Clinical trial NCT03073525
Conditions: Advanced Gynecological Cancers Ovarian Cancer Cervical Cancer Uterine Cancer
Keywords: Stage IIIb Stage IV Ovarian Cancer Cervical Cancer Uterine Cancer Immunotherapy
Sponsor: Gradalis, Inc.
Start date: 2017-05-31; Completion date: 2022-05-18
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The clinical trial was a companion study to protocol CL-PTL-119 (A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of Vigil Engineered Autologous Tumor Cell Immunotherapy in Subjects with Stage IIIb-IV Ovarian Cancer in Clinical Complete Response following Surgery and Primary Chemotherapy (VITAL) NCT02346747). Participants who had investigational product (Vigil) successfully made but were not eligible to enroll onto the VITAL study or previously randomized to placebo were given the opportunity to participate in this protocol. The main goal of this clinical trial was to determine the safety of combining Vigil therapy with atezolizumab.

Detailed description:
The clinical trial was intended as a companion study to protocol CL-PTL-119 (VITAL study; NCT 02346747). Subjects who had tumor harvested at surgery and Vigil successfully manufactured, but then were ineligible for randomization onto the VITAL study or previously randomized to placebo, and also in subjects who have recurrent ovarian cancer were offered the opportunity to participate in this protocol. The trial was a multi-center, randomized, 3-part, open label study of Vigil, the checkpoint inhibitor atezolizumab and the combination of the two agents, in subjects with treatment refractory or recurrent epithelial ovarian cancer, or other gynecological cancers (i.e., cervical, uterine).

Part 1 was a safety run-in cohort and intervention (Vigil plus atezolizumab) was combined. The first 3 subjects registered in the trial were assigned to Part 1.

Part 2 was conducted after Part 1 participants completed combination therapy without dose-limiting toxicity. The purpose of Part 2 was to determine if Vigil given first then in sequence with atezolizumab would enhance immunotherapeutic anticancer activity. The overall efficacy of administration sequence was assessed.

Eligible subjects were randomized to receive two cycles of Vigil alone (n= 11) or two cycles of atezolizumab alone (n=10), followed by combination treatment with both of the agents.

Part 3 was an expansion cohort to allow subjects who completed all cycles of Part 2 to continue on atezolizumab alone, after Cycle 12. In this study, only 1 subject from Part 2 received additional treatment with atezolizumab. Pre-approval by sponsor was required by the sponsor before allowing subjects to continue treatment with atezolizumab in Part 3.

Subjects remained on treatment until disease progression or death or product toxic effect. Disease progression was determined radiographically by local investigators using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Part 1, radiological assessment of tumor response was performed at baseline and every third cycle thereafter. Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis was obtained at tissue procurement and at any time after the end of cycle 3. Whole blood for correlative studies (immune function) was obtained at baseline, prior to study agent administration at the start of cycle 3 and every third cycle thereafter.

Part 2, radiological assessment of tumor response was performed at baseline, at the end of cycle 2 of single agent therapy, and every third cycle thereafter. Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis was obtained at tissue procurement, prior to the start of combination therapy and at any time after the end of cycle 3. Whole blood for correlative studies (immune function) was obtained at baseline, prior to study agent administration at the start of cycle 3 (the first cycle of combination therapy) and every third cycle thereafter.

Part 3 schedule of assessments continued from Part 2 in which the following was assessed every third cycle: radiological assessments, tumor biopsy (if available), and whole blood collection for correlative studies.

The safety evaluation included recording of AEs and SAEs, and changes from baseline in laboratory evaluations, vital signs, electrocardiograms, and physical examinations.

Treatment was administered on an outpatient basis. A study cycle is defined as 21 days (3 weeks). Treatment was allowed to continue unless documented disease progression, discontinuation for toxicity, withdrawal of consent, or meeting other criteria for withdrawal from study. After progression, participants were contacted annually for three years for documentation of survival status information.

Arms: arm 1: This was a safety run in and intervention was combined. The first three participants received Vigil immunotherapy at a concentration of 1x10e7 cells/dose given via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses. Atezolizumab was administered at a dose of 1200 mg as an intravenous infusion every 3 weeks. 1 cycle = 21 days. arm 2: After Part 1 participants completed completed combination therapy without dose-limiting toxicity, then Part 2 participants randomized to Vigil first received two cycles of Vigil alone, then Vigil and atezolizumab given in sequence (Vigil administered first, followed 30 minutes later by atezolizumab)

Vigil immunotherapy was administered at a concentration of 1 x 10e6 or 1 x 107 cells/dose given via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses. Atezolizumab was administered at a dose of 1200 mg as an intravenous infusion every 3 weeks, with a maximum of 12 doses. When Vigil and atezolizumab was given together, Vigil

1 cycle = 21 days arm 3: After Part 1 participants completed completed combination therapy without dose-limiting toxicity, then Part 2 participants randomized to atezolizumab first received two cycles of atezolizumab alone, then Vigil and atezolizumab given in sequence (Vigil administered first, followed 30 minutes later by atezolizumab).

Vigil immunotherapy was administered at a concentration of 1 x 10e6 or 1 x 107 cells/dose given via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses. Atezolizumab was administered at a dose of 1200 mg as an intravenous infusion every 3 weeks, with a maximum of 12 doses. 1 cycle = 21 days arm 4: Participants who completed all cycles of Part 2 were pre-approved by the sponsor for inclusion into Part 3. Atezolizumab alone was administered at a dose of 1200 mg as an intravenous infusion every 3 weeks. 1 cycle = 21 days
Interventions: intervention 1: Vigil intervention 2: Atezolizumab
Intervention descriptions: intervention 1: The Vigil vaccine is made up of irradiated autologous tumor cells which have been electroporated ex vivo with the Vigil plasmid designed to suppress expression of both the TGFβ1 and TGFβ2 proteins while simultaneously expressing rhGMCSF protein. intervention 2: Atezolizumab was prepared and administered at the FDA approved dose and schedule as described in the U.S. Package Insert (USPI). The initial dose was administered over one hour and if well tolerated, subsequent infusions may have been administered over 30 minutes.

Atezolizumab in formulation F03 (1200 mg per vial) was administered in 250 mL 0.9% NaCl IV infusion bags and infusion lines equipped with 0.2 μm in-line filters.

Protocol documents:
Prot_SAP_001.pdf: 
Page 1 
 
 
 
PROTOCOL TITLE: 
A Randomized, Intra-patient Crossover, Safety, 
Biomarker and Anti-Tumor Activity Assessment of 
the Combination of Atezolizumab and Vigil in 
Patients with Advanced Gynecological Cancers 
PROTOCOL NUMBER: 
CL-PTL-126 
STUDY AGENT(S): 
Atezolizumab (TECENTRIQ™, MPDL3280A) 
 
Vigil (bi-shRNAfurin and GMCSF) Autologous Tumor 
Cell Immunotherapy 
SPONSOR: 
Gradalis, Inc. 
2545 Golden Bear Drive, Suite 110 
Carrollton, TX 75006 
Phone: (214) 442-8124 
Fax: (214) 442-8101 
PROTOCOL DATE: 
Amendment No. 3 dated September 26, 2018 
Amendment No 2. dated December 30, 2017 
Amendment No. 1 dated April 5, 2017 
Initial Protocol dated December 13, 2016 
 
 
 


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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
PROTOCOL TITLE: 
A Randomized, Intra-patient Crossover, Safety, 
Biomarker and Anti-Tumor Activity Assessment of 
the Combination of Atezolizumab and Vigil in 
Patients with Advanced Gynecological Cancers 
 
PROTOCOL NUMBER: 
CL-PTL-126 
 
STUDY AGENT(S): 
Atezolizumab (TECENTRIQ™, MPDL3280A) 
 
Vigil (bi-shRNAfurin and GMCSF) Autologous Tumor 
Cell Immunotherapy 
 
SPONSOR: 
Gradalis, Inc. 
2545 Golden Bear Drive, Suite 110 
Carrollton, TX 75006 
Phone: (214) 442-8124 
Fax: (214) 442-8101 
 
PROTOCOL DATE: 
Amendment No. 3 dated September 26, 2018 
Amendment No 2. dated December 30, 2017 
Amendment No. 1 dated April 5, 2017 
Initial Protocol dated December 13, 2016 
 
I have read and understand the contents of the indicated clinical protocol and will adhere to the 
trial requirements as presented, including all statements regarding confidentiality.  In addition, 
should I choose to participate as an investigator, I and my sub-investigator(s) agree to conduct 
the study as outlined herein, in accordance with Good Clinical Practices (GCPs), the 
Declaration of Helsinki, in compliance with the obligations and requirements of clinical 
investigators and all other requirements listed in Title 21 Code of Federal Regulations (CFR) 
Part 312. 
 
 
 
 
Name of Investigator (please print) 
 
Signature of Investigator 
 
 
 
Date 
 
 
 
 
 


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TABLE OF CONTENTS 
INVESTIGATOR PROTOCOL SIGNATURE PAGE .................................................................... 2 
TABLE OF CONTENTS ............................................................................................................... 3 
ABBREVIATIONS ........................................................................................................................ 5 
SYNOPSIS .................................................................................................................................... 8 
STUDY SCHEMA ....................................................................................................................... 16 
 
Unmet Medical Need in Ovarian Cancer .................................................................. 17 
 
Rationale for Immunotherapy in Ovarian Cancer ...................................................... 18 
 
Vigil ........................................................................................................................... 19 
 
Vigil Clinical Experience ............................................................................................ 20 
 
Primary objective(s) .................................................................................................. 23 
 
Secondary objective(s) ............................................................................................. 24 
 
Sample Size .............................................................................................................. 27 
 
Tissue Procurement Inclusion Criteria: ..................................................................... 27 
 
Tissue Procurement Exclusion Criteria: .................................................................... 27 
 
Study Enrollment Inclusion Criteria ........................................................................... 28 
 
Study Enrollment Exclusion Criteria .......................................................................... 29 
 
Withdrawal from Study Treatment ............................................................................ 30 
 
Subject Screening and Registration .......................................................................... 31 
 
Study Treatment Administration ................................................................................ 31 
6.2.1 
Schedule, Dose and Administration ................................................................... 31 
6.2.2 
Dose Reduction / Escalation .............................................................................. 32 
 
Toxicity ...................................................................................................................... 33 
 
Treatment beyond Initial Progression in Select Cases ............................................. 34 
 
Schedule of Assessments ......................................................................................... 34 
 
Part 3, Continuation with Single Agent Atezolizumab ............................................... 35 
 
Ethics and Regulatory Considerations ...................................................................... 35 
 
IRB/IEC ..................................................................................................................... 35 
 
Written Informed Consent ......................................................................................... 36 


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Confidentiality of Records ......................................................................................... 36 
 
Modification of Protocol ............................................................................................. 36 
 
Protocol Questions and Deviations ........................................................................... 36 
 
Tumor Measurements and Response (RECIST 1.1) ................................................ 37 
 
Preparation of atezolizumab ..................................................................................... 37 
 
Vigil Investigational Product ...................................................................................... 39 
 
Safety Analysis ......................................................................................................... 39 
 
Attribution of Causality .............................................................................................. 44 
 
Atezolizumab Infusion Reactions .............................................................................. 44 
 
Risks Associated with Atezolizumab ......................................................................... 44 
 
Vigil Expected Side Effects ....................................................................................... 45 
 
Recording of an Adverse Event ................................................................................ 45 
 
Serious Adverse Event Reporting ............................................................................. 46 
 
Overdose .................................................................................................................. 46 
 
Indication for Taking Subjects Off Study ................................................................... 46 
 
Safety Analysis ......................................................................................................... 47 
 
Efficacy Analysis ....................................................................................................... 47 
 
Sample Size Justification .......................................................................................... 47 
 
Documentation .......................................................................................................... 47 
 
Case Report Form Procedures ................................................................................. 48 
APPENDIX A: PERFORMANCE STATUS SCALE ................................................................... 49 
APPENDIX B: SCHEDULE OF ASSESSMENTS ...................................................................... 50 
APPENDIX C: ATEZOLIZUMAB EXPANSION SCHEDULE OF ASSESSMENTS .................. 52 
APPENDIX D: NCI COMMON TOXICITY CRITERIA FOR ADVERSE EVENTS (CTCAE), 
VERSION 4.0. ............................................................................................................................. 53 
REFERENCES ........................................................................................................................... 54 
 
 


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ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine transaminase (also referred to as SGPT) 
ANC 
Absolute neutrophil count 
APC 
Antigen Presenting Cells 
AST 
Aspartate transaminase (also referred to as SGOT) 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
cCR 
Clinically defined Complete Response 
CgA 
Chromogranin A 
CHD 
Carcinoid heart disease 
CMV 
Cytomegalovirus 
CO2 
Total carbon dioxide  
CRF 
Case report form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DC 
Dendritic cell(s) 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
Enzyme-Linked ImmunoSorbent Assay 
ELISPOT 
Enzyme-Linked ImmunoSorbent Spot 
ER 
Endoplasmic reticulum 
FANG™ 
bi-shRNAfurin and GMCSF Augmented Autologous Tumor 
Cell Immunotherapy 
FL 
Flt-3-Ligand 
GEP-NETs 
gastroenteropancreatic neuroendocrine tumors 
GMCSF 
Granulocyte Macrophage-Colony Stimulating Factor 
GMP 
Good Manufacturing Practice 
GVAX 
GMCSF Secreting autologous or allogenic tumor vaccine 
H2RA 
H2 receptor antagonist 
HLA 
Human Leukocyte Antigen 
ID 
intradermal 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IL 
Infiltrating lymphocytes 
IRB 
Institutional Review Board 


