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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02736565
Recruitment Status : Active, not recruiting
First Posted : April 13, 2016
Last Update Posted : March 20, 2020
Sponsor:
Information provided by (Responsible Party):
Gradalis, Inc.

Tracking Information
First Submitted Date  ICMJE April 4, 2016
First Posted Date  ICMJE April 13, 2016
Last Update Posted Date March 20, 2020
Actual Study Start Date  ICMJE October 2016
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2020)
To determine the safety and maximum tolerated dose of intravenous administration of Bifunctional shRNA (pbishRNA™) EWS/FLI1 Type 1 Lipoplex in participants with advanced Ewing's sarcoma. [ Time Frame: From first dose and up to 60 days following the last treatment. ]
Safety assessments will include physical evaluations, performance status, laboratory assessments and vital signs. Toxicities will be graded and reported according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0). If 1 of 3 subjects within a dose cohort experiences a DLT, that dose cohort will be expanded to six subjects provided no further subjects experience a DLT. If no further subjects experience a DLT, dose-escalation may continue. If ≥2 subjects within a dose cohort experiences a DLT, this will define the DLT dose level and the MTD will have been exceeded. If no further subjects experience a DLT, dose-escalation may resume per escalation schema. The preceding dose level will be expanded to a total of 6 subjects and, if ≤1 subject experiences a DLT, that dose level will be considered the maximum tolerated dose (MTD). Once the presumptive MTD is reached, an additional 6 subjects will be treated at that dose, designated the expanded MTD dose cohort.
Original Primary Outcome Measures  ICMJE
 (submitted: April 7, 2016)
Safety: adverse events as assessed by CTCAE v4.0 [ Time Frame: 1 year ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
  • To assess disease response for different cohorts following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration at different dose(s). [ Time Frame: From Baseline and quarterly thereafter until progressive disease is noted, an average of 1.3 years. ]
    Radiological assessment of tumors, chest, abdomen, and pelvis to include, at a minimum, CT (or MRI), used to evaluate measurable or non-measurable disease. To be obtained at baseline and quarterly thereafter (+/- 4 weeks) until progressive disease is noted. For those subjects with CT or MRI evidence of response following the administration of the study agent, a confirmatory scan will be performed one month later.
  • To assess the pharmacokinetics of pbi-shRNA™ EWS/FLI1 Type 1 plasmid. [ Time Frame: From Cycle 1 Week 1 Day 1 and until Cycle 2 Week 1 Day 1, approximately 8 weeks. ]
    Serum for pharmacokinetics (PK) analysis will be collected on Cycle 1 Week 1 Day 1, Cycle 1 Week 6 Day 4, and Cycle 2 Week 1 Day 1 at the following time points (±10%): 30 minutes prior to study agent administration and at the following time points after the initiation of study agent administration: 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours.
  • To assess ctDNA (EWSR-FLI1) levels and compare to tumor burden and disease response prior to and following pbi-shRNA™ EWS/FLI1 Type 1 lipoplex administration. [ Time Frame: From Cycle 1 Week 1 Day 1 and until the last even cycle where product was administered, about 1 year. ]
    Blood for circulating tumor DNA analysis will be collected at Cycle 1 Week 1 Day 1, Cycle 1 Week 3 Day 1, Cycle 2 Week 1 Day 1 prior to product infusion and every even cycle thereafter at Week 1 Day 1 prior to product infusion.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2016)
Efficacy measured by Clinical Response and RECIST [ Time Frame: 1 year ]
Disease Response
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pbi-shRNA™ EWS/FLI1 Type 1 LPX in Subjects With Advanced Ewing's Sarcoma
Official Title  ICMJE Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (LPX) in Subjects With Advanced Ewing's Sarcoma
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-Investigational New Drug (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.

Detailed Description

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. Patients will be accrued in 3- patient dose escalation cohorts using the following escalation schema (50%→33%→25%→25%→25%) at a starting IV dose of 0.04 mg/kg.

