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Clinical Trial to Evaluate the Efficacy of Gene Therapy for Pyruvate Kinase Deficiency

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT06422351
Recruitment Status : Not yet recruiting
First Posted : May 21, 2024
Last Update Posted : May 22, 2024
Sponsor:
Information provided by (Responsible Party):
Rocket Pharmaceuticals Inc.

Brief Summary:
This is an open-label Phase II trial to evaluate the efficacy of a hematopoietic cell-based gene therapy for patients with Pyruvate Kinase Deficiency (PKD).

Condition or disease Intervention/treatment Phase
Pyruvate Kinase Deficiency Biological: RP-L301 Phase 2

Detailed Description:
Autologous hematopoietic stem cells from mobilized peripheral blood will be transduced ex vivo (outside the body) with a lentiviral vector carrying a correct copy of the deficient PKLR (Pyruvate Kinase L/R) gene. The corrected stem cells will be infused intravenously back into the patient to correct the hematological manifestations of the disease.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Clinical Trial to Evaluate the Efficacy of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the Codon Optimized Red Cell Pyruvate Kinase (coRPK) Gene in Subjects With Pyruvate Kinase Deficiency
Estimated Study Start Date : August 2024
Estimated Primary Completion Date : November 2026
Estimated Study Completion Date : January 2029


Arm Intervention/treatment
Experimental: Participant Group/Arm
RP-L301 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKLR (Pyruvate Kinase L/R) gene
Biological: RP-L301
Autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKLR (Pyruvate Kinase L/R) gene
Other Name: Intervention/Treatment




Primary Outcome Measures :
  1. Improvement in Anemia [ Time Frame: 12 months post-infusion ]
    Hemoglobin (Hb) level increase of ≥1.5g/dL at 12 months post-infusion, compared to baseline.


Secondary Outcome Measures :
  1. Durability Improvement anemia sustained [ Time Frame: 24 months post-infusion ]
    Time to Hemoglobin level increase of ≥1.5g/dL post-infusion, compared to baseline.

  2. Resolution of anemia [ Time Frame: 12 months post-infusion ]
    Hemoglobin level within normal range (≥ lower limit of normal) at 12 months post-infusion.

  3. Reduction of transfusion requirements [ Time Frame: 12 months post-infusion ]
    • a: ≥50% reduction in Pyruvate Kinase Deficiency (PKD)-related Red Blood Cells (RBC) transfusion requirements in the 12 months post-infusion, relative to the annualized event rate for 24 months prior to enrollment; or,
    • b: Absence of PKD-related RBC transfusion requirements in the 12 months post-infusion.

  4. Improvements of hemolysis parameters (bilirubin) [ Time Frame: 12 months post-infusion ]
    Improvements in bilirubin, each evaluated at 12 months post-infusion, compared to baseline.

  5. Improvements of hemolysis parameters (Lactate Dehydrogenase (LDH)) [ Time Frame: 12 months post-infusion ]
    Improvements in Lactate Dehydrogenase (LDH), each evaluated at 12 months post-infusion, compared to baseline.

  6. Improvements of hemolysis parameters (erythropoietin) [ Time Frame: 12 months post-infusion ]
    Improvements in erythropoietin, each evaluated at 12 months post-infusion, compared to baseline.

  7. Improvements of hemolysis parameters (reticulocyte) [ Time Frame: 12 months post-infusion ]
    Improvements in reticulocyte, each evaluated at 12 months post-infusion, compared to baseline.

  8. Peripheral blood genetic correction [ Time Frame: 12 months post-infusion ]
    Genetic correction demonstrated by vector copy number (VCN) of 0.1 in Peripheral Blood mononuclear cells, evaluated at 12 months post-infusion.

  9. Improvement in fatigue [ Time Frame: 12 months post-infusion ]

    Improvement in fatigue as compared with baseline, as assessed by:

    • Age ≥18: FACIT Fatigue; or,
    • Age <18: PROMIS Fatigue Short Form 10a

  10. Improvement in dyspnea [ Time Frame: 12 months post-infusion ]

    Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by:

    • PROMIS Dyspnea Severity SF10; or,
    • Dyspnea severity

  11. Improvement in jaundice [ Time Frame: 12 months post-infusion ]

    Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by:

    • jaundice severity evaluated at 12 months post-infusion; or,
    • and jaundice severity

  12. Safety and tolerability of RP-L301 [ Time Frame: 24 months post-infusion ]
    Incidence, type, severity, frequency, time to onset, and duration of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), clinical laboratory abnormalities, and adverse events of special interest (AESIs).

  13. Evaluate durable resolution of anemia [ Time Frame: 24 months post-infusion ]
    Hemoglobin (Hb) level within normal range (≥ lower limit of normal).

  14. Evaluate durable resolution of transfusion requirements (where relevant). [ Time Frame: 24 months post-infusion ]
    1. ≥50% reduction in Pyruvate Kinase Deficiency (PKD)-related Red Blood Cell (RBC) transfusion requirements in the 24 months post-infusion, relative to the annualized event rate for 24 months prior to enrollment; or,
    2. Absence of PKD-related RBC transfusion requirements in the 24 months post-infusion.