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Abbreviation 
Term 
irRC 
immune related Response Criteria 
LAK 
Lymphokine-activated killer 
LAR 
Long acting repeatable 
LLC 
Large latent complex 
MHC 
Major histocompatibility complex 
MLR 
Mixed lymphocyte reaction 
MR 
Mannose receptor 
NCI 
National Cancer Institute 
NED 
No evidence of disease 
NET 
neuroendocrine tumor 
NK 
Natural Killer 
NKT 
Natural Killer T cell(s) 
NSCLC 
Non small cell lung cancer 
ORR 
Overall Response Rate 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-L 
Programmed cell death protein ligand 
PI 
Principal Investigator 
PNET 
Pancreatic neuroendocrine tumor 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
Radiofrequency ablation 
SD 
Stable disease 
SLC 
Small latent complex 
SOC 
Standard of care 
SSR 
Somatostatin receptors 
STZ 
streptozocin 
TAA 
Tumor Associated Antigens 
TAP 
transporter associated with Ag processing 
TCR 
T cell receptor 
TGF 
Transforming growth factor- 
TIL 
Tumor infiltrating lymphocytes 
TNF 
Tumor necrosis factor 
Treg 
Regulatory T cell 


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Abbreviation 
Term 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limits of normal 
USPI 
U.S. Package Insert 
VEGF 
Vascular endothelial growth factor 
WNL 
Within normal limits 
 
 
 


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SYNOPSIS 
Hypothesis: 
 
The interferon gamma ELISPOT assay is a commonly used biomarker of T-cell activation in 
clinical trials of anti-viral and experimental anti-tumor immunotherapies.  Vigil autologous 
tumor cell immune therapy has induced ELISPOT positivity in 100% (31 of 31) of patients 
treated in a Phase 2 clinical trial in ovarian cancer.  Several immune checkpoint inhibitors 
have been tested for anti-tumor activity in advanced ovarian cancer and induce responses in 
approximately 15%-20% of patients.  These relatively low response rates may be a 
consequence of a low rate of immune activation in ovarian cancer in general.  By safely 
combining Vigil therapy with immune checkpoint inhibitors we may broaden and potentially 
deepen the responsiveness of tumors which are largely unresponsive to checkpoint inhibitors 
alone. 
Summary: 
 
This is a 3-part safety study of Vigil in combination with checkpoint inhibitor atezolizumab, in 
patients with treatment refractory or recurrent epithelial ovarian cancer, or other gynecological 
cancers (i.e. cervical, uterine). 
 
This study is intended as a companion study to protocol CL-PTL-119, A Randomized, Double 
Blind, Placebo-Controlled Phase 2 Trial of Vigil Engineered Autologous Tumor Cell 
Immunotherapy in Subjects with Stage IIIb-IV Ovarian Cancer in Clinical Complete Response 
following Surgery and Primary Chemotherapy, otherwise known as the VITAL study.  Patients 
who have tumor harvested at surgery and Vigil successfully manufactured, but then are 
ineligible for randomization onto the VITAL study or previously randomized to placebo, will be 
offered the opportunity to participate in this protocol. 
 
Subjects enrolled will either be: 
 
Patients with recurrent ovarian cancer. Furthermore, subjects who have previously 
received Vigil on this study may be considered for re-procurement for manufacture of 
Vigil (after consultation and approval from Sponsor) and re-enrolled into Part 2 (see 
below). 
OR 
 
Patients with ovarian cancer who failed to meet the eligibility criteria for Protocol CL-
PTL-119 because of failure to achieve a complete clinical response following primary 
debulking surgery and standard paclitaxel/carboplatin therapy,  
OR 
 
Patients who failed to meet the eligibility criteria for Protocol CL-PTL-119 because of a 
histologic diagnosis of another gynecological cancer (i.e., cervical, uterine) and not 
ovarian cancer. 
OR 
 
Patients who were randomized on Protocol CL-PTL-119 and were subsequently 
unblinded at recurrence and were assigned to the placebo arm. 
 


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The primary objective of the study is to determine the safety of the Vigil and atezolizumab 
combination.  Secondary objectives include determination of the immune response rate to 
Vigil alone, atezolizumab alone and the combination of the two agents.  In patients with 
measureable disease, anti-tumor activity as assessed by RECIST 1.1 criteria, will also be 
summarized and correlated to baseline tumor mutation burden, baseline PD-L1 expression, 
post treatment TIL infiltration, change in PD-L1 expression and circulating tumor cell 
response.  Overall assessment of time to progression and survival will also be summarized 
for each cohort.  Assuming no untoward adverse effects from the combination of Vigil with 
atezolizumab, the treatment of 20-25 patients should be sufficient to assess safety and 
provide an estimate of the immune response rate and RECIST response rate. 
 
Part 1 
The first part will be a safety run-in where the initial 3 subjects registered will receive the 
combination of Vigil plus atezolizumab.  Part 1 will evaluate the safety of Vigil in combination 
with atezolizumab. 
 
Vigil immunotherapy will be administered at a concentration of 1x107 cells/dose given via 
intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses.  
Atezolizumab will be administered at the FDA approved dose and schedule as described in 
the U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 
1200mg as an intravenous infusion every 3 weeks.  The initial dose is to be administered over 
one hour and if well tolerated, subsequent infusions may be administered over 30 minutes.  
Vigil should be administered first, followed 30 minutes later by atezolizumab. 
 
The first subject to receive the combination of Vigil plus atezolizumab must complete the first 
21-day cycle of combination therapy without serious, unexpected toxicity before the 
enrollment of any patients into Part 2 can occur. 
 
Part 2 
Part 2 is a randomized, open label intra-patient crossover study of Vigil, the checkpoint 
inhibitor atezolizumab and the combination of the two agents.  Eligible patients will be 
randomized to receive two cycles of Vigil alone or two cycles of atezolizumab alone, followed 
by combination treatment with both agents. 
 
Vigil immunotherapy will be administered at a concentration of 1 x 106 or 1x107 cells/dose 
given via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 
doses. 
 
Atezolizumab will be administered at the FDA approved dose and schedule as described in 
the U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 
mg as an intravenous infusion every 3 weeks, with a maximum of 12 doses.  The initial dose 
is to be administered over one hour and if well tolerated, subsequent infusions may be 
administered over 30 minutes. When combined, Vigil should be administered first, followed 30 
minutes later by atezolizumab. 
 
Atezolizumab related safety events, include, but are not limited to immune related 
pneumonitis, hepatitis, colitis, endocrinopathies, meningitis/encephalitis, neuropathies and 


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pancreatitis are to be managed per the guidelines in the USPI.  For combination treatment, 
the occurrence of a Grade 3 or 4 toxicity attributed to Vigil will result in the cessation of Vigil 
dosing and continuation of single agent atezolizumab only. 
 
Part 3 
Part 3 is an expansion cohort that allows for subjects who have completed all cycles of Part 2 
as noted above to continue on atezolizumab alone, after Cycle 12.  Eligible subjects will be 
pre-approved by Sponsor for inclusion into Part 3.  Subjects may continue on single agent 
atezolizumab until disease progression. 
 
Atezolizumab will be administered at the FDA approved dose and schedule as described in 
the U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 
mg as an intravenous infusion every 3 weeks. 
 
Atezolizumab related safety events include, but are not limited to immune related 
pneumonitis, hepatitis, colitis, endocrinopathies, meningitis/encephalitis, neuropathies and 
pancreatitis are to be managed per the guidelines in the USPI. 
 
Part 1, radiological assessment of tumor response will be performed at baseline and every 
third cycle thereafter.  Tumor biopsy for correlative studies including scoring of tumor 
infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis will be obtained at tissue 
procurement and at any time after the end of cycle 3.  Whole blood for correlative studies 
(immune function) will be obtained at baseline, prior to study agent administration at the start 
of cycle 3 and every third cycle thereafter. 
 
Part 2, radiological assessment of tumor response will be performed at baseline, at the end of 
cycle 2 of single agent therapy, and every third cycle thereafter.  Tumor biopsy for correlative 
studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression 
analysis will be obtained at tissue procurement, prior to the start of combination therapy and 
at any time after the end of cycle 3.  Whole blood for correlative studies (immune function) will 
be obtained at baseline, prior to study agent administration at the start of cycle 3 (the first 
cycle of combination therapy) and every third cycle thereafter. 
 
Part 3 schedule of assessments are noted in Appendix C.  The schedule will continue from 
Part 2 in which the following will be assessed every third cycle: radiological assessments, 
tumor biopsy (if available), and whole blood collection for correlative studies. 
 
The safety evaluation will include AEs, SAEs, and changes from baseline in laboratory 
evaluations, vital signs, electrocardiograms, and physical examinations. The number and 
percentage of subjects reporting treatment-emergent AEs will be summarized overall and by 
the worst Common Terminology Criteria for Adverse Events (CTCAE) grade, system organ 
class, and preferred term.  Similarly, the number and percentage of subjects reporting 
treatment-emergent AEs considered related to investigational product will be summarized.  At 
each level of subject summarization, a subject will be counted once using the highest grade 
and level of causality if one or more occurrences of the same system organ class/preferred 
term is reported.  Adverse events will be graded according to the National Cancer Institute 


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(NCI) CTCAE v4.03 and coded using the Medical Dictionary for Regulatory Activities. 
Laboratory abnormalities will be graded according to the NCI CTCAE v4.03, if applicable. 
Objective(s): 
Primary Objective(s): 
 
To evaluate and characterize the tolerability and safety profile of Vigil combined with 
atezolizumab. 
 
Secondary Objective(s): 
 
To determine immune response rate and duration of conversion in subjects who are 
treated with Vigil, Atezolizumab and the combination of the two agents. 
 
To determine the ORR by RECIST 1.1 in subjects who are treated with the combination 
of Vigil and atezolizumab. 
 
To determine PD-L1 signal expression at baseline and follow up tumor biopsy (when 
available). 
 
To determine TIL infiltration at baseline and follow up tumor biopsy (when available). 
 
To determine PFS and estimate OS in treated patients. 
Number of Patients: 
 
Approximately 20-25 subjects will be enrolled. 
Tissue Procurement Inclusion Criteria: 
 
Subjects will be eligible for tissue procurement for the Vigil manufacturing process, if they 
meet all of the following criteria: 
 
1. Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous, clear cell, 
or endometrioid ovarian, fallopian tube or primary peritoneal carcinoma 
2. Age ≥ 18 years. 
3. Estimated survival ≥ 6 months. 
4. ECOG Performance Status ≤ 1 
5. Metastatic disease 
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) or ascites fluid estimated 
volume ≥ 500mL (from a primary or secondary paracentesis, 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 informed protocol specific 
consent for tissue harvest or a parental/guardian informed consent and pediatric 
assent when appropriate. 
 
 
 


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Tissue Procurement Exclusion Criteria: 
 
Subjects meeting any of the following criteria are not eligible for tissue procurement for the 
Vigil manufacturing: 
 
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 history of allergies or sensitivities to gentamicin. 
7. 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. 
8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) less than 21 days prior to tissue 
procurement. 
 
Study Enrollment Inclusion Criteria: 
 
Subjects will be eligible for registration into the trial if they meet all of the following inclusion 
criteria: 
 
1. Successful manufacturing of at least 4 vials of Vigil. 
2. One of the following: 
a. Failure to meet the eligibility criteria for Protocol CL-PTL-119 due to i) histology 
of ovarian cancer and failure to achieve a complete clinical response following 
primary debulking surgery and standard paclitaxel/carboplatin therapy OR, ii) 
a histologic diagnosis of another gynecologic malignancy which is not ovarian 
cancer. 
b. Recurrent ovarian cancer. 
c. Randomized on Protocol CL-PTL-119 and were subsequently unblinded at 
recurrence and were assigned to the placebo arm. 
3. ECOG performance status (PS) ≤ 1 (or ≤ 2 due to carcinoid syndrome) 


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4. Estimated survival ≥ 6 months. 
5. Measurable per RECIST 1.1 or evaluable disease. 
6. Adequate organ and bone marrow function as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500 per mm3) 
b. Platelets ≥100 × 109/L (100,000 per mm3) 
c. Hemoglobin ≥9.0 g/dL (5.59 mmol/L) 
d. Creatinine clearance (CrCL) >50 mL/min by the Cockcroft-Gault formula or 
by 24-hour urine collection for determination of creatinine clearance: 
Females: 
CrCL (mL/min) 
=Weight (kg) × (140 – Age) × 0.85 
72 × serum creatinine (mg/dL) 
e. Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to 
patients with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
evidence of hemolysis or hepatic pathology) who will be allowed in 
consultation with their physician. 
f. 
AST and ALT ≤2.5 × ULN in patients with no liver metastasis 
g. AST or ALT ≤5 × ULN in patients with liver metastasis 
h. TSH within institutional limits. If TSH is greater or less than institutional limits 
patients may participate if their T4 is within normal limits (WNL); patients may 
be on a stable dose of replacement thyroid medication; dose adjustments are 
allowed if needed 
7. Subject has recovered to CTCAE Grade 1 or better from all adverse events 
associated with prior therapy or surgery (or ≤ 2 due to carcinoid syndrome) 
8. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered 
to CTCAE Grade 2 or better 
9. Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by the IPs (Vigil and/or atezolizumab) may be included (e.g., hearing loss) after 
consultation with the Principal Investigator 
10. Subjects who are not rendered surgically sterile as a result of surgery for ovarian 
cancer, must have, 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. 
11. Ability to understand and the willingness to sign a written informed protocol specific 
consent. 
12. Willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
13. Patients must have fully recovered from chemotherapy associated toxicities prior to 
starting treatment on this protocol.   
 
