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

• Sponsor: Gradalis, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02511132
• Collaborator: (none)
• Enrollment: 22
• Locations: 6
• Arms: 3
• Actual Duration (Months): 58.4
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Ewing's Sarcoma	Biological: Vigil; Drug: Temozolomide; Drug: Irinotecan; Drug: Gemcitabine; Drug: Docetaxel	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: Feb 10, 2016
• Actual Primary Completion Date: Nov 12, 2018
• Actual Study Completion Date: Dec 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Vigil Alone Vigil immunotherapy 1.0 x 107 cells/injection; minimum of 4 to a maximum of 12 administrations every 28 days	Biological: Vigil; Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.; Other Names: formerly known as FANG™ bi-shRNAfurin and GMCSF Autologous Tumor Cell Immunotherapy
Active Comparator: Part 1: Gemicitabine and Docetaxel 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.	Drug: Gemcitabine; 675 mg/m2 IV at a rate of 10 mg/m2/min on Day 1 and Day 8 every 21 days; Other Names: GEMZAR ; Drug: Docetaxel; 75 mg/m2 IV administered on Day 8 and every 21 days; Other Names: TAXOTERE
Experimental: Part 2: Vigil plus Temozolomide and Irinotecan (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.	Biological: Vigil; Vigil 1.0 x 10e7 cells/injection, minimum of 4 to a maximum of 12 administrations.; Other Names: formerly known as FANG™ bi-shRNAfurin and GMCSF Autologous Tumor Cell Immunotherapy ; Drug: Temozolomide; oral temozolimidetemozolomide 100 mg/m2 daily (Days 1 - 5, total dose 500 mg/m2/cycle); Other Names: TEMODAR ; Drug: 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; Other Names: CAMPTOSAR

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events Determined by Laboratory Assessments and Physical Examinations [30 days of last treatment dosing]

   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.

Secondary Outcome Measures

1. Progression Free Survival [Estimated median 1.3 years]

   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.

2. Overall Survival [Estimated median 2 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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) Metastatic disease

• Refractory or intolerant to ≥ 2 lines of systemic chemotherapy (Part 1) or Refractory or intolerant to at least 1 line of systemic chemotherapy (Part 2)

• Planned standard of care surgical procedure (e.g., tumor biopsy or palliative resection or thoracentesis) and expected availability of a cumulative mass of ~10-30 grams tissue ("golf-ball" size) or pleural fluid estimated volume ≥ 500mL (must be primary tap) 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 informed consent document for tissue harvest

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 history of allergies or sensitivities to gentamicin

• Known hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80 that would preclude treatment with docetaxel (Part 1 only)

• 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.

• Known HIV or chronic Hepatitis B or C infection

Study Enrollment Inclusion Criteria:

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

• Successful manufacturing of at least 4 vials of Vigil

• Karnofsky performance status (KPS) ≥60% (Part 1) or KPS ≥80% (Part 2)

• Estimated survival ≥ 4 months (Part 1) or estimated survival of ≥6 months (Part 2)

• 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

• 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.

• 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
2	Nicklaus Children's Hospital (Miami Children's Health System)	Miami	Florida	United States	33155
3	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
4	Cleveland Clinic Children's	Cleveland	Ohio	United States	44195
5	Mary Crowley Cancer Research Centers	Dallas	Texas	United States	75230
6	TOPA - Medical City Dallas Pediatric Hematology-Oncology	Dallas	Texas	United States	75230

Sponsors and Collaborators

• Gradalis, Inc.

