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Alkylating Agents

Vigil immunotherapy 1.0 x 107 cells/injection; minimum of 4 to a maximum of 12 administrations every 28 days

Gemcitabine 675 mg/m2 IV at 10 mg/m2/min D1 and Docetaxel 75 mg/m2 IV starting on D8 and given every 21 days.

(i) oral temozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle), (ii) irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously (iii) peg-filgrastim 100μg/kg (Day 6) subcutaneously (optional and may be administered at home), and (iv) Vigil 1.0 x 107 cells/injection, intradermally on Day 15 and every 3 weeks thereafter. One cycle = 21 days.

Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.

Vigil

oral temozolimidetemozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle)

irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously

675 mg/m2 IV at a rate of 10 mg/m2/min on Day 1 and Day 8 every 21 days

75 mg/m2 IV administered on Day 8 and every 21 days

John Nemunaitis, MD

A two-part trial in patients with metastic Ewing's sarcoma. Participants in Part 1 will be randomized to receive either Vigil immunotherapy or gemcitabine and docetaxel with the objective of comparing the overall survival between the two arms. Participants enrolled in Part 2 will receive Vigil immunotherapy in combination of temozolomide and irinotecan with the objective to determine the safety profile of the combination treatment.

Part 1 Methodology:

This is a multicenter, 1:1 randomized Phase IIb study of intradermal autologous Vigil immunotherapy (1.0 x 10e7 cells/injection; minimum of 4 to a maximum of 12 administrations) versus gemcitabine / docetaxel in patients with metastatic Ewing's sarcoma Family of Tumors (ESFT) refractory or intolerant to at least 2 prior lines of chemotherapy. Patients undergoing a standard surgical procedure (e.g., tumor biopsy or palliative resection) may have tumor tissue harvested for manufacture of investigational product. Patients meeting eligibility criteria including manufacture of a minimum of 4 immunotherapy doses will be randomized to receive either (1) intradermal Vigil every 28 days for 4-12 administrations, or (2) gemcitabine 675 mg/m2 IV at 10 mg/m2/min D1 and D8 and docetaxel 75 mg/m2 IV D8 every 21 days. The primary trial objective is to determine the overall survival of patients treated with Vigil versus gemcitabine/docetaxel. Randomization may occur as early as vaccine is released (typically 3 - 4 weeks following tumor procurement) but no later than 8 weeks following tumor procurement. Randomization of patients will be stratified by Karnofsky Performance Status (KPS) ≥ 80% vs \< 80%.

Patients will be managed in an outpatient setting. Hematologic function, liver enzymes, renal function and electrolytes will be monitored monthly. Blood for immune function analyses including IFNγ-ELISPOT analysis of cytotoxic T cell response to autologous tumor antigens will be collected at tissue procurement, baseline, and prior to product administration at Cycles 2, 4, end of treatment, and every 6 months thereafter.

Part 2 Methodology:

Based on the limited accrual to Part 1 of this study, Gradalis is opening Part 2 of this clinical protocol to assess the safety of Vigil immunotherapy in combination with irinotecan and temozolomide. Part 2 will be conducted at the same centers as Part 1, studying intradermal autologous Vigil cancer vaccine (1.0 x 10e7 cells/injection; minimum of 4 to a maximum of 12 administrations) in patients with metastatic Ewing's sarcoma Family of Tumors (ESFT) refractory or intolerant to at least 1 prior line of chemotherapy. Patients undergoing a standard surgical procedure (e.g., tumor biopsy or palliative resection) may have tumor tissue harvested for manufacture of investigational product. Patients meeting eligibility criteria including manufacture of a minimum of 4 immunotherapy doses of Vigil will be registered to receive: (i) oral temozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle), (ii) irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously (iii) peg-filgrastim 100μg/kg (Day 6) subcutaneously (optional and may be administered at home), and (iv) Vigil 1.0 x 107 cells/injection, intradermally on Day 15 and every 3 weeks thereafter. One cycle = 21 days. Registration onto Part 2 may occur as early as one week but no later than 8 weeks following tumor procurement. Vigil is typically released approximately 3 weeks after the completion of the two-day manufacturing process.

Patients 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 response to autologous tumor antigens will be collected at tissue procurement, post-procurement screening and prior to Day 15 Vigil administration at Cycles 2, 4, end of treatment, and every 6 months thereafter. Blood for ctDNA analysis will be collected prior to chemotherapy administration at baseline, Cycle 2 - Week 1 Day 1, Cycle 4 - Week 1 Day 1, and EOT.

Part 1: Participants will be randomized 1:1 to receive Vigil immunotherapy alone or gemcitabine / docetaxel. Part 2 participants will be a single group of subjects to receive Vigil immunotherapy in combination with irinotecan and temozolomide.

A Two-part Phase IIb Trial of Vigil (Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Immunotherapy) in Ewing's Sarcoma

A 2-part Trial Comparing Overall Survival of Patients With Metastatic Ewing's Sarcoma Treated With Vigil Versus Gemcitabine and Docetaxel and to Determine Safety Profile of Vigil in Combination With Irinotecan and Temozolomide.

To determine safety profile of Vigil immunotherapy in combination with irinotecan and temozolomide with 30 days of last dose in patients with metastatic Ewing's sarcoma refractory or intolerant to at least 1 prior line of systemic chemotherapy.

• To determine safety profile of Vigil immunotherapy in combination with irinotecan and temozolimidetemozolomide in patients with metastatic Ewing's sarcoma refractory or intolerant to at least 1 prior line of systemic chemotherapy.

Progression Free Survival (PFS) is defined as the time from randomization to the event of disease recurrence/progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) or death due to any cause. To determine the progression free survival of subjects dosed with Vigil immunotherapy in combination with irinotecan and temozolomide.

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.

Gradalis, Inc.

Vigil immunotherapy 1.0 x 107 cells/injection; minimum of 4 to a maximum of 12 administrations every 28 days

Vigil: Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.

Part 1: Vigil Alone

Gemcitabine 675 mg/m2 IV at 10 mg/m2/min D1 and Docetaxel 75 mg/m2 IV starting on D8 and given every 21 days.

Gemcitabine: 675 mg/m2 IV at a rate of 10 mg/m2/min on Day 1 and Day 8 every 21 days

Docetaxel: 75 mg/m2 IV administered on Day 8 and every 21 days

Part 1: Gemicitabine and Docetaxel

(i) oral temozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle), (ii) irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously (iii) peg-filgrastim 100μg/kg (Day 6) subcutaneously (optional and may be administered at home), and (iv) Vigil 1.0 x 107 cells/injection, intradermally on Day 15 and every 3 weeks thereafter. One cycle = 21 days.

Vigil: Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.

Temozolomide: oral temozolimidetemozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle)

Irinotecan: irinotecan 50 mg/m2 daily (Days 1 - 5, total dose 250mg/m2/cycle), orally or irinotecan 20mg/m2 daily (Days 1 - 5, total dose 100mg/m2/cycle ), intravenously

Part 2: Vigil Plus Temozolomide and Irinotecan

Vigil immunotherapy 1.0 X 10\^7 cells/injection; minimum of 4 to a maximum of 12 administrations every 28 days.

Part 2: Vigil in Combination With Temozolomide and Irinotecan

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Due to limited accrual to Part 1 of this study (rare disease), Gradalis opened Part 2 of this clinical protocol to assess the safety of Vigil immunotherapy in combination with irinotecan and temozolomide. Both parts of the study led to small numbers of subjects analyzed.

Spots Global Cancer Trial Database for ewing's sarcoma family of tumors, esft, sarcoma