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Stem Cell Gene Therapy for Cystinosis

Primary Purpose

Lysosomal Storage Diseases, Cystinosis

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
Sponsored by
University of California, San Diego
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lysosomal Storage Diseases focused on measuring Cystinosis, Lysosomal Storage Disorders, LSD

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

The following criteria must be met by all subjects considered for study participation.

  1. Cohorts 1 and 2: Male or female subject is ≥ 18 years of age.
  2. Cohort 3: Male or female subject is ≥ 14 years of age.
  3. Subject is diagnosed with cystinosis, i.e., early onset of Fanconi syndrome, and history of elevated white blood cell cystine level and/or history of or presence of cystine crystals in the eye.
  4. Subject has a Karnofsky Performance Status or age-dependent Lansky Performance of ≥ 60.
  5. If subject has had a kidney transplant, he or she must be at least one-year post kidney transplant status.
  6. Subject has adequate hematologic function:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 1000/mm^3
    2. Platelet count ≥ 100 x 1000/mm^3
    3. Hemoglobin ≥ 9.0 gm/dL
  7. Subject has an adequate hepatic function:

    1. Bilirubin ≤ 2.0 mg/ dL
    2. ALT ≤ 3 x institution's upper limit of normal (ULN) U/L
  8. Subject has an adequate renal function:

    1. Serum creatinine <2x ULN mg/dL
    2. Creatinine clearance ≥ 50 mL/min/1.73 m^2
  9. Subject has adequate coagulation:

    1. PT/aPTT ≤ 1.2 x ULN seconds
    2. INR ≤ 2
  10. Subject has adequate thyroid function (with or without thyroid replacement therapy):

    1. TSH 0.27-4.2 mIU/mL
    2. Total T4 ≤ 2 x ULN mcg/dL
  11. If female: female of childbearing potential (i.e., not surgically sterile [tubal ligation, hysterectomy, or bilateral oophorectomy] or not at least 2 years naturally postmenopausal) agrees to remain sexually abstinent or utilize the same acceptable form of highly effective contraception from screening through two years post-transplant.

    The acceptable forms of contraception for this study include hormonal contraceptives (oral, implant, transdermal patch, or injection) associated with inhibition of ovulation at a stable dose for at least 3 months prior to screening, barrier (condom with spermicide, diaphragm with spermicide), intrauterine device, or a partner who has been vasectomized for at least 6 months and has documented medical assessment of surgical success of a vasectomy.

    Note: males with cystinosis are sterile.

  12. If male: males must agree to remain sexually abstinent or utilize an acceptable form of highly effective contraception from screening through two years post-transplant.
  13. Subject is willing and able to comply with the study restrictions and requirements.
  14. Subject is willing to provide written informed consent/permission/assent prior to participation in the study.
  15. Subject must be willing to refrain from donating sperm after receiving the conditioning regimen. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm banking prior to administration of conditioning regimen will be recommended.
  16. Subject must be willing to refrain from donating blood, organs, tissues, or cells for transplantation from 30 days prior to screening through any time after CTNS-RD-04 treatment.
  17. Subject must be willing and must be able (in the judgment of the investigator) to discontinue his or her cysteamine therapy (oral and/or eye drop).

Exclusion Criteria:

  1. Subject has an active, uncontrolled, acute bacterial, viral, or fungal infection during screening or within 30 days prior to starting the conditioning regimen.
  2. Subject has positive serology at screening for any of the following:

    1. Human Immunodeficiency Virus (HIV) 1-2
    2. Human T-cell Lymphotropic Virus (HTLV) - I/II
    3. Hepatitis B core and Hepatitis B PCR positive
    4. Hepatitis C Virus (HCV)
    5. Rapid Plasma Reagin (RPR)
    6. Chagas' Disease (T. curzi)
    7. QuantiferonTB
    8. Nucleic Acid Test (NAT) for HIV
    9. West Nile Virus (WNV)
  3. Subject has a known clinically significant immunodeficiency disorder.
  4. Subject is a female of childbearing potential that is nursing, planning a pregnancy or has a positive serum pregnancy test.
  5. Subject has received a prior marrow or stem cell transplantation or is planning to receive one within 90 days of study initiation.
  6. Subject has had an active bleeding disorder within 90 days prior to screening OR requires anticoagulation therapy prior to treatment with ex vivo gene therapy.
  7. Subject has an active malignancy or history of malignancy including lymphoma (except primary, cutaneous basal cell or squamous cell cancer appropriately treated prior to transplantation).
  8. Subject has an end-stage renal disease (defined as GFR <15 mL/min) and is already on a transplantation list or who may be planning to register for a kidney transplant within 90 days of study initiation.
  9. Subject has impaired pulmonary function (based on FVC or FEV1 of <50% predicted, or an FEV1/FVC ratio less than age- and gender-specific normal threshold value).
  10. Subject has impaired cardiac function within 90 days prior to screening including any of the following:

