A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Determine the Efficacy and Safety of CMB305 in Unresectable Locally-advanced or Metastatic NY-ESO-1+ Synovial Sarcoma Participants Following First Line Systemic Anti-cancer Therapy (V943-003, IMDZ-04-1702)
Phase: PHASE3
Conditions: Synovial Sarcoma, Cancer, Soft Tissue Sarcoma, Sarcoma, Metastatic Sarcoma
Sponsor: Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Official Protocol Title: 
NCT number: 
NCT03520959
19-September-2018
Document Date: 
A Phase 3, Randomized, Double-blind, Placebo-controlled 
Study to Determine the Efficacy and Safety of CMB305 in 
Unresectable Locally-advanced or Metastatic NY-ESO-1+ 
Synovial Sarcoma Subjects Following First-line Systemic Anti-
cancer Therapy 

CMB305 
Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 1 of 94 
CLINICAL TRIAL PROTOCOL: IMDZ-04-1702 
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to 
Determine the Efficacy and Safety of CMB305 in Unresectable 
Locally-advanced or Metastatic NY-ESO-1+ Synovial Sarcoma Subjects 
Following First-line Systemic Anti-cancer Therapy 
Study Number: 
IMDZ-04-1702 
Study Phase: 
3 
Product Name: 
CMB305 (sequentially administered LV305 [lentiviral vector encoding New 
York esophageal squamous cell carcinoma-1 {NY-ESO-1} gene] and G305 
[NY-ESO-1 recombinant protein plus glucopyranosyl lipid A stable emulsion 
{GLA-SE}]) 
IND Number: 
16181 
Indication: 
Unresectable locally-advanced or metastatic synovial sarcoma 
Sponsor: 
Immune Design Corp. (IMDZ) 
Sponsor Address: 
IMDZ 
1616 Eastlake Ave. E, Suite 310 
Seattle, WA 98102 USA 
Medical Monitor: 
 
  
 
Protocol Date and Version: 
19 September 2018, Version 2.1 DK 
Confidentiality Statement 
This document contains proprietary and confidential information of Immune Design Corp. (IMDZ). Acceptance 
of this document constitutes agreement by the recipient that no previously unpublished information contained 
herein will be published or disclosed without the prior written approval of IMDZ, with the exception that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate institutional review boards (IRBs)/independent ethics committees (IEC) 
under the condition that the personnel have agreed to keep this information confidential. The foregoing shall not 
apply to disclosure required by governmental regulations or laws; however, IMDZ shall be promptly notified of 
any such disclosure. 
 
 
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CMB305 
Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 2 of 94 
SPONSOR’S AND INVESTIGATOR’S SIGNATURE PAGE 
Study Number: 
IMDZ-04-1702 
Product Name(s): 
CMB305 
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Determine the 
Efficacy and Safety of CMB305 in Unresectable Locally-advanced or Metastatic 
NY-ESO-1+ Synovial Sarcoma Subjects Following First-line Systemic Anti-cancer 
Therapy 
Document Date: 
19 September 2018 V2.1 DK 
As principal investigator, I agree to: 
• 
Keep all documentation supplied to me or 
developed by me concerning this study, and that 
has not been previously published, in the strictest 
confidence. This documentation includes, but is not 
limited to, this study protocol, the CMB305 
Investigator’s Brochure and electronic case report 
forms (eCRFs). Maintain all information supplied 
by the sponsor in confidence and, when this 
information is submitted to an IRB/IEC, ethical 
review committee, or another group, it will be 
submitted with a designation that the material is 
confidential. 
• 
Not commence without prior written approval of a 
properly constituted institutional review board 
(IRB) or independent ethics committee (IEC). No 
changes will be made to the study protocol without 
prior written approval of Immune Design Corp. 
(IMDZ) and the IRB/IEC, except where necessary 
to eliminate an immediate hazard to subjects 
• 
Implement and conduct the study diligently and in 
strict compliance with the protocol, Good Clinical 
Practice (GCP), and all applicable laws and 
regulations. 
• 
Accurately transfer all required data from each 
subject’s source document to the eCRFs. Keep a 
complete and accurate accounting during and at the 
completion of the trial of all procedures performed 
with the drug provided by the sponsor. 
• 
Allow authorized representatives of IMDZ or 
regulatory authority representatives to conduct 
on-site visits to review and audit the study 
documentation. I will personally meet with these 
representatives at mutually convenient times to 
answer any trial-related questions. 
I have read this protocol and agree to conduct the study as outlined herein, in accordance with International Council 
for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices 
and comply with the obligations and requirements of clinical investigators and all other requirements listed 
in 21 Code of Federal Regulations (CFR) Part 312. 
 
 
Investigator’s printed name 
 
 
 
 
 
Investigator’s signature 
 
Date (DD/MMM/YYYY) 
 
 
 
Institution’s name 
 
 
 Medical Monitor 
Sponsor’s responsible officer 
 
 
 
 
 
Signature 
 
Date (DD/MMM/YYYY) 
 
