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Gene Therapy for Pyruvate Kinase Deficiency (PKD)
Recruiting
I'm InterestedTrial ID: NCT04105166
Purpose
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).
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
Stanford Investigator(s)
Eligibility
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.
Intervention(s):
biological: RP-L301
Recruiting
I'm InterestedContact Information
Stanford University
School of Medicine
300 Pasteur Drive
Stanford,
CA
94305
Elisabeth Merkel