    1. Myocardial infarction
    2. Clinically significant abnormal electrocardiogram (ECG)
    3. Ejection fraction of < 40%
    4. Uncontrolled arrhythmia
    5. Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension).
  11. Subject has a severe or uncontrolled medical disorder (e.g., pancreatitis, severe liver disease, unstable diabetes mellitus) that would, in the investigators' opinion, impair their ability to receive study treatment and follow the study procedures.
  12. Subject has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Busulfan or allergy or contraindication to use of other agents used in the study, including iohexol, acid-citrate-dextrose Formula A (ACDA), G-CSF or plerixafor.
  13. Subject has a known history of drug or alcohol addiction.
  14. Subject has undergone major surgery within 90 days (or longer if not fully recovered) prior to screening.
  15. Subject is receiving cytotoxic or immunosuppressive agents, other than for kidney transplant, within 60 days prior to screening or requires treatment with such agents prior to treatment with ex vivo gene therapy.
  16. Subject has previously received gene therapy at any time.
  17. Subject is currently receiving or anticipates receiving another investigational agent, device, or procedure from 30 days prior to screening through study completion.
  18. Subject has any condition, in the opinion of the investigator, that compromises compliance with study requirements.

Sites / Locations

  • University of California San Diego

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Gene Therapy with CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)

Arm Description

This is a single arm study without randomization. Eligible subjects will receive the final product: CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST).

Outcomes

Primary Outcome Measures

Evaluation of safety - Absence of Severe Adverse Events (SAEs) due to the investigational product
Safety and tolerability will be assessed in terms of incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Evaluation of safety - Absence of Replication-Competent Lentivirus (RCL)
Safety and tolerability will be measured by number of subjects with Replication Competent Lentivirus (RCL)
Evaluation of safety - Absence of genotoxicity
Safety and tolerability will be measured by absence of insertional mutagenesis, monoclonal expansion.
Evaluation of safety - Event-free survival
Safety and tolerability will be measured by Event-free survival over the 24 months after stem cell transplantation

Secondary Outcome Measures

Evaluation of efficacy - Change in cystine levels
Efficacy will be measured by evaluating the impact of treatment with CTNS-RD-04 on cystine levels in the blood, and cystine crystal counts in the intestinal mucosa and skin, and eye with the help of Mass Spectrometry and Confocal Microscopy.
Evaluation of efficacy - To evaluate the effect of treatment with CTNS-RD-04 on clinical disease outcomes
Among other evaluations, clinical efficacy will be measured by evaluating the effect on clinical disease outcomes including: Kidney Function (test: measure Serum Cystatin C levels, unit: score from 1 to 5 based on the stage of dialysis); (test: measure serum and urine phosphate levels, unit: mg/dL); Vision (test: Pachymetry, unit: millimeter); (test: Anterior Segment - Optical Coherence Tomography, unit: millimeter or millimeter square); Muscle strength (test: grip strength, unit: scale between 0/5 and 5/5); Pulmonary function (test: Spirometry, unit: percentage); Neurological and Psychometric function (test: Beery Test of Visual Motor Integration, neurological examination to evaluate motor coordination, tone, strength, and reflexes, unit: numerical score).
Evaluation of efficacy - Change in Quality of Life
Efficacy will be measured by evaluating changes in quality of life with the help of Health-Related Quality of Life (HRQoL) which will assess the impact of treatment with CTNS-RD-04 on quality of life.

