGA scan,
  • Poorly-controlled hypertension as determined by history of recorded BP in previous year with systolic >135 or diastolic >95 mmHg.
  • Pulmonary evaluation: baseline oxygen saturation of <85% or DLCO< 40% (corrected for Hb).
  • Renal evaluation: serum creatinine >1.5x upper limit of normal for age or GFR<60 mL/min/1.73 m2
  • Hepatic evaluation: serum conjugated (direct) bilirubin > 2x upper limit of normal for age as per local laboratory or ALT and AST > 5 times upper limit of normal as per local laboratory
  • Hematologic evaluation: Leukopenia (WBC< 3x103/uL) or neutropenia (ANC < 1.0x103/uL) or thrombocytopenia (platelet count < 100x103/uL)
  • PT/INR or PTT >1.5x upper limit of normal or other clinically significant bleeding disorder
  • Serum ferritin >1,000 ng/ml. (Potential subjects with serum ferritin >1,000 will be referred back to their physician for more specific evaluation {e.g. MRI or liver biopsy}, and consideration of iron chelation therapy, if indicated. If successful and serum ferritin comes below 1,000 ng/ml, subjects may be reconsidered for enrollment).
  • Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV or parvovirus B19, based on positive blood PCR
  • Psychiatric evaluation: psychiatric disorder or neurologic disease that would impair the informed consent process or cooperation with the clinical trial performance
  • Pregnancy
  • Cancer or other malignant disease.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02247843

Contacts
Contact: Gary Schiller, MD 310-206-5755 gschiller@mednet.ucla.edu
Contact: Fabrizia Urbinati, PhD 310-794-1884 furbinati@ucla.edu

Locations
United States, California
University of California, Los Angeles (UCLA) Recruiting
Los Angeles, California, United States, 90095
Contact: Mary E. Sehl, MD    310-206-8477 ext 21169    msehl@mednet.ucla.edu   
Contact: Gary Schiller, MD    310-206-5755    gschiller@mednet.ucla.edu   
Principal Investigator: Gary Schiller, MD         
Sub-Investigator: Donald B Kohn, MD         
Sub-Investigator: Theodore B Moore, MD         
Sub-Investigator: Sarah Larson, MD         
Sub-Investigator: Gay M Crooks, MD         
Sub-Investigator: Satiro DeOliveira, MD         
Sub-Investigator: Lonnie Zeltzer, MD         
Sub-Investigator: David Gjertson, MD         
Sponsors and Collaborators
Donald B. Kohn, M.D.
California Institute for Regenerative Medicine
University of Southern California
Investigators
Study Director: Mary Sehl, MD University of California, Los Angeles
Principal Investigator: Gary Schiller, MD University of California, Los Angeles
  More Information

Publications:
Responsible Party: Donald B. Kohn, M.D., Professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT02247843     History of Changes
Other Study ID Numbers: Lenti/βAS3-FB
Study First Received: September 20, 2014
Last Updated: January 5, 2017

Keywords provided by Donald B. Kohn, M.D., University of California, Los Angeles:
Sickle Cell Disease (SCD)
Gene Therapy
Lentiviral Vector
Beta Globin

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on July 21, 2017