VITA: Vigil + Irinotecan and Temozolomide in Ewing's Sarcoma

Sponsor

Gradalis, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03495921

Collaborator

(none)

114

Enrollment

Locations

Arms

58.3

Anticipated Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 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	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 Design

Study Type:

Interventional

Anticipated Enrollment :

114 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).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 :

Aug 21, 2018

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

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 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 Names: 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 Names: Temodar

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

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 Names:

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

Other Names:

Camptosar

Camptothecin-11

CPT-11

Drug: Temozolomide

Other Names:

Temodar

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [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

Overall Survival (OS) [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Tissue Procurement Inclusion 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 / 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.
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:

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:

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 or 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:

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:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
2	Southern California Permanente Medical Group	Los Angeles	California	United States	90027
3	UCLA Children's Health Center	Los Angeles	California	United States	90095
4	Stanford Children's Health	Palo Alto	California	United States	94304
5	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
6	Nicklaus Children's Hospital	Miami	Florida	United States	33155
7	Dana-Farber/Boston Children's Cancer and Blood Disorders	Boston	Massachusetts	United States	02215
8	Washington University Siteman Cancer Center	Saint Louis	Missouri	United States	63110
9	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
10	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
11	Duke Children's Hospital and Health Center; Duke Cancer Institute	Durham	North Carolina	United States	27710
12	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
13	Cleveland Clinic	Cleveland	Ohio	United States	44195
14	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
15	Texas Oncology - Pediatrics	Dallas	Texas	United States	75230
16	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
17	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109