Full Information

First Posted
February 6, 2019
Last Updated
March 28, 2023
Sponsor
University of California, San Diego
Collaborators
California Institute for Regenerative Medicine (CIRM), Cystinosis Research Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03897361
Brief Title
Stem Cell Gene Therapy for Cystinosis
Official Title
A Phase 1/2 Study to Determine Safety and Efficacy of Transplantation With Autologous Human CD34+ Hematopoietic Stem Cells (HSC) From Mobilized Peripheral Blood Stem Cells (PBSC) of Patients With Cystinosis Modified by Ex Vivo Transduction Using pCCL-CTNS or pCDY.EFS.CTNS.T260I Lentiviral Vector and Will Include Transduction Enhancer When Required During Manufacturing
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 8, 2019 (Actual)
Primary Completion Date
November 2024 (Anticipated)
Study Completion Date
November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Diego
Collaborators
California Institute for Regenerative Medicine (CIRM), Cystinosis Research Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is a Phase 1/2 clinical trial that will assess the safety and efficacy of enriched gene-corrected hematopoietic stem cells isolated from patients affected with cystinosis. (Investigational Product: CTNS-RD-04 or CTNS-RD-04-LB, where the suffix "-LB" stands for LentiBOOST)
Detailed Description
Cystinosis is a rare inherited recessive disease belonging to the family of Lysosomal Storage Disorders and is characterized by lysosomal accumulation of cystine in all the cells of the body leading to multi-organ failure. Cystinosis has a devastating impact on the affected individuals, primarily children, and young adults, even with cysteamine treatment. The prevalence of cystinosis is 1 in 100,000 to 1 in 200,000. The gene involved in cystinosis is the gene CTNS that encodes for the transmembrane lysosomal cystine transporter - cystinosin. The current standard of care does not prevent the progression of the disease and significantly impacts the quality of life of patients with cystinosis. For this study, up to 6 subjects meeting eligibility criteria will be transplanted following a 3-cohort staggered treatment design with 2 subjects per cohort. The first 2 cohorts will consist of 4 adults (18 years or older), potentially followed by a cohort consisting of 2 adolescents or adults (> 14 years old). Following the informed consent process, enrolled subjects will be screened to confirm full eligibility for participation. Eligible subjects will undergo hematopoietic stem cell (HSC) mobilization and collection (leukapheresis). A portion of cells will be kept as "back-up" for rescue purpose if necessary, and a portion will be ex vivo gene-modified with a lentiviral vector, pCCL-CTNS or pCDY.EFS.CTNS.T260I, to express CTNS gene (product name: CTNS-RD-04). Clinical manufacturing for patients in Cohort 3 will introduce a transduction enhancer LentiBOOST (product name for these patients will be CTNS-RD-04-LB, where the suffix "-LB" stands for LentiBOOST). The subjects will receive marrow cytoreduction with busulfan prior to infusion of CTNS-RD-04. Subjects will discontinue cysteamine treatment during the assessment period. The assessment follow-up period will include an initial 2 years of active end-point evaluations, where the subjects will be evaluated at 3-, 6-, 9-, 12-, 18- and 24-months post-transplantation. A Long-Term Follow-Up study (LTFU) for a total 15-year follow-up period will be offered to all subjects. The objectives of this Phase 1/2 clinical study are to assess the safety/tolerability of CTNS-RD-04, and its efficacy through a number of clinical, molecular and biochemical assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lysosomal Storage Diseases, Cystinosis
Keywords
Cystinosis, Lysosomal Storage Disorders, LSD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This study will include up to 6 subjects and follows a 3-cohort staggered treatment design with 2 subjects per cohort. The first 2 cohorts will consist of 4 adults (18 years or older), potentially followed by a cohort consisting of 2 adolescents or adults (>14 years old).
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Gene Therapy with CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
Arm Type
Experimental
Arm Description
This is a single arm study without randomization. Eligible subjects will receive the final product: CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST).
Intervention Type
Genetic
Intervention Name(s)
CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
Intervention Description
Peripheral blood autologous CD34+ enriched cell fraction transduced with lentiviral vector, pCCL-CTNS or pCDY.EFS.CTNS.T260I, that contains the human CTNS complementary deoxyribonucleic acid (cDNA) sequence.
