Clinical trial NCT04105166: Gene Therapy for Pyruvate Kinase Deficiency (PKD)
Official title: Gene Therapy for Pyruvate Kinase Deficiency (PKD): A Phase I Clinical Trial to Evaluate the Safety of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the Codon Optimized Red Cell Pyruvate Kinase (coRPK) Gene in Adult and Pediatric Subjects With PKD
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Pyruvate Kinase Deficiency
Keywords: hemolytic anemia
anemia
gene therapy
Lead sponsor: Rocket Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2019-09-26
Enrollment: 5
Sex: ALL
Minimum age (years): 8
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Initial safety evaluation will occur in an adult cohort (n=2) patients, followed by pediatric patients ages 8-17 (n=2-3).
Primary purpose: TREATMENT

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

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 PKD gene. The corrected stem cells will be infused intravenously back to the patient with the goal of correcting the hematological manifestations of the disease.

Eligibility criteria: Inclusion Criteria:

* PKD diagnosis with a confirmed PKLR mutation.
* Adult Cohort ≥18 years old and \<50 years for the initial 2 patients enrolled; Pediatric Cohort ≥8-17 years for the next 2-3 patients.
* History of severe, transfusion-dependent anemia, defined as:

  1. At least 6 red blood cell transfusion episodes over a prior 12-month period and Hb levels \<9.5 g/dL in the previous 12 months despite splenectomy OR
  2. At least 3 red blood cell transfusion episodes per year over 2 prior years (in the absence of precipitating events such as infection or surgery) and Hb levels \<9.5 g/dL in the previous 12 months despite prior splenectomy.

     OR
  3. Hb levels \<8.0 g/dL despite prior splenectomy in the absence of transfusions (documented during 2 or more assessments during the prior 1-2 years) regardless of transfusion requirements.
* Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant exclusion criteria.
* Availability of detailed medical records, including transfusion requirements, for at least the prior 2 years.
* Willing and able to read and correctly understand the patient information sheet and provide consent (or informed assent for minors) regarding study participation.
* Negative serum pregnancy test for female patients of childbearing potential.

Exclusion Criteria:

* Presence of other known causes of hemolysis (in addition to 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 G6PD deficiency is considered an incidental finding.
* 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.
* Any evidence of severe iron overload that, per Investigator discretion, warrants exclusion.
* Evidence of bridging fibrosis, cirrhosis or active hepatitis on liver biopsy. Liver biopsy is required when liver iron concentration (LIC) is ≥15 mg/g on T2\* magnetic resonance imaging (MRI) of liver. If a liver biopsy has been performed less than 6 months prior to enrollment, it does not need to be repeated.
* Significant medical conditions including documented HIV infection, active viral hepatitis, poorly-controlled hypertension, pulmonary hypertension cardiac arrhythmia or congestive heart failure; pulmonary hypertension or ATEs (including stroke or myocardial infarction) within the 6 prior months.
* 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.
* Uncontrolled seizure disorder.
* Cardiac T2\*\<10 ms by magnetic resonance imaging (MRI) or left ventricular ejection fraction (LVEF) \<45% by echocardiogram or multiple gated acquisition (MUGA) scanning.
* Hepatic dysfunction as defined by: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5× the upper limit of normal.(ULN).
* Renal dysfunction as defined as serum creatinine \> ULN. Patients with creatinine above ULN may be eligible pending documentation of a GFR ≥60 mL/min/1.73m2 as calculated by the Modification of Diet in Renal Disease equation (Stevens 2006), the revised Schwartz formula (for patients under 18 years old) (Schwartz 2009), or 24-hour urine collection.
* 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%.
* Any medical or other contraindication for both leukapheresis and BM harvest procedure as determined by the treating Investigator.
* Any medical or psychiatric condition that in the opinion of the Investigator renders the subject unfit for trial participation or at higher than acceptable risk for participation.
* Poor functional status, evidenced by Karnofsky Index \<70 in adults or Lansky \<70 in children.
* Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed.
* 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. Women not willing to use highly effective contraceptive methods during the complete study period.

Primary outcomes:
measure: Evaluation of the safety and toxicity of RP-L301: number of participants with treatment-related adverse events
timeFrame: 2 years
Secondary outcomes:
measure: Genetic correction following administration of RP-L301
timeFrame: 2 years
measure: Transfusion independence
timeFrame: 1 year
measure: Reduction in transfusion requirements
timeFrame: 1 year
measure: Clinically significant reduction in anemia
timeFrame: 2 years
measure: Reduction of hemolysis
timeFrame: 1 year
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesús
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
Study officials:
affiliation: Hospital Universitario Fundación Jiménez Díaz
name: José Luis López Lorenzo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Ami Shah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Fundación Jiménez Díaz
name: Julián Sevilla Navarro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: