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Vigil + Irinotecan and Temozolomide in Ewing's Sarcoma

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ClinicalTrials.gov Identifier: NCT03495921
Recruitment Status : Recruiting
First Posted : April 12, 2018
Last Update Posted : September 10, 2018
Sponsor:
Information provided by (Responsible Party):
Gradalis, Inc.

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.

Condition or disease Intervention/treatment Phase
Ewing Sarcoma Ewing Family of Tumors Ewing's Tumor Metastatic Ewing's Sarcoma Metastatic Biological: Vigil Drug: Irinotecan Drug: Temozolomide Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
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
Official Title: 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
Actual Study Start Date : August 21, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : July 1, 2022


Arm Intervention/treatment
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.

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

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

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.

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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.



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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Metastatic disease
  6. Recurrence or refractory to 1 line of systemic chemotherapy.
  7. 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) or pleural fluid estimated volume ≥ 500mL (from a primary or secondary thoracentesis, yielding in a high volume of tumor cells) for immunotherapy manufacture.
  8. Tumor intended for immunotherapy manufacture is not embedded in bone and does not contain luminal tissue (e.g. bowel, ureter, bile duct).
  9. 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 ≥1,500/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

  4. 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.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03495921


Contacts
Contact: Gladice Wallraven 214-442-8124 info@gradalisinc.com

Locations
United States, Arkansas
Arkansas Children's Hospital Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Catherine Redinger, RN    501-364-4290    RedingerCatherineL@uams.edu   
United States, Florida
Mayo Clinic Florida Not yet recruiting
Jacksonville, Florida, United States, 32224
Contact: Steven Attia, MD    904-953-7290    Attia.Steven@mayo.edu   
Nicklaus Children's Hospital Not yet recruiting
Miami, Florida, United States, 33155
Contact: Coraly Diaz-Gamboa, BS    786-624-2853    coraly.diaz@NicklausHealth.org   
United States, Massachusetts
Dana-Farber/Boston Children's Cancer and Blood Disorders Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Steven DuBois, MD    617-632-5460    Steven_Dubois@dfci.harvard.edu   
United States, Missouri
Washington University Siteman Cancer Center Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Michele Landeau    314-747-9488    landeaum@wustl.edu   
United States, Ohio
Cincinnati Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact    513-636-2799    cancer@cchmc.org   
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact    513-636-2799    cancer@cchmc.org   
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Peter Anderson, MD    216-445-4044    andersp@ccf.org   
Contact: Stacey Zahler, MD    216-445-3588    zahlers@ccf.org   
United States, Pennsylvania
Fox Chase Cancer Center Not yet recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Sujana Movva, MD    215-728-4300    Sujana.Movva@fccc.edu   
United States, Texas
Texas Oncology - Pediatrics Not yet recruiting
Dallas, Texas, United States, 75230
Contact: Maurizio Ghisoli, MD    972-566-6647    Maurizio.Ghisoli@usoncology.com   
Sponsors and Collaborators
Gradalis, Inc.
Investigators
Study Director: Luisa Manning, MD Gradalis, Inc.

Additional Information:
Publications:

Responsible Party: Gradalis, Inc.
ClinicalTrials.gov Identifier: NCT03495921     History of Changes
Other Study ID Numbers: CL-PTL-130
First Posted: April 12, 2018    Key Record Dates
Last Update Posted: September 10, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Gradalis, Inc.:
ESFT
Immunotherapy
Phase 3

Additional relevant MeSH terms:
Neoplasms
Sarcoma
Sarcoma, Ewing
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Irinotecan
Camptothecin
Temozolomide
Dacarbazine
Modafinil
Armodafinil
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Wakefulness-Promoting Agents
Central Nervous System Stimulants
Cytochrome P-450 CYP3A Inducers
Cytochrome P-450 Enzyme Inducers
Physiological Effects of Drugs