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Vigil + Irinotecan and Temozolomide in Ewing's Sarcoma (VITA)

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ClinicalTrials.gov Identifier: NCT03495921
Recruitment Status : Active, not recruiting
First Posted : April 12, 2018
Last Update Posted : February 4, 2021
Sponsor:
Information provided by (Responsible Party):
Gradalis, Inc.

Tracking Information
First Submitted Date  ICMJE February 15, 2018
First Posted Date  ICMJE April 12, 2018
Last Update Posted Date February 4, 2021
Actual Study Start Date  ICMJE August 21, 2018
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
Progression Free Survival (PFS) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years ]
Progression Free Survival (PFS) is defined as the time from randomization to the event of disease recurrence/progression or death due to any cause. PFS of subjects dosed with Vigil immunotherapy in combination with irinotecan and temozolomide vs. irinotecan and temozolomide will be compared.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2019)
  • Overall Survival (OS) [ Time Frame: From date of randomization until date of death from any cause, whichever came first, assessed up to 5 years ]
    OS is defined as time from randomization to death or to the date of last follow-up. The date of last follow-up confirming survival will be used as the censoring date for subjects who are alive and/or do not have a known date of death. OS of subjects with relapsed or refractory Ewing's sarcoma dosed with Vigil immunotherapy in combination with irinotecan and temozolomide will be determined and compared.
  • Radiological Tumor Assessment [ Time Frame: Through study completion and then follow up, approximately 2 years ]
    The objective response rate (RECIST 1.1) of patients with metastatic Ewing's sarcoma refractory or intolerant to 1 prior line of systemic chemotherapy treated with Vigil immunotherapy dosed with Vigil immunotherapy in combination with irinotecan and temozolomide will be compared.
  • Vigil Manufacturing Success Rate [ Time Frame: From manufacturing start date until 4 weeks post manufacturing for each tissue procurement. ]
    Vigil Manufacturing Success Rate will be defined as passing cell number, cell viability, efficacy, and purity tests.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • ELISPOT conversion rate [ Time Frame: Through study completion and then follow up, approximately 3 years ]
    Whole blood for correlative studies (ELISPOT and ctDNA) will be obtained at baseline, prior to chemotherapy administration at Cycles 2 and 4, End of Treatment, and every 6 months after EOT (IFA only).
  • Overall Survival (OS) [ Time Frame: From date of randomization until date of death from any cause, whichever came first, assessed up to 5 years ]
    OS is defined as time from randomization to death or to the date of last follow-up. The date of last follow-up confirming survival will be used as the censoring date for subjects who are alive and/or do not have a known date of death. OS of subjects with relapsed or refractory Ewing's sarcoma dosed with Vigil immunotherapy in combination with irinotecan and temozolomide will be determined and compared.
  • Radiological Tumor Assessment [ Time Frame: Through study completion and then follow up, approximately 2 years ]
    The objective response rate (RECIST 1.1) of patients with metastatic Ewing's sarcoma refractory or intolerant to 1 prior line of systemic chemotherapy treated with Vigil immunotherapy dosed with Vigil immunotherapy in combination with irinotecan and temozolomide will be compared.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vigil + Irinotecan and Temozolomide in Ewing's Sarcoma
Official Title  ICMJE A Multi-Center Phase III, Randomized, Open-Label Trial of Vigil (Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy) in Combination With Irinotecan and Temozolomide as a Second-Line Regimen for Ewing's Sarcoma
Brief Summary This is a multicenter, 1:1 randomized Phase III study of intradermal autologous Vigil immunotherapy (1.0 x 10e6 cells/injection; minimum of 4 to a maximum of 12 administrations) in combination with irinotecan and temozolomide in subjects with metastatic Ewing's sarcoma Family of Tumors (ESFT) refractory/intolerant or recurrent to 1 prior line of chemotherapy. Participants undergoing a standard surgical procedure (e.g., tumor biopsy or palliative resection) may have tumor tissue harvested for manufacture of the investigational product, Vigil.
Detailed Description Participants will be managed in an outpatient setting. Hematologic function, liver enzymes, renal function and electrolytes will be monitored. Blood for immune function analyses including IFNγ-ELISPOT analysis of cytotoxic T cell activation in response to autologous tumor antigens will be collected at tissue procurement, post-procurement screening and Day 1 (prior to chemotherapy administration) at Cycles 2, 4, and 6, end of treatment (EOT), 3 months after EOT, and every 6 months thereafter. Blood for ctDNA analysis will be collected at tissue procurement, prior to chemotherapy administration at baseline and on Day 1 prior to chemotherapy administration at Cycles 2, 3, 4, and 6, and EOT.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Group A (i) oral temozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle), (ii) oral irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), and (iii) Vigil 1.0 x 10e6 cells/injection cells/injection, intradermally on Day 15.

or

Group B (i) (oral temozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle), and (ii) oral irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle).

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Biological: Vigil
    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.
    Other Names:
    • Engineered Autologous Tumor Cell Immunotherapy
    • FANG
    • IND14205
    • Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy
  • Drug: Irinotecan
    Irinotecan injectable formulation will be obtained. This will be drawn up into oral syringes (1 cycle of 5 doses) and dispensed to the subject with instructions to refrigerate until administration. Irinotecan may be mixed with cranberry-grape juice immediately before administration to mask the bitter flavor and administered once daily on Days 1 through 5 of each 3-week cycle.
    Other Names:
    • Camptosar
    • Camptothecin-11
    • CPT-11
  • Drug: Temozolomide
    Temozolomide capsules may be opened and mixed in apple sauce or juice if unable to swallow whole capsules. Temozolomide is administered on Days 1 through 5 of each 3-week course and given at least 1 hour before Irinotecan.
    Other Name: Temodar
Study Arms  ICMJE
  • Experimental: Vigil + Irinotecan and Temozolomide

    Group A Schedule:

    Temozolomide 100 mg/m2 daily, oral, Days 1 - 5, every 21 days Irinotecan 50 mg/m2 daily, oral, Days 1 - 5, every 21 days Vigil 1.0 x 10e6 cells/injection, intradermal, Day 15, every 21 days for a minimum of 4 administrations to a maximum of 12 administrations depending on quantity of Vigil manufactured from surgical specimens and so long as the patient is clinically stable and without disease progression.

    Subjects may receive repeat cycles of treatment until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

    Interventions:
    • Biological: Vigil
    • Drug: Irinotecan
    • Drug: Temozolomide
  • Active Comparator: Irinotecan and Temozolomide

    Group B Schedule:

    Temozolomide 100 mg/m2 daily, oral, Days 1 - 5, every 21 days Irinotecan 50 mg/m2 daily, oral, Days 1 - 5, every 21 days

    Subjects may receive repeat cycles of treatment until disease progression, unacceptable toxicity, withdrawal of consent or other criterion is met for discontinuation from study.

    Within 6 weeks of second relapse or progression, subjects randomized to Group B, will be allowed to cross-over to receive single agent Vigil every 21 days following End of Treatment assessments. Subjects who cross-over may receive up to 12 doses of Vigil depending upon the quantity of Vigil manufactured. Cross-over must occur within 2 years of End of Treatment assessments of Group B enrollment.

    Interventions:
    • Drug: Irinotecan
    • Drug: Temozolomide
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: February 13, 2019)
114
Original Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
140
Estimated Study Completion Date  ICMJE July 1, 2023
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Tissue Procurement Inclusion Criteria:

  1. Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).
  2. Age ≥ 2 years.
  3. Estimated survival ≥ 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%.
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 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 NCT03495921
Other Study ID Numbers  ICMJE CL-PTL-130
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
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 February 2021

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