Palliative radiotherapy is permitted provided: 
a. More than 3 weeks have elapsed between the end of radiotherapy and the first 
dose of study therapy, AND 
b. The irradiated lesion(s) (unless measurable progression after irradiation) 
cannot be used as target lesions. 


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Study Enrollment Exclusion Criteria: 
 
In addition to the procurement exclusion criteria, subjects (both with Vigil manufactured and 
undergoing procurement) will NOT be eligible for study registration and enrollment if meeting 
any of the following criteria: 
 
1. Participation in another clinical study with an investigational product within the last 3 
weeks prior to study start. 
2. Receipt of steroid therapy within the 2 weeks of the first dose of study therapy. 
3. Live vaccine used for the prevention of infectious disease administered < 30 days 
prior to the start of study therapy. NOTE: Subjects, if enrolled, should not receive 
live vaccine during the study and for 5 months after the last dose of atezolizumab. 
4. Post-surgery complication that in the opinion of the treating investigator would 
interfere with the subject’s study participation or make it not in the best interest of 
the subject to participate. 
5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction. 
6. Female subjects who are pregnant, breast-feeding or of reproductive potential who 
are not employing an effective method of birth control defined in the protocol.  
Effective contraception is required for women receiving atezolizumab for 5 months 
after the last dose. 
7. Any condition that, in the opinion of the investigator, would interfere with evaluation 
of study treatment or interpretation of patient safety or study results. 
8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, 
monoclonal antibodies, other investigational agent) less than 21 days prior to the 
first dose of study drug or less than 6 weeks for nitrosourea or mitomycin C.  
9. Receipt of any anti-cancer therapy between tissue procurement on CL-PTL-126 and 
first dose of study drug. 
Medication and Dose(s): 
 
Part 1 
The first three subjects will receive Vigil in combination with atezolizumab on Day 1 every 3 
weeks. 
 
Part 2 
Subjects will be randomized to receive two cycles of Vigil alone or two cycles of atezolizumab 
alone, followed by combination treatment with both agents. 
 
 
Vigil immunotherapy will be administered at a concentration of 1 x 106 or 1 x 107 
cells/dose via intradermal injection every 3 weeks for a minimum of 4 administrations 
and a maximum of 12 administrations (depending on the quantity of Vigil manufactured 
from surgical specimens). 


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 
Atezolizumab will be administered at the FDA approved dose and schedule as 
described in the U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered 
at a dose of 1200 mg as an intravenous infusion every 3 weeks.  The initial dose is to 
be administered over one hour and if well tolerated, subsequent infusions may be 
administered over 30 minutes. 
 
When administered in combination on the same day (Day 1), Vigil should be 
administered first, followed 30 minutes later by atezolizumab. 
 
Duration: 
 
Patients should continue the combination of Vigil with atezolizumab until disease progression 
(by RECIST 1.1) is documented, or toxicity supervenes.  Depending on the number of doses 
of Vigil manufactured, it is expected that 4 to12 doses of Vigil will be administered.  Once Vigil 
doses are exhausted, subjects whose disease is stable or responding may continue to 
receive single agent atezolizumab until disease progression.   
Efficacy Assessments: 
 
Immune activation will be assessed at the start of Cycle 3 and every third cycle 
thereafter. 
 
Durability of immune response will also be assessed. 
 
Anti-tumor activity will be assessed via RECIST 1.1 criteria as determined by the 
investigator at Cycle 3 and every third cycle thereafter.  
 
In consenting patients with tumor accessible for biopsy, the change in TIL infiltration 
and PD-L1 expression will be assessed by comparing tumor specimens from pre-
study procurement to biopsy material obtained after at least one cycle of 
combination therapy with Vigil plus atezolizumab. 
Safety Assessments: 
The safety evaluation will include AEs, SAEs, AESIs and changes from baseline in laboratory 
evaluations, vital signs, electrocardiograms, and physical examinations. 
 
Adverse events will be recorded from time of first dose of Vigil and/or atezolizumab, 
throughout the treatment period and including the follow-up period. 
 
30 days following the last study treatment or until another therapy has been initiated, 
whichever is earlier, regardless of causality. 
 
SAEs and AESIs are to be followed for 30 days after the last dose of study drug or 
the initiation of new therapy, whichever is earlier. 
 
 
 


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STUDY SCHEMA 
21-day cycle 
 
 
 
 


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 BACKGROUND 
 
 Unmet Medical Need in Ovarian Cancer 
 
The majority of women diagnosed with cancer of the ovary present in an advanced stage 
(Jemal, Siegel et al. 2009) with 5-year survival rates of 59% for Stage IIIa, 52% for Stage IIIb, 
39% for Stage IIIc (Heintz, Odicino et al. 2006), and 17% for Stage IV (American Cancer 
Society).   
 
The established standard of care for newly diagnosed ovarian cancer is maximal de-bulking 
surgery followed by 6 months of chemotherapy with paclitaxel and carboplatin.  About 75% of 
patients will be in complete remission following this front-line management. 
 
Unfortunately, approximately 75% of the women with Stage III/IV ovarian cancer who achieve a 
complete clinical response will relapse, as will 50% of those achieving pathologic complete 
response, with a median time to relapse of 16-24 months following chemotherapy, depending 
on risk factors (Gadducci, Sartori et al. 1998; Markman, Liu et al. 2003; Gadducci, Cosio et al. 
2005).  Once relapsed, ovarian cancer is incurable, and the goals of treatment are primarily to 
prevent further disease progression and to palliate symptoms of advancing cancer. 
 
A variety of treatment options are available for relapsed ovarian cancer.  The type of treatment 
offered depends on the timing of relapse.  Women who relapse 6 months or more after 
completion of chemotherapy are generally considered platinum sensitive and are treated with 
platinum doublet regimens such as carboplatin plus paclitaxel or carboplatin plus gemcitabine.  
Women who progress while receiving platinum doublet therapy or relapse in less than 6 months 
after completion of platinum doublet chemotherapy are considered platinum resistant.  These 
patients generally receive sequential single agent chemotherapy with drugs such as pegylated 
liposomal doxorubicin, topotecan, weekly paclitaxel or the targeted agent olaparib, used only in 
patients whose tumor expresses BRCA mutations. 
 
The anti-angiogenic agent bevacizumab has been found to improve relapse free and 
progression free survival when combined with initial chemotherapy or with chemotherapy 
following relapse.  Dosing recommendations for bevacizumab in ovarian cancer allow for the 
continuation of single agent bevacizumab following the completion of chemotherapy until such 
time as the patient’s disease progresses or toxicity intervenes. 
 
A number of studies have attempted to improve outcome in ovarian cancer by administering 
maintenance therapy after patients have achieved a complete response following standard 
paclitaxel/carboplatin combination therapy.  None of these studies have demonstrated any 
advantage in relapse free (Sabbatini, Harter et al. 2013) or overall survival (Markman, Liu et al. 
2009; Sabbatini, Harter et al. 2013) and (Burger, Brady et al. 2011; Perren, Swart et al. 2011).  
In addition, a meta-analysis of randomized controlled trials of maintenance chemotherapy in 
1644 women accrued to 8 trials concluded no significant difference in three-, five- and 10-year 
OS or PFS (Mei, Chen et al. 2013).  A subsequent, independent trial-sequential analysis of 
these same data reached the same conclusion (Messori, Fadda et al. 2013). 


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In summary, the poor survival in advanced ovarian cancer is due both to late diagnosis, as well 
as to the lack of effective therapy for patients who relapse. The clinical course of ovarian cancer 
patients is marked by periods of remission and relapse of sequentially shortening duration until 
chemotherapy resistance develops. Therefore, new treatment modalities and paradigms are 
needed in order to significantly improve the prognosis of women diagnosed with epithelial 
ovarian cancer. 
 
 Rationale for Immunotherapy in Ovarian Cancer 
 
One promising avenue of clinical research in ovarian cancer is the use of immunotherapy, 
including immune checkpoint inhibitors and cellular immunotherapies.  An increasing body of 
data indicates that antitumor immunity impacts the clinical outcome of ovarian cancer. Recent 
reports have detailed how ovarian cancer cells can acquire potential escape mechanisms to 
evade host immunity via several immunosuppressive factors, including a loss of MHC 
expression and the upregulation of immunosuppressive factors including TGF-beta, indoleamine 
2,3-dioxygenase (IDO) and cyclooxygenase (COX-1 and COX-2). 
 
Increased expression of immunosuppressive TGF isoforms in ovarian tumor as compared with 
normal ovarian tissue has been reported (Henriksen, Gobl et al. 1995; Bristow, Baldwin et al. 
1999) with significant increases in TGF1 in both primary (2.9 fold; p ≤ 0.002) and recurrent (4.4 
fold; p ≤ 0.002) ovarian cancer (Bristow, Baldwin et al. 1999).  Secreted TGFβ from ovarian 
cancer cells generate immunosuppressive Treg cells (CD4+CD25+) from peripheral 
CD4+CD25- cells (Li, Ye et al. 2007).  Both Treg tumor infiltration and the granzyme 
B+/FOX3p+ ratio are associated with poor outcome in patients with high-grade serous ovarian 
carcinoma treated with neoadjuvant chemotherapy (Polcher, Braun et al. ; Milne, Kobel et al. 
2009).  The CD8/Treg ratio is also a prognostic indicator (Sato, Olson et al. 2005). 
 
An additional immunosuppressive mechanism shown to be active in the ovarian cancer tumor 
microenvironment is enhanced immune checkpoint signaling via B7/CTLA4 and PD-1/PD-L1.  
The increasing knowledge of these immunosuppressive mechanisms in ovarian cancer 
highlights the importance of developing new treatment strategies in ovarian cancer.  This study 
aims to explore the application of one such novel strategy, the combination of immune 
checkpoint inhibitor therapy and autologous cellular immunotherapy. 
 
Following their successful development in other solid tumors like melanoma and non-small cell 
lung cancer, several immune checkpoint inhibitors are now being developed as therapeutics in 
ovarian cancer.  The immune checkpoint inhibitors target molecules which dampen the normal 
human immune response and prevent uncontrolled immune stimulation.  In ovarian cancer, 
cancer cells and tumor associated myeloid cells have been found to over express the ligand 
PD-L1 (Curiel, Wei et al. 2003; Liu, Chen et al. 2008; Abiko, Mandai et al. 2013), and 
expression of PD-L1 has been associated with decreased tumor infiltrating lymphocytes (TILs) 
and poor overall survival (Hamanishi, Mandai et al. 2007).  These immune inhibitory proteins 
are overexpressed in the tumor microenvironment and prevent normal immune surveillance. 
 
By blocking these inhibitory molecules, anti-cancer immune responses are restored and 
enhanced.  In animal models, blockade of PD-1 and PD-L1 has been shown to eradicate tumors 


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through reprogramming of tumor microenvironment (Duraiswamy, Kaluza et al. 2013).  In Phase 
I/II studies with several of the immune checkpoint inhibitors directed against PD-1 or PD-L1, 
single agent response rates of approximately 6% to 20% were observed in patients with 
advanced, relapsed ovarian cancer.  Durable partial responses as well as some complete 
responses were reported.  As a result, several of these agents have progressed to Phase III 
clinical trials. 
 
 Vigil 
 
Vigil immunotherapy is one of the more advanced cellular immunotherapies being studies in 
clinical trials.  It is composed of autologous tumor cells harvested from the patient at the time of 
initial de-bulking surgery which are then transfected extra-corporeally, 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 (TGFβ-1 and TGFβ-2). Following manufacture, Vigil is 
administered to the patient from whom the tumor was harvested, via intra-dermal injection, once 
per month.  The rationale for the Vigil construct is outlined below. 
 
Dendritic cells prime antigen-specific immune responses (Zeng, Wang et al. 2001) and express 
diverse receptors that allow for the recognition and capture of antigens in peripheral tissues like 
the dermis.  They process this material efficiently into the MHC Class I and II presentation 
pathways, upregulate costimulatory molecules upon maturation, and migrate to secondary 
lymphoid tissues (Banchereau, Briere et al. 2000) where they present the antigens to T cells. 
 
Increasing evidence suggests that GMCSF is involved in the augmentation of tumor antigen 
presentation by dendritic cells (DCs) (Dranoff, Jaffee et al. 1993; Huang, Golumbek et al. 1994).  
It has been shown to induce a subset of DCs that are superior for the phagocytosis of apoptotic 
tumor cells (Young and Inaba 1996; Pulendran, Lingappa et al. 1997; Shen, Reznikoff et al. 
1997).  It evokes higher levels of co-stimulatory molecules, which is characteristic of greater 
functional maturation and more efficient T cell stimulation, thereby broadening the arsenal of 
induced lymphocyte effector mechanisms (Murtaza, Kuchroo et al. 1999).  GMCSF also 
promotes the presentation of lipid antigens by dendritic cells which in turn leads to activation of 
Natural Killer T cells (NKT cells) a population of lymphocytes that may be pivotal in both 
endogenous and therapeutic responses to tumors (Smyth, Crowe et al. 2002). 
 