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Ages Eligible for Study:   8 Years to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Pyruvate Kinase Deficiency (PKD) diagnosis with a confirmed PK-LR mutation
  2. Significant anemia defined as:

    • Hemoglobin (Hb) levels <9.5 g/dL documented during 2 or more assessments in the 12 months prior to screening and either:

      1. at least 6 Red Blood Cell (RBC) transfusion episodes over the 12- month period prior to screening or
      2. at least 3 Red Blood Cell (RBC) transfusion episodes each year for 2 years prior to screening; or
    • Hemoglobin (Hb) levels <8.5 g/dL irrespective of transfusions (documented during 2 or more assessments during the prior 2 years); or
    • Hemoglobin (Hb) levels <10.0 g/dL irrespective of transfusions (documented during 2 or more assessments during the prior 2 years) and the presence of either:

      • Fatigue or energy-related symptoms limiting activities of daily living (The National Cancer Institute Common Terminology Criteria for Adverse Events v 5.0 (NCI CTCAE v5.0 grade 3)); or
      • Fatigue or energy-related symptoms limiting activities of daily living (The National Cancer Institute Common Terminology Criteria for Adverse Events v 5.0 (NCI CTCAE v5.0 grade 2)) not responsive to available medical therapy; or
      • Icterus limiting social interactions, education or work activities and not responsive to available medical therapy;
  3. Subject age: age ≥8 years and ≤55 years
  4. Prior splenectomy
  5. Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant exclusion criteria
  6. Availability of detailed medical records, including accurate transfusion history and blood count assessments, for the prior 2 years
  7. Willing and able to read and correctly understand the patient information sheet and provide consent (or informed assent for minors) regarding study participation, willing and able to comply with all study-related procedures including follow-up visits.
  8. Negative serum pregnancy test for female subjects of childbearing potential.

Exclusion Criteria

  1. Presence of other known causes of hemolysis (in addition to Pyruvate Kinase Deficiency (PKD)). Patients with concurrent G6PD deficiency diagnosed during pre-study evaluation may be considered for eligibility if in the opinion of the Investigator, the hemolytic anemia is the result of PKD and the Glucose-6-phosphate dehydrogenase (G6PD) deficiency is considered an incidental finding.
  2. A venous thromboembolic event (VTE; i.e., pulmonary embolism or deep vein thrombosis) or arteriothromboembolic event (ATE; including unstable angina, myocardial infarction, stroke or transient ischemic attack) during the prior 12 months.
  3. Evidence of bridging fibrosis, cirrhosis or active hepatitis on liver biopsy.

    1. Liver biopsy is required when liver iron concentration (LIC) is ≥15 mg/g on T2* magnetic resonance imaging (MRI) of liver.
    2. If a liver biopsy has been performed less than 6 months prior to enrollment, it does not need to be repeated.
  4. Cardiac T2* <10 ms by magnetic resonance imaging (MRI) or left ventricular ejection fraction (LVEF) <45% by echocardiogram or multiple gated acquisition scan (MUGA).
  5. Any evidence of severe iron overload beyond parameters stipulated in exclusion criteria 3 and 4 that, per Investigator discretion, warrants exclusion.
  6. Significant medical conditions including documented HIV (human immunodeficiency virus) infection, active viral hepatitis, poorly controlled hypertension, pulmonary hypertension, cardiac arrhythmia or congestive heart failure; or arteriothromboembolic events (ATEs) (including stroke or myocardial infarction) within the 12 prior months.
  7. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer or another carcinoma in situ. Patients with previously resected solid organ malignancies or definitively treated hematologic malignancies may be eligible if there has been no evidence of active malignancy during the prior 3 years.
  8. Uncontrolled seizure disorder.
  9. Hepatic dysfunction as defined by Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5× the upper limit normal (ULN).
  10. Renal dysfunction defined as serum creatinine >upper limit normal (ULN). Patients with creatinine above ULN may be eligible pending documentation of a glomerular filtration rate ≥60 mL/min/1.73m2 as calculated by Modification of Diet in Renal Disease equation (Stevens 2006), or 24-hour urine collection.
  11. Pulmonary dysfunction as defined by either:

    1. Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) OR
    2. Clinically significant pulmonary disease that may impair ability to tolerate study procedures and treatments.
  12. Any medical or other contraindication for leukapheresis as determined by the treating Investigator.
  13. Any medical or psychiatric condition that in the opinion of the Investigator renders the patient unfit for trial participation or at higher than acceptable risk for participation.
  14. Poor functional status evidenced by Karnofsky Index <70 in subjects ≥16 years old and Lansky Play-Performance Scale <70 in subjects <16 years old.
  15. Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed. Patients who are receiving mitapivat in non-investigational settings are eligible provided they discontinue mitapivat at least 90 days prior to the start of mobilization.
  16. Pregnant women or women with a positive serum pregnancy test at screening or breast feeding or planning to become pregnant within the next 24 months. Female participants or female partners of male participants not willing to use highly effective contraceptive methods during the complete study period.
  17. Previous allogeneic or other hematopoietic stem cell transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06422351


Contacts
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Contact: Rocket Clinical Trials 646-627-0033 PKDclinicaltrial@rocketpharma.com

Locations
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United States, California
Stanford University
Palo Alto, California, United States, 94305
Contact: Ami Shah, MD    650-497-8953    scgt_clinical_trials_office@lists.stanford.edu   
Principal Investigator: Ami J. Shah, MD         
Spain
Hospital Infantil Universitario Niño Jesús
Madrid, Spain, 28009
Hospital Universitario Fundación Jiménez Díaz
Madrid, Spain
Sponsors and Collaborators
Rocket Pharmaceuticals Inc.
Investigators
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Principal Investigator: Ami Shah, MD Stanford University
Principal Investigator: Julian Sevilla Navarro, MD, PhD Hospital Infantil Universitario Niño Jesús
Principal Investigator: José Luis López Lorenzo, MD Hospital Universitario Fundación Jiménez Díaz
Study Director: Elieen Nicoletti, MD Rocket Pharmaceuticals Inc.
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Responsible Party: Rocket Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT06422351    
Other Study ID Numbers: RP-L301-0124
First Posted: May 21, 2024    Key Record Dates
Last Update Posted: May 22, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Anemia, Hemolytic, Congenital Nonspherocytic
Pyruvate Metabolism, Inborn Errors
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases