Clinical Trial Results:
Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I):A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced with a Lentiviral Vector Encoding the ITGB2 Gene
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Summary
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EudraCT number |
2020-000517-33 |
Trial protocol |
GB |
Global end of trial date |
12 Sep 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Aug 2025
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First version publication date |
06 Aug 2025
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Other versions |
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Summary report(s) |
RP-L201-0318 CSR_Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RP-L201-0318
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03812263 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Rocket Pharmaceuticals, Inc
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Sponsor organisation address |
9 Cedarbrook Drive, Cranbury, United States, 08512
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Public contact |
Chief Medical Officer, Rocket Pharmaceuticals, Inc, 01 646440-9100, js@rocketpharma.com
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Scientific contact |
Chief Medical Officer, Rocket Pharmaceuticals, Inc, 01 646440-9100, js@rocketpharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002562-PIP01-19 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Sep 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Sep 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Trial Phase I :
• To characterize the safety and toxicity associated with infusion of investigational product:autologous CD34+ cells transduced with the therapeutic LV (Chim-CD18-WPRE LV)
Trial Phase II
• Survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post-investigational product infusion without allogeneic HSCT.
• Characterization of the safety and toxicity associated with infusion of the investigational product: autologous CD34+ cells transduced with the therapeutic LV (Chim-CD18- WPRE LV).
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Protection of trial subjects |
The investigational product RP-L201 is an ex vivo lentiviral vector (LV) gene therapy, consisting of autologous hematopoietic stem cells transduced with Chim-CD18-WPRE LV, which encodes the human ITGB2 gene.
The treatment procedure includes CD34+ cells that were mobilized and harvested through peripheral blood apheresis, followed by enrichment, transduction, and final cryopreservation. Two weeks prior to mobilization and one week before IP infusion, patients received ustekinumab. Intravenous IP infusion was preceded by busulfan conditioning.
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Background therapy |
When at least 2 × 10^6 viable CD34+ cells per kilogram of body weight were available for infusion, the patients received myeloablative conditioning with intravenous busulfan over the course of 4 days and received marne-cel 1 or 2 days later. The target for the busulfan dose was a cumulative exposure of the area under the curve of 65 mg per liter per hour, which could be modified to 75 mg per liter per hour on the basis of evolving knowledge regarding myeloablative busulfan dosing in primary immunodeficiencies and other noncancerous genetic hematopoietic disorders. | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
01 May 2019
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Regulatory reason | ||
Long term follow-up duration |
13 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 6
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Worldwide total number of subjects |
9
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EEA total number of subjects |
1
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
3
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Children (2-11 years) |
6
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The number of subjects planned was 9. In Phase 1 of the trial, 2 subjects were treated to determine the safety/AE profile associated with the IP treatment. Seven additional subjects were to be enrolled in Phase 2 (to a total of 9 subjects). | ||||||
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Pre-assignment
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Screening details |
Patients aged at least 3 months with a confirmed diagnosis of severe LAD-I and at least one prior significant bacterial or fungal infection, except for patients with documented ITGB2 mutation and clinical history consistent with LAD-I (or known family history). Patients for whom an HLA-identical sibling donor transplant was available were excluded. | ||||||
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Pre-assignment period milestones
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Number of subjects started |
9 | ||||||
Number of subjects completed |
9 | ||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
This was an adaptive design, 2 phase, open label, single arm study using an infusion of RP-L201.
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Arms
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Arm title
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Single arm | ||||||
Arm description |
This was an adaptive design, 2 phase, open label, single arm study using an infusion of RP-L201. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
RP-L201
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Investigational medicinal product code |
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Other name |
marnetegragene autotemcel
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Pharmaceutical forms |
Dispersion for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
During all trial phases, IP infusion (and antecedent busulfan conditioning) was considered feasible if ≥ 2 ×10^6 viable CD34+ cells/kg of body weight were available for infusion following transduction and cryopreservation and complied with specifications.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Of 9 total subjects, there were 4 male, and 5 female subjects enrolled in the study. 7 subjects were <48 months of age at screening, including 3 subjects under 12 months of age. The median age at screening was 36.0 months and at infusion was 42 months. Most subjects were from the United States. | |||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Single arm
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Reporting group description |
This was an adaptive design, 2 phase, open label, single arm study using an infusion of RP-L201. | ||
Subject analysis set title |
Overall trial
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Of 9 total subjects, there were 5 male, and 4 female subjects enrolled in the study. 7 subjects were <48 months of age at screening, including 3 subjects under 12 months of age. The median age at screening was 36.0 months and at infusion was 42 months. Most subjects were from the United States.