 
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CMB305 
Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 3 of 94 
SYNOPSIS 
Sponsor: 
Immune Design Corp. (IMDZ) 
Name of Finished Product: 
CMB305 
Name of Active Ingredients: 
• 
LV305 (lentiviral vector [LV] encoding New York esophageal squamous cell carcinoma-1 
[NY-ESO-1] gene)  
• 
G305 (NY-ESO-1 recombinant protein plus glucopyranosyl lipid A in stable emulsion 
[GLA-SE])  
Study Title: 
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Determine the Efficacy and Safety 
of CMB305 in Unresectable Locally-advanced or Metastatic NY-ESO-1+ Synovial Sarcoma Subjects 
Following First-line Systemic Anti-cancer Therapy 
Study Number: 
IMDZ-04-1702 
Study Phase: 3 
Primary Objective:  
• 
Evaluate the efficacy of CMB305 versus placebo using: 
o Progression-free survival (PFS), by investigator assessment, using Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 
o Overall survival (OS) 
Secondary Objectives: 
• 
Evaluate the efficacy of CMB305 versus placebo using: 
o Time- to-next treatment (TTNT) 
o Distant metastasis-free survival (DMFS) 
o Objective response rate (ORR) (defined by RECIST v1.1) 
• 
Evaluate the safety and tolerability of CMB305 versus placebo 
• 
Evaluate subject quality of life (QoL) 
Exploratory Objective: 
o Evaluate the anti-NY-ESO-1 immune response and histologic and molecular changes in 
peripheral blood and tumor tissue and their association with clinical outcomes 
Study Design: 
This is a global, randomized, double-blind, placebo-controlled, phase 3 study designed to evaluate the 
efficacy and safety of the CMB305 vaccine regimen versus placebo in subjects with synovial sarcoma 
expressing NY-ESO-1.  
To be eligible, subjects must be receiving a first-line systemic anti-cancer therapy for unresectable 
locally-advanced or metastatic synovial sarcoma and have no evidence of progression at the time of 
randomization.  
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
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Page 4 of 94 
The study will consist of 5 periods: Pre-screening, Screening, Treatment, Post-treatment, and 
Long-term Follow-up.  
The schedule of events is presented in Table 1 for the Pre-Screening and Screening periods and in 
Table 2 for the Treatment through the Long-term Follow-up periods. Study flow diagrams for subjects 
who received either a course of 4 cycles, 6 cycles, or 8 cycles of first-line systemic anti-cancer therapy 
are presented in Appendix 5, Figure 4, Figure 5 or Figure 6, respectively. A study flow diagram for 
subjects who have had local regional therapy after first-line systemic anti-cancer therapy is presented in 
Appendix 5, Figure 7. 
Pre-screening period: 
The Pre-screening period of up to 151 days (Day -180 to Day -29) commences at the time the subject 
and/or their legally authorized representative sign the Pre-screening informed consent form 
(ICF)/assent form. The Pre-screening period ends at the time the subject and/or their legally authorized 
representative sign the Main Study ICF/assent form. 
Before any Pre-screening procedures are performed, subjects aged ≥18 years or legally authorized 
representatives of subjects <18 years will provide written consent on the Pre-screening ICF, and 
subjects aged 12 to <18 years will provide written assent. At the time of Pre-screening, subjects must 
still be receiving treatment with first-line systemic anti-cancer therapy. The following will be evaluated 
during the Pre-screening visit: 
• 
Radiographic disease response assessment obtained at the standard-of-care time point by the 
investigator using RECIST v1.1   
• 
Immunohistochemistry (IHC) test for the presence of NY-ESO-1 in an archival tumor tissue or 
fresh tumor tissue biopsy (tumor tissue may be from an archived sample obtained within 
18 months before signing the Pre-screening ICF/assent form)  
Once the investigator confirms 1) the subject has no evidence of progression (using RECIST v1.1) and 
2) the IHC test results for NY-ESO-1 are positive (≥1% expression), then the subject and/or their 
legally authorized representative will sign the Main Study ICF/assent form.  
Screening period: 
The duration of the Screening period of up to 28 days (Day -28 to Day -1) and begins on the date the 
subject and/or their legally authorized representative sign the Main Study ICF/assent form and ends at 
time of randomization. 
After satisfying the Pre-screening criteria, subjects aged ≥18 years and legally authorized 
representatives of subjects <18 years will provide written consent on the Main Study ICF, and subjects 
aged 12 to <18 years will provide written assent for study participation. Once the appropriate Main 
Study ICF/assent form is signed, subjects will undergo additional eligibility assessments and the 
investigator will confirm there is no evidence of progression (using RECIST v1.1). The disease status 
will be assessed by the investigator (using RECIST v1.1) through comparison of the most recent 
baseline images obtained during Screening to both 1) the images obtained prior to initiation of first-line 
systemic anti-cancer therapy and 2) the images obtained per standard-of-care during first-line systemic 
anti-cancer therapy to confirm there is no evidence of progression prior to randomization. Investigator 
assessment of radiographic images confirming best response (stable disease [SD] or better) to first-line 
systemic anti-cancer therapy using RECIST v1.1 will be entered into an electronic case report form 
(eCRF). Subjects who have a tumor response of SD with evidence of ≥15% to 20% increase in tumor 
burden will be submitted for Central Review to adjudicate the investigator’s assessment of tumor 
response prior to randomization. Radiographic images from both Screening and Pre-Screening will also 
be submitted to an independent review committee (IRC) for storage. The stored images will be 
available for evaluation by a central reader, if requested by the sponsor. After completion of Screening 
assessments and confirmation that the subject has met all eligibility requirements, the subject will be 
randomly assigned to one of the treatment arms using a central randomization system on Day 1.  
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 5 of 94 
Treatment period: 
The Treatment period will begin on the day of randomization (Day 1), which is to be within 28 days 
after the last dose of first-line systemic anti-cancer therapy or the last day of local regional therapy, if 
applicable, and will continue until investigator-determined progressive disease (PD) (using RECIST 
v1.1), unacceptable toxicity, or 1 year after the first dose, whichever occurs first.  
Subjects who meet eligibility criteria will be randomly assigned in a 1:1 ratio to receive one of the 
following centrally randomized treatments: 
o Arm A: Placebo 
o Arm B: CMB305 
An interactive response technology (IRT) system will use the following stratification factors at the time 
of randomization: 
o Disease status at screening: locally advanced unresectable (LAUR) vs metastatic 
o Tumor response during screening: stable disease (SD)/partial response (PR) vs complete 
response (CR)/no evidence of disease (NED)  
o Baseline presence of anti-NY-ESO-1 antibody (yes vs no) 
Subjects who are randomly allocated to the placebo arm will not be permitted to cross-over to the 
CMB305-containing treatment arm at any time before study closure.  
Tumor imaging assessments will be performed every 8 weeks after Day 1 and radiographic evidence of 
disease progression will be determined by the investigator using RECIST v1.1. Subjects with a global 
deterioration of health status requiring discontinuation of study treatment but without objective 
evidence of disease progression (symptomatic deterioration) will be considered as having PD for the 
purpose of determining PFS. Radiographic images (e.g., computed tomography [CT] scan or magnetic 
resonance imaging [MRI]) will also be submitted to an independent review committee (IRC) for 
storage and will be available for evaluation by a central reader, if requested by the sponsor. Details for 
the collection and evaluation of radiographic images are included in the Radiology Manual provided to 
the study sites.  
Tumor biopsy samples for NY-ESO-1 expression will be obtained from all subjects during the Pre-
screening period (either archival tumor tissue or a fresh biopsy sample).  All subjects will provide 
peripheral blood samples for anti-NY-ESO-1 antibody assay for stratification during screening.  
Quality of life will be assessed up to 12 months from Day 1. 
Safety will be monitored by evaluating the frequency and severity of adverse events (AEs), serious 
adverse events (SAEs), clinical laboratory abnormalities, immunogenicity, and persistence. Local 
laboratory test values will be used for treatment decisions and subject care; central laboratory test 
values will be used in the analysis of safety.  
In addition, at only select US sites, the following will be collected: 
Peripheral blood samples for the anti-NY-ESO-1 T cell and antibody assays will be obtained prior to 
start of study treatment from subjects on Day 1, Day 92, and Day 365 for subjects who have not had a 
progression event. A tumor biopsy will be obtained at screening, Day 92, and Day 365 for subjects who 
have not had a progression event. An additional tumor biopsy at time of progression event will be 
encouraged.    
Post-treatment period (for subjects who discontinue study treatment for reasons other than disease 
progression): 
The Post-treatment period will begin at the end of treatment and will continue until 
investigator-determined radiographic PD (using RECIST v1.1) is documented.  
Subjects will continue to undergo imaging until the time of disease progression. At the time of disease 
progression, subjects will enter the Long-term Follow-up period. 
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 6 of 94 
Long-term Follow-up period: 
The Long-term Follow-up period will begin at the time investigator-determined PD (using 
RECIST v1.1) is documented and will continue for up to 5 years, until the date of death, or until 
sponsor notification of study closure.  
Study Population:  
Approximately 248 subjects who have synovial sarcoma expressing NY-ESO-1 will be enrolled and 
randomly assigned in a 1:1 ratio to treatment with CMB305 or placebo. 
Inclusion Criteria: 
1. Have documented histologic diagnosis of synovial sarcoma (may be confirmed by the presence 
of t(X;18) (p11:q11) translocation or B cell lymphoma 6 corepressor [BCOR] rearrangement) 
and have disease that is unresectable locally-advanced or metastatic prior to the start of first-
line systemic anti-cancer therapy. Unresectable is defined as having evidence of positive 
surgical margins after resection of primary disease or a documented surgical consultation with 
assessment of an inability of resection to provide clear margins.  
2. Have IHC test results from tumor biopsy for NY-ESO-1 that are positive (≥1% expression). 
3. At the time of Pre-screening, subjects must be receiving a first-line anthracycline or 
ifosfamide-containing systemic anti-cancer therapy regimen (single agent ifosfamide, single 
agent anthracycline, combination anthracycline plus ifosfamide, or combination anthracycline 
plus olaratumab). Subjects must have received at least 4 cycles but no more than 8 cycles of 
therapy (or no more than 180 days of systemic anti-cancer therapy). Subjects who have 
received local regional therapy (surgical resection, radiotherapy, radiofrequency ablation, or 
cryotherapy) are eligible if they meet the following: 
a. Subjects whose disease converted to operable after completion of first-line 
chemotherapy are eligible, if local regional therapy (surgical resection, radiotherapy, 
radiofrequency ablation or cryotherapy) is completed within the 180-day period from 
the date of the first dose of first-line systemic anti-cancer therapy. Please note that an 
extension of this 180-day may be allowed per Section 3.3 of the protocol. 
b. Subjects whose disease remains inoperable after completion are eligible, if 
radiotherapy is completed within the 180-day period from the date of the first dose of 
first-line systemic anti-cancer therapy and there is no evidence of progressive disease 
prior to initiation of radiotherapy. Please note that an extension of this 180-day period 
may be allowed per Section 3.3 of the protocol. 
c. Subjects who have PD ≤6 months after date of last dose of adjuvant/neoadjuvant 
systemic anti-cancer therapy or date of last day of local regional therapy are not 
eligible. 
4. Must have documentation of no evidence of disease progression of the tumor during or after 
completion of first line systemic anti-cancer therapy as determined by the investigator using 
RECIST v1.1 guidelines. Subjects who have a tumor response of SD with evidence of ≥15% to 
20% increase in tumor burden will be submitted for Central Review to adjudicate the 
investigator’s assessment of tumor response prior to randomization. Subjects with NED are 
eligible. 
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
6. Age ≥12 years. 
7. Have a life expectancy of at least 6 months, as determined by the investigator. 
8. If a female of child-bearing potential (FCBP), willing to undergo pregnancy testing and agree 
to use at least 1 highly-effective contraceptive method; such methods include combined 
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
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Page 7 of 94 
estrogen and progesterone-containing hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), or progesterone only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner or true sexual abstinence (when this is in line with the preferred and usual lifestyle of 
the subject, refraining from heterosexual intercourse during the entire period of risk associated 
with study treatments) during the dosing period and for 1 month (which is the duration of a 
menstruation cycle) after administration of the last dose of CMB305. More stringent 
contraception criteria should be followed if requested by local regulatory authorities.  
9. If male and sexually active with a FCBP, must be surgically sterile (i.e., vasectomy) or agree to 
use highly-effective contraception, such as latex condom, during the dosing period and for 
3 months (which is the duration of a sperm cycle) after administration of the last dose of 
CMB305. More stringent contraception criteria should be followed if requested by local 
regulatory authorities. 
10. Have recovered from the toxic effects (except alopecia) to grade 2 or better from systemic 
anti-cancer therapy according the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.03 (or newer). 
Exclusion Criteria: 
1. Have received the last dose of first-line systemic anti-cancer therapy or date of most recent 
local regional therapy >28 days prior to Day 1. 
2. Have received prior anti-NY-ESO-1 therapy. 
3. Have received first-line systemic anti-cancer therapy other than an anthracycline-containing or 
ifosfamide-containing regimen (single agent anthracycline, single agent ifosfamide, 
combination anthracycline plus ifosfamide, or combination anthracycline plus olaratumab). 
4. Have received treatment with systemic immunomodulatory agents (including, but not limited 
to, interleukin-2) within 28 days prior to administration of the first dose of CMB305 
(i.e., Day 1) or 5 half-lives of the drug, whichever occurs sooner. 
5. Have significant immunosuppression from: 
a. Concurrent, recent (≤21 days prior to administration of the first CMB305 dose 
[i.e., Day 1]), or anticipated need for chronic treatment with systemic immunosuppressive 
dose of corticosteroids (the use of physiologic doses of corticosteroids may be approved 
after consultation with the sponsor). The use of topical or inhaled corticosteroids and 
mineralocorticoids (e.g., fludrocortisone) is allowed. 
b. Other immunosuppressive medications (≤21 days prior to administration of the first 
CMB305 dose [i.e., Day 1]) including, but not limited to, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents or conditions 
such as common variable hypogammaglobinemia. 
6. Have psychiatric, other medical illness, or any other condition that, in the opinion of the 
investigator, prevents compliance with the study procedures or the ability to provide valid 
informed consent (or assent for subjects 12 to <18 years of age). 
7. Have a history of uncontrolled autoimmune disease. Uncontrolled disease is defined as one 
requiring chronic supra-physiologic doses of systemic steroids or other forms of 
immunosuppression or that requires a recently increased or newly prescribed dose within 
28 days of Screening. 
8. Have significant electrocardiogram (ECG) finding or cardiovascular disease, such as New 
York Heart Association cardiac disease (>Class II), myocardial infarction within the previous 
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
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Page 8 of 94 
3 months before administration of the first dose of CMB305 (i.e., Day 1), unstable arrhythmias, 
or unstable angina. 
9. Have inadequate organ function as evidenced by: 
a. Marrow:  
i. Absolute neutrophil count (ANC) ≤1000/mm3 
ii. Platelets <75,000/mm3 
iii. Hemoglobin (Hgb) <8 g/dL 
iv. Lymphocytes ≤800/mm3. 
b. Hepatic:  
i. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0× the upper 
limit of normal (ULN) for subjects without liver metastases or ≥5× ULN for subjects 
with liver metastases  
ii. Total serum bilirubin >1.5× ULN (or direct bilirubin ≥1.5 ULN for subjects with total 
bilirubin levels <1.5× ULN). Subjects with Gilbert’s disease may be included if their 
total bilirubin is <3.0 mg/dL). 
c. Renal: 
i. Creatinine clearance <0.5 x LLN.  
d. For subjects not using blood thinners:  
i. Prothrombin time (PT) >1.5× ULN or international normalized ratio (INR) 
>1.5× ULN 
ii. Partial thromboplastin time (PTT) >1.5× ULN 
iii. Subjects using blood thinners must be able to modify their normal dosing regimen to 
allow for injections of investigational product. 
10. History of other cancer within 3 years (except for appropriately treated carcinoma in situ of the 
cervix, non-melanoma skin carcinoma, Stage I uterine cancer, localized prostate cancer treated 
with curative intent, ductal carcinoma in situ treated surgically with curative intent, or other 
cancers with a similar outcome). 
11. Evidence of active tuberculosis or recent (<1 week prior to first scheduled dosing on Day 1) 
clinically-significant infection requiring systemic therapy. (Prophylactic antibiotics [e.g., for 
prevention of a urinary tract infection or chronic obstructive pulmonary disease] are permitted.) 
12. Evidence of active hepatitis B (HepB), hepatitis C (HepC), or human immunodeficiency virus 
(HIV) infection:  
a. Active HepB is defined as having a positive HepB surface antigen (HBsAg) test result at 
Screening.  
b. Subjects with past/resolved HepB infection (defined as having a negative HBsAg test and a 
positive antibody to HepB core antigen [anti-HBc] antibody test) are eligible. HepB viral 
DNA results must be negative in these subjects prior to the first scheduled dosing on 
Day 1.  
c. Subjects with test results positive for HepC antibody are eligible only if polymerase chain 
reaction (PCR) testing is negative for HepC viral RNA.  
d. Subjects who are HIV positive. 
13. Have had live, attenuated vaccine administered within 28 days prior to the first scheduled 
dosing on Day 1 or anticipate that such a live, attenuated vaccine will be required during the 
study. 
14. Have a history of brain metastasis. 
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
Confidential 
Page 9 of 94 
15. Have received cancer therapies, including chemotherapy, radiation, biologic or kinase 
inhibitors, granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony 
stimulating factor (GM-CSF) within 3 weeks prior to the first scheduled CMB305 dosing. 
16. A FCBP who is pregnant, is planning to become pregnant, or is breast feeding; or a male who 
is sexually active with a FCBP who is planning to become pregnant. 
17. Hypersensitivity to an ingredient of either LV305 or G305  
Reference Product, Dose, and Mode of Administration: 
Arm A:  
• 
Matching placebo for LV305 will be normal saline and will be administered subcutaneously 
(SC) on Days 1, 22, 50, and 78. 
• 
Matching placebo for G305 will be administered intramuscularly (IM) on Days 36, 64, 92, and 
then at 8-week intervals up to 1 year or until investigator-determined PD (using RECIST v1.1) 
is documented or unacceptable toxicity, whichever occurs first. The G305 placebo will have 
2 components: 
o Matching placebo for the NY-ESO-1 component of G305 will be normal saline 
o Matching placebo for the GLA-SE component of G305 will be the non-active stable 
emulsion (SE) 
Test Product, Dose, and Mode of Administration:  
Arm B: CMB305 (sequentially administered LV305 and G305) 
• 
LV305 at a dose of 4 × 1010 vector genomes (vg) will be administered SC on Days 1, 22, 50, 
and 78. 
• 
G305 is composed of 5 µg GLA-SE admixed with 250 µg of NY-ESO-1 protein. G305 will be 
administered IM on Days 36, 64, 92, and then at 8-week intervals up to 1 year or until 
investigator-determined PD (using RECIST v1.1) is documented or unacceptable toxicity, 
whichever occurs first. 
Duration of Treatment:  
Subjects in Arm A will receive placebo according to the same schedule for CMB305 for up to 1 year 
after Day 1 or until investigator-determined PD (using RECIST v1.1) is documented or the occurrence 
of unacceptable toxicity, whichever occurs first. 
Subjects in Arm B will receive CMB305 induction through Day 92 and then booster vaccines at 
8-week intervals up to 1 year after Day 1 or until investigator-determined PD (using RECIST v1.1) is 
documented or the occurrence of unacceptable toxicity, whichever occurs first. 
 