The immune suppressor functions of TGFβ are likely to play a major role in modulating the 
effectiveness of cancer immunotherapy.  TGFβ inhibits GMCSF induced maturation of bone 
marrow derived dendritic cells (DCs) (Yamaguchi, Tsumura et al. 1997) as well as expression of 
MHC Class II and co-stimulatory molecules (Geissmann, Revy et al. 1999).  It has been shown 
that antigen presentation by immature DCs result in T cell unresponsiveness (Steinman, 
Hawiger et al. 2003).  TGFβ also inhibits activated macrophages (Ashcroft 1999) including their 
antigen presenting function (Du and Sriram 1998; Takeuchi, Alard et al. 1998).  The ubiquitous 
expression of the TGFβ isoforms as well as the inhibitory effects of these isoforms have on 
GMCSF immune stimulatory function provide a strong rationale for combining TGFβ 
suppression and GMCSF upregulation within a single immunotherapeutic construct. 
 


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Within the Vigil construct, the suppression of TGFβ isoforms is achieved by knocking down the 
expression of furin.  Furin is a member of the subtilisin-like proprotein convertase family, an 
upstream regulator of the TGFβ isoforms.  Furin is required for proteolytic activation of both 
TGFβ-1 and TGFβ-2.  High levels of furin mRNA and furin protein are widely expressed in 
human tumors and, specifically, in ovarian tumors (Page, Klein-Szanto et al. 2007) where the 
gene  is differentially expressed (compared to normal human ovarian surface epithelium cell 
lines) and the level appears to be inversely correlated with survival (Page, Klein-Szanto et al. 
2007).  The presence of furin in tumor cells likely contributes significantly to the maintenance of 
tumor directed, TGFβ-mediated peripheral immune tolerance (Pesu, Watford et al. 2008).  Down 
regulation of furin can be expected to simultaneously reduce TGFβ-1 and TGFβ-2 levels.  
Indeed, this has been demonstrated consistently in the manufacture of Vigil for completed and 
ongoing clinical trials. 
 
 Vigil Clinical Experience 
 
Since the initiation of clinical trials with Vigil in 2009, over 160 patients have received treatment 
with the therapy and over 900 doses have been administered in completed and ongoing studies.  
The most frequently reported adverse reactions attributed to Vigil engineered cell administration 
are injection site reactions which are mild to moderate in intensity, consisting primarily of 
redness and swelling at the injection site.  These occur in essentially all Vigil treated patients.  
To date, there have been no severe or life threatening (CTC Grade 3 or 4) adverse events 
attributed to Vigil treatment. 
 
An early report (Senzer et. al. 2012) summarized the initial experience in 27 patients treated 
with the Vigil cellular immunotherapy construct (named FANG at the time), and in a matched 
control group of 18 patients.  All patients underwent surgery for procurement of tumor tissue and 
manufacture of Vigil, however, the matched control group of 18 patients did not receive Vigil due 
to patient choice (14), failure to satisfy eligibility criteria (2) or failure of manufacture (2).  Patient 
characteristics and dosing information are summarized in Table 1 below. 
 
Table 1. Patient Characteristics 
 
Characteristic 
No Vigil 
(n = 18) 
Vigil  
(n = 27) 
All 
(n = 45) 
Age (years) 
Mean    
Median   
Range   
 
56 
56 
39–73 
 
59 
62 
26–84 
 
57 
57 
26-84 
Gender 
Male  
Female  
 
9 
9 
 
8 
19 
 
17 
28 
Dose level 
1.0 × 10e7 cells/ml 
2.5 × 10e7 cells/ml 
Vaccine failure  
 
8 
8 
2 
 
10 
17 
N/A 
 
18 
25 
2 


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Both GMCSF transgene expression and downregulation of expression of TGFβ1 and TGFβ2 
were apparent in all successfully manufactured Vigil preparations.  Mean post-transfection 
GMCSF expression increased from 7.3 to 1,108 pg/106 cells/ml.  Mean TGFβ1 and β2 
knockdown were 93.5% and 92.5%, respectively. 
 
Of the Vigil treated patients, 4 out of 27 had rapidly progressive disease after 1 or 2 injections of 
Vigil and were removed from study.  The remaining 23 patients had stable disease as their best 
response to therapy and received between 3 and 11 monthly injections of Vigil.  Median survival 
of the Vigil treated patients was 554 days when measured from tissue procurement and was not 
reached when measured from start of Vigil treatment.  The 18 patients who had tumor 
harvested but did not receive Vigil therapy survived a median of 132 days from tissue 
procurement (p < 0.0001).  There were no apparent differences in response to treatment, 
survival or safety profile by dose level of the Vigil construct. 
 
The interferon gamma ELISPOT assay was piloted as a clinical biomarker of immune activation 
in 18 of 27 Vigil treated patients on the study.  Only 1 of 18 patients demonstrated immune 
activation at baseline.  Nine of 18 patients converted to ELISPOT positivity by month 4 of Vigil 
treatment and remained positive throughout treatment and in some cases for up to 6 months 
afterwards.  A tenth patient was noted to convert to ELISPOT positivity at 6 months after the 
start of Vigil.  Interestingly, the survival of ELISPOT positive patients was significantly longer 
than that of patients who failed to convert to positivity (p = 0.045 from time of tissue 
procurement or p = 0.025 from start of Vigil treatment). 
 
The association of TGFβ expression with poor outcome in ovarian cancer coupled with the 
safety, biomarker and survival correlations reported in the first-in-human study, provided the 
basis for a randomized Phase 2 study of Vigil Immunotherapy as maintenance therapy in 
women who achieved complete clinical response (cCR) following surgical de-bulking and 
standard, paclitaxel/carboplatin chemotherapy.  Following surgery and chemotherapy, patients 
in the control arm underwent regular observation for recurrence, which is current standard of 
care (SOC).  Patients randomized to the control arm were permitted to cross-over and receive 
their Vigil at the time of recurrence. 
 
Eligible patients were initially randomized 2 (Vigil): 1 (SOC).  Patients received 1.0 x 107 cells / 
intradermal injection of Vigil once per month for up to 12 doses as long as sufficient material 
was available.  Tumor procurement needed to be sufficient to supply a minimum of 4 monthly 
injections in order for a patient to be entered into the study.  Treatment was continued until 
disease recurrence or exhaustion of the patient’s vaccine supply.  Clinical adverse events, as 
reported by the patient, were assessed continuously. Other scheduled safety assessments 
included monthly physical examination, performance status, height, weight, vital signs and 
laboratory evaluations.  The primary efficacy endpoint was recurrence free survival assessed 
radiographically by the investigators. CA-125 was monitored at baseline, monthly for the first 
year, every 3 months ± 2 weeks for the second and third year. 
 
Serial immune function analysis including ELISPOT analysis of mononuclear cell function to 
pre-processed autologous tumor cells was monitored at baseline (screening), prior to Vigil 
injection and at Months 2, 4, 6 and at end of treatment (EOT).  A positive response was defined 
as > 10 ELISPOTs induced per 106 peripheral blood mononuclear cells (PBMC) and twice 
baseline response. 


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Results are reported in a total of 42 patients, 31 in the Vigil arm and 11 in the control arm.  The 
original randomized design was abandoned after 21 patients were randomized into the Vigil arm 
of the study and 11 to the control arm, when the sponsor decided to initiate a definitive Phase 3 
study.  At that time, an additional 10 patients who were completing chemotherapy were allowed 
to receive Vigil without randomization.  
 
A total of 241 intradermal (ID) injections of Vigil were administered to the 31 patients.  The most 
frequent treatment emergent adverse events, considered related to therapy were injection site 
reactions of CTCAE Grade 1 or 2, which occurred in essentially all Vigil treated patients.  There 
were no CTCAE Grade 3 or 4 treatment related adverse events amongst the Vigil treated 
patients. 
 
At baseline, 30 of 31 Vigil treated patients and 10 of 11 control patients demonstrated negative 
ELISPOT reactivity prior to Vigil treatment at time of randomization.  One Vigil treated patient 
was actually ELISPOT positive at baseline and one control patient was inevaluable for ELISPOT 
reactivity.  Following Vigil injection a positive ELISPOT response was observed in 31 of the 31 
Vigil treated patients (median ELISPOT reactivity was 134; range, 12-448 spots).  The positive 
responses were first observed at Month 2 (n=28), 3 (n=1), 4 (n=1) and 9 (n=1).  In the control 
arm, 7 of the 8 patients who relapsed and elected to cross over to receive Vigil, were ELISPOT 
negative at the time of relapse and converted to positive ELISPOT by Month 2. 
 
Comparison of RFS from time of procurement between Vigil or control patients following 
consolidation treatment with carboplatin/paclitaxel is summarized in Table 2 and shown in 
Figure 1.  Control RFS is consistent with historical expectation (mean RFS 16 months/481 
days).  On the other hand, Vigil response data suggests improved RFS, 27 months/826 days by 
Kaplan Meier analysis (p=0.033, log-rank).  Analysis of the high median ELISPOT positive 
population vs. low median ELISPOT population did not reveal a difference in time to relapse 
duration or overall relapse rate.  RFS from time of treatment was a mean/median of 304/195 
days in the control arm and 563/352 days in the Vigil arm (p=0.13) 
 
Table 2. Relapsed Free Survival 
Group 
N 
% of 
Recurrences 
Mean 
RFS (days) 
Median 
RFS (days) 
p-value 
Control 
11 
82% 
15.8 
12.4 
0.033 log-rank 
p=0.039 Cox 
HR 0.43 95% CI 
(0.19, 0.96) 
Vigil 
31 
61% 
27.1 
19.8 
 
 
 


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Figure 1. RFS 
 
 
On the basis of these results, a definitive comparison of maintenance Vigil vs. standard 
observation is underway in women with epithelial ovarian cancer who have achieved a complete 
clinical response following surgical de-bulking and standard paclitaxel/carboplatin chemotherapy 
(CL-PTL-119).  The study, A Randomized, Double Blind, Placebo Controlled trial of Vigil 
Autologous Tumor Cell Immunotherapy in Subjects with Stage IIIb-IV Ovarian Cancer in Clinical 
Complete Response following Surgery and Primary Chemotherapy is otherwise known as the 
VITAL study. 
 
This study is intended as a companion to VITAL for those women who fail to achieve a complete 
clinical response following standard chemotherapy and are thus ineligible for randomization. 
 
 STUDY RATIONALE 
 
Early clinical results with both the checkpoint inhibitors and Vigil in ovarian cancer are 
promising.  Given the complementary mode of action of the two agents, it is sensible to explore 
a combination of the two immunotherapy modalities. 
 
 OBJECTIVES 
 
 Primary objective(s) 
 
To evaluate and characterize the tolerability and safety profile of Vigil combined with 
atezolizumab. 


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 Secondary objective(s) 
 
 
To determine immune response rate and duration of conversion in subjects who are 
treated with Vigil, atezolizumab and the combination of the two agents. 
 
To determine the ORR by RECIST 1.1 in evaluable subjects who are treated with the 
combination of Vigil and atezolizumab. 
 
To determine PD-L1 signal expression at baseline and follow up tumor biopsy (when 
available). 
 
To determine TIL infiltration at baseline and follow up tumor biopsy (when available). 
 
To determine PFS and estimate OS in treated patients. 
 
 STUDY DESIGN 
 
This is a 3-part safety study of Vigil in combination with checkpoint inhibitor atezolizumab, in 
patients with treatment refractory or recurrent epithelial ovarian cancer, or other gynecological 
cancers (i.e. cervical, uterine). 
 
This study is intended as a companion study to protocol CL-PTL-119, A Randomized, Double 
Blind, Placebo-Controlled Phase 2 Trial of Vigil Engineered Autologous Tumor Cell 
Immunotherapy in Subjects with Stage IIIb-IV Ovarian Cancer in Clinical Complete Response 
following Surgery and Primary Chemotherapy, otherwise known as the VITAL study or 
previously randomized to placebo.  Patients who have tumor harvested at surgery and Vigil 
successfully manufactured, but then are ineligible for randomization onto the VITAL study, will 
be offered the opportunity to participate in this protocol. 
 
Subjects enrolled will either be: 
 
 
Patients with recurrent ovarian cancer. Furthermore, subjects who have previously 
received Vigil on this study may be considered for re-procurement for manufacture of 
Vigil (after consultation and approval from Sponsor) and re-enrolled into Part 2 (see 
below). 
OR 
 
Patients with ovarian cancer who failed to meet the eligibility criteria for Protocol CL-
PTL-119 because of failure to achieve a complete clinical response following primary 
debulking surgery and standard paclitaxel/carboplatin therapy,  
OR 
 
Patients who fail to meet the eligibility criteria for Protocol CL-PTL-119 because of a 
histologic diagnosis of another gynecological cancer (i.e., cervical, uterine) and not 
ovarian cancer. 
OR 
 
Patients who were randomized on Protocol CL-PTL-119 and were subsequently 
unblinded at recurrence and were assigned to the placebo arm. 
 


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The primary objective of the study is to determine the safety of the Vigil and atezolizumab 
combination.  Secondary objectives include determination of immune response rate to Vigil 
alone, atezolizumab alone and the combination of the two agents.  In patients with measureable 
disease, anti-tumor activity as assessed by RECIST 1.1 criteria, will also be summarized and 
correlated to baseline tumor mutation burden, baseline PD-L1 expression, post treatment TIL 
infiltration, change in PD-L1 expression and circulating tumor cell response.  Overall 
assessment of time to progression and survival will also be summarized for each cohort.  
Assuming no untoward adverse effects from the combination of Vigil with atezolizumab, the 
treatment of 20-25 patients should be sufficient to assess safety and provide an estimate of the 
immune response rate and RECIST response rate. 
 