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End point title |
HSCT-free survival | |||||||||
End point description |
The primary objective(s) of the study were HSCT-free survival, determined by the proportion of subjects alive at least 1-year post-IP and alive at age 2 (24 months) without allogeneic HSCT for subjects less than 1 year of age at study enrollment, and characterization of the safety and toxicity associated with the IP.
The study met its primary endpoint of survival at least 1-year post-infusion of IP without allogeneic HSCT and at age 2 years without allogeneic HSCT for subjects less than 12 months of age at enrollment with a statistically significant p-value at 1 year of 0.0002 (vs. anticipated transplant-free survival of 39%). No treated subject died or required allogeneic HSCT during the study. The transplant-free survival probability at every timepoint was therefore 1.0.
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End point type |
Primary
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End point timeframe |
The primary efficacy endpoint was survival, defined as the proportion of patients alive at least 1-year post-IP infusion without allogeneic HSCT and at age 2 without allogeneic HSCT for patients less than 1 year of age at study enrollment.
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Statistical analysis title |
Overall trial | |||||||||
Statistical analysis description |
Reporting a single arm trial of n=9 patients,
Of 9 total subjects, there were 4 male, and 5 female subjects enrolled in the study. 7 subjects were <48 months of age at screening, including 3 subjects under 12 months of age. The median age at screening was 36.0 months and at infusion was 42 months. Most subjects were from the United States.
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Comparison groups |
Single arm v Overall trial
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Number of subjects included in analysis |
18
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | |||||||||
P-value |
= 0.0002 [2] | |||||||||
Method |
exact binomial test | |||||||||
Confidence interval |
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| Notes [1] - Due to the small sample size, the exact confidence interval based on binomial distribution was calculated. The Kaplan-Meier survivor function and the Nelson-Aalen cumulative hazard function were estimated for those endpoints for which the time to event occurrence was recorded. Descriptive statistics (mean, median, standard deviation, quartiles, minimum and maximum) are presented for the values of quantitative endpoints and their absolute and relative changes from baseline at scheduled visits. [2] - For the primary efficacy end point of HSCT-free survival, we calculated the P value using an exact binomial test against the null hypothesis of 39%, and the 95% confidence interval using Clopper–Pearson method for an exact binomial proportion. |
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End point title |
EFS without graft failure and without aGvHD grade 2 to 4 | |||||||||
End point description |
Survival with no graft failure or acute GVHD of grades 2 to 4.
The study met the secondary endpoint of EFS without any incidences of GF or aGvHD grade 2 to 4 in all 9 subjects. At the end of the study, there have been no events of GF or GvHD, acute or chronic. An EFS and an OS of 100% were reported, indicating the favorable tolerability of the IP.
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End point type |
Secondary
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End point timeframe |
24 months
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| Notes [3] - Reporting a single arm trial of n=9 subjects. [4] - Reporting a single arm trial of n=9 subjects. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Reduction in the incidence of significant infections | |||||||||
End point description |
Marked reduction in 1) the incidence of significant infections, defined as requiring hospitalization or parenteral antimicrobials, 2) of infection-related hospitalizations, and 3) of prolonged infection-related hospitalizations (≥7 days), analyzed per patient and across the entire cohort, comparing event rates pre-infusion to those following hematologic reconstitution.
The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower.
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End point type |
Secondary
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End point timeframe |
24 months
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| Notes [5] - Reporting a single arm trial of n=9 subjects. [6] - Reporting a single arm trial of n=9 subjects. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
LV VCN in blood and BM cells | |||||||||
End point description |
Chim-CD18-WPRE LV VCN in blood and BM cells, as determined via quantitative Polymerase Chain Reaction (PCR) or digital droplet PCR at specified time points pre- and post-infusion, including assessment of the percentage of patients with PBMC and PB CD15+ cell VCN of at least 0.1.
