Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene

NCT ID: NCT01852071

Last Updated: 2022-08-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-02
• Study Completion Date: 2018-08-27

Brief Summary

The aim of this study is to assess the safety and efficacy of autologous transplantation of hematopoietic stem cells (CD34+ cells) from the bone marrow (BM) of ADA-deficient SCID infants and children following human ADA cDNA transfer by the EFS-ADA lentiviral vector. The level of gene transfer in blood cells and immune function will be measured as endpoints.

Detailed Description

The study is open to twenty (20) infants and children diagnosed with ADA-deficient SCID who did not have a medically eligible, human leukocyte antigen (HLA)-identical sibling donor for bone marrow transplantation. The EFS-ADA lentiviral vector with the human ADA cDNA will be used to transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects will receive 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety is the primary endpoint. During the follow-up phase, the investigators aim to determine whether the cells could engraft and produce mature cells that contain and express the corrected ADA gene in the absence of pegademase bovine (PEG-ADA) enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate the level of immune reconstitution, will be performed in the first and second years of the study.

Conditions

ADA-SCID

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Gene Therapy

Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells

Group Type: EXPERIMENTAL

Infusion of autologous EFS-ADA LV CD34+ (OTL-101)

Intervention Type: GENETIC

autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously

busulfan

Intervention Type: DRUG

Busulfan is used for non-myeloablative conditioning

PEG-ADA ERT

Intervention Type: DRUG

PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Interventions

Infusion of autologous EFS-ADA LV CD34+ (OTL-101)

autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously

Intervention Type: GENETIC

busulfan

Busulfan is used for non-myeloablative conditioning

Intervention Type: DRUG

PEG-ADA ERT

PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Intervention Type: DRUG

Other Intervention Names

OTL-101

Eligibility Criteria

Inclusion Criteria

-Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or confirmed ADA gene mutation(s) known to cause disease , AND

B. Evidence of severe combined immunodeficiency based on either:

1. Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR

2. Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on

1. lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count <300 cells/mcL) OR

2. severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, <10% of the response of the normal control of the day, or stimulation index <10)

• Ineligible for matched sibling allogeneic bone marrow transplantation: absence of a medically eligible HLA-identical sibling, with normal immune function, who may serve as an allogeneic bone marrow donor
• Signed written informed consent according to guidelines of the Institutional Review Board (IRB) (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) IRB

Exclusion Criteria

1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days of entering this trial.

2. Hematologic

1. Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years of age).

2. Neutropenia (absolute granulocyte count <500/mm3.

3. Thrombocytopenia (platelet count < 150,000/mm3, at any age).

4. International Normalised Ratio (INR) or Prothrombin Time (PT) > 2 times the upper limits of normal or Partial Thromboplastin Time (PTT) > 2.33 times the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded).

5. Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).

6. Prior allogeneic Hematopoietic Stem Cell Transplant (HSCT) with cytoreductive conditioning

3. Infectious

a. Evidence of infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA Polymerase Chain Reaction (PCR) within 90 days prior to bone marrow harvest. If other infection is present, it must be under control (e.g. stable or decreasing viral load) at the time of screening

4. Pulmonary

1. Resting O2 saturation by pulse oximetry < 95% on room air.

2. Chest x-ray indicating active or progressive pulmonary disease.

5. Cardiac

1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.

2. Uncorrected congenital cardiac malformation with clinical symptomatology.

3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.

4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.

6. Neurologic

1. Significant neurologic abnormality by examination.

2. Uncontrolled seizure disorder.

7. Renal

1. Renal insufficiency: serum creatinine >= 1.2 mg/dl, or >= 3+ proteinuria.

2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale.

8. Hepatic/GI:

1. Serum transaminases > 5 times the upper limit of normal (ULN).

2. Serum bilirubin > 2 times ULN.

3. Serum glucose > 1.5 times ULN.

4. Intractable severe diarrhea.

9. Oncologic

1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)

2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells

3. Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells

10. Known sensitivity to Busulfan

11. General

1. Expected survival < 6 months.

2. Pregnant.

3. Major congenital anomaly.

4. Ineligible for autologous HSCT by the criteria at the clinical site.

5. Other conditions which in the opinion of the principal investigator and/or co-investigators, contra-indicate the bone marrow harvest, the administration of busulfan, infusion of transduced cells or indicate the patient or patient's parents/primary caregivers inability to follow protocol.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

National Human Genome Research Institute (NHGRI)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Orchard Therapeutics

INDUSTRY

Sponsor Role: collaborator

University of California, Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Donald B. Kohn, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Donald B Kohn, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Locations

Mattel Children's Hospital, UCLA

Los Angeles, California, United States

Mark O. Hatfield Clinical Research Center, NIH

Bethesda, Maryland, United States

Countries

United States

References

Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu PY, Gschweng E, Cooper A, Tisdale JF, Weinberg KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu XJ, Smogorzewska M, Wayne AS, Rosenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X, Gjertson D, Yang OO, Balamurugan A, Bauer G, Ireland JA, Engel BC, Podsakoff GM, Hershfield MS, Blaese RM, Parkman R, Kohn DB. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012 Nov 1;120(18):3635-46. doi: 10.1182/blood-2012-02-400937. Epub 2012 Sep 11.

Reference Type: BACKGROUND

PMID: 22968453 (View on PubMed)

Carbonaro DA, Zhang L, Jin X, Montiel-Equihua C, Geiger S, Carmo M, Cooper A, Fairbanks L, Kaufman ML, Sebire NJ, Hollis RP, Blundell MP, Senadheera S, Fu PY, Sahaghian A, Chan RY, Wang X, Cornetta K, Thrasher AJ, Kohn DB, Gaspar HB. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. doi: 10.1038/mt.2013.265. Epub 2013 Nov 20.

Reference Type: BACKGROUND

PMID: 24256635 (View on PubMed)

Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.

Reference Type: DERIVED

PMID: 33974366 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U01AI100801

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2P01HL073104

Identifier Type: NIH

Identifier Source: secondary_id

View Link

0910-1006

Identifier Type: OTHER

Identifier Source: secondary_id

EFS-ADA

Identifier Type: -

Identifier Source: org_study_id