Part 1 
The first part will be a safety run-in where the initial 3 subjects registered will receive the 
combination of Vigil plus atezolizumab.  Part 1 will evaluate the safety of Vigil in combination 
with atezolizumab. 
 
Vigil immunotherapy will be administered at a concentration of 1x107 cells/dose given via 
intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses.  
Atezolizumab will be administered at the FDA approved dose and schedule as described in the 
U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 mg as 
an intravenous infusion every 3 weeks.  The initial dose is to be administered over one hour and 
if well tolerated, subsequent infusions may be administered over 30 minutes.  Vigil should be 
administered first, followed 30 minutes later by atezolizumab. 
 
The first subject to receive the combination of Vigil plus atezolizumab must complete the first 
21-day cycle of combination therapy without serious, unexpected toxicity before the enrollment 
of any patients into Part 2 can occur. 
 
Part 2 
Part 2 is a randomized, open label intra-patient crossover study of Vigil, the checkpoint inhibitor 
atezolizumab and the combination of the two agents.  Eligible patients will be randomized to 
receive two cycles of Vigil alone or two cycles of atezolizumab alone, followed by combination 
treatment with both agents. 
 
Vigil immunotherapy will be administered at a concentration of 1 x 106 or 1x107 cells/dose given 
via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses. 
 
Atezolizumab will be administered at the FDA approved dose and schedule as described in the 
U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 mg as 
an intravenous infusion every 3 weeks, with a maximum of 12 doses.  The initial dose is to be 
administered over one hour and if well tolerated, subsequent infusions may be administered 
over 30 minutes. When combined, Vigil should be administered first, followed 30 minutes later 
by atezolizumab. 
 
Atezolizumab related safety events include, but are not limited to immune related pneumonitis, 
hepatitis, colitis, endocrinopathies, meningitis/encephalitis, neuropathies and pancreatitis are to 
be managed per the guidelines in the USPI.  For combination treatment, the occurrence of a 


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Grade 3 or 4 toxicity attributed to Vigil will result in the cessation of Vigil dosing and continuation 
of single agent atezolizumab only. 
 
Part 3 
Part 3 is an expansion cohort that allows for subjects who have completed all cycles of Part 2 as 
noted above to continue on atezolizumab alone, after Cycle 12.  Eligible patients will be pre-
approved by Sponsor for inclusion into Part 3.  Subjects may continue on single agent 
atezolizumab until disease progression. 
 
Atezolizumab will be administered at the FDA approved dose and schedule as described in the 
U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 mg as 
an intravenous infusion every 3 weeks. 
 
Atezolizumab related safety events include, but are not limited to immune related pneumonitis, 
hepatitis, colitis, endocrinopathies, meningitis/encephalitis, neuropathies and pancreatitis are to 
be managed per the guidelines in the USPI. 
 
Part 1, radiological assessment of tumor response will be performed at baseline and every third 
cycle thereafter.  Tumor biopsy for correlative studies including scoring of tumor infiltrating 
lymphocyte (TIL) and PD-1 / PD-L1 expression analysis will be obtained at tissue procurement 
and at any time after the end of cycle 3.  Whole blood for correlative studies (immune function) 
will be obtained at baseline, prior to study agent administration at the start of cycle 3 and every 
third cycle thereafter. 
 
Part 2, radiological assessment of tumor response will be performed at baseline, at the end of 
cycle 2 of single agent therapy and every third cycle thereafter.  Tumor biopsy for correlative 
studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression 
analysis will be obtained at tissue procurement, prior to the start of combination therapy and at 
any time after the end of cycle 3.  Whole blood for correlative studies (immune function) will be 
obtained at baseline, at the start of cycle 3 (the first cycle of combination therapy) and every 
third cycle thereafter. 
 
Part 3 schedule of assessments are noted in Appendix C.  The schedule will continue from Part 
2 in which the following will be assessed every third cycle: radiological assessments, tumor 
biopsy (if available), and whole blood collection for correlative studies. 
 
The safety evaluation will include all adverse events (AEs), serious adverse events (SAEs) and 
adverse events of special interest (AESIs) as well as changes from baseline in laboratory 
evaluations, vital signs, electrocardiograms, and physical examinations. The number and 
percentage of subjects reporting treatment emergent AEs will be summarized overall and by the 
worst Common Terminology Criteria for Adverse Events (CTCAE) grade, system organ class, 
and preferred term.  Similarly, the number and percentage of subjects reporting treatment-
emergent AEs considered related to investigational product will be summarized.  At each level 
of subject summarization, a subject will be counted once using the highest grade and level of 
causality if one or more occurrences of the same system organ class/preferred term is reported.  
Adverse events will be graded according to the National Cancer Institute (NCI) CTCAE v4.03 


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and coded using the Medical Dictionary for Regulatory Activities. Laboratory abnormalities will 
be graded according to the NCI CTCAE v4.03, if applicable. 
 
 STUDY POPULATION 
 
 Sample Size 
 
Approximately 20-25 subjects will be enrolled. 
 
 Tissue Procurement Inclusion Criteria: 
 
Subjects will be eligible for tissue procurement for the Vigil manufacturing process, if they meet 
all of the following criteria: 
 
1. Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous, clear cell, or 
endometrioid ovarian, fallopian tube or primary peritoneal carcinoma 
2. Age ≥ 18 years. 
3. Estimated survival ≥ 6 months. 
4. ECOG Performance Status ≤ 1 
5. Metastatic disease 
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) or ascites fluid estimated volume ≥ 500mL (from 
a primary or secondary paracentesis, 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 informed protocol specific 
consent for tissue harvest or a parental/guardian informed consent and pediatric assent 
when appropriate. 
 
 Tissue Procurement Exclusion Criteria: 
 
Subjects meeting any of the following criteria are not eligible for tissue procurement for the Vigil 
manufacturing: 
 
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. 


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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 history of allergies or sensitivities to gentamicin. 
7. 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. 
8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) less than 21 days prior to tissue procurement. 
 
 Study Enrollment Inclusion Criteria 
 
Subjects will be eligible for registration into the trial if they meet all of the following inclusion 
criteria: 
 
1. Successful manufacturing of at least 4 vials of Vigil. 
2. One of the following: 
a. Failure to meet the eligibility criteria for Protocol CL-PTL-119 due to i) histology 
of ovarian cancer and failure to achieve a complete clinical response following 
primary debulking surgery and standard paclitaxel/carboplatin therapy OR, ii) a 
histologic diagnosis of another gynecologic malignancy which is not ovarian 
cancer. 
b. Recurrent ovarian cancer 
c. Randomized on Protocol CL-PTL-119 and were subsequently unblinded at 
recurrence and were assigned to the placebo arm. 
3. ECOG performance status (PS) ≤ 1 (or ≤ 2 due to carcinoid syndrome). 
4. Estimated survival ≥ 6 months. 
5. Measureable per RECIST 1.1 or evaluable disease. 
6. Adequate organ and bone marrow function as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500 per mm3) 
b. Platelets ≥100 × 109/L (100,000 per mm3) 
c. Hemoglobin ≥9.0 g/dL (5.59 mmol/L) 
d. Creatinine clearance (CrCL) >50 mL/min by the Cockcroft-Gault formula or by 
24-hour urine collection for determination of creatinine clearance: 
Females: 
CrCL (mL/min)  
= Weight (kg) × (140 – Age) × 0.85 
72 × serum creatinine (mg/dL) 
e. Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to patients 
with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that 
is predominantly unconjugated in the absence of evidence of hemolysis or 
hepatic pathology) who will be allowed in consultation with their physician. 
f. 
AST and ALT ≤2.5 × ULN in patients with no liver metastasis 


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g. AST or ALT ≤5 × ULN in patients with liver metastasis 
h. TSH within institutional limits. If TSH is greater or less than institutional limits 
patients may participate if their T4 is within normal limits (WNL); patients may be 
on a stable dose of replacement thyroid medication; dose adjustments are 
allowed if needed 
7. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated 
with prior therapy or surgery (or ≤ 2 due to carcinoid syndrome). 
8. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to 
CTCAE Grade 2 or better 
9. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by 
the IPs (Vigil and/or atezolizumab) may be included (e.g., hearing loss) after consultation 
with the Principal Investigator 
10. Subjects who are not rendered surgically sterile as a result of surgery for ovarian cancer, 
must have, 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. 
11. Ability to understand and the willingness to sign a written informed protocol specific 
consent. 
12. Willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
13. Patients must have fully recovered from chemotherapy associated toxicities prior to 
starting treatment on this protocol.   
 
Palliative radiotherapy is permitted provided: 
a. More than 3 weeks have elapsed between the end of radiotherapy and the first 
dose of study therapy, AND 
b. The irradiated lesion(s) (unless measurable progression after irradiation) cannot 
be used as target lesions. 
 
 Study Enrollment Exclusion Criteria 
 
In addition to the procurement exclusion, subjects (both with Vigil manufactured and undergoing 
procurement) will NOT be eligible for study registration and enrollment if meeting any of the 
following criteria: 
 
1. Participation in another clinical study with an investigational product within the last 3 
weeks prior to study start. 
2. Receipt of steroid therapy within the 2 weeks of the first dose of study therapy. 
3. Live vaccine used for the prevention of infectious disease administered < 30 days prior 
to the start of study therapy. NOTE: Subjects, if enrolled, should not receive live vaccine 
during the study and for 5 months after the last dose of atezolizumab. 
4. Post-surgery complication that in the opinion of the treating investigator would interfere 
with the subject’s study participation or make it not in the best interest of the subject to 
participate. 
5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fridericia’s Correction. 
6. Female subjects who are pregnant, breast-feeding or of reproductive potential who are 
not employing an effective method of birth control defined in the protocol.  Effective 
contraception is required for women receiving atezolizumab for 5 months after the last 
dose. 


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7. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal 
antibodies, other investigational agent) less than 21 days prior to the first dose of study 
drug or less than 6 weeks for nitrosourea or mitomycin C.  
9. Receipt of any anti-cancer therapy between tissue procurement on CL-PTL-126 and first 
dose of study drug. 
 
Patients should continue the combination of Vigil with atezolizumab until disease progression is 
documented, or toxicity supervenes.  Depending on the number of doses of Vigil manufactured, 
it is expected that 4 to12 doses of Vigil will be administered.  Once Vigil doses are exhausted, 
subjects whose disease is stable or responding, may continue to receive single agent 
atezolizumab until disease progression. 
 
 Withdrawal from Study Treatment 
 
Subjects will be taken off study treatment if any of the following occur: 
 
1. An AE that, in the opinion of the Investigator or the Sponsor, contraindicates further 
dosing. 
2. Patients with disease progression assessed by RECIST 1.1 criteria as determined by the 
investigator will not receive further Vigil or atezolizumab treatment. 
3. The patient experiences unacceptable (≥Grade 3) toxicity felt to be related to treatment 
with Vigil, atezolizumab, or study related procedure that persists for >2 weeks. 
4. Persisting Grade 3 or 4 toxicity unrelated to treatment, defined as failing to normalize 
within 4 weeks. 
5. ≥ Grade 3 allergic reactions related to Vigil or atezolizumab. 
6. Grade 2 autoimmune reactions unless there is evidence of clinical benefit. 
7. ≥ Grade 3 autoimmune reactions. 
8. An intercurrent illness, which would in the judgment of the investigator, affects 
assessments of clinical status to a significant degree or requires discontinuation of study 
treatment. 
9. Non-protocol therapy is administered during study treatment. 
10. Non-compliant with protocol or treatment. 
11. Patient refuses to continue treatment. 
12. Sponsor discontinuation of the protocol. 
 
The date of and reason for discontinuation must be noted in the subject’s source document.  
Every effort should be made to complete the appropriate assessments. 
 
At any time, subjects are free to discontinue Vigil and/or atezolizumab without prejudice to 
further treatment. A subject who decides to discontinue Vigil and/or atezolizumab will always be 
asked about the reason(s) for discontinuation and the presence of any AE.  If possible, they will 
be seen and assessed by an Investigator.  Adverse events will be recorded from time of first 
dose of Vigil and/or atezolizumab, throughout the treatment period and including the follow-up 
period: 


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 
30 days following the last study treatment or until another therapy has been initiated, 
whichever is earlier, regardless of causality. 
 
SAEs and AESIs are to be followed for 30 days after the last dose of study drug or the 
initiation of new therapy, whichever is earlier. 
 
The Study Physician should be notified of any ongoing AE that may delay treatment or 
necessitate permanent discontinuation of treatment. 
 
The date of and reason for discontinuation must be noted in the electronic Case Report Form 
(CRF).  Every effort should be made to complete the appropriate assessments. 
 
 INVESTIGATIONAL PLAN 
 
 Subject Screening and Registration 
 
Written documentation of full, unconditional IRB approval of the protocol and consent document 
must be on file before a subject can be screened.  Study participation begins once written 
informed consent is obtained. 
 
The Research Nurse or Clinical Research Coordinator will register the subject via email 
addressed to the Sponsor. 
 
Please allow 48 hours for subject registration as the subject’s source documents will be 
reviewed to ensure they meet the inclusion/exclusion criteria.  Once confirmed, the site will be 
notified of eligibility by the Sponsor. 
 
 Study Treatment Administration 
 
Treatment will be administered on an outpatient basis. 
 
6.2.1 
Schedule, Dose and Administration 
 
Subjects will receive Vigil and atezolizumab according to the schedule outlined in Appendix B. 
 
A study cycle is defined as 21 days (3 weeks). 
 
Vigil immunotherapy will be administered at a concentration of 1 x 106 or 1x107 cells/dose given 
via intradermal injection every 3 weeks for a minimum of 4 doses and a maximum of 12 doses. 
 
Atezolizumab will be administered at the FDA approved dose and schedule as described in the 
U.S. Package Insert (USPI).  Thus, atezolizumab is to be administered at a dose of 1200 mg as 
an intravenous infusion every 3 weeks.  The initial dose is to be administered over one hour and 
if well tolerated, subsequent infusions may be administered over 30 minutes. 


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The sites of injection for Vigil will be rotated between the right and left upper arms.  If the 
ipsilateral axillary lymph nodes were radiated or surgically removed during prior therapy, 
alternative sites will be used.  Subjects receiving Vigil will be observed for at least 30 minutes 
following administration. 
 
Investigational treatment may continue unless documented disease progression, discontinuation 
for toxicity, withdrawal of consent, or meeting other criteria for withdrawal from study detailed in 
Section 5.6. 
 
6.2.2 
Dose Reduction / Escalation 
 
Dose reduction or dose increase is not allowed for Vigil or atezolizumab. 
 
Dose Holding Criteria 
 
Both atezolizumab and Vigil should be held for any of the following AEs.  Cycles held for toxicity 
should be made up (that cycle number is delayed rather than skipped).  Atezolizumab and Vigil 
held may be resumed in patients whose AEs recover to Grade 0-1, with the exception of rash, 
which should recover to Grade 2 or better. 
 
 
Grade 2 pneumonitis 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and 
up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 
times ULN 
 
Grade 2 or 3 diarrhea or colitis 
 
Symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, or 
Grade 3 or 4 hyperglycemia 
 
Grade 2 ocular inflammatory toxicity 
 
Grade 2 or 3 pancreatitis, or Grade 3 or 4 increases in amylase or lipase levels (greater 
than 2.0 times ULN)  
 
Grade 3 or 4 infection 
 
Grade 2 infusion-related reactions 
 
Grade 3 rash 
 
Grade 2 nephritis 
 
Based on the mechanism of action of atezolizumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune related Adverse Events (irAEs) during the conduct 
of this study.  Potential irAEs include immune related colitis, pneumonitis, hepatitis, and 
endocrinopathies. Subjects should be monitored for signs and symptoms of irAEs.  Subjects 
should be monitored for signs and symptoms of irAEs.  In the absence of an alternate etiology 
(e.g., infection or PD) signs or symptoms of colitis, pneumonitis, hepatitis, and endocrinopathy 
should be considered to be immune-related. 
 
Study Regimen Delay 


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 
Cycles held for toxicity should be made up and not deleted. 
 
Dosing of atezolizumab and Vigil may be restarted when toxicity is ≤ Grade 1 severity 
with the exception of rash which may be ≤ Grade 2. 
 
In case of immune related adverse events, treatment with atezolizumab and Vigil may be 
delayed for up to 15 weeks (12 weeks for steroid therapy plus 3 weeks for gradual 
steroid tapering to a dose of ≤ 10 mg/day of prednisone. 
 
Subjects who delay treatment for more than 15 weeks due to toxicities will be considered 
off study treatment (see Section 6.3 Withdrawal). 
 
Treatment delay not related to toxic events (including subjects unable to adhere to dose 
schedule) may not extend for more than three days unless due to symptoms related to 
disease or infection in which case up to a 4-week delay is allowed. 
 
If ≥ one 2-week delay due to disease or infection occurs, subject status must be 
reviewed by sponsor. 
 
Atezolizumab should be permanently discontinued for any of the following AEs: 
 
 
Any life-threatening or Grade 4 AE 
 
Grade 3 or 4 pneumonitis 
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times upper 
limit of normal or total bilirubin >3 times upper limit of normal 
 
Diarrhea with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (Grade 4) stool incontinence, need for intravenous hydration for more than 24 
hours, gastrointestinal hemorrhage, and gastrointestinal perforation 
 
Grade 4 hypophysitis 
 
Myasthenic syndrome/myasthenia gravis, Guillain-Barré or meningoencephalitis (all 
grades) 
 
Grade 3 or 4 ocular inflammatory toxicity 
 
Grade 4 or any grade of recurrent pancreatitis 
 
Grade 3 or 4 infusion-related reactions 
 
Grade 4 rash 
 
Grade 3 or 4 nephritis 
 
Myocarditis (all grades)  
 
For combination treatment, the occurrence of a Grade 3 or 4 toxicity attributed to Vigil will result 
in the cessation of Vigil dosing and continuation of single agent atezolizumab only. 
 
Please reference https://www.gene.com/download/pdf/tecentriq_prescribing.pdf for full 
prescribing information regarding atezolizumab. 
 
 Toxicity 
 
Toxicities will be graded and reported according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) Version 4.03 as linked in Appendix C. This document can also be 
downloaded from the Cancer Therapy Evaluation Program (CTEP) home page 
<http://ctep.cancer.gov>. 


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Adverse events will be summarized using the MedDRA coding system or higher.  The NCI-
CTCAE will be used for AE grading.  All AEs, regardless of severity, will be followed by the 
Treating Physician until resolution is satisfactory. 
 
 Treatment beyond Initial Progression in Select Cases 
 
There is accumulating evidence that some subjects treated with immune system stimulating 
agents may appear to demonstrate progression of disease by conventional response criteria 
before demonstrating clinical objective responses and/or stable disease and ultimately survival 
benefit. This phenomenon has been observed in studies with inhibitors of both the CTLA-4 and 
PD-1/PD-L1 pathways. It may be that enhanced inflammation within tumors initially leads to an 
increase in tumor size or newly visible small lesions. Over time, both the malignant and 
inflammatory portions of the mass may then decrease leading to overt signs of clinical 
improvement.  Alternatively, in some individuals the kinetics of tumor growth may initially 
outpace anti-tumor immune activity followed, with sufficient time, by clinically apparent anti-
tumor activity.  Therefore, select subjects may be allowed to continue study therapy after 
investigator-assessed RECIST 1.1 progression and with agreement by the study Medical 
Monitor if the subject is determined to be deriving clinical benefit, tolerating study drug and 
meeting the following criteria: 
 
1. Absence of symptoms and signs indicating clinically significant PD indicating disease 
progression. 
2. No decline in ECOG performance status. 
3. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
 
If subsequent imaging shows an objective response or stable disease relative to baseline, 
treatment with study agents will continue.  If subsequent imaging again shows PD, patients will 
be discontinued from study therapy. 
 
 Schedule of Assessments 
 
The schedule of assessments for the trial is shown in Appendix B.  If a required observation or 
procedure is missed, documentation is required in CRF and in the subject’s source documents, 
to explain the reason for this protocol deviation. 
 
Based on findings during the study or during the follow up portion of the trial, Gradalis may 
request for additional blood and / or tissue samples from subjects during a routine blood draw or 
scheduled biopsy.  Collection of whole blood (40ml) and / or tissue samples (via biopsy or 
clinically indicated surgical removal) will be optional and used to study the effects of the study 
agent (included, but not limited to testing of biomarkers, predictors or biological responses, 
toxicity, relationship between genotype and study agent responses). 
 
Should Gradalis request for additional blood or tissue, the clinical site will present the option of 
the procurement to the participant and obtain written informed consent. 


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 Part 3, Continuation with Single Agent Atezolizumab 
 
Subjects who complete Cycles 3 – 12 of the combination study regimen, may continue 
administration of atezolizumab as long as they are in stable disease or better.  Subjects may 
continue atezolizumab monotherapy until disease recurrence / progression.  The schedule of 
assessments for subjects continuing with single agent atezolizumab is shown in Appendix C. 
 
 
CONDUCT OF THE STUDY 
 
 Ethics and Regulatory Considerations 
 
This study must have the approval of a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC).  Before the investigational product is shipped to the 
investigator, the investigator will provide Gradalis, Inc. with an electronic copy of the IRB or IEC 
approval letter stating that the study protocol and informed consent forms have been reviewed 
and approved. 
 
 
IRB/IEC 
 
This trial can be undertaken only after review and full approval of the protocol and Subject 
Informed Consent Forms have been obtained from a properly constituted IRB/IEC.  This written 
approval must be dated and it must clearly identify the protocol, any amendments, the Subject 
Informed Consent Forms, and any applicable recruiting materials and subject compensation 
programs approved. 
 
The decision concerning the conduct of the study will be made in writing to Gradalis, Inc.  
Copies of this decision and of all IRB/IEC correspondence will be kept on file at the study site; 
copies will be provided to the Sponsor for storage in the electronic Trial Master File. 
 
During the trial, the PI is required to send various documents to the IRB/IEC for review in 
accordance with site institutional policies: 
 
 
All protocol amendments and Subject Informed Consent Form revisions. 
 
Reports of Serious Adverse Events. 
 
Protocol Deviations as required by IRB Guidelines 
 
The PI provides Gradalis, Inc. with the necessary assurance that an IRB/IEC is responsible for 
the initial and continuing review and approval of the proposed clinical study in accordance with 
21 CFR 312.60.  At least once a year, the IRB/IEC will be asked to review and re-approve the 
clinical trial protocol; the request must be documented in writing.  At the end of the trial, the PI 
will notify the IRB/IEC that the trial has been completed. 
 


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Written Informed Consent 
 
The informed consent document should meet the requirements of the latest version of the 
Declaration of Helsinki and any applicable regulations and guidelines.  It must be approved by 
an IRB or IEC. 
 
Prior to entry into the trial and before any protocol-required procedures are performed, the 
Investigator must explain the nature of the trial, its intended purpose, and the implications of 
participation to potential subjects or to their legal representatives.  They will be told about the 
possible risks and benefits, and the possible adverse experiences.  They will be informed that 
subjects’ participation is voluntary, and that they may withdraw consent to participate at any 
time.  They will also be informed that if subjects choose not to participate in the trial alternative 
treatments are available; such refusal will not prejudice further treatment of their disease.  
Potential subjects or their legal representatives must be given the opportunity to ask questions 
about the trial protocol and the procedures involved. 
 
Finally, each subject will be told that his or her records may be accessed by authorized 
personnel of Gradalis, Inc. and other authorized individuals without violating the subject’s 
confidentiality, to the extent permitted by the applicable laws and/or regulations.  By signing the 
written Subject Informed Consent Forms, the subject or his or her legal representative is 
authorizing such access.  Following this explanation and prior to entry into the trial, the written, 
dated, and signed Subject Informed Consent Form must be obtained from each subject or his or 
her legal representative; a copy will be given to the person signing the form. 
 
 
Confidentiality of Records 
 
The Investigator is required to retain, in a confidential manner, sufficient information on each 
subject (i.e., full name, current address, and social security number) so that the subject may be 
contacted by the FDA, Gradalis, Inc., or by their affiliates should the need arise. 
 
 
Modification of Protocol 
 
Any changes to this protocol that affect study objectives, study design, study procedures, 
subject population, or significant administrative procedures will require a formal amendment to 
the protocol.  Any proposed protocol amendments must be sent in writing to the applicable IRB.  
Prior to implementation, an amendment must be approved by the Gradalis, Inc., and approved 
by the applicable IRB or IEC. 
 
General administrative changes to the protocol are minor corrections and/or clarifications that 
do not affect the manner in which the study is to be conducted. Such administrative changes will 
be agreed upon by the Gradalis, Inc., and will be documented in a memorandum.  The 
applicable IRB or IEC will be notified of administrative changes according to applicable IRB 
guidelines. 
 
 
Protocol Questions and Deviations 


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When evaluating a potential subject or while a subject is on study, protocol questions can be 
directed to the Gradalis Medical Monitor via email or phone using the contact information 
provided in the Contact Information section of the Study Reference Manual. 
 
 
EVALUATION OF TUMORS 
 
 
Tumor Measurements and Response (RECIST 1.1) 
 
Response and progression will also be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1.  The guidelines are available online at: 
European Organization for Research and Treatment of Cancer (EORTC) RECIST Web page, 
https://www.eortc.be/Recist/documents/RECISTGuidelines.pdf 
 
 
ATEZOLIZUMAB INVESTIGATIONAL PRODUCT 
 
Atezolizumab will be provided by Roche / Genentech and distributed by Gradalis, Inc. 
 
Atezolizumab is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as a colorless to 
slightly-yellow, sterile, preservative-free clear liquid solution intended for IV administration. The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than 
the stated volume to enable delivery of the entire 20 mL volume. The atezolizumab drug product 
is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, pH 5.8 (Phase III formulation). 
 
Atezolizumab must be refrigerated at 2−8 °C (36−46 °F) upon receipt until use. Atezolizumab 
vials should not be used beyond the expiration date provided by the manufacturer. No 
preservative is used in atezolizumab drug product; therefore, the vial is intended for single use 
only. Discard any unused portion of drug left in a vial. Vial contents should not be frozen or 
shaken and should be protected from direct sunlight. 
 