 
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Immune Design Corp. 
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19 September 2018 v2.1 DK 
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Efficacy Assessments: 
Primary: 
• 
PFS, by investigator assessment, using RECIST v1.1 
• 
OS 
Secondary: 
• 
TTNT 
• 
DMFS  
• 
ORR (defined by RECIST v1.1) 
• 
Safety and tolerability 
• 
QoL evaluated using the EuroQol 5-Dimension 5 Level (EQ-5D-5L) for subjects ≥18 years of 
age or using the EuroQol 5-Dimension Youth (EQ-5D-Y) for subjects 12 to <18 years of age 
Exploratory: 
• 
Intratumoral and peripheral blood anti-NY-ESO-1 immune changes 
Safety Assessments: 
• 
The nature, frequency, and severity of AEs and SAEs 
• 
Clinical laboratory parameters (hematology, chemistry, and urinalysis), as measured by the 
central laboratory 
• 
Vital sign measurements (blood pressure, heart rate, temperature, and respiratory rate) 
Statistical Methods:  
Multiple Comparisons: 
The study is to be conducted with PFS and OS as 2 primary endpoints with the goal to support 
regulatory approval based on PFS or OS. The overall type I error probability is specified to be 1-sided 
0.025 with success for either 1 of the 2 primary endpoints defining study success using the Bonferroni 
method to specify that each endpoint will be evaluated using a type I error probability of 1-sided 
0.0125 to protect the overall type I error probability. 
Sample Size Calculation: 
A total of 248 subjects will be randomly allocated in a 1:1 ratio such that 124 subjects will be in each 
of the 2 treatment arms. The study is powered at 90% with 179 death events required to detect a hazard 
ratio (HR) of 0.59, which corresponds to a 41% reduction in the risk of death, and an approximately 
69% increase in median survival compared with placebo median survival of 20 months, and uses a 
1-sided log-rank test, with an alpha of 0.0125, a 1:1 randomization ratio, and an interim OS 
non-binding futility analysis with the boundary HR = 1.0 at 67% of information time (120 death events 
from the 179 required death events for the final OS analysis). A total of 248 subjects will yield the 
179 events required, under the assumption of 24 months for enrollment (25% of subjects enrolled in the 
first year and 75% of subjects enrolled in the second year) plus 42 additional months for follow-up.  
With 141 PFS events, the study is powered at 90% to detect a HR of 0.55, which corresponds to a 45% 
reduction in the risk of PFS events (either disease progression or death), and an approximately 
82% increase in median PFS compared with the placebo median PFS of 4 months, and uses a 1-sided 
log-rank test, with an alpha of 0.0125, and a 1:1 randomization ratio. 
 
 
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Immune Design Corp. 
Clinical Trial Protocol: IMDZ-04-1702 
19 September 2018 v2.1 DK 
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Page 11 of 94 
Analysis Sets: 
For the purpose of statistical analysis, there are 3 analysis sets: Intent-to-Treat set (ITT), Efficacy 
Evaluable set (EE), and Safety set. 
• 
The ITT set consists of all subjects randomized. All analyses of this set will be based on the 
randomized treatment arm to which the subjects are assigned. Efficacy analyses performed on 
the ITT set will be considered to be the primary indicator of efficacy. 
• 
The EE set consists of all subjects without major protocol violations, who have received at 
least 1 dose of study drug, and have the baseline and at least 1 post-baseline tumor assessment 
available. The EE set will be analyzed according to the treatment received. Efficacy analyses 
performed in the EE set will be considered to be supportive.  
• 
The Safety set consists of all subjects taking any amount of study drug. The Safety set is the 
primary set for safety analyses including AEs and clinical laboratory data. Study treatment 
exposure also will be summarized using the Safety set. Analyses performed in the Safety set 
will be considered to be supportive. 
Primary Efficacy Analyses: 
The 2 primary efficacy endpoints of PFS and OS will be compared between CMB305 and placebo. OS 
is defined as the time from randomization to the date of death. PFS by investigator’s assessment is 
defined as the time from randomization to the investigator-determined (using RECIST v1.1) date of 
disease progression or death. Radiographic images will be collected and assessed using RECIST v1.1 
until the time the subject begins a new line of treatment.  
For the purpose of the PFS analysis, any one of the following events, whichever occurs first, will be 
used: 
• 
Disease progression per RECIST v1.1 (See Appendix 1, Table 7 [Eisenhauer 2009]) 
• 
Symptomatic deterioration (global health deterioration) as described by RECIST v1.1 
• 
For subjects with NED at the time of randomization, any new malignant lesion that occurs after 
randomization per RECIST v1.1 (See Appendix 1, Table 8.) 
Otherwise, subjects who do not have disease progression or have not died will be censored at the date 
when the last tumor imaging assessment determines a lack of progression. If a subject begins a new 
anti-cancer therapy or has radiotherapy, surgery, or other local regional therapy at a lesion site prior to 
documented progression, the subject will be censored at the last assessment where the subject was 
documented as progression free prior to the intervention. Subjects with 2 or more missing response 
assessments (except for subjects with symptomatic deterioration) prior to a visit with documented 
progression (or death) will be censored at the last visit where the subject was documented to be 
progression free. Progression-free survival by investigator’s assessment, will be the primary PFS 
analysis. Progression-free survival by independent radiological review will be the supportive analysis.  
The null hypothesis, which is that there is no difference in OS/PFS between CMB305 and placebo, will 
be tested using a stratified log-rank test stratified by: disease status at screening (locally advanced 
unresectable versus metastatic), tumor response during screening (PR/SD versus CR/NED) and 
baseline presence of anti-NY-ESO-1 antibody (yes versus no). 
The null hypothesis will be rejected, and it will be concluded that OS/PFS on CMB305 is superior to 
that on placebo in subjects with synovial sarcoma if the 1-sided p value at the final analysis for the 
stratified log-rank test is less than the pre-specified alpha of 0.0125 as discussed above in the Multiple 
Comparisons section. The associated HR and its 2-sided 97.5% and 95% confidence interval (CI) will 
be provided using the stratified Cox proportional hazard model. The Kaplan-Meier curve will 
summarize OS/PFS graphically by treatment arm. Tabular summaries of the Kaplan-Meier curves, 
including the median, will be provided by treatment. The 1-year and 18-month OS/PFS rate will be 
 
