A Two-part Phase IIb Trial of Vigil (Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy) in Ewing's Sarcoma
Condition: Ewing's Sarcoma
MeSH terms: Sarcoma; Sarcoma, Ewing
Intervention: Vigil; Temozolomide; Irinotecan; Gemcitabine; Docetaxel
Intervention description: Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.; oral temozolimidetemozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle); irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously; 675 mg/m2 IV at a rate of 10 mg/m2/min on Day 1 and Day 8 every 21 days; 75 mg/m2 IV administered on Day 8 and every 21 days
Intervention MeSH terms: Gemcitabine; Docetaxel; Irinotecan; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Part 1: Participants will be randomized 1:1 to receive Vigil immunotherapy alone or gemcitabine / docetaxel. Part 2 participants will be a single group of subjects to receive Vigil immunotherapy in combination with irinotecan and temozolomide.
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 2 Years
Healthy volunteers: No
Keywords: Ewing's Sarcoma Family of Tumors, ESFT, Sarcoma; Soft Tissue Sarcoma

Summary:

      A two-part trial in patients with metastic Ewing's sarcoma. Participants in Part 1 will be
      randomized to receive either Vigil immunotherapy or gemcitabine and docetaxel with the
      objective of comparing the overall survival between the two arms. Participants enrolled in
      Part 2 will receive Vigil immunotherapy in combination of temozolomide and irinotecan with
      the objective to determine the safety profile of the combination treatment.
    

Eligibility criteria:

        Tissue Procurement Inclusion Criteria:

        Patients will be eligible for tissue procurement for the Vigil manufacturing process, if
        they meet all of the following criteria:

          -  Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT)

          -  Age ≥2 years

          -  Estimated survival ≥ 6 months

          -  Evidence of EWS translocation by FISH or RT-PCR or Next Generation Sequencing (NGS)
             Metastatic disease

          -  Refractory or intolerant to ≥ 2 lines of systemic chemotherapy (Part 1) or Refractory
             or intolerant to at least 1 line of systemic chemotherapy (Part 2)

          -  Planned standard of care surgical procedure (e.g., tumor biopsy or palliative
             resection or thoracentesis) and expected availability of a cumulative mass of ~10-30
             grams tissue ("golf-ball" size) or pleural fluid estimated volume ≥ 500mL (must be
             primary tap) for immunotherapy manufacture

          -  Tumor intended for immunotherapy manufacture is not embedded in bone and does not
             contain luminal tissue (e.g., bowel, ureter, bile duct)

          -  Ability to understand and the willingness to sign a written informed consent document
             for tissue harvest

        Tissue Procurement Exclusion Criteria:

        Patients meeting any of the following criteria are not eligible for tissue procurement for
        the Vigil manufacturing:

          -  Medical condition requiring any form of chronic systemic immunosuppressive therapy
             (steroid or other) except physiologic replacement doses of hydrocortisone or
             equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily)
             for < 30 days duration

          -  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

          -  Brain metastases unless treated with curative intent (gamma knife or surgical
             resection) and without evidence of progression for ≥ 2 months

          -  Any documented history of autoimmune disease with exception of Type 1 diabetes on
             stable insulin regimen, hypothyroidism on stable dose of replacement thyroid
             medication, vitiligo, or asthma not requiring systemic steroids

          -  Known history of allergies or sensitivities to gentamicin

          -  Known hypersensitivity reactions to docetaxel or to other drugs formulated with
             polysorbate 80 that would preclude treatment with docetaxel (Part 1 only)

          -  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 patient's participation for the full duration
             of the study, or is not in the best interest of the patient to participate, in the
             opinion of the treating Investigator.

          -  Known HIV or chronic Hepatitis B or C infection

        Study Enrollment Inclusion Criteria:

        Patients will be eligible for registration if they meet all of the following inclusion
        criteria:

          -  Successful manufacturing of at least 4 vials of Vigil

          -  Karnofsky performance status (KPS) ≥60% (Part 1) or KPS ≥80% (Part 2)

          -  Estimated survival ≥ 4 months (Part 1) or estimated survival of ≥6 months (Part 2)

          -  Normal organ and marrow function as defined below:

               -  Absolute granulocyte count ≥1,500/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

          -  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.

          -  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.

          -  Ability to understand and the willingness to sign a written informed protocol specific
             consent

        Study Enrollment Exclusion Criteria:

        Measureable disease is not a requirement for enrollment onto the trial.

        In addition to the procurement exclusion criteria, patients will NOT be eligible for study
        registration and randomization if meeting any of the following criteria:

          -  Any anti-neoplastic therapy between tissue procurement for Vigil manufacture and start
             of study therapy

          -  Live vaccine used for the prevention of infectious disease administered < 30 days
             prior to the start of study therapy

          -  Post-surgery complication that in the opinion of the treating investigator would
             interfere with the patient's study participation or make it not in the best interest
             of the patient to participate