Investigators

• Study Director: John Nemunaitis, MD, Gradalis, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 12, 2017

More Information

Publications

• Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, Pappen BO, Whiting S, Rao D, Senzer N, Nemunaitis J. Three-year Follow up of GMCSF/bi-shRNA(furin) DNA-transfected Autologous Tumor Immunotherapy (Vigil) in Metastatic Advanced Ewing's Sarcoma. Mol Ther. 2016 Aug;24(8):1478-83. doi: 10.1038/mt.2016.86. Epub 2016 Apr 25.
• Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, Pappen BO, LaNoue J, Kumar P, Nemunaitis D, Roth A, Nemunaitis J, Whiting S, Senzer N, Fletcher FA, Nemunaitis J. Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma. Mol Ther. 2015 Jun;23(6):1103-1109. doi: 10.1038/mt.2015.43. Epub 2015 Mar 19.
• Ghisoli M, Rutledge M, Stephens PJ, Mennel R, Barve M, Manley M, Oliai BR, Murphy KM, Manning L, Gutierrez B, Rangadass P, Walker A, Wang Z, Rao D, Adams N, Wallraven G, Senzer N, Nemunaitis J. Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy. J Pediatr Hematol Oncol. 2017 May;39(4):e183-e186. doi: 10.1097/MPH.0000000000000822.
• Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, Lifshitz S, Magee M, Oh J, Mill SW, Bedell C, Higgs C, Kumar P, Yu Y, Norvell F, Phalon C, Taquet N, Rao DD, Wang Z, Jay CM, Pappen BO, Wallraven G, Brunicardi FC, Shanahan DM, Maples PB, Nemunaitis J. Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. Mol Ther. 2012 Mar;20(3):679-86. doi: 10.1038/mt.2011.269. Epub 2011 Dec 20.

• Responsible Party: Gradalis, Inc.
• ClinicalTrials.gov Identifier: NCT02511132
• Other Study ID Numbers: CL-PTL-121
• First Posted: Jul 29, 2015
• Last Update Posted: Jul 22, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gradalis, Inc.: Ewing's Sarcoma Family of Tumors, ESFT, Sarcoma; Soft Tissue Sarcoma
• Additional relevant MeSH terms: Sarcoma; Sarcoma, Ewing; Gemcitabine; Docetaxel; Irinotecan; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Part 1: Vigil Alone	Part 1: Gemicitabine and Docetaxel	Part 2: Vigil in Combination With Temozolomide and Irinotecan
Arm/Group Description	Vigil immunotherapy 1.0 X 10^7 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.
Period Title: Overall Study
STARTED	5	8	9
COMPLETED	5	7	9
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Part 1: Vigil Alone	Part 1: Gemicitabine and Docetaxel	Part 2: Vigil in Combination With Temozolomide and Irinotecan	Total
Arm/Group Description	Vigil immunotherapy 1.0 X 10^7 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.	Total of all reporting groups
Overall Participants	5	8	9	22
Age (Count of Participants)
<=18 years	0 0%	4 50%	3 33.3%	7 31.8%
Between 18 and 65 years	5 100%	4 50%	6 66.7%	15 68.2%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 60%	6 75%	4 44.4%	13 59.1%
Male	2 40%	2 25%	5 55.6%	9 40.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%	1 12.5%	1 11.1%	3 13.6%
Not Hispanic or Latino	4 80%	7 87.5%	8 88.9%	19 86.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 12.5%	0 0%	1 4.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	5 100%	7 87.5%	9 100%	21 95.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	8 100%	9 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events Determined by Laboratory Assessments and Physical Examinations
Description	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.
Time Frame	30 days of last treatment dosing

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1: Vigil Alone	Part 1: Gemcitabine and Docetaxel	Part 2: Vigil in Combination With Temozolomide and Irinotecan
Arm/Group Description	Vigil immunotherapy 1.0 X 10^7 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.
Measure Participants	5	8	9
Count of Participants [Participants]	5 100%	6 75%	9 100%

2. Secondary Outcome

Title	Progression Free Survival
Description	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.
Time Frame	Estimated median 1.3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1: Vigil Alone	Part 1: Gemicitabine and Docetaxel	Part 2: Vigil in Combination With Temozolomide and Irinotecan
Arm/Group Description	Vigil immunotherapy 1.0 X 10^7 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.
Measure Participants	5	8	9
Count of Participants [Participants]	5 100%	6 75%	9 100%

3. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	Estimated median 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1: Vigil Alone	Part 1: Gemcitabine and Docetaxel	Part 2: Vigil in Combination With Temozolomide and Irinotecan
Arm/Group Description	Vigil immunotherapy 1.0 X 10^7 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.
Measure Participants	5	8	9
Count of Participants [Participants]	3 60%	6 75%	5 55.6%

Adverse Events

Time Frame	Adverse events were recorded for the duration of a patient's study treatment: from the first dose of the Investigational Product to 30 days following the last study treatment (up to 10 months).
Arm/Group Title	Part 1: Vigil Alone		Part 1: Gemicitabine and Docetaxel		Part 2: Vigil Plus Temozolomide and Irinotecan
Arm/Group Description	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.		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		(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
All Cause Mortality
	Part 1: Vigil Alone		Part 1: Gemicitabine and Docetaxel		Part 2: Vigil Plus Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		8/8 (100%)		9/9 (100%)
Serious Adverse Events
	Part 1: Vigil Alone		Part 1: Gemicitabine and Docetaxel		Part 2: Vigil Plus Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		5/8 (62.5%)		5/9 (55.6%)
Blood and lymphatic system disorders
Febrile Neutropenia	0/5 (0%)	0	1/8 (12.5%)	1	1/9 (11.1%)	1
Gastrointestinal disorders
Nausea / Vomiting / Diarrhea	0/5 (0%)	0	0/8 (0%)	0	2/9 (22.2%)	4
General disorders
Disease Progression	0/5 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1
Pain	0/5 (0%)	0	1/8 (12.5%)	1	1/9 (11.1%)	1
Fever	0/5 (0%)	0	1/8 (12.5%)	1	1/9 (11.1%)	1
Edema Limbs	1/5 (20%)	1	0/8 (0%)	0	0/9 (0%)	0
Immune system disorders
Anaphylaxis	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Infections and infestations
Empyema	0/5 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1
Pneumonia	0/5 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1
Investigations
Lymphocyte count decreased	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Platelet count decreased	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	1/5 (20%)	1	0/8 (0%)	0	1/9 (11.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ewing's sarcoma	1/5 (20%)	1	0/8 (0%)	0	0/9 (0%)	0
Nervous system disorders
Headache	0/5 (0%)	0	1/8 (12.5%)	2	1/9 (11.1%)	1
Brain Mass	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	0/5 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1
Dyspnea	1/5 (20%)	1	0/8 (0%)	0	0/9 (0%)	0
Skin and subcutaneous tissue disorders
Blisters	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Facial Swelling	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Vascular disorders
Hypertension	0/5 (0%)	0	1/8 (12.5%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Part 1: Vigil Alone		Part 1: Gemicitabine and Docetaxel		Part 2: Vigil Plus Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		5/8 (62.5%)		9/9 (100%)
Blood and lymphatic system disorders
Anemia	1/5 (20%)	2	3/8 (37.5%)	3	6/9 (66.7%)	23
Neutropenia	0/5 (0%)	0	0/8 (0%)	0	4/9 (44.4%)	6
Gastrointestinal disorders
Fatigue	1/5 (20%)	1	3/8 (37.5%)	3	5/9 (55.6%)	13
Diarrhea	0/5 (0%)	0	0/8 (0%)	0	5/9 (55.6%)	13
Vomiting	0/5 (0%)	0	2/8 (25%)	2	6/9 (66.7%)	12
General disorders
Nausea	1/5 (20%)	1	3/8 (37.5%)	4	5/9 (55.6%)	12
Investigations
Platelet Count Decreased	0/5 (0%)	0	3/8 (37.5%)	6	1/9 (11.1%)	1
Metabolism and nutrition disorders
Hypokalemia	0/5 (0%)	0	1/8 (12.5%)	1	3/9 (33.3%)	11
Nervous system disorders
Headache	0/5 (0%)	0	2/8 (25%)	4	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Rash	0/5 (0%)	0	2/8 (25%)	3	0/9 (0%)	0

Limitations/Caveats

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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.