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Pbi-shRNA™ EWS/FLI1 Type 1 LPX in Subjects With Advanced Ewing's Sarcoma

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. Identifier: NCT02736565
Recruitment Status : Recruiting
First Posted : April 13, 2016
Last Update Posted : March 20, 2019
Information provided by (Responsible Party):
Gradalis, Inc.

Brief Summary:

Ewing's sarcoma characterized by the t(11; 22) (q24; q12) translocation at several but prioritized breakpoint sites, resulting in the EWS/FLI1 fusion gene is the second most frequently diagnosed primary malignant bone tumor in the US with an annual incidence, from birth to age 20, of 2.9 cases per million population. The survival rate for patients with high-risk recurrent disease (relapse < 2 years) is < 10% at 5 years. Moreover, of patients who progress after second line treatment, eighty percent do not achieve a second complete response and of these patients < 10% survive one year. Refractory patients to both frontline and second line therapy have even worse prognosis.

The EWS/FLI1 gene is well known as the driver gene of Ewing's sarcoma. We designed a novel pbi-shRNA™ EWS/FLI1 Type 1 LPX which has demonstrated sufficient specificity, safety and efficacy in animal testing to justify Phase I testing. Clinical safety (no ≥ grade 3 product related toxic effect) and target specific activity has been observed with other bi-shRNA products involving 147 cancer patients (698 separate dose administrations) (BB-IND 14205; BB-IND 14938). Moreover, safety has been observed with IV delivery of pbi-shRNA™ EWS/FLI1 Type 1 LPX in murine and swine testing via multidose IV administration.

Study testing of pbi-shRNA™ EWS/FLI1 Type 1 LPX will involve patients (≥age 8) with advanced Ewing's sarcoma. The first 3 subjects enrolled onto the study as well as the first subject enrolled into each dose cohort must be 16 years of age or older. pbi-shRNA™ EWS/FLI1 Type 1 LPX will be given via intravenous infusion twice a week for 4 weeks (e.g. Mon and Thurs, preferred) for a total of 8 infusions of the product per cycle followed by a 2 week washout period. Patients will be accrued in 3-patient dose escalation cohorts using the following escalation schema (50% to 33% to 25% to 25% to 25%) at a starting IV dose of 0.04 mg/kg.

Condition or disease Intervention/treatment Phase
Ewing's Sarcoma Biological: pbi-shRNA™ EWS/FLI1 Type 1 LPX Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (LPX) in Subjects With Advanced Ewing's Sarcoma
Actual Study Start Date : October 2016
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : February 2020

Arm Intervention/treatment
Experimental: pbi-shRNA™ EWS/FLI1 Type 1 LPX

Subjects will accrue in 3 to 6-subject escalation cohorts up to a dose of 0.156mg/kg of DNA / single dose.

An intravenous infusion will be administered twice a week for 4 weeks (e.g. Mon and Thurs, preferred) for a total of 8 infusions of the product per cycle followed by 2 weeks of rest. Treatment may continue as long as there is clinical benefit, no evidence of disease progression, and no other withdrawal criteria are met.

Biological: pbi-shRNA™ EWS/FLI1 Type 1 LPX
Other Name: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex

Primary Outcome Measures :
  1. Safety: adverse events as assessed by CTCAE v4.0 [ Time Frame: 1 year ]
    Review of adverse events

Secondary Outcome Measures :
  1. Efficacy measured by Clinical Response [ Time Frame: 1 year ]
    Disease Response

Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Subjects will be eligible for registration if they meet all of the following inclusion criteria:

Inclusion Criteria:

  1. Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).
  2. Age ≥8 years.
  3. Evidence of EWS translocation fusion by FISH or RT-PCR or NGS.
  4. Evidence of Type 1 fusion by molecular diagnostics.
  5. Refractory or intolerant to standard of care.
  6. ECOG performance status (PS) = 0-2, or Karnofsky PS ≥60% or Lansky PS ≥60%.
  7. Normal organ and marrow function as defined below:

    Absolute granulocyte count ≥1,000/mm3 Absolute lymphocyte count ≥400/mm3 Platelets ≥100,000/mm3 Total bilirubin ≤ institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤2x institutional upper limit of normal Creatinine <1.5 mg/dL

  8. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade 2 or better.
  9. If female of childbearing potential, has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a negative serum test will be required for study entry.
  10. Ability to understand and the willingness to sign a written informed protocol specific consent. Pediatric patients must sign an assent with a parent or legal guardian sign a written informed consent, per institutional guidelines.

Subjects will NOT be eligible for study registration and enrollment if meeting any of the following criteria:

Exclusion Criteria:

  1. Anti-cancer chemotherapy, biologic therapy or immunotherapy within 3 weeks or radiation therapy within 2 weeks of first infusion.
  2. Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 3 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers are allowed if definitively resected.
  3. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
  4. History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the Investigator.
  5. Known HIV or chronic Hepatitis B or C infection.

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 identifier (NCT number): NCT02736565

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Contact: Gladice Wallraven 214-442-8124

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United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Morgan Coleman   
Principal Investigator: Emily Slotkin, MD         
United States, Texas
Mary Crowley Cancer Research Centers Completed
Dallas, Texas, United States, 75230
Sponsors and Collaborators
Gradalis, Inc.
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Study Director: John Nemunaitis, MD Gradalis, Inc.

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Responsible Party: Gradalis, Inc. Identifier: NCT02736565     History of Changes
Other Study ID Numbers: CL-PTL-001
First Posted: April 13, 2016    Key Record Dates
Last Update Posted: March 20, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Gradalis, Inc.:
askin tumor
neuroectodermal tumor
soft tissue

Additional relevant MeSH terms:
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Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue