Clinical Trials /

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

NCT02736565

Description:

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.

Related Conditions:
  • Ewing Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pbi-shRNA™ EWS/FLI1 Type 1 LPX in Subjects With Advanced Ewing's Sarcoma
  • Official Title: Phase I Trial of Pbi-shRNA™ EWS/FLI1 Type 1 Lipoplex (LPX) in Subjects With Advanced Ewing's Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: CL-PTL-001
  • NCT ID: NCT02736565

Conditions

  • Ewing's Sarcoma
  • Ewing Family of Tumors
  • Ewing's Tumor Metastatic
  • Ewing's Sarcoma Metastatic
  • Ewing's Tumor Recurrent
  • Rare Diseases
  • Sarcoma

Interventions

DrugSynonymsArms
pbi-shRNA™ EWS/FLI1 Type 1 LPXpbi-shRNA™ EWS/FLI1 Type 1 Lipoplexpbi-shRNA™ EWS/FLI1 Type 1 LPX

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
pbi-shRNA™ EWS/FLI1 Type 1 LPXExperimentalSubjects 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.
  • pbi-shRNA™ EWS/FLI1 Type 1 LPX

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:8 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the safety and maximum tolerated dose of intravenous administration of Bifunctional shRNASTMN1 (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 Issue:
Description: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.

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gradalis, Inc.

Trial Keywords

  • metastatic
  • askin tumor
  • neuroectodermal tumor
  • pNET
  • sarcoma
  • soft tissue
  • ESFT
  • Immunotherapy

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