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
概览
- 阶段
- 1 期
- 干预措施
- CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
- 疾病 / 适应症
- Lysosomal Storage Diseases
- 发起方
- University of California, San Diego
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Safety and tolerability: Total number of adverse events (AEs) per participant (pre- and post-dose to end of study)
- 状态
- 已完成
- 最后更新
- 3个月前
概览
简要总结
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)
详细描述
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.
研究者
Stephanie Cherqui
Professor
University of California, San Diego
入排标准
入选标准
- •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 ≥
- •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
排除标准
- •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
研究组 & 干预措施
Gene Therapy with CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
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).
干预措施: CTNS-RD-04 or CTNS-RD-04-LB (where the suffix "-LB" stands for LentiBOOST)
结局指标
主要结局
Safety and tolerability: Total number of adverse events (AEs) per participant (pre- and post-dose to end of study)
时间窗: From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.
The total count of all adverse events (AEs) recorded for each dosed participant reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Events were coded using MedDRA v24.0. The outcome is the total count of AEs per participant. Excludes ongoing AEs at end of study that are captured in separate long-term follow-up study. Unit of Measure: Count (events per participant)
Safety and tolerability: Aggregate number of adverse events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) severity (pre-dose and post-dose to end of study)
时间窗: From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.
The total aggregate count of all graded adverse events (AEs) recorded for all dosed participants reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Events were coded using MedDRA v24.0 and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The outcome is the total count of AEs per grade (Mild, Moderate, Severe, Life Threatening, Death). Excludes ongoing AEs at end of study that are captured in separate long-term follow-up study. Unit of Measure: Count (events) - separate counts for each CTCAE grade.
Safety and tolerability: Aggregate number of adverse events (AEs) by relationship to study treatment (pre-dose and post-dose to end of study)
时间窗: From the first pre-dose safety visit to the end of the treatment period (e.g., 24 months post-dose) or the participant's last safety-assessment visit, whichever occurs later.
The total aggregate count of all adverse events (AEs) categorized by relationship to the study treatment recorded for all dosed participants reported at any scheduled study visit starting with the first pre-dose safety visit (i.e., the first visit after informed consent and before the first administration of study drug) and continuing through the end of the treatment period. Relationship to the study treatment was determined using the standard categories defined in the protocol: • Related (probably or possibly related) • Unrelated (not related, unlikely related). Each AE was coded with MedDRA v24.0. The outcome reported is the study-wide total count of AEs in each relationship category. Excludes ongoing AEs at end of study that are captured in separate long-term follow-up study. Unit of Measure: Count (events) - separate counts for each relationship category (Related, Unrelated)
Safety and tolerability: Clinical laboratory values for white blood cell, absolute monocyte, and platelet counts at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Clinical laboratory values for white blood cell, absolute monocyte, and platelet counts at baseline, 12 month and 24 month post-infusion study visits. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: White blood cell count (1000/mmHg\^3), Absolute monocyte count (1000/mmHg\^3), Platelet count (1000/mmHg\^3) where mmHG\^3 is millimeters of mercury cubed- raw individual values
Safety and tolerability: Systolic and diastolic blood pressure at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Systolic and diastolic blood pressure at baseline, 12 month and 24 month post-infusion study visits. Measurement taken with the subjects positioned supine, seated or semi-fowlers. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: blood pressure in millimeters of mercury (mmHg) - raw individual values
Safety and tolerability: Heart rate at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Heart rate at baseline, 12 month and 24 month post-infusion study visits. Measurement taken with the subjects positioned supine, seated or semi-fowlers. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: beats per minute (BPM) - raw individual values
Safety and tolerability: Body temperature at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Body temperature at baseline, 12 month and 24 month post-infusion study visits. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: degrees Celsius - raw individual values
Safety and tolerability: Respiratory rate at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Respiratory rate at baseline, 12 month and 24 month post-infusion study visits. Measurement taken with the subjects positioned supine, seated or semi-fowlers. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: breaths per minute - raw individual values
Safety and tolerability: Electrocardiogram (ECG) ventricular rates at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Electrocardiogram (ECG) ventricular rates at baseline, 12 month and 24 month post-infusion study visits. ECG recordings will be obtained using standard 12-lead resting ECGs with a bandwidth of 0.05-100 Hz and a minimum sampling rate of 500 Hz. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: ECG beats per minute (BPM) - raw individual values
Safety and tolerability: Electrocardiogram (ECG) intervals including PR interval, QRS interval, QT interval and QTc Bazett at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.
时间窗: Baseline, 12 months post-infusion, 24 months post-infusion
Electrocardiogram (ECG) intervals including PR interval, QRS interval, QT interval and QTc Bazett at baseline, 12 month and 24 month post-infusion study visits. ECG recordings are obtained using standard 12-lead resting ECGs with a bandwidth of 0.05-100 Hz and a minimum sampling rate of 500 Hz. No summary statistics will be reported - each participant-level value will be uploaded as individual participant data. Unit of Measure: ECG Intervals in milliseconds (ms) - raw individual values
Safety: Number of dosed participants showing evidence (positive or negative) of genotoxicity as determined by polyclonal expansion and insertional mutagenesis.
时间窗: Up to 24 months post transplant.
Number of dosed participants that show evidence (positive or negative) of polyclonal expansion and insertional mutagenesis as measured in whole blood collected at several timepoints throughout the study (Baseline, 1-, 3-, 6-, 12-, 18-, 24-, months post-transplant) using vector integration site (VIS) analysis. VIS is performed through LTR-based PCR amplification and Illumina sequencing. Clonal abundance is monitored using the Sonic Abundance method. Unit of Measure: Participants
次要结局
- Efficacy: Cystine levels in leukocytes and granulocytes at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.(Baseline, 12 months post-infusion, 24 months post-infusion.)
- Efficacy: Clinical laboratory values of estimated glomerular filtration rate (eGFR) at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.(Baseline, 12 months post-infusion, 24 months post-infusion)
- Efficacy: Clinical laboratory values of thyroxine (T4) endocrine levels at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.(Baseline, 12 months post-infusion, 24 months post-infusion)
- Efficacy: Clinical laboratory values thyroid-stimulating hormone (TSH) endocrine levels at baseline, 12 month and 24 month post-infusion study visits reported at individual participant level.(Baseline, 12 months post-infusion, 24 months post-infusion)
- Transduction Efficiency: Vector copy number (VCN) in peripheral blood at 12 month and 24 month post-infusion study visits reported at individual participant level.(12 months post-infusion and 24 months post-infusion)