 
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provided by treatment. The final PFS analysis will be conducted when a total of 141 PFS events occur. 
The final OS analysis will be conducted when a total of 179 deaths occur. 
Secondary Efficacy Analyses: 
The secondary efficacy endpoints of TTNT, DMFS, ORR, and QoL using the EQ-5D-5L or EQ-5D-Y 
will be compared between treatment arms. 
The secondary efficacy endpoints will only be evaluated if at least 1 of the 2 primary efficacy 
endpoints demonstrate superiority for CMB305 over placebo. Furthermore, to control the overall 
family-wise Type I error rate at 1-sided α = 0.025 for the secondary efficacy endpoints, the secondary 
efficacy endpoint of TTNT will be tested first at 1-sided alpha of 0.025. DMFS will be tested at 1-sided 
alpha of 0.025 only if TTNT shows significant improvement. 
Exploratory Analyses: 
The baseline anti-NY-ESO-1 immune response and histologic and molecular changes in peripheral 
blood and tumor tissue and their association with clinical outcomes will be explored. In addition, a 
relationship between an induced anti-NY-ESO-1 immune response as well as tumor tissue changes 
during study treatment and clinical outcomes will be evaluated using peripheral blood and tumor tissue 
biopsies collected during study treatment at select sites.   
Safety Analyses: 
Safety will be assessed primarily based on reported AEs. A treatment-emergent adverse event (TEAE) 
is an AE with an onset on or after the initiation of study treatment, or a pre-existing condition that 
worsens after initiation of study treatment (i.e., increase in severity). Medical events of interest, 
immune-mediated events and AEs that occur more than 30 days after the last dose, and that are deemed 
as related to the study drug will be included as TEAEs. TEAEs occurring from the time of the first dose 
through 30 days after the last dose of the study drug and medical events of interest, immune-mediated 
events and related AEs will be summarized. All AEs will be coded using the Medical Dictionary for 
Regulatory Affairs® (MedDRA v20.0 or newer). TEAEs will be tabulated by system organ class, 
preferred term, treatment, and will be further categorized by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE [v4.03 or newer]) grade, and by relationship to 
the study drug. Clinically significant laboratory abnormalities will be reported as AEs. The incidence 
of each AE will be provided as the total number of subjects that experience the AE, as well as the 
percentage of the population that this represents. If an AE is reported more than once during treatment 
for a given subject, the worst grade of severity and the most conservative relationship will be presented 
in the summary tables. 
AEs will also be listed for individual subjects, along with information regarding onset, duration, grade, 
relationship to the study drug, and outcome. AEs that lead to withdrawal from study treatment will be 
listed and summarized. Tabulations and listings of SAEs and deaths will also be generated. 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
obtained from the local laboratory as defined by the list of reference ranges from the investigational 
site local laboratory. In some cases, significant changes in local laboratory values within the normal 
range will require similar judgment. An abnormal laboratory value performed by the local laboratory 
that is not already associated with an AE is to be recorded as an AE only if any one of the following 
criteria is met: 
• 
An action on the study drug is made as a result of the abnormality 
• 
Intervention for management of the abnormality is required 
• 
At the discretion of the investigator should the abnormality be deemed clinically significant 
 
 
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Data Monitoring Committee and Interim Analysis: 
A data monitoring committee (DMC) will be established with the responsibility of safeguarding the 
interest of study subjects and maintaining the overall integrity of the study. The DMC will review 
safety data periodically during the study and will evaluate the results of final PFS analysis and a 
planned interim OS analysis to assess futility with the possibility of a recommendation for stopping the 
study early because of futility. The OS non-binding futility boundary is set to be HR=1.0. It will be 
conducted at 67% of information time (120th death event from the 179 required death events for final 
OS analysis). If deemed necessary by the DMC, unblinded data may be reviewed on a case-by-case 
basis. The sponsor will remain blinded to study treatment until either 1 of the 2 primary endpoints is 
met or until the study has been stopped early. Details of the DMC function will be governed by a DMC 
Charter developed by the sponsor and accepted by DMC members. 
Date of Original Approved Protocol: 30 January 2018 
Date of Most Recent Protocol Amendment (if applicable): 19 September 2018 
 
 
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TABLE OF CONTENTS 
SPONSOR’S AND INVESTIGATOR’S SIGNATURE PAGE .................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................14 
LIST OF TABLES .......................................................................................................................18 
LIST OF FIGURES .....................................................................................................................18 
LIST OF APPENDICES .............................................................................................................18 
PROTOCOL REVISION HISTORY ........................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................20 
1.0 
INTRODUCTION............................................................................................................23 
1.1 
Background ............................................................................................................23 
1.1.1 
CMB305 Is a “Prime-boost” Immunotherapy Targeting NY-ESO-1 ...23 
1.1.2 
Overview of Data Generated from Initial Clinical Development of 
CMB305 ................................................................................................24 
1.1.3 
Synovial Sarcoma: An Ultra-Rare Disease with a Serious Unmet 
Medical Need ........................................................................................26 
2.0 
STUDY OBJECTIVES ....................................................................................................28 
2.1 
Primary Objective ..................................................................................................28 
2.2 
Secondary Objectives.............................................................................................28 
2.3 
Exploratory Objective ............................................................................................29 
3.0 
INVESTIGATIONAL PLAN .........................................................................................29 
3.1 
Overall Study Design and Plan ..............................................................................29 
3.1.1 
Pre-screening Period .............................................................................29 
3.1.2 
Screening Period ...................................................................................30 
3.1.3 
Treatment Period ...................................................................................30 
3.1.4 
Post-treatment Period (For Subjects Who Discontinue Study 
Treatment for Reasons Other Than Disease Progression) ....................32 
3.1.5 
Long-term Follow-up Period.................................................................32 
3.2 
Rationale for Study Design and Control Group .....................................................38 
3.3 
Study Duration and Dates ......................................................................................39 
4.0 
STUDY POPULATION SELECTION ..........................................................................40 
4.1 
Study Population ....................................................................................................40 
4.2 
Inclusion Criteria ...................................................................................................40 
4.3 
Exclusion Criteria ..................................................................................................42 
5.0 
STUDY TREATMENTS .................................................................................................44 
5.1 
Description of Treatments......................................................................................44 
5.1.1 
CMB305 ................................................................................................44 
 
 
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5.1.1.1 
LV305 ............................................................................................44 
5.1.1.2 
G305 ...............................................................................................45 
5.1.2 
Placebo ..................................................................................................46 
5.1.2.1 
LV305 Placebo...............................................................................46 
5.1.2.2 
G305 Placebo .................................................................................46 
5.2 
Treatments Administered .......................................................................................46 
5.3 
Selection and Timing of Dose for Each Subject ....................................................47 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................48 
5.5 
Blinding..................................................................................................................48 
5.6 
Treatment Modification and Discontinuation ........................................................48 
5.6.1 
Treatment Interruptions .........................................................................48 
5.6.2 
Treatment Delay ....................................................................................49 
5.6.3 
Treatment Discontinuation ....................................................................49 
5.7 
Concomitant Therapy.............................................................................................49 
5.8 
Restrictions ............................................................................................................50 
5.8.1 
Prior Therapy ........................................................................................50 
5.8.2 
Prohibited Concomitant Therapy ..........................................................50 
5.9 
Treatment Compliance ...........................................................................................51 
5.10 
Packaging and Labeling .........................................................................................51 
5.11 
Storage and Accountability ....................................................................................51 
6.0 
STUDY PROCEDURES .................................................................................................52 
6.1 
Informed Consent or Assent ..................................................................................52 
6.2 
Demographics and Medical History ......................................................................52 
6.3 
Efficacy Assessments.............................................................................................53 
6.3.1 
Tumor Imaging and Response ..............................................................53 
6.3.1.1 
Imaging at Pre-screening ...............................................................53 
6.3.1.2 
Imaging at Screening .....................................................................54 
6.3.1.3 
Imaging During Treatment to the Time of Disease Progression ...54 
6.3.2 
Immune Response Assessments ............................................................54 
6.3.3 
Tumor Biopsy .......................................................................................56 
6.3.4 
ECOG ....................................................................................................56 
6.3.5 
QoL Assessment ...................................................................................56 
6.4 
Safety Assessments ................................................................................................57 
6.4.1 
Physical Examination ............................................................................57 
6.4.2 
Vital Signs .............................................................................................57 
6.4.3 
Clinical Laboratory Tests ......................................................................57 
 
 
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6.4.3.1 
Laboratory Parameters ...................................................................57 
6.4.3.2 
Sample Collection, Storage, and Shipping ....................................58 
6.4.4 
Electrocardiogram .................................................................................58 
6.4.5 
Concomitant Medication Use ................................................................58 
6.4.6 
LV305 Persistence ................................................................................59 
6.4.7 
Adverse Events Assessments ................................................................59 
6.4.7.1 
Adverse Event Collection Period ...................................................59 
6.4.7.2 
Adverse Event Reporting ...............................................................60 
6.4.7.3 
Serious Adverse Event Reporting ..................................................60 
6.4.7.4 
Medical Event of Interest Reporting ..............................................61 
6.4.7.5 
Definitions of Adverse Event.........................................................61 
6.4.7.6 
Adverse Event Severity..................................................................64 
6.4.7.7 
Relationship ...................................................................................64 
6.4.7.8 
Clinical Laboratory Adverse Events ..............................................65 
6.4.8 
Pregnancy ..............................................................................................66 
6.4.9 
HIV Screening Assessment ...................................................................66 
6.4.10 
Immune-mediated Events......................................................................67 
6.5 
Removal of Subjects from the Trial or Study Drug ...............................................67 
6.5.1 
Removal from Trial ...............................................................................67 
6.5.2 
Removal from Study Drug ....................................................................68 
6.6 
Appropriateness of Measurements .........................................................................68 
7.0 
PLANNED STATISTICAL METHODS .......................................................................69 
7.1 
Determination of Sample Size ...............................................................................69 
7.2 
Analysis Sets ..........................................................................................................69 
7.3 
Demographics and Baseline Characteristics ..........................................................69 
7.4 
Primary Endpoints .................................................................................................70 
7.5 
Secondary Endpoints .............................................................................................70 
7.6 
Exploratory Assessments or Analyses ...................................................................70 
7.7 
Efficacy Analysis ...................................................................................................70 
7.7.1 
Primary Efficacy Analyses:...................................................................70 
7.7.2 
Secondary Efficacy Analyses:...............................................................71 
7.7.2.1 
Time to Next Treatment .................................................................71 
7.7.2.2 
Distant Metastasis-Free Survival ...................................................72 
7.7.2.3 
Other Secondary Efficacy Endpoints .............................................72 
7.8 
Safety Analysis ......................................................................................................72 
7.9 
Exploratory Analysis .............................................................................................73 
 
 
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7.10 
Multiplicity ............................................................................................................73 
7.11 
Data Monitoring Committee and Interim Analysis ...............................................73 
8.0 
ADMINISTRATIVE CONSIDERATIONS ..................................................................74 
8.1 
List of Personnel and Organizations Responsible for Conduct of the Study .........74 
8.2 
Trial Sponsor:.........................................................................................................74 
8.3 
Sponsor’s Medical Monitor: ..................................................................................74 
8.4 
Clinical Trial Agreement .......................................................................................74 
8.5 
Financial Disclosure by the Investigator................................................................74 
8.6 
Clinical Study Registration and Results Disclosure ..............................................75 
8.7 
Institutional Review Board or Independent Ethics Committee Approval .............75 
8.8 
Ethical Conduct of the Study .................................................................................75 
8.9 
Subject Information, Consent, and Assent .............................................................75 
8.9.1 
Assent for Subjects Under the Age of Consent (Pediatric Subjects) ....76 
8.10 
Subject Confidentiality ..........................................................................................76 
8.11 
Quality Control and Assurance ..............................................................................77 
8.12 
Study Files and Materials.......................................................................................77 
8.13 
Monitoring of the Study .........................................................................................78 
8.14 
Protocol Amendments ............................................................................................79 
8.15 
Audits and Inspections ...........................................................................................79 
8.16 
Electronic Case Report Forms and Study Records ................................................79 
8.17 
Data Monitoring Committee ..................................................................................80 
8.18 
Protocol Compliance ..............................................................................................81 
8.19 
Retention of Data ...................................................................................................81 
8.20 
Clinical Study Report .............................................................................................81 
8.21 
Publication and Disclosure Policy .........................................................................82 
9.0 
REFERENCE LIST .........................................................................................................83 
 
 
 
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LIST OF TABLES 
Table 1 
Schedule of Events for the Pre-Screening and Screening Periods .........................33 
Table 2 
Schedule of Events for the Treatment Period through Long-term Follow-up 
Period .....................................................................................................................35 
Table 3 
At Select US Sites Only:  Immune Response Assessments ...................................55 
Table 4 
Clinical Laboratory Tests (Central Laboratory) ....................................................58 
Table 5 
Adverse Event Severity Assessment ......................................................................64 
Table 6 
Assessment of Relationship ...................................................................................65 
Table 7 
Time Point Response: Subjects with Target (+/- non-target) Disease ...................87 
Table 8 
Disease Response Assessment on Study for Subjects with no Evidence of 
Disease at Study Day 1 ..........................................................................................87 
 
LIST OF FIGURES 
Figure 1 
CMB305 Prime/Boost Regimen ............................................................................23 
Figure 2 
GLA Structure ........................................................................................................46 
Figure 3 
CMB305 or Matching Placebo Dosing Regimen ..................................................47 
Figure 4 
Study Flow Diagram for Subjects Receiving 4-Cycles of First-Line Systemic 
Anti-Cancer Therapy .............................................................................................91 
Figure 5 
Study Flow Diagram for Subjects Receiving 6-Cycles of First-Line Systemic 
Anti-Cancer Therapy .............................................................................................92 
Figure 6 
Study Flow Diagram for Subjects Receiving 8-Cycles of First-Line Systemic 
Anti-Cancer Therapy .............................................................................................93 
Figure 7 
Study Flow Diagram for Subjects Receiving Local Regional Therapy .................94 
 
LIST OF APPENDICES 
Appendix 1: 
Determination of Tumor Response ........................................................................87 
Appendix 2: 
ECOG .....................................................................................................................88 
Appendix 3: 
EUROQOL 5-DIMENSION 5-LEVEL .................................................................89 
Appendix 4: 
EUROQOL 5-DIMENSION-YOUTH ..................................................................90 
Appendix 5: 
Study Flow Diagrams for Subjects Receiving 4-cycles, 6-cycles and 8-cycles 
of First-line Systemic Anti-Cancer Therapy or Local Regional Therapy. .............91 
 
 
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PROTOCOL REVISION HISTORY 
Version 
Date 
Comment 
00 
16 November 2017 
Initial Release 
1.0 
30 January 2018 
IMDZ has revised the protocol to call PFS and OS the “two primary 
endpoints” for this study.  Revisions were made to the Study Synopsis on 
Page 10, 11, 12, and 13; Section 7.4, Primary Endpoints on Page 69; 
Section 7.7.1, Primary Efficacy Analyses on Page 69; Section 7.7.2, 
Secondary Efficacy Endpoints on Page 70; Section 7.10, Multiplicity on 
Page 72; and Section 7.11, Data Monitoring Committee and Interim 
Analysis on Page 72. 
IMDZ has revised the protocol to state that the efficacy analysis performed 
on the ITT set will be the primary indicator of efficacy, and the efficacy 
analyses performed on the EE and Safety sets will be supportive. Revisions 
were made to the Study Synopsis on Page 11 and to Section 7.2 Analysis 
Sets on Page 68. 
Additional revisions made for clarity and consistency 
2.0 
27 April 2018 
The main revisions completed in Version 2.0 of the study protocol are the 
following: 
1. Updated and clarified study stratification factors at the time of 
randomization 
2. Updated Inclusion Criteria to clarify eligibility of subjects who 
have received first-line systemic anti-cancer therapy 
3. Updated Exclusion Criteria to specify which anthracycline-
containing and ifosfamide-containing regimens are allowed 
4. Clarified language regarding collection of plasma for immune 
response assessment and potential exploratory biomarkers for 
CMB305 immunogenicity 
5. Included conduct of a pre-specified sensitivity analysis based on 
the number of cycles and type of prior therapy 
(neoadjuvant/adjuvant chemotherapy and surgery and/or 
radiotherapy) 
6. Added Treatment Modification and Discontinuation Section 
(Section 5.6) 
7. Clarified that treatment modifications (dose reductions or 
increases) will not be permitted as a result of DMC reviews. 
2.1 DK 
19 September 2018 
The main revisions completed in Version 2.1 DK of the study protocol: 
1. Section 4.2 Inclusion Criteria and Section 6.4.8: Updated and 
clarified to contraceptive advice with ‘highly affective’ and ‘true 
sexual abstinence’ 
2. Section 5.5 Blinding: Updated that in emergency situations, the 
responsibility to break the treatment code resides solely with the 
investigator 
3. Section 1.1.2 added language for C131 Arm E clearing the safety 
period for higher dose of LV305   
4. Synopsis and Section 4.3 Exclusion: “17. Hypersensitivity to an 
ingredient of either LV305 or G305” 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
antibody to hepatitis B core antigen 
anti-TNF 
anti-tumor necrosis factor 
AST 
aspartate aminotransferase 
BCOR 
B cell lymphoma 6 corepressor rearrangement 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CR 
complete response 
CT 
computed tomography 
DC 
dendritic cell 
DC-SIGN 
dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin receptor (CD209) 
DMC 
data monitoring committee 
DMFS 
distant metastasis-free survival 
DMPC 
dimyristoylphosphatidylcholine 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EE 
Efficacy Evaluable  
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
EQ-5D-Y 
EuroQol 5-Dimension Youth 
ESMO 
European Society for Medical Oncology 
FCBP 
female of child-bearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GLA 
glucopyranosyl lipid A 
GLA-SE 
glucopyranosyl lipid A stable emulsion 
GLP 
Good Laboratory Practice 
GM-CSR 
granulocyte-macrophage colony-stimulating factor 
GMP 
Good Manufacturing Practice 
HbsAg 
hepatitis B surface antigen 
HEENT 
head, eyes, ears, nose, and throat 
HepB 
hepatitis B 
 
 
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HepC 
hepatitis C 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
IM 
intramuscular(ly) 
IMDZ 
Immune Design Corp. 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
IRT 
interactive response technology 
ITT 
intent to treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
LV 
lentiviral vector 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MEOI 
medical event of interest 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NED 
no evidence of disease 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NY-ESO-1 
New York esophageal squamous cell carcinoma-1 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PBMC  
peripheral blood mononuclear cells  
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Rev 
Regulator of Expression of Virion Proteins (lentivirus accessory protein) 
RR 
response rate 
 
 
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SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SD 
stable disease 
SE 
stable emulsion 
SINV 
Sindbis virus 
SINVar1 
Sindbis virus envelope glycoprotein 
STS 
soft tissue sarcoma 
TEAE 
treatment-emergent adverse event 
TLR4 
toll-like receptor 4 
TTNT 
time-to-next treatment 
ULN 
upper limit of normal 
US 
United States  
vg 
vector genome 
WHO 
World Health Organization 
 
 
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1.0 
INTRODUCTION 
1.1 
Background 
1.1.1 
CMB305 Is a “Prime-boost” Immunotherapy Targeting NY-ESO-1 
Immune Design Corp. (IMDZ) is developing a first-in-class in vivo dendritic cell (DC)- targeting 
active immunotherapy, designated as CMB305 and shown in Figure 1, which combines 
2 different safe and active immunotherapy products administered sequentially in a “prime-boost” 
vaccination regimen to maximize the immune response against NY-ESO-1. One product is 
LV305, a lentiviral vector (LV) derived from the ZVex platform that encodes the NY-ESO-1 
cancer testes antigen and is designed to “prime” the immune system by targeting RNA antigen 
delivery to DCs in vivo. The other product is G305, an immune system “boost” component, 
which is a recombinant NY-ESO-1 protein admixed with the adjuvant glucopyranosyl lipid A 
stable emulsion (GLA-SE), an agonist of toll-like receptor 4 (TLR4) that is highly expressed on 
DCs. The tumor antigen targeted by the CMB305 regimen is the cancer testes antigen, 
NY-ESO-1, which is virtually absent in healthy tissues, but is expressed in many tumor types 
and often associated with a worse prognosis (Gnjatic 2006; Nicholaou 2006; Jungbluth 2001a; 
Komarov 2017). 
Figure 1 
CMB305 Prime/Boost Regimen  
 
Each LV305 dose = 4×1010 vg; each G305 dose = 5 μg dose of GLA plus 250 μg of NY-ESO-1 protein. 
 
Development of CMB305 addresses multiple shortcomings of prior cancer vaccines including 
vaccines targeting DCs ex vivo (Sabado 2017; Anguille 2014). The CMB305 mechanism of 
action is based on the selective in vivo targeting of DCs (LV305) to generate killer T cells and 
the generation of CD4 T cell “help” by the “boost” component, G305, to induce a broad and 
 
 
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long-lasting adaptive anti-NY-ESO-1 immune response involving CD8+ and CD4+ T cells and 
antibodies, as well as other effector immune cells. CMB305-induced anti-NY-ESO-1 immune 
responses become detectable mainly during the third month of administration. 
Compared with other vectors previously used for immunization, such as adenovirus or vaccinia, 
LV305 selectively transduces the NY-ESO-1 RNA antigen to DCs, is replication-incompetent, 
which minimizes inflammation, and selectively activates the transduced DC to enhance its 
antigen presentation capabilities (Butler 2011). These attributes of LV305 contribute to its 
favorable safety profile and its association with potentially superior and long-term memory 
anti-NY-ESO-1 immune responses.  
1.1.2 
Overview of Data Generated from Initial Clinical Development of CMB305 
Individual components of the CMB305 regimen, LV305 and G305, were first evaluated in 
separate phase 1 studies, followed by a phase 1 study of the CMB305 regimen: 
• ID-LV305-2013-001 is a phase 1, open-label study designed to evaluate the safety, 
tolerability, and immunogenicity of intradermally (ID) administered LV305 in subjects 
with locally-advanced, relapsed, or metastatic cancer expressing NY-ESO-1  
• G305/IDC-G305-2013-001 is a phase 1, open-label, multiple ascending dose study 
evaluating the safety, tolerability, and immunogenicity of the intramuscular (IM) 
NY-ESO-1 protein with GLA-SE adjuvant in subjects with unresectable or metastatic 
cancer expressing NY-ESO-1  
• IMDZ-C131 is a phase 1, open-label study designed to evaluate the safety, tolerability, 
and immunogenicity of ID or subcutaneously (SC) administered CMB305 in subjects 
with locally-advanced, relapsed, or metastatic cancer expressing NY-ESO-1 
Based on the mechanism of action, rapid tumor shrinkage is not expected from CMB305 therapy, 
and clinical benefit should be assessed beyond disease progression as determined by 
conventional RECIST. Thus, CMB305 clinical development is focused on understanding long-
term benefit including overall survival (OS) in the early clinical studies.  
While subjects with different NY-ESO-1+ solid tumors including several types of soft tissue 
sarcoma (STS) have been enrolled in the LV305-2013-001 and IMDZ-C131 clinical studies, 
subjects with synovial sarcoma emerged as the primary focus of clinical development due to the 
uniformly high expression level of NY-ESO-1 in these tumors. Thirty-four NY-ESO-1+ subjects 
with synovial sarcoma were treated on studies LV305-2013-001 and IMDZ-C131. The vast 
majority of subjects with synovial sarcoma in both studies received prior systemic 
chemotherapy, had metastatic disease, and a high level of NY-ESO-1 expression by 
immunohistochemistry (IHC) (Somaiah 2017a; Somaiah 2017b), which is associated with a 
worse prognosis (Nicholaou 2006; Jungbluth 2001a; Van Tine 2016; Komarov 2017).  
 
 
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Induction of anti-NY-ESO-1 immune response is an important pharmacodynamic marker of 
activity for LV305 and CMB305, and possibly a predictive marker of a better clinical outcome. 
LV305 and CMB305 resulted in anti-NY-ESO-1 immune responses and extended tumor growth 
stabilization in subjects with NY-ESO-1+ sarcoma. However, CMB305 induced stronger and 
broader immune responses than LV305 alone such as: stronger T cell responses in each 
ELISPOT, in more samples per subject and in more subjects; induction of anti-NY-ESO-1 
antibodies (not observed with LV305); and antigen spreading in more than 35% of subjects 
versus less than 20% of subjects who were treated with LV305. Other NY-ESO-1 vaccine trials 
reported an association of (1) induction of anti-NY-ESO-1 immune responses with improved 
survival in subjects with ovarian cancer and melanoma (Szender 2017; Odunsi 2012), and 
(2) integrated anti-NY-ESO-1 immune responses with survival in subjects with melanoma 
(Yuan 2011).  
Safety has been established for two dose levels of LV305 (1×1010 vector genomes (vg)/mL and 
4×1010 vg/mL) in combination with G305 (5 µg GLA-SE plus 250 µg NY-ESO-1 protein) in the 
previous IMDZ-C131 study.  In the IMDZ-C131 study, the dose of the LV305 component of 
CMB305 was increased from 1×1010 vg to 4×1010 vg (1×1010 vg single injection in each upper 
extremity and each lower extremity, total 4 injections administered subcutaneously). The G305 
dose is unchanged (5 µg GLA-SE plus 250 µg NY-ESO-1 protein). This increase in LV305 dose 
is being implemented to maximize potential clinical benefit of CMB305 without compromising 
safety.  
The dose at 4x1010 vector genomes has been evaluated in Arm E of IMDZ-C131. Nine subjects 
with soft tissue sarcoma were evaluated at this higher dose of LV305.  No Serious Adverse 
Events, Medical Events of Interest, or Dose-Limiting Toxicities were reported. The data were 
reviewed by the Data Monitoring Committee (DMC) and this Committee regarded LV305 to be 
well tolerated and to continue the study at the (4×1010 vg/mL) and G305 (5 µg GLA-SE plus 
250 µg NY-ESO-1 protein). 
Data for each component, LV305 and CMB305, are discussed because the LV305 component is 
essential for priming the anti-NY-ESO-1 immune response in subjects receiving the CMB305 
regimen. Long-term follow-up approaching 24 and 12 months for studies LV305-2013-001 and 
IMDZ-C131, respectively, indicate that LV305 and CMB305 therapy may lead to a 
substantial improvement in OS in subjects with NY-ESO-1+ synovial sarcoma who received 
multiple prior therapies compared with the published survival data. For subjects with synovial 
sarcoma enrolled in the LV305-2013-001 study, median OS has not yet been reached; and for the 
IMDZ-C131 study, median OS is 19.3 months. The 12-month OS rate is 84% and 73%, and the 
18-month OS rate is 76% and 55% on LV305-2013-001 study and IMDZ-C131 study, 
respectively (Somaiah 2017a). Overall, OS for subjects with NY-ESO-1+ STS, including those 
with synovial sarcoma on LV305 and CMB305 therapy, compares favorably with currently 
approved agents for recurrent STS where OS ranges from 12.4 to 13.5 months, and, more 
specifically, for metastatic synovial sarcoma where median OS after 1 or 2 lines of prior 
chemotherapy is reported at 11.7 and 7.8 months, respectively (Savina 2017). Importantly, 
 
 
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CMB305 therapy avoids serious toxicity with a significantly improved safety profile when 
compared with available systemic therapy for subjects with synovial sarcoma.  
Biomarker data analyses from studies LV305-2013-001 and IMDZ-C131 showed that subjects 
who developed an anti-NY-ESO-1 immune response measured by either T cells or antibodies 
had a trend to a better OS when compared with subjects without an induction of immune 
response. This effect on OS was evident in subjects who had an increase in anti-NY-ESO-1 
immunity from baseline and in those who developed a de novo immune response while on 
therapy. Thus, the induction of anti-NY-ESO-1 immune response by CMB305 therapy appears to 
convey a survival advantage compared with subjects without an induction of immune response. 
1.1.3 
Synovial Sarcoma: An Ultra-Rare Disease with a Serious Unmet Medical Need 
Synovial sarcoma, a distinct STS subtype, which affects younger subjects, is an ultra-rare disease 
(United States [US] incidence of between 900−1000 subjects) with a high unmet medical need 
(Lange 2014; Thway 2014). Currently, there is no therapy approved specifically for subjects with 
synovial sarcoma. Instead, therapies approved for the heterogeneous group of STS are often used 
and are associated with clinical outcomes that vary by sarcoma subtype.  
Synovial sarcoma is a distinct subtype of STS with a pathognomonic translocation t(X;18) 
resulting in SS18-SSX1, SS18-SSX2, and rarely SS18-SSX4 fusion transcripts with distinct 
clinical features and outcomes (Ladanyi 2002; Lange 2014). B cell lymphoma 6 corepressor 
rearrangement (BCOR) upregulation is emerging as a common downstream pathway for 
synovial sarcoma with either typical SS18-SSX transcript or with rare fusion variants, such as 
SS18L1-SSX (Kao 2017). Approximately one-third of synovial sarcomas occur in childhood, 
and the peak incidence is in the third decade of life, with nearly 50% of synovial sarcomas 
occurring in subjects younger than 30 years of age (Ferrari 2004; Lange 2014). 
Metastatic disease occurs in approximately 50% of subjects at the time of diagnosis with 80% of 
subjects having pulmonary lesions (Spurrell 2005). Greater than 80% of synovial tumors express 
NY-ESO-1, which is associated with a worse prognosis (Nicholaou 2006; Jungbluth 2001a; 
Van Tine 2016; Gnjatic 2006; Komarov 2017). Though subjects with synovial sarcoma are often 
younger, have better performance status, and relative chemosensitive disease, survival outcomes 
remain limited in subjects with non-curative, locally-advanced unresectable disease, and 
metastatic disease. There is a paucity of published literature on expected outcomes for subjects 
with synovial sarcoma, and no prospective randomized trial has demonstrated benefit in this 
population. 
For subjects with non-curative locally-advanced disease or metastatic disease, chemotherapy is a 
palliative treatment in the vast majority of cases. In this setting, toxicity should not outweigh the 
potential benefits resulting from chemotherapy (Sleijefer 2005). National Comprehensive Cancer 
Network (NCCN) guidelines version 2.2017 and European Society for Medical Oncology 
(ESMO) Clinical Recommendations 2008 for STS recommend palliative chemotherapy as the 
primary treatment for unresectable disease or disseminated metastases. NCCN guidelines include 
 
 
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single agents (e.g., dacarbazine, doxorubicin, epirubicin, or ifosfamide) or anthracycline-based 
combination regimens (doxorubicin or epirubicin with ifosfamide and/or dacarbazine) for 
subjects with unresectable locally-advanced or metastatic disease. NCCN guidelines for subjects 
with tumors that become resectable upon completion of first-line chemotherapy (amenable to 
local regional therapy) are intentionally non-specific (NCCN). The survival of subjects with STS 
and metastatic disease is comparable to those who develop delayed metastatic disease. There is 
no improved survival observed for subjects with metastectomy (Kane 2002). 
A phase 3 study of doxorubicin alone versus the combination of intensified doxorubicin plus 
ifosfamide in advanced or metastatic STS showed no difference in the primary endpoint of OS, 
14.3 months versus 12.8 months (hazard ratio [HR] = 0.83 with a 95% confidence interval 
[CI] = 0.67–1.03) but a significantly higher secondary endpoint of median progression-free 
survival (PFS) with the combination regimen, 7.4 months versus 4.6 months (HR = 0.74 with a 
95% CI = 0.60–0.90). The overall response was 26% (2% complete response [CR], 25% partial 
response [PR]) for the combination therapy and 14% (1% CR, 13% PR) for single-agent 
doxorubicin. Fifty percent of subjects completed 6 cycles on the doxorubicin-alone arm versus 
51% of subjects on the combination arm (Judson 2014). A recent phase 2 study of doxorubicin 
plus olaratumab versus single-agent doxorubicin demonstrated a median PFS of 6.6 months and 
median OS of 26.5 months for subjects with STS. The median number of infusions was 7 in the 
doxorubicin plus olaratumab arm versus 4 infusions in the doxorubicin single-agent arm 
(Tap 2016). The NCCN guidelines recommend combination therapy with doxorubicin and 
olaratumab for use in STS histologies for which an anthracycline-containing regimen is 
appropriate. The combination of olaratumab and doxorubicin now replaces doxorubicin alone as 
a first-line treatment option (Helwick 2017). 
Ifosfamide is an active regimen with acceptable toxicity (van Oosterom 2002) and has 
demonstrated significant activity in treating advanced sarcomas with a response rate (RR) of 
approximately 30% when used as a single agent (Rosen 1994). Standard-dose ifosfamide is 
active in the first-line treatment of subjects with advanced STS (overall response rates [ORRs] of 
10%–25%) (Riedel 2012). In a single-center retrospective analysis, the median number of cycles 
of high-dose ifosfamide was 4 (Rahal 2012), and in a phase 3 trial of ifosfamide administered in 
2 schedules, 20% of subjects receiving a dose of 3 g/m2 and 30.8% receiving a dose of 9 g/m2 
completed 6 cycles (Lorigan 2007). Ifosfamide is the only drug that consistently shows RRs 
similar to doxorubicin without the cardiotoxicity. Synovial sarcoma in particular is thought to be 
highly sensitive to ifosfamide (Tascilar 2007). 
A limited number of retrospective reviews have evaluated first-line practice patterns in synovial 
sarcoma. In a post-hoc analysis of a prospectively gathered database of subjects with synovial 
sarcoma, the frequency of different first-line chemotherapy regimens showed that 33% received 
combination ifosfamide/doxorubicin (RR 58.6%), 27% received single-agent ifosfamide 
(RR 25%), and 18% received single-agent doxorubicin (RR 25%) (Spurrell 2005). In a review of 
15 European Organization for Research and Treatment of Cancer prospective first-line synovial 
sarcoma trials, 35.8% of subjects received combination ifosfamide/doxorubicin (ORR 32.2%) 
 
 
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and 13.4% of subjects received single-agent ifosfamide (ORR 33.3%). Even though not 
statistically significant, ifosfamide seemed to be the most active drug when compared with 
anthracycline alone (Vlenterie 2016). In a single-institution retrospective review of subjects with 
synovial sarcoma treated with high-dose ifosfamide, the ORR was 44% and median PFS was 
11.6 months (Rahal 2012). 
A recent observational study on patterns of care and outcomes in synovial sarcoma found that of 
188 subjects treated, 37% did not receive an anthracycline in the first line and 61% did not 
receive polychemotherapy. The authors concluded that a combination of doxorubicin with a 
second drug, such as ifosfamide, should be used only after careful discussion with the subject on 
the benefit/risk ratio of this approach, particularly when tumor shrinkage is expected to improve 
the symptoms or clinical benefits (Savina 2017). This study also reported 49% of subjects 
received some form of local regional therapy of metastatic disease. One of the factors associated 
with a higher probability of 5-year survival was locoregional treatment of metastases 
(OR = 7.41; 95% CI, 4.42–12.41). However, no guidelines exist on how to best integrate local 
regional therapy (Savina 2017). 
Preliminary IMDZ clinical data demonstrate that CMB305 may provide an advantage over or 
complement available approved therapies for subjects with synovial sarcoma. CMB305 therapy 
leads to extended tumor growth arrest in NY-ESO-1+ subjects who have evidence of progression 
prior to start of treatment. Long-term follow-up of phase 1 subjects indicate that CMB305 
therapy may lead to a substantial improvement in OS in subjects with NY-ESO-1+ synovial 
sarcoma who received multiple prior therapies when compared with the published survival data 
(Savina 2017). Importantly, CMB305 therapy avoids serious toxicity with a significantly 
improved safety profile when compared with available systemic therapy for treatment of subjects 
with synovial sarcoma. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is to: 
• Evaluate the efficacy of CMB305 versus placebo using: 
o PFS, by investigator assessment, using RECIST v1.1 
o OS 
2.2 
Secondary Objectives  
The secondary objectives of this study are to: 
• Evaluate the efficacy of CMB305 versus placebo using: 
o Time- to-next treatment (TTNT) 
o Distant metastasis-free survival (DMFS) 
o Objective response rate (ORR) (defined by RECIST v1.1) 
 
 
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• Evaluate the safety and tolerability of CMB305 versus placebo 
• Evaluate subject quality of life (QoL) 
2.3 
Exploratory Objective 
• Evaluate the anti-NY-ESO-1 immune response and histologic and molecular changes in 
peripheral blood and tumor tissue and their association with clinical outcomes 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a global, randomized, double-blind, placebo-controlled, phase 3 study designed to 
evaluate the efficacy and safety of the CMB305 vaccine regimen versus placebo in subjects with 
synovial sarcoma expressing NY-ESO-1.  
To be eligible, subjects must be receiving a first-line systemic anti-cancer therapy for 
unresectable locally-advanced or metastatic synovial sarcoma and have no evidence of 
progression at the time of randomization. 
The study will consist of 5 periods: Pre-screening, Screening, Treatment, Post-treatment, and 
Long-term Follow-up.  
The schedule of events for the Pre-screening and Screening periods is presented in Table 1 and 
the schedule of events for the Treatment through the Long-term Follow-up periods is presented 
in Table 2. Study flow diagrams for subjects who received a course of 4 cycles, 6 cycles, or 
8 cycles of first-line systemic anti-cancer therapy are presented in Appendix 5, Figure 4, 
Figure 5, or Figure 6, respectively. A study flow diagram for subjects who have had a local 
regional therapy after first-line systemic anti-cancer therapy is presented in Appendix 5, 
Figure 7. 
3.1.1 
Pre-screening Period 
The Pre-screening period is up to 151 days (Day -180 to Day -29) and commences at the time the 
subject and/or their legally authorized representative sign the Pre-screening informed consent 
form (ICF)/assent form. The Pre-screening period ends at the time the Main Study ICF/assent 
form is signed. 
Before any Pre-screening procedures are performed, subjects (aged ≥18 years) and legally 
authorized representatives of subjects <18 years will provide written consent on the 
Pre-screening ICF and subjects aged 12 to <18 years will provide written assent. At the time of 
Pre-screening, subjects must still be receiving treatment with first-line systemic anti-cancer 
therapy. The following will be evaluated during the Pre-screening visit: 
• Radiographic disease response assessment obtained at the standard-of-care time point by 
the investigator using RECIST v1.1   
 
 
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• Immunohistochemistry (IHC) test for the presence of NY-ESO-1 in an archival tumor 
tissue or fresh tumor tissue biopsy (tumor tissue may be from an archived sample 
obtained within 18 months before signing the Pre-screening ICF/assent form) 
Once the investigator confirms 1) the subject has no evidence of progression (using 
RECIST v1.1) and 2) the IHC test results for NY-ESO-1 are positive (≥1% expression), then the 
subject and/or their legally authorized representative will sign the Main Study ICF/assent form.  
3.1.2 
Screening Period 
The duration of the Screening period is 28 days (Day -28 to Day -1) and begins on the date the 
subject and/or their legally authorized representative sign the Main Study ICF/assent form and 
ends at time of randomization. 
After satisfying the Pre-screening criteria, subjects (aged ≥18 years) and legally authorized 
representatives of subjects <18 years will provide written consent on the Main Study ICF and 
subjects aged 12 to <18 years will provide written assent for study participation. Once the 
appropriate Main Study ICF/assent form is signed, subjects will undergo additional eligibility 
assessments and the investigator will confirm there is no evidence of progression (using 
RECIST v1.1). The disease status will be assessed by the investigator (using RECIST v1.1) 
through a comparison of the most recent baseline images obtained during Screening to both  
1) the images obtained prior to initiation of first-line systemic anti-cancer therapy and  
2) the images obtained per standard-of-care during first-line systemic anti-cancer therapy to 
confirm there is no evidence of progression prior to randomization. Investigator assessment of 
radiographic images confirming best response (stable disease [SD] or better) to first-line 
systemic anti-cancer therapy using RECIST v1.1 will be entered into an electronic case report 
form (eCRF). Subjects who have a tumor response of SD with evidence of ≥15% to 20% 
increase in tumor burden will be submitted for Central Review to adjudicate the investigator’s 
assessment of tumor response prior to randomization. Radiographic images from both Screening 
and Pre-screening will also be submitted to an independent review committee (IRC) for storage. 
The stored images will be available for evaluation by a central reader, if requested by the 
sponsor. After completion of Screening assessments and confirmation that the subject has met all 
eligibility requirements, the subject will be randomly assigned to one of the treatment arms using 
central randomization system on Day 1.  
3.1.3 
Treatment Period 
The Treatment period will begin on the day of randomization (Day 1), which is to be within 
28 days after the last dose of first-line systemic anti-cancer therapy or last day of local regional 
therapy, if applicable, and will continue until investigator-determined progressive disease (PD) 
(using RECIST v1.1), unacceptable toxicity, or 1 year after the first dose, whichever occurs first.  
 