Primary Outcome Measure Information:
Title
Evaluation of safety - Absence of Severe Adverse Events (SAEs) due to the investigational product
Description
Safety and tolerability will be assessed in terms of incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame
Up to 24 months post transplant.
Title
Evaluation of safety - Absence of Replication-Competent Lentivirus (RCL)
Description
Safety and tolerability will be measured by number of subjects with Replication Competent Lentivirus (RCL)
Time Frame
Up to 24 months post transplant.
Title
Evaluation of safety - Absence of genotoxicity
Description
Safety and tolerability will be measured by absence of insertional mutagenesis, monoclonal expansion.
Time Frame
Up to 24 months post transplant.
Title
Evaluation of safety - Event-free survival
Description
Safety and tolerability will be measured by Event-free survival over the 24 months after stem cell transplantation
Time Frame
Up to 24 months post transplant.
Secondary Outcome Measure Information:
Title
Evaluation of efficacy - Change in cystine levels
Description
Efficacy will be measured by evaluating the impact of treatment with CTNS-RD-04 on cystine levels in the blood, and cystine crystal counts in the intestinal mucosa and skin, and eye with the help of Mass Spectrometry and Confocal Microscopy.
Time Frame
Up to 24 months post transplant.
Title
Evaluation of efficacy - To evaluate the effect of treatment with CTNS-RD-04 on clinical disease outcomes
Description
Among other evaluations, clinical efficacy will be measured by evaluating the effect on clinical disease outcomes including: Kidney Function (test: measure Serum Cystatin C levels, unit: score from 1 to 5 based on the stage of dialysis); (test: measure serum and urine phosphate levels, unit: mg/dL); Vision (test: Pachymetry, unit: millimeter); (test: Anterior Segment - Optical Coherence Tomography, unit: millimeter or millimeter square); Muscle strength (test: grip strength, unit: scale between 0/5 and 5/5); Pulmonary function (test: Spirometry, unit: percentage); Neurological and Psychometric function (test: Beery Test of Visual Motor Integration, neurological examination to evaluate motor coordination, tone, strength, and reflexes, unit: numerical score).
Time Frame
Up to 24 months post transplant.
Title
Evaluation of efficacy - Change in Quality of Life
Description
Efficacy will be measured by evaluating changes in quality of life with the help of Health-Related Quality of Life (HRQoL) which will assess the impact of treatment with CTNS-RD-04 on quality of life.
Time Frame
Up to 24 months post transplant.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The following criteria must be met by all subjects considered for study participation. Cohorts 1 and 2: Male or female subject is ≥ 18 years of age. Cohort 3: Male or female subject is ≥ 14 years of age. Subject is diagnosed with cystinosis, i.e., early onset of Fanconi syndrome, and history of elevated white blood cell cystine level and/or history of or presence of cystine crystals in the eye. Subject has a Karnofsky Performance Status or age-dependent Lansky Performance of ≥ 60. If subject has had a kidney transplant, he or she must be at least one-year post kidney transplant status. Subject has adequate hematologic function: Absolute neutrophil count (ANC) ≥ 1.5 x 1000/mm^3 Platelet count ≥ 100 x 1000/mm^3 Hemoglobin ≥ 9.0 gm/dL Subject has an adequate hepatic function: Bilirubin ≤ 2.0 mg/ dL ALT ≤ 3 x institution's upper limit of normal (ULN) U/L Subject has an adequate renal function: a. Serum creatinine <2x ULN mg/dL Subject has adequate coagulation: PT/aPTT ≤ 1.2 x ULN seconds INR ≤ 2 Subject has adequate thyroid function (with or without thyroid replacement therapy): TSH 0.27-4.2 mIU/mL Total T4 ≤ 2 x ULN mcg/dL If female: female of childbearing potential (i.e., not surgically sterile [tubal ligation, hysterectomy, or bilateral oophorectomy] or not at least 2 years naturally postmenopausal) agrees to remain sexually abstinent or utilize the same acceptable form of highly effective contraception from screening through two years post-transplant. The acceptable forms of contraception for this study include hormonal contraceptives (oral, implant, transdermal patch, or injection) associated with inhibition of ovulation at a stable dose for at least 3 months prior to screening, barrier (condom with spermicide, diaphragm with spermicide), intrauterine device, or a partner who has been vasectomized for at least 6 months and has documented medical assessment of surgical success of a vasectomy. Note: males with cystinosis are sterile. If male: males must agree to remain sexually abstinent or utilize an acceptable form of highly effective contraception from screening through two years post-transplant. Subject is willing and able to comply with the study restrictions and requirements. Subject is willing to provide written informed consent/permission/assent prior to participation in the study. Subject must be willing to refrain from donating sperm after receiving the conditioning regimen. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm banking prior to administration of conditioning regimen will be recommended. Subject must be willing to refrain from donating blood, organs, tissues, or cells for transplantation from 30 days prior to screening through any time after CTNS-RD-04 treatment. Subject must be willing and must be able (in the judgment of the investigator) to discontinue his or her cysteamine therapy (oral and/or eye drop). Exclusion Criteria: Subject has an active, uncontrolled, acute bacterial, viral, or fungal infection during screening or within 30 days prior to starting the conditioning regimen. Subject has positive serology at screening for any of the following: Human Immunodeficiency Virus (HIV) 1-2 Human T-cell Lymphotropic Virus (HTLV) - I/II Hepatitis B core and Hepatitis B PCR positive Hepatitis C Virus (HCV) Rapid Plasma Reagin (RPR) Chagas' Disease (T. curzi) QuantiferonTB Nucleic Acid Test (NAT) for HIV West Nile Virus (WNV) Subject has a known clinically significant immunodeficiency disorder. Subject is a female of childbearing potential that is nursing, planning a pregnancy or has a positive serum pregnancy test. Subject has received a prior marrow or stem cell transplantation or is planning to receive one within 90 days of study initiation. Subject has had an active bleeding disorder within 90 days prior to screening OR requires anticoagulation therapy prior to treatment with ex vivo gene therapy. Subject has an active malignancy or history of malignancy including lymphoma (except primary, cutaneous basal cell or squamous cell cancer appropriately treated prior to transplantation). Subject has an end-stage renal disease (defined as GFR <15 mL/min) and is already on a transplantation list or who may be planning to register for a kidney transplant within 90 days of study initiation. Subject has impaired pulmonary function (based on FEV1 of <=50% of predicted or DLCO of <=40 % of predicted and gender-specific normal threshold value). Subject has impaired cardiac function within 90 days prior to screening including any of the following: Myocardial infarction Clinically significant abnormal electrocardiogram (ECG) Ejection fraction of < 40% Uncontrolled arrhythmia Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension). Subject has a severe or uncontrolled medical disorder (e.g., pancreatitis, severe liver disease, unstable diabetes mellitus) that would, in the investigators' opinion, impair their ability to receive study treatment and follow the study procedures. Subject has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Busulfan or allergy or contraindication to use of other agents used in the study, including iohexol, acid-citrate-dextrose Formula A (ACDA), G-CSF or plerixafor. Subject has a known history of drug or alcohol addiction. Subject has undergone major surgery within 90 days (or longer if not fully recovered) prior to screening. Subject is receiving cytotoxic or immunosuppressive agents, other than for kidney transplant, within 60 days prior to screening or requires treatment with such agents prior to treatment with ex vivo gene therapy. Subject has previously received gene therapy at any time. Subject is currently receiving or anticipates receiving another investigational agent, device, or procedure from 30 days prior to screening through study completion. Subject has any condition, in the opinion of the investigator, that compromises compliance with study requirements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephanie Cherqui, Ph.D.
Organizational Affiliation
University of California, San Diego (UCSD)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
23089735
Citation
Harrison F, Yeagy BA, Rocca CJ, Kohn DB, Salomon DR, Cherqui S. Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis. Mol Ther. 2013 Feb;21(2):433-44. doi: 10.1038/mt.2012.214. Epub 2012 Oct 23.
Results Reference
result
PubMed Identifier
25186209
Citation
Naphade S, Sharma J, Gaide Chevronnay HP, Shook MA, Yeagy BA, Rocca CJ, Ur SN, Lau AJ, Courtoy PJ, Cherqui S. Brief reports: Lysosomal cross-correction by hematopoietic stem cell-derived macrophages via tunneling nanotubes. Stem Cells. 2015 Jan;33(1):301-9. doi: 10.1002/stem.1835.
Results Reference
result

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Stem Cell Gene Therapy for Cystinosis

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