A Trial to Evaluate Safety and Efficacy of RP-L401-0120 in Subjects With Infantile Malignant Osteopetrosis

Study Overview
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Brief Summary
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The primary objective of this Phase 1 study is to evaluate the therapeutic safety and feasibility of the investigational product (IP), RP-L401.

Detailed Description
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This is a non-randomized Phase 1 study to evaluate the preliminary safety and efficacy of hematopoietic gene therapy consisting of autologous CD34+ enriched hematopoietic cells transduced with the lentiviral vector (LV) carrying the human TCIRG1 transgene (RP-L401) in pediatric patients with IMO. Following myeloablative conditioning patients will receive an infusion of the genetically modified hematopoietic stem and progenitor cells (HSPCs).

Official Title
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A Phase I Clinical Trial for Gene Therapy in Infantile Malignant Osteopetrosis (IMO) to Evaluate the Safety and Preliminary Efficacy of Autologous CD34+ Enriched Cells Transduced With a LV Vector Encoding the TCIRG1 Gene

Conditions
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Infantile Malignant Osteopetrosis

Intervention / Treatment
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* Biological: RP-L401


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A confirmed diagnosis of IMO with documented TCIRG1 mutation. Age at least 1 month with minimum weight of 4 kg Absence of debilitating hydrocephalus (defined as hydrocephalus at NCI CTCAE v5.0 Grade 3 or higher persisting despite shunt or similar procedural intervention). Lansky Play Scale of at least 60% Preserved hepatic function (AST/ALT ≤3.0 ULN; bilirubin ≤1.5 ULN; to minimize potential for excessive toxicity from busulfan conditioning) No concomitant medical or other conditions that would represent a contraindication to autologous hematopoietic stem cell transplant. Absolute neutrophil count of ≥500/mm3 and platelet count of ≥25,000/mm3 No prior allogeneic or other hematopoietic stem cell transplant. Availability of a non-autologous rescue (back-up) hematopoietic stem cell donor/source Exclusion Criteria: Availability of medically-feasible HLA-matched sibling donor for allogeneic HSCT. Any medical or other contraindication for either apheresis or autologous transplant as determined by the Investigator. Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer or another carcinoma in situ. Uncontrolled seizure disorder. Renal dysfunction as defined by a glomerular filtration rate <30 mL/min/1.73m2 or dialysis dependence. Serious infections with persistent bloodstream pathogens at time of trial entry Pulmonary dysfunction as defined by either: Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) or Oxygen saturation (by pulse oximetry) <90% resulting from pulmonary conditions (intermittent hypoxia secondary to IMO-related choanal atresia will not be considered exclusionary)

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental - RP-L401<br>RP-L401 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic cells transduced with lentiviral vector carrying the TCIRG1 transgene | Biological: RP-L401<br>* CD34+ enriched hematopoietic stem cells from pediatric subjects with infantile malignant osteopetrosis transduced ex vivo with lentiviral vector carrying the TCIRG1 transgene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Evaluation of safety associated with treatment with RP-L401 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of vector copy number (VCN) after infusion of RP-L401 | Evaluation of the presence of gene-modified blood and bone marrow cells post infusion via blood and bone marrow assessments | 2 years | 
| Assessment of endocrine and metabolic status after infusion of RP-L401 | Evaluation of normalization of serum calcium levels via a blood assessment | 2 years | 
| Assessment of blood counts after infusion of RP-L401 | Evaluation of the stabilization or improvement in blood counts as assessed by NCI CTACE | 2 years | 
| Assessment of bone abnormalities after infusion of RP-L401 | Evaluation of the qualitative improvement in bone formation via x-ray studies | 2 years | 
| Assessment of auditory status after infusion of RP-L401 | Evaluation of the stabilization or improvement in hearing loss via auditory tests | 2 years | 
| Assessment of ophthalmology status after infusion of RP-L401 | Evaluation of optical abnormalities via visual assessments of the eye | 2 years | 
| Assessment of hepatosplenomegaly after infusion of RP-L401 | Evaluation of hepatosplenomegaly improvement via abdominal ultrasound | 2 years | 
| Assessment of head, mouth and gum abnormalities | Photographic documentation of head, mouth and gums to assess disease stabilization, progression or improvement | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Impaired bone resorption, Deficient osteoclast development, Autosomal Recessive Disorder, Musculoskeletal Diseases, Bone Diseases, Hypocalcemia, Bone marrow failure