A Trial For Participants With Ewing's Sarcoma Treated With Vigil in Combination With Irinotecan and Temozolomide
Condition: Ewing Sarcoma; Ewing Family of Tumors; Ewing's Tumor Metastatic; Ewing's Sarcoma Metastatic; Ewing's Tumor Recurrent; Rare Diseases; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma, Ewing; Neoplasms
MeSH terms: Neoplasms; Sarcoma; Sarcoma, Ewing; Neoplasms by Histologic Type; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Bone Neoplasms; Neoplasms, Bone Tissue; Rare Diseases
Intervention: Vigil; Irinotecan; Temozolomide
Intervention description: Vigil is composed of autologous tumor cells harvested from the patient at the time of initial de-bulking surgery which are then transfected extracorporeally, with a plasmid encoding for the gene for GM-CSF, an immune-stimulatory cytokine, and a bifunctional, short hairpin RNA which specifically knocks down the expression of furin, the critical convertase responsible for production of the two TGβ isoforms.; Injectable formulation of irinotecan was distributed from central supplier. 1 Cycle (5 doses of 50 mg/m2 per syringe) was drawn into provided oral syringes and dispenses to the subject with instructions to refrigerate until administration.; Dose: 100 mg/m2 daily, oral Schedule: Days 1-5, every 21 days Administered at least 1 hour before Irinotecan.
Intervention MeSH terms: Irinotecan; Camptothecin; Temozolomide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants were randomized 1:1 to either Group A (Vigil + irinotecan and temozolomide) or Group B (irinotecan and temozolomide alone). Participants randomized to Group B were able to receive Vigil (Cross-Over) after confirmation of progression by central radiologist and sponsor approval.
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 2 Years
Healthy volunteers: No
Keywords: ESFT; Immunotherapy; Phase 3; irinotecan; temozolomide; First Relapse; Second Line; Vigil; vaccine; orphan drug; soft bone; pediatric; FLI; EWS; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents

Summary:

      The goal of this clinical trial was to compare participants with first relapse or refractory
      Ewing's sarcoma when treated with investigational product (Vigil) in addition to the standard
      treatment of irinotecan and temozolomide compared to the standard treatment of irinotecan and
      temozolomide alone. The main question it aimed to answer is "Will participants who receive
      Vigil in addition to irinotecan and temozolomide have a prolonged time to progression and
      improved quality of life compared to the participants who receive irinotecan and temozolomide
      alone?".
    

Eligibility criteria:

        Tissue Procurement Inclusion Criteria:

          1. Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).

          2. Age greater than or equal to 2 years.

          3. Estimated survival greater than or equal to 6 months.

          4. Evidence of EWS translocation by FISH or RT-PCR or Next Generation Sequencing (NGS).
             If available, NGS sequencing report should be submitted to Gradalis.

          5. Recurrence or refractory to 1 line of systemic chemotherapy, including but not limited
             to doxorubicin, vincristine, and ifosfamide.

          6. Planned standard of care surgical procedure (e.g., tumor biopsy or palliative
             resection or thoracentesis) and expected availability of a cumulative soft-tissue mass
             of ~10-30 grams tissue ("grape" to "golf-ball" size / approximately 2 cm total
             diameter on imaging) or pleural fluid estimated volume ≥ 500mL (from a primary or
             secondary thoracentesis, yielding in a high volume of tumor cells) for immunotherapy
             manufacture.

          7. Tumor intended for immunotherapy manufacture is not embedded in bone and does not
             contain luminal tissue (e.g. bowel, ureter, bile duct).

          8. Ability to understand and the willingness to sign a written protocol specific informed
             consent for tissue harvest or a parental/guardian informed consent and pediatric
             assent when appropriate.

        Tissue Procurement Exclusion Criteria:

          1. 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.

          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. 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.

          5. Known HIV or chronic Hepatitis B or C infection.

          6. Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC).

          7. Known hypersensitivity to irinotecan or its excipients.

          8. Known history of allergies or sensitivities to gentamicin.

          9. 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.

        Study Enrollment Inclusion Criteria:

          1. Completed manufacture of at least 4 vials of Vigil.

          2. Karnofsky performance status (KPS) / Lansky performance status (LS) ≥80 percent.

          3. Normal organ and marrow function as defined below:

             Absolute granulocyte count ≥1,000/mm3, Absolute lymphocyte count ≥400/mm3, Platelets
             ≥75,000/mm3, Hemoglobin ≥ 8.0 mg/dL, Total bilirubin ≤ institutional upper limit of
             normal*, AST(SGOT)/ALT(SGPT) ≤2x institutional upper limit of normal, Creatinine <1.5
             mg/dL

             * documented Gilbert's syndrome may be considered after medical monitor review

          4. Subject has recovered to CTCAE Grade 1 (except for parameters noted in Item 3, above)
             or better from all adverse events associated with prior therapy or surgery.
             Pre-existing motor or sensory neurologic pathology or symptoms, or dermatologic must
             be recovered to CTCAE Grade 2 or better.

          5. 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.

          6. Ability to understand and the willingness to sign a written informed protocol specific
             consent or a parental/guardian informed consent and pediatric assent when appropriate.

        Study Enrollment Exclusion Criteria:

        In addition to the procurement exclusion criteria, subjects will NOT be eligible for study
        registration and randomization if meeting any of the following additional criteria:

          1. Any anti-neoplastic therapy between tissue procurement for Vigil manufacture and start
             of study therapy.

          2. Live vaccine used for the prevention of infectious disease administered < 30 days
             prior to the start of study therapy.

          3. 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.

        Inclusion Criteria for Cross-Over:

        Group B subjects will be eligible for cross-over, if they meet all of the following
        criteria:

          1. Evidence of radiologic disease progression by RECIST 1.1 after enrollment into Group
             B.

          2. Successful manufacturing of at least 4 vials of Vigil.

          3. Karnofsky performance status (KPS) / Lansky performance status (LS) ≥70%.

          4. Normal organ and marrow function as defined below:

             Absolute granulocyte count ≥1,000/mm3 Absolute lymphocyte count ≥400/mm3 Platelets
             ≥75,000/mm3 Total bilirubin ≤ institutional upper limit of normal AST(SGOT)/ALT(SGPT)
             ≤2x institutional upper limit of normal Creatinine <1.5 mg/dL

             *documented Gilbert's syndrome may be considered after medical monitor review.

          5. Subject has recovered to CTCAE Grade 1 (except for parameters noted in Item 4, above)
             or better from all adverse events associated with prior therapy or surgery.
             Preexisting motor, sensory neurologic pathology or symptoms, or dermatologic
             toxicities must be recovered to CTCAE Grade 2 or better.

          6. 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.

          7. Ability to understand and the willingness to sign a written informed protocol specific
             consent or a parental/guardian informed consent and pediatric assent when appropriate.

        Exclusion Criteria for Cross-Over:

        In addition to the Procurement and Study Enrollment exclusion criteria, Subjects will not
        be eligible for cross-over if meeting any of the following criteria:

          1. With the exception of irinotecan and temozolomide while on study, any anti-neoplastic
             therapy between tissue procurement for Vigil manufacture and start of study therapy.

          2. Live vaccine used for the prevention of infectious disease administered < 30 days
             prior to the start of study therapy.