If 1 of 3 subjects within a dose cohort experiences a Dose Limiting Toxicity (DLT), that dose cohort will be expanded to six subjects provided no further subjects experience a DLT. If no further subjects experience a DLT, dose-escalation may continue. If ≥2 subjects within a dose cohort experiences a DLT, this will define the DLT dose level and the Maximum Tolerated Dose (MTD) will have been exceeded.

The preceding dose level will be expanded to a total of 6 subjects and, if ≤1 subject experiences a DLT, that dose level will be considered the maximum tolerated dose (MTD). If no further subjects experience a DLT, dose-escalation may resume per escalation schema.

Once the presumptive MTD is reached, an additional 6 subjects will be treated at that dose, designated the expanded MTD dose cohort.

Serum for pharmacokinetics (PK) analysis will be collected on Cycle 1, Week 1, Day 1 (C1W1D1), Cycle

1, Week 6, Day 4; and Cycle 2, Week 1, Day 1 at following time points (±10%):30 minutes prior to administration and at the following time points after initiation of study agent administration: 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours and 48 hours.

Serum for cytokine analysis will be collected on Cycle 1, Week 1, Day 1 at following time points (±10%): 2 hours, 6 hours, and 24 hours. Serum for cytokine analysis will also be collected on Cycle 2, Week 1, Day 1 and Cycle 3, Week 1, Day 1, at following time points (±10%): 30 minutes prior to administration and at 6 hours after initiation of study agent administration.

Blood for analysis of RNA mechanism will be collected prior to administration of the study agent and 48 hours after study agent administration (with a 10% window). Blood for RNA will be collected at the first and last dose of each cycle (e.g. C1W1D1, C1W6D4).

Blood for circulating tumor DNA (ctDNA) analysis will be collected at Cycle 1 Week 1 Day 1, Cycle 1 Week 3 Day 1, Cycle 2 Week 1 Day 1 prior to product infusion and every even cycle thereafter at Week 1 Day 1 prior to product infusion.

If available, a biopsy or pleural fluid will be collected 1 to 3 weeks prior to Cycle 1 Week 1 Day 1 and 72 hours after the last dose of Cycle 1.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Ewing's Sarcoma
  • Ewing Family of Tumors
  • Ewing's Tumor Metastatic
  • Ewing's Sarcoma Metastatic
  • Ewing's Tumor Recurrent
  • Rare Diseases
  • Sarcoma
Intervention  ICMJE Biological: pbi-shRNA™ EWS/FLI1 Type 1 LPX
Other Name: pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex
Study Arms  ICMJE 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.

Intervention: Biological: pbi-shRNA™ EWS/FLI1 Type 1 LPX
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 25, 2018)
28
Original Estimated Enrollment  ICMJE
 (submitted: April 7, 2016)
22
Estimated Study Completion Date  ICMJE February 2022
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. Subjects must have failed surgery (if resectable), radiation (if no function-preserving surgical approach at primary site, unresectable primary following induction chemotherapy, residual microscopic or gross disease after surgery or inadequate margins), and the following chemotherapy agents: doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide.
  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. Normal pulmonary function as defined as FEV1/FVC greater than 70% in adults or greater than 80% in individuals between 8 and 18 years of age.
  9. 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.
  10. 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.
  11. 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. Patients with PET avid disease only will be excluded.
  4. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months.
  5. History of or current evidence of thrombosis.
  6. 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.
  7. Known HIV or chronic Hepatitis B or C infection.
  8. Have signs and symptoms consistent with an active infection.
  9. Live vaccination for the prevention of infectious disease administered <30 days prior to the start of study therapy or inactivated vaccination <14 days prior to the start of study therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02736565
Other Study ID Numbers  ICMJE CL-PTL-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Gradalis, Inc.
Study Sponsor  ICMJE Gradalis, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Luisa Manning, MD Gradalis, Inc.
PRS Account Gradalis, Inc.
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP