A Two-part Phase IIb Trial of Vigil in Ewing's Sarcoma

Overview

About this study

The purpose of this study is to determine the overall survival of patients treated with Vigil versus gemcitabine/docetaxel.

 

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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). If available, NGS sequencing report should be submitted to Gradalis.
  • Recurrence or refractory to 1 line of systemic chemotherapy including but not limited to doxorubicin, vincristine and ifosfamide.
  • 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 / approximate 2 cm total diameter on imaging) and/or pleural fluid estimated volume ≥ 500mL (from a primary or secondary thoracentesis, yielding in a high volume of tumor cells) 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 protocol specific informed consent for tissue harvest or a parental/guardian informed consent and pediatric assent when appropriate.

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 HIV or chronic Hepatitis B or C infection.
  • Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC).
  • Known hypersensitivity to irinotecan or its excipients.
  • Known history of allergies or sensitivities to gentamicin.
  • 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:

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

  • Completed manufacture of at least 4 vials of Vigil.
  • Karnofsky performance status (KPS) / Lansky performance status (LS) ≥80%.
  • 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
  • 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, sensory neurologic pathology or symptoms, or dermatologic 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 or a parental/guardian informed consent and pediatric assent when appropriate.

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.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Steven Attia, D.O.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

  • Ewing sarcoma is a highly resistant disease with a <10% chance of survival at 5 years after failure of frontline chemotherapy. This is a case report of an Ewing sarcoma patient with metastatic disease recurrence <2 years after standard chemotherapy/radiation who achieved a durable and sustained complete response after 2 series of treatments with Vigil (GMCSF/bi-shRNA furin DNA autologous tumor immunotherapy) serially manufactured from first and second recurrences with ELISPOT assay correlation. Results support justification of further testing of Vigil with ELISPOT assay as a biomarker to assess level of immune response and correlation with disease control. Read More on PubMed
  • Ewing's sarcoma is a devastating rare pediatric cancer of the bone. Intense chemotherapy temporarily controls disease in most patients at presentation but has limited effect in patients with progressive or recurrent disease. We previously described preliminary results of a novel immunotherapy, FANG (Vigil) vaccine, in which 12 advanced stage Ewing's patients were safely treated and went on to achieve a predicted immune response (IFNγ ELISPOT). We describe follow-up through year 3 of a prospective, nonrandomized study comparing an expanded group of Vigil-treated advanced disease Ewing's sarcoma patients (n = 16) with a contemporaneous group of Ewing's sarcoma patients (n = 14) not treated with Vigil. Long-term follow-up results show a survival benefit without evidence of significant toxicity (no ≥ grade 3) to Vigil when administered once monthly by intradermal injection (1 × 10e(6) cells/injection to 1 × 10e(7) cells/injection). Specifically, we report a 1-year actual survival of 73% for Vigil-treated patients compared to 23% in those not treated with Vigil. In addition, there was a 17.2-month difference in overall survival (OS; Kaplan-Meier) between the Vigil (median OS 731 days) and no Vigil patient groups (median OS 207 days). In conclusion, these results supply the rational for further testing of Vigil in advanced stage Ewing's sarcoma. Read More on PubMed
  • We report on 12 consecutive patients with advanced/metastatic Ewing's sarcoma who were treated as a separate cohort of a phase 1 trial of FANG autologous immunotherapy (1 × 10(6)-2.5 × 10(7) cells/intradermal injection each month for minimum 4 months). Safety and clinical response were monitored. Patient immune response to unmodified autologous tumor cells was assessed by gamma interferon-enzyme-linked immunospot (γIFN-ELISPOT) assay using peripheral blood mononuclear cells from baseline (pretreatment) and multiple postvaccination time points. None of the 12 patients (47 vaccinations) developed grade 2/3/4 drug-related toxicity. Median product release granulocyte-macrophage colony-stimulating factor expression was 1,941 pg/10(6) cells, and TGFβ1and TGFβ2 knockdown were 99 and 100%, respectively. Eight patients were assessed for ELISPOT response to autologous tumor cells at baseline and all (100%) were negative. In contrast, follow-up ELISPOT response at month 1 or month 4 (one patient) after FANG was positive in all eight patients. One patient achieved a partial tumor response (38% tumor reduction, RECIST 1.1). The Kaplan-Meier estimated survival of these 12 patients at 1 year was 75%. In this phase 1 study in patients with Ewing's sarcoma, FANG immunotherapy was well tolerated, elicited a tumor-specific systemic immune response in all patients, and was associated with favorable 1-year survival. Further clinical testing is indicated. Read More on PubMed
  • We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified. Read More on PubMed

Study Results Summary

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Supplemental Study Information

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