 
Preparation of atezolizumab 
 
Atezolizumab in formulation F03 (1200 mg per vial) will be administered in 250 mL 0.9% NaCl 
IV infusion bags and infusion lines equipped with 0.2 μm in-line filters. The IV bag may be 
constructed of PVC or PO; the IV infusion line may be constructed of PVC or PE; and the 0.2 
μm in-line filter may be constructed of PES. The use of administration supplies composed of 
materials other than those listed should be avoided if possible. Atezolizumab must be prepared 
and diluted under appropriate aseptic conditions as it does not contain antimicrobial 
preservatives. The solution for infusion should be used immediately to limit microbial growth in 
case of potential accidental contamination. If not used immediately, in-use storage time and 
conditions prior to use are the responsibility of the user. The dose solution prepared for IV bag 


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delivery may be stored at 2−8 °C (36−46 °F) and/or at room temperature for up to a total in-use 
storage time of 8 hours. 
 
The initial dose of atezolizumab will be delivered over 60 (± 15 minutes). If the first infusion is 
tolerated without infusion-associated adverse events, then the second infusion may be delivered 
over 30 (± 10 minutes). If the 30-minute infusion is well tolerated, then all subsequent infusions 
may be delivered over 30 (± 10 minutes). 
 
The subject’s vital signs (heart rate, respiratory rate, blood pressure, temperature, and O2 
saturation) should be determined up to 60 minutes before each atezolizumab infusion. Vital 
signs should also be obtained during or after the atezolizumab infusion if clinically indicated. No 
premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for subsequent infusions at the discretion of the treating physician after 
consultation with the Medical Monitor. 
 
Storage 
 
All study drugs should be kept in a secure place under appropriate storage conditions. The dose 
solution prepared for IV bag delivery may be stored at 2−8 °C (36−46 °F) and/or at room 
temperature for up to a total in-use storage time of 8 hours. 
 
Compliance 
 
The administration of all study drugs (including Vigil and/or atezolizumab) should be recorded in 
the appropriate sections of the CRF.  Treatment compliance will be assured by site 
reconciliation of the medication dispensed and returned. 
 
Accountability 
 
The study drug provided for this study will be used only as directed in the study protocol.  Drug 
accountability should be performed until the patient stops study treatment completely.  Study 
site personnel will account for all study drugs received at the site, for all unused study drugs, 
and for appropriate destruction of study drugs.  Certificates of delivery, destruction, and return 
should be available. 
 
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records.  Upon completion of the study, copies of 
investigational product accountability records will be returned to the product manufacturer.  All 
unused investigational product will be returned to a product manufacturer’s authorized depot or 
disposed of upon authorization by product manufacturer. 
 
 
VIGIL PRODUCT INFORMATION 
 


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 Vigil Investigational Product 
 
Vigil is made up of irradiated autologous tumor cells which have been electroporated ex vivo 
with the Vigil plasmid designed to suppress expression of both the TGFβ1 and TGFβ2 proteins 
while simultaneously expressing rhGMCSF protein. 
 
 Safety Analysis 
 
Vigil plasmid employed in the generation of this product has been tested for identity, sterility, 
purity and strength. 
 
Irradiated Gene Modified Tumor Cells 
 
To ensure safety, all gene-modified tumor cells to be used in Vigil administrations must be 
irradiated with a dose of 10,000 cGy prior to freezing.  This is the same irradiation process as 
for the TAG vaccine, BB-IND 13650 and prior vaccines (Belagenpumatucel-L and GVAX® 
published trial results and BB-IND 13401 and BB-IND 12118) (Kumar 2009; Maples PB 2009; 
Maples PB 2009).  The selection of this radiation dose is based on the desire to utilize the 
lowest possible radiation dose for the transfected cells to optimize the level and duration of 
bifunctional shRNAfurin transcription and GMCSF protein production and maximize the safety of 
vaccine cell injections at the same time.  In addition, investigators have demonstrated that 
irradiating cultured tumor cells of different histologic origins at 10,000 cGy completely arrests 
tumor colony formation. 
 
Preparation 
 
Reference the Pharmacy Reference Manual for preparation and handling information. 
 
Vigil concentrate: 1.0 x 106 or 1.0 x 107cells per injection in a volume of 1mL. 
 
Route of administration: Intradermal injection 
 
Storage and Shipping 
 
Frozen, unopened vials are stored in the vapor phase of Liquid Nitrogen below -150° C at 
Gradalis.  Each Vigil concentrate will be shipped individually in a portable liquid nitrogen tank.  
This shipping container will be able to sustain temperature fluctuations for up to 10 days. This 
will enable sufficient time to reach the different clinical site pharmacies. 
 
Request for investigational product for Day 1 administration must occur via email or phone at 
least 1 week prior to the anticipated visit date.  Gradalis designated quality assurance personnel 
will confirm feasibility of release and transport the product.  Subjects will be randomized up to 
14 days prior to the subject receiving their first dose of atezolizumab or Vigil administration. 


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Vigil Transfer 
 
All manufactured Vigil will be stored and shipped in the vapor phase of liquid nitrogen until ready 
for use.  The site will request for Vigil shipment via email when the study agent is needed for 
subject administration. 
 
Once the Vigil request is made, the Gradalis QA staff will confirm that eligibility criteria have 
been met and approved by the Medical Monitor.  Gradalis QA staff will coordinate shipment of 
the product with the site. 
 
At the site, investigational product preparation must be prepared by the Pharmacist or designee. 
 
Please reference the Pharmacy Reference Manual for preparation and handling information. 
 
 
CONCOMITANT THERAPY 
 
All concomitant treatments taken during study participation, including blood and blood products, 
must be reported on the source documentation. 
 
EMLA® may be utilized at the injection site prior to Vigil administration. 
 
The following medications and interventions, unless otherwise specified, are prohibited from the 
time of study screening until the End of Treatment visit: 
 
Systemic anti-cancer therapy, including chemotherapy, radiotherapy, or endocrine therapy other 
than those required per protocol are prohibited from the time of study screening until the End of 
Treatment visit. 
 
Any investigational drug or device other than Vigil is prohibited from the time of study screening 
until the End of Treatment visit. 
 
Systemic—oral, IV, injectable—corticosteroids (e.g., dexamethasone) should be avoided in 
subjects who receive Vigil.  If deemed by the investigator to be necessary, short term (<30 
days) systemic steroids ≤ 0.25 mg/kg (max 10mg) prednisone-equivalent per day and inhaled 
steroids are permitted while on protocol. Other steroid regimens and/or immunosuppressives 
are prohibited. 
 
Subjects should be provided with full supportive care measures, as clinically indicated, and in 
accordance with institutional standards. Such care includes medication for pain control and 
symptom management, antibiotics, bisphosphonates, antiemetics, colony stimulating factors, 
and transfusions of blood or blood products.  Treatment for drug-related adverse events should 
be administered at the discretion of the investigator. 


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Localized radiotherapy is permitted for palliation of painful lesions at the investigator’s 
discretion. However, medical management in place of radiation therapy should be used if 
clinically appropriate. 
 
Inactivated influenza and pneumococcal vaccines are allowed on study, if deemed appropriate 
by the investigator.  Live vaccines are prohibited while on study. 
 
 
BLOOD DONATION 
 
Subjects should not donate blood while participating in this study or for at least 90 days 
following the last infusion of atezolizumab or until 28 days after the last dose of Vigil, whichever 
occurs longest. 
 
 
OCCUPATIONAL SAFETY 
 
Study medications are not expected to pose significant occupational safety risks to 
investigational staff under normal conditions of use and administration. However, precautions 
should be taken to avoid direct contact with study medication.  Biosafety Level 1 practices shall 
be employed with this study medication.  Reference the Pharmacy Reference Manual. 
 
 
ADVERSE EVENTS 
 
Adverse Event and Serious Adverse Event Definitions 
 
Adverse Event 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including a 
clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
 


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Serious Adverse Event 
 
An AE (experience) or reaction occurring at any dose should be classified as a serious adverse 
event (SAE) if any of the following occur: 
 
 
Initial or prolonged hospitalization  
 
A life-threatening condition (i.e. an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it was more severe)  
 
Significant disability/incapacity (i.e. the AE resulted in a substantial disruption of the 
subject’s ability to carry out normal life functions) 
 
Congenital anomaly/birth defect 
 
It does not meet any of the above serious criteria, but may jeopardize the subject or may 
require surgical or medical intervention to prevent one of the outcomes listed above. 
 
Death 
 
Definition of Adverse Events of Special Interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the atezolizumab and may require close monitoring and rapid communication 
by the investigator to the sponsor.  An AESI may be serious or non-serious.  The rapid reporting 
of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 
 
AESIs for atezolizumab include but are not limited to events with a potential inflammatory or 
immune-related mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy.  
These AESIs are being closely monitored in clinical studies with atezolizumab monotherapy and 
combination therapy.  An immune-related adverse event (irAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-related mechanism of 
action and where there is no clear alternate etiology.  Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to exclude alternate etiologies and support an 
irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes of the irAE. 
 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Medical Monitor. 
 
AESIs for this study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
o Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 


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o Treatment-emergent ALT or AST  3  baseline value in combination with clinical 
jaundice 
 
Suspected transmission of an infectious agent by the study treatment, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product.  This term applies only when a 
contamination of study treatment is suspected. 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
 
Hepatitis, including AST or ALT  10  ULN  
 
Systemic lupus erythematosus  
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Criteria for Hy’s Law (FDA Guidance 2009) 
 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug  
 
Among trial subjects showing such aminotransferase elevations, often with 
aminotransferases much greater than 3 x ULN, one or more also show elevation of 
serum total bilirubin to >2 x ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase)  
 
No other reason can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or 
acute liver disease; or another drug capable of causing the observed injury. 
 
Unexpected Adverse Event 
 
An unexpected event is any AE that is not identified in nature, severity or frequency in the 
Clinical Investigator’s brochure or the drug package insert. 
 
 


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Grading Adverse Events 
 
Adverse events (AEs) will be recorded throughout the trial. Toxicities and AEs will be graded 
and reported using the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 as 
linked in Appendix D. 
 
Adverse events will be summarized using the MedDRA coding system or higher.  The NCI-
CTCAE will be used for AE grading.  All AEs, regardless of severity, will be followed by the 
Treating Physician until resolution is satisfactory. 
 
 Attribution of Causality 
 
The relationship of each event will be assessed by the Treating Physician and recorded on the 
CRF. 
 
 Atezolizumab Infusion Reactions 
 
Severe infusion reactions have occurred in patients in clinical trials of atezolizumab. Infusion 
related reactions occurred in 1.3% (25/1978) of patients across clinical trials, 1.7% (9/523) of 
patients with urothelial carcinoma, and 1.6% (16/1027) of patients with NSCLC. Interrupt or slow 
the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue 
atezolizumab in patients with Grade 3 or 4 infusion reactions. 
 
 Risks Associated with Atezolizumab 
 
Refer to the Atezolizumab Investigator's Brochure for a detailed description of anticipated safety 
risks for atezolizumab. 
 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating agents.  
Systemic immune activation should be included in the differential diagnosis for patients who, in 
the absence of an alternative etiology, develop a sepsis-like syndrome after administration of 
atezolizumab, and the initial evaluation should include the following: 
 
 
CBC with peripheral smear 
 
PT, PTT, fibrinogen, and D-dimer 
 
Ferritin 
 
Triglycerides 
 
AST, ALT, and total bilirubin 
 
LDH 
 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 


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If systemic immune activation is still suspected after the initial evaluation, contact the Medical 
Monitor for additional recommendations. 
 
 Vigil Expected Side Effects 
 
Vigil immunotherapy have been previously administered to patients with cancer.  Side effects 
were minimal, the most frequent of which included local reactions at the site of injection.  
Potential adverse events are listed below. 
 
Local skin reactions at the site of injection: 
 
Erythema, tenderness, induration, urticaria/rash, pruritus. 
 
Other expected adverse events: 
 
Fever, myalgias/arthralgias, chills/rigors, nausea, fatigue, headache, thrombocytopenia and 
other cytopenias, hyperglycemia, vomiting, hypotension, infection at the immunization site. 
 
In addition, there may also be a risk of autoimmune disease development, although to date no 
evidence of this has been seen in any vaccination study.  There may also be worsening of 
tumor related symptoms secondary to immune related attack on subject’s tumor. 
 
 Recording of an Adverse Event 
 
Adverse events will be recorded for the duration of a subject’s study treatment (following the first 
dose of Investigational Product, Vigil and/or atezolizumab), and for up to 30 days following the 
last study treatment or until another therapy has been initiated, whichever is earlier, regardless 
of causality. 
 
SAEs and AESIs should be recorded for the duration of the study treatment and for up to 30 
days following the last study treatment or the initiation of new therapy, whichever is earlier. 
 
All AEs, regardless of causal relationship are to be recorded in the eCRF and source 
documentation.  Additional information about each event, such as treatment required, eventual 
outcome, and whether or not therapy had to be interrupted or dosages reduced, will be noted in 
source documents and recorded on the eCRF. 
 
Pre-existing conditions will be recorded at baseline on the Medical History Form. If a pre-
existing condition does not change, it does not have to be reported as an AE on subsequent 
cycles. 
 


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 Serious Adverse Event Reporting 
 
All SAEs and AESIs will be reported within 24 hours of notification by the site via email or fax to 
Gradalis, Inc.  This includes any death from any cause while a subject is receiving the study 
agent on this protocol, or  30 days following the last dose of the protocol study agent. 
 
The site will supply as much information as is available at the time of the initial SAE or AESI 
reporting (study number, subject study number, onset date, relationship, subject demographics, 
event, dosing regimen of study agent).  All SAEs or AESIs must be followed until resolution. 
 