• Sustained genetic cell correction in PBMCs and CD15+ cells (VCN) were observed in all subjects.
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End point type |
Secondary
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End point timeframe |
24 months
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| Notes [7] - Reporting a single arm trial of n=9 subjects. [8] - Reporting a single arm trial of n=9 subjects. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change in the CD18 expression from pre- to post-infusion | ||||
End point description |
Change in the CD18 expression from pre- to post-infusion (and increased expression of additional β-2 integrin components CD11a and CD11b) in PB neutrophils, as determined by flow cytometry, including assessment of the percentage of patients with CD18 expression on at least 10% of neutrophils.
Neutrophil CD18 expression has been stable and significantly exceeded target threshold levels in all subjects with 24-month post-infusion follow-up.
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End point type |
Secondary
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End point timeframe |
24-months
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| No statistical analyses for this end point | |||||
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End point title |
Decrease (from pre-infusion) of LAD-I-associated neutrophilia and leukocytosis | ||||||||||||
End point description |
Decrease (from pre-infusion) of LAD-I-associated neutrophilia and leukocytosis.
Circulating levels of neutrophils and WBCs decreased to age-appropriate (normal) ranges in most subjects (8/9) after IP-mediated restoration of functional CD18 on leukocyte surfaces.
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End point type |
Secondary
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End point timeframe |
24-months
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| Notes [9] - Reporting a single arm trial n=9. [10] - Reporting a single arm trial n=9. |
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Statistical analysis title |
Statistical methods | ||||||||||||
Statistical analysis description |
The frequency of qualitative endpoints is described by the cumulative incidence and its 95% confidence interval.
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Comparison groups |
Single arm v Overall trial
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Number of subjects included in analysis |
18
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Analysis specification |
Pre-specified
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Analysis type |
other [11] | ||||||||||||
P-value |
= 0.0002 [12] | ||||||||||||
Method |
exact binomial test | ||||||||||||
Confidence interval |
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| Notes [11] - Due to the small sample size, the exact confidence interval based on binomial distribution was calculated. The Kaplan-Meier survivor function and the Nelson-Aalen cumulative hazard function were estimated for those endpoints for which the time to event occurrence was recorded. Descriptive statistics (mean, median, standard deviation, quartiles, minimum and maximum) are presented for the values of quantitative endpoints and their absolute and relative changes from baseline at scheduled visits. [12] - For the primary efficacy end point of HSCT-free survival, we calculated the P value using an exact binomial test against the null hypothesis of 39%, and the 95% confidence interval using Clopper–Pearson method for an exact binomial proportion. |
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End point title |
Resolution of LAD-I-related skin rash or periodontal abnormalities | |||||||||
End point description |
Resolution (partial or complete) of any underlying LAD-I-related skin rash or periodontal abnormalities as determined by the treating Investigator. Lesions were to be graded based on interval changes from baseline to show worsening, no change, partial improvement, or resolution of lesions.
Seven patients who had LAD-I–related skin lesions before marne-cel infusion showed improvement and subsequent lesion resolution without additional medical interventions (i.e., antimicrobial agents, anti-inflammatory agents, or skin graft). No new serious lesions or rashes developed after infusion in any patient. The patients showed normal wound healing after gene therapy.
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End point type |
Secondary
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End point timeframe |
24-months
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| Notes [13] - Reporting a single arm trial of n=9 subjects. [14] - Reporting a single arm trial of n=9 subjects. |
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Throughout trial 24 months
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Adverse event reporting additional description |
Safety in this study included AEs and SAEs
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Assessment type |
Systematic | ||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||
Dictionary version |
25
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Reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Overall trial | ||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Jul 2018 |
Version 1.0 |
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18 Sep 2018 |
Version 1.1 |
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06 Nov 2018 |
Version 1.2 |
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22 May 2019 |
Version 1.3 |
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05 Aug 2019 |
Version 1.4 |
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19 Dec 2019 |
Version 1.5 |
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31 Jan 2020 |
Version 2.0 |
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01 Apr 2020 |
Version 2.1 |
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02 Oct 2020 |
Version 2.2 |
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07 Jun 2021 |
Version 2.3 |
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03 Feb 2023 |
Version 3.0 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/40305711 |
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