Gradalis, Inc. 
2545 Golden Bear Drive, Suite 110 
Carrollton, TX  75006 
Vigil@gradalisinc.com 
Direct: (214) 442-8124 
Fax: (214) 442-8101 
 
Gradalis, Inc. and Genentech, Inc. will report adverse events to the FDA in compliance with 21 
CFR 312.32. 
 
 Overdose 
 
An overdose is defined as a subject receiving a dose of atezolizumab in excess of that specified 
in the Investigator’s Brochure, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with atezolizumab, with or without associated AEs/SAEs, is 
required to be reported within 24 hours of knowledge of the event to the sponsor and Sponsor 
Partner Patient Safety or designee using the designated Safety e-mailbox. If the overdose 
results in an AE, the AE must also be recorded as an AE.  Overdose does not automatically 
make an AE serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE. There is 
currently no specific treatment in the event of an overdose of atezolizumab. 
 
The investigator will use clinical judgment to treat any overdose. 
 
 SUBJECT COMPLETION AND WITHDRAWAL 
 
 Indication for Taking Subjects Off Study 
 
The Investigator must notify the sponsor at any time following discontinuation of a subject on 
study for the occurrence of a serious or unexpected AE associated with the use of the study 
medication. 


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 STATISTICAL CONSIDERATIONS 
 
 Safety Analysis 
 
The safety evaluation will include AEs, AESIs, SAEs, and changes from baseline in laboratory 
evaluations, vital signs, electrocardiograms, and physical examinations. The number and 
percentage of subjects reporting treatment emergent AEs will be summarized overall and by the 
highest Common Terminology Criteria for Adverse Events (CTCAE) grade, system organ class, 
and preferred term, with a breakdown by dose and tumor type. Similarly, the number and 
percentage of subjects reporting treatment-emergent AEs considered related to investigational 
product will be summarized. At each level of subject summarization, a subject will be counted 
once using the highest grade and level of causality if one or more occurrences of the same 
system organ class/preferred term is reported. Adverse events will be graded according to the 
National Cancer Institute (NCI) CTCAE v4.03 and coded using the Medical Dictionary for 
Regulatory Activities. Laboratory abnormalities will be graded according to the NCI CTCAE 
v4.03, if applicable. 
 
 Efficacy Analysis 
 
For each cohort, the ORR will be estimated, along with its two-sided exact binomial 95% 
confidence interval. The definitions of the response-related endpoints and corresponding time-
to-event endpoints will be based on the programmatically-derived response from the 
investigator’s recorded measurements and assessments for target, non-target, and new lesions 
according to RECIST 1.1. The distributions of PFS and OS will be estimated within each cohort 
using the Kaplan-Meier method. 
 
 Sample Size Justification 
 
The sample size for this study is not based on statistical considerations.  The results of this trial 
will be used to help design future studies. 
 
 STUDY RECORDS 
 
 Documentation 
 
A log of all subjects evaluated for this protocol must be maintained at each site.  Subjects 
excluded from admission will be provided with a clear explanation of the specific reasons why 
they have been excluded from the study.  Subjects who have tumor tissue procured will be 
assigned a subject identification number. 
 
For each subject treated with the study drug(s), the Research Coordinator is required to prepare 
and maintain case histories that include all observations and other data pertinent to the 


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investigation.  This will include all source documents needed to verify the accuracy of all 
observations and other data contained in the eCRFs on each study subject. 
 
The Investigator or his/her designee is required to retain the records related to the trial for a 
period of 2 years following the date a marketing application is approved for the indication being 
investigated.  If no application is to be filed or if the application is not approved for such 
indication, the records must be retained until 2 years after the investigation is discontinued and 
the regulatory agencies are notified. 
 
The Investigator shall retain study drug disposition records and source documents for the 
maximum period required by the country and institution in which the study will be conducted, or 
for the period specified by Gradalis, whichever is longer.  The Investigator must contact 
Gradalis, Inc. prior to destroying any records associated with the study. 
 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB).  Notice of such 
transfer will be given in writing to Gradalis, Inc. 
 
 Case Report Form Procedures 
 
Data for this study will be captured in the CRFs.  The investigator or his/her designee is 
responsible for recording all data relating to the trial on the eCRFs in accordance with the site’s 
contract with Gradalis.  The investigator must verify that all data entries on the CRFs are 
accurate and correct. 
 
 


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APPENDIX A: PERFORMANCE STATUS SCALE 
 
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of light or sedentary 
nature—(e.g., light housework or 
office work). 
2 
In bed <50% of the time. 
Ambulatory and capable of all self 
care, but unable to carry out any 
work activities; up and about > 50% 
of waking hours. 
3 
In bed >50% of the time.  Capable 
only of limited self-care, confined to 
bed or chair >50% of waking hours. 
4 
100% bedridden.  Completely 
disabled; cannot carry out any self 
care; totally confined to bed chair. 
5 
Dead 
 
 


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APPENDIX B: SCHEDULE OF ASSESSMENTS 
1 cycle = 3 weeks 
Pre-Study1 
Screening 
Cycle 1 
Cycle 2 
Cycles 3, 
6, 9, 12 
Cycles 4, 
5, 7, 8, 10, 
11 
EOT 
(30 days)2 
Response 
Follow-Up 
(quarterly)3 
Survival 
(3 years)4 
Visit Window 
 
-2 weeks 
±5 days 
+/- 7 days 
±4 weeks 
Informed Consent 
X 
within 4 
weeks 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
X 
 
 
Symptom-Directed Physical Exam5 
 
 
X 
X 
X 
X 
X 
 
 
Performance Status (ECOG) 
 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs (including weight)6 
X 
X 
X 
X 
X 
X 
X 
 
 
Toxicity (adverse events) 
 
 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X7 
X8 
Radiological Tumor Assessment9 
 
within 4 
weeks 
 
 
X10 
 
X11 
X 
 
Triplicate Electrocardiogram (ECG) 
 
X 
 
 
X 
 
X 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistry12 
X 
X 
X 
X 
X 
X 
X 
 
 
                                                
1 Pre-Study assessments including medical history, physical exam, CBC and Serum Chemistry may be obtained from medical records from standard preoperative hematology and 
chemistry panels. 
2 End of Treatment visit will occur 30 days (+ 5 days) after the last treatment or prior to commencement of subsequent treatment. 
3 Subjects that discontinue study treatment before disease progression will have radiological assessment of disease quarterly until disease progression. 
4 Assessment performed annually after disease progression. 
5 Symptom-Directed Physical Exam performed by a medical provider.   
6 Vital signs (including weight) must be obtained predose. Vital signs (heart rate, respiratory rate, blood pressure, temperature, and O2 saturation) should also be obtained within 60 
minutes prior to each atezolizumab infusion.  
7 Collect any post study therapies taken after participation in the study. 
8 Collect any post study therapies taken after participation in the study. 
9 Radiological Tumor Assessment to include chest, abdomen, and pelvis.  Assessment will be done per RECIST criteria for measurable disease. 
10 Radiological Tumor Assessment will be performed at baseline and every third cycle thereafter. 
11 Radiological Tumor Assessment performed at End of TX if not done within the previous 45 days. 
12 Serum Chemistry to include creatinine, glucose, total protein, blood urea nitrogen, total carbon dioxide, albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase 
and/or alanine transaminase and electrolytes (total calcium, chloride, potassium, sodium). 


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1 cycle = 3 weeks 
Pre-Study1 
Screening 
Cycle 1 
Cycle 2 
Cycles 3, 
6, 9, 12 
Cycles 4, 
5, 7, 8, 10, 
11 
EOT 
(30 days)2 
Response 
Follow-Up 
(quarterly)3 
Survival 
(3 years)4 
Visit Window 
 
-2 weeks 
±5 days 
+/- 7 days 
±4 weeks 
CA-12513 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH14 
 
X 
 
 
X 
 
 
 
 
Pregnancy Test (if applicable) 
 
X 
 
 
 
 
 
 
 
Immune Function Analysis15 
≤ 1 week of 
tumor 
procurement 
X 
 
 
X 
 
X 
X 
 
Tissue Procurement 
X 
 
 
 
 
 
 
 
 
Vigil Administration16 
 
 
Part 1: Both 
Part 2: Vigil or Atezolizumab 
X 
X 
 
 
 
Atezolizumab Administration17 
 
 
X 
X 
 
 
 
Site Injection Assessment18 
 
 
X 
X 
X 
X 
 
 
 
Tumor Biopsy 
 
 
 
 
X19 
 
 
 
 
Phone Contact 
X 
 
 
 
 
 
 
 
X 
 
 
                                                
13 Obtain results from medical records when available. 
14 TSH will be collected at screening and every third cycle thereafter.  
15 Immune Function Analysis sample will be collected at baseline, prior to study agent administration at Cycle 3 and every 3 cycles thereafter. 
16 Vigil Administration every 3 weeks on Day 1 as long as sufficient material is available and patient is deemed appropriate to continue.  When combined, Vigil should be administered 
first, followed 30 minutes (+/- 5 min) later by atezolizumab. 
17 Atezolizumab is to be administered at a dose of 1200 mg as an intravenous infusion on Day 1 every 3 weeks.  The initial dose is to be administered over one hour and if well tolerated, 
subsequent infusions may be administered over 30 minutes. 
18 Assessment of injection site will occur during the Vigil post-dose observation period and through 24 hours after Vigil dosing through patient contact. 
19 Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis will be obtained at tissue procurement, prior to Cycle 
3 combination dosing (for individuals in Part 2) and at any time after the end of Cycle 3. 


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APPENDIX C: ATEZOLIZUMAB EXPANSION SCHEDULE OF ASSESSMENTS 
1 cycle = 3 weeks 
Each Cycle 
EOT 
(30 days)1
Response Follow-
Up (quarterly)2 
Survival 
(3 years)3 
Visit Window 
±5 days 
±5 days 
±7 days 
±4 weeks 
Physical Exam 
 
X 
 
 
Symptom-Directed Physical Exam4 
X 
 
 
 
Performance Status (ECOG) 
X 
X 
 
 
Vital Signs (including weight) 
X5 
X 
 
 
Toxicity (AESI/SAEs) 
X 
X 
 
 
Concomitant Medications 
X 
X 
X6 
X7 
Radiological Tumor Assessment8 
X9 
X10 
X 
 
Triplicate ECG (recommended) 
Recommended per use with 
checkpoint inhibitors11
 
 
CBC with differential 
X 
X 
 
 
Serum Chemistry12 
X 
X 
 
 
TSH (recommended) 
Recommended per use with 
checkpoint inhibitors13 
 
 
Immune Function Analysis14 
X 
X 
 
 
Atezolizumab Administration15 
X 
 
 
 
CA-12516 
X 
X 
X 
X 
Tumor Biopsy17 
X 
X 
 
 
Phone Contact 
 
 
 
X 
 
                                                
1 End of Treatment visit will occur 30 days (+ 5 days) after the last treatment or prior to commencement of subsequent treatment. 
2 Subjects that discontinue study treatment before disease progression will have radiological assessment of disease quarterly until 
disease progression. 
3 Assessment performed annually after disease progression. 
4 Symptom-Directed Physical Exam performed by a medical provider.   
5 Vital signs (heart rate, respiratory rate, blood pressure, temperature, and O2 saturation) should be obtained within 60 minutes prior 
to atezolizumab infusion. 
6 Collect any post study therapies taken after participation in the study. 
7 Collect any post study therapies taken after participation in the study. 
8 Radiological Tumor Assessment to include chest, abdomen, and pelvis.  Assessment will be done per RECIST criteria for measurable 
disease. 
9 Radiological Tumor Assessment will be performed every third cycle. 
10 Radiological Tumor Assessment performed at End of TX if not done within the previous 45 days. 
11Due to potential risk of myocarditis associated with atezolizumab use, it is recommended that cardiac function be monitored prior 
to and periodically during treatment with atezolizumab. Triplicate ECGs performed periodically during treatment with atezolizumab 
may help identify potential cardiac events; however, Institutional standard practice for monitoring cardiac function during use of 
checkpoint inhibitors should be used throughout treatment with atezolizumab. 
12 Serum Chemistry to include creatinine, glucose, total protein, blood urea nitrogen, total carbon dioxide, albumin, total bilirubin, 
alkaline phosphatase, and aspartate transaminase and/or alanine transaminase and electrolytes (total calcium, chloride, potassium, 
sodium). 
13 Per atezolizumab package insert (Section 5.4 – Thyroid Disorders); Thyroid function should be monitored prior to and periodically 
during treatment with atezolizumab. Package insert and institutional practice should be followed throughout treatment with 
atezolizumab. 
14 Immune Function Analysis sample will be collected every 3 cycles. 
15 Atezolizumab is to be administered at a dose of 1200 mg as an intravenous infusion (over 30 minutes) on Day 1 every 3 weeks.   
16 Obtain results from medical records when available. 
17 Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis 
will be obtained at any time when available. 


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APPENDIX D: NCI COMMON TOXICITY CRITERIA FOR ADVERSE EVENTS (CTCAE), 
VERSION 4.0. 
 
Publish Date: June 14. 2010 
 
As of June 14, 2010, NCI has introduced version 4.03 of the Common Toxicity Criteria for 
Adverse Events. These may be obtained at the following web link http://ctep.cancer.gov. 
 
DO NOT USE CTC VERSION 3.0 TO GRADE TOXICITIES IN THIS STUDY! 
 
 
 
 


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