 
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Subjects who meet eligibility criteria will be randomly assigned in a 1:1 ratio to receive one of 
the following centrally randomized treatments: 
• Arm A: Placebo 
• Arm B: CMB305 
An interactive response technology (IRT) system will use the following stratification factors at 
the time of randomization: 
• Disease status at screening: locally advanced unresectable (LAUR) vs metastatic 
• Tumor response during screening: stable disease (SD)/partial response (PR) vs complete 
response (CR)/no evidence of disease (NED)  
• Baseline presence of anti-NY-ESO-1 antibody (yes vs no) 
Subjects who are randomly allocated to the placebo arm will not be permitted to cross-over to the 
CMB305-containing treatment arm at any time before study closure.  
Tumor imaging assessments will be performed every 8 weeks after Day 1 and radiographic 
evidence of disease progression will be determined by the investigator using RECIST v1.1. 
Subjects with a global deterioration of health status requiring discontinuation of study treatment 
but without objective evidence of disease progression (symptomatic deterioration) will be 
considered as having PD for the purpose of determining PFS. Radiographic images (e.g., 
computed tomography [CT] scan or magnetic resonance imaging [MRI]) will also be submitted 
to an IRC for storage and will be available for evaluation by a central reader, if requested by the 
sponsor. Details for the collection and evaluation of radiographic images are included in the 
Radiology Manual provided to the study sites.  
Tumor biopsy samples for NY-ESO-1 expression will be obtained from all subjects during the 
Pre-screening period as described in Section 3.1.1 (either archival tumor tissue or a fresh biopsy 
sample). All subjects will provide peripheral blood samples for anti-NY-ESO-1 antibody assay at 
the screening visit for stratification.  
Quality of life will be assessed up to 12 months from Day 1. 
Safety will be monitored by evaluating the frequency and severity of adverse events (AEs), 
serious adverse events (SAEs), clinical laboratory abnormalities, immunogenicity and 
persistence of LV305. Local laboratory test values will be used for treatment decisions and 
subject care; central laboratory test values will be used in the analysis of safety.  
In addition, at only select US sites, the following will be collected: 
Peripheral blood samples for the anti-NY-ESO-1 T cell and antibody assays will be obtained 
prior to start of study treatment from subjects on Day 1, Day 92, and Day 365 for subjects who 
have not had a progression event. A tumor biopsy will be obtained at screening, Day 92, and 
Day 365 for subjects who have not had a progression event. An additional tumor biopsy at time 
of progression event will be encouraged.    
 
 
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3.1.4 
Post-treatment Period (For Subjects Who Discontinue Study Treatment for 
Reasons Other Than Disease Progression) 
The Post-treatment period will begin at the end of treatment and will continue until 
investigator-determined radiographic PD (using RECIST v1.1) is documented.  
Subjects will continue to undergo imaging until the time of disease progression. At the time of 
disease progression, subjects will enter the Long-term Follow-up period. 
3.1.5 
Long-term Follow-up Period 
The Long-term Follow-up period will begin at the time investigator-determined PD (using 
RECIST v1.1) is documented and will continue for up to 5 years, until the date of death, or until 
sponsor notification of study closure.  
 
 
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Table 1 
Schedule of Events for the Pre-Screening and Screening Periods 
 
Pre-Screening  
Perioda 
Screening  
Periodb 
Visit 
1 
2 
Timeline – Day(s) Day-180 to Day-29 Day -28 to Day -1 
Procedures 
 
 
Informed consent/assentc 
X 
X 
Obtain or collect tumor sample for IHC testing of NY-ESO-1 expressiond 
X 
 
Collect fresh tumor sample to assess tumor biomarkers (frozen and 
FFPE) at select U.S. sites 
 
X 
Investigator review of tumor response to first-line systemic anti-cancer 
therapy using RECIST v1.1e 
X 
 
Obtain images collected at the standard-of-care time point for the first 
evaluation of response to first-line systemic anti-cancer therapy f 
X 
 
Tumor imaging (CT/MRI) for baseline tumor response assessmentg 
 
X 
Inclusion and exclusion criteria 
 
X 
Demographics and medical history 
 
X 
Tumor-specific therapy history 
 
X 
Record prior and concomitant medications  
 
X 
Blood for chemistry laboratory testsh 
 
X 
Blood for hematology laboratory testsh 
 
X 
Blood for coagulation tests laboratory testsh 
 
X 
HIV, hepatitis B (HepB), and hepatitis C (HepC) testsh 
 
X 
Blood for anti-NY-ESO-1 plasma ELISAi 
 
X 
Blood for circulating tumor genomicsj 
 
X 
Urinalysish 
 
X 
Pregnancy testk 
 
X 
Vital sign measurementsl 
 
X 
Physical examinationm 
 
X 
12-lead electrocardiogram 
 
X 
ECOG  
 
X 
QoL assessment 
 
X 
Blood for LV305 persistence  
 
X 
CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ELISA = Enzyme-linked 
immunosorbent assay; HIV = human immunodeficiency virus; ICF = informed consent form; 
IHC = immunohistochemistry; MRI = magnetic resonance imaging; NY-ESO-1 = New York esophageal squamous 
cell carcinoma-1; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors 
a The Pre-screening period is up to 151 days (Day -180 to Day -29) and is the time from the subject and/or their 
legally authorized representative signing the Pre-screening ICF/assent form to the time of signing the Main study 
ICF/assent form. The Pre-Screening can commence at any time after first dose of first-line systemic anti-cancer 
therapy. 
 
 
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b The duration of the Screening period is 28 days (Day -28 to Day -1) and begins on the date the subject and/or 
their legally authorized representative sign the Main study ICF/assent form. At Day 1, subjects must have 
documented completion of first-line systemic anti-cancer therapy and must have received at least 4 to 8 cycles of 
therapy (or no more than 180 days of systemic anti-cancer therapy). 
c Two informed consents (subjects aged ≥18 years and legally authorized representatives of subjects aged 
12 to <18 years) or assents (subjects aged 12 to <18 years) will be used in this study. The Pre-screening 
ICF/assent form will allow for IHC testing of the tumor sample (fresh or archival) for the presence of NY-ESO-1 
and review of the tumor images (CT or MRI) collected before administration of the first dose of first-line 
systemic anti-cancer therapy and at the subsequent standard-of-care time point for the first evaluation of response 
to first-line systemic anti-cancer therapy. The Main study ICF/assent must be signed before any Screening study-
related procedures are initiated. Before the Main study ICF/assent can be signed, results of IHC testing for the 
presence of NY-ESO-1 (≥1% expression) must be available from the central laboratory, and the 
investigator-evaluated tumor response (using RECIST v1.1) to first-line systemic anti-cancer therapy must be 
documented. 
d At Pre-screening, a tumor sample (fresh or archival) will be collected or obtained for the IHC testing by the 
central laboratory for the presence of NY-ESO-1 expression (≥1% expression). Archival tumor tissue or fresh 
tumor tissue will be obtained from a biopsy or a resected tumor lesion, as appropriate (tumor tissue may be from 
a sample obtained within 18 months before signing the Pre-screening ICF/assent form). 
e Obtain images (CT or MRI) collected before administration of the first dose of first-line systemic anti-cancer 
therapy. Images will be assessed by the investigator using RECIST v1.1. Investigator assessment of all target and 
non-target lesions and tumor response assessment will be captured in the eCRF. Subjects who have a tumor 
response of stable disease with evidence of ≥15% to 20% increase in tumor burden will be submitted for central 
review to adjudicate the investigator’s assessment of tumor response prior to randomization.   
f 
Obtain and review images (CT or MRI) collected at the standard-of-care time point for the first evaluation of 
response to first-line systemic anti-cancer therapy. The subject’s response to first-line systemic anti-cancer 
therapy will be assessed by the investigator using RECIST v1.1 and documented in the eCRF. 
g Tumor imaging (CT or MRI) will be performed after completion of the planned 4-cycles to 8-cycles of first-line 
systemic anti-cancer therapy for the evaluation of response at baseline, as assessed by the investigator using 
RECIST v1.1. The images collected at this time point will serve as the baseline assessment for the efficacy 
evaluations. These images must be collected within 28 days after the date of last dose of first-line systemic 
anti-cancer therapy. 
h Results from the central laboratory will be used to determine eligibility and for the safety analysis. Laboratory 
tests performed by the central laboratory will include: chemistry with liver function tests, lactate dehydrogenase, 
alkaline phosphatase, albumin, hematology with complete blood count with differential, HIV, HepB, and HepC. 
Coagulation samples will be drawn only at Screening and shipped to the central laboratory (prothrombin time, 
partial thromboplastin time, and international normalized ratio) for analysis. Urinalysis will be conducted at the 
central laboratory. All laboratory assessments to be performed are listed in Table 4. 
i 
The peripheral blood on all subjects must be collected Day -28 to Day -7 during Screening and will be used for 
plasma ELISA testing; results of the assessment will be used for stratification and randomization.  
j 
For circulating tumor genomics, please see lab manual. 
k For FCBP, serum pregnancy testing will be performed during Screening. 
l 
Vital sign measurements will include body temperature, heart rate, respiratory rate, and resting systolic and 
diastolic blood pressure. 
m At Screening, the physical examination should include an evaluation of organ systems, including, but not limited 
to, head and neck; chest and lungs; cardiac; gastrointestinal; neurologic; endocrine; and musculoskeletal and 
integument. Other organ systems should be evaluated as directed by medical history or current symptoms. 
Measurements of body weight and height will be obtained. 
 
 
 
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Table 2 
Schedule of Events for the Treatment Period through Long-term Follow-up Period 
 
Treatment Period 
Post-Treatment 
Periodc 
Long-term 
Follow-up Periodd 
Prime Phase 
Boost Phase 
Follow-up 
Follow-up 
Visit 
3 
4 
5 
6 
7 
8 
9 
10+ 
Timeline – Week(s) 
1 
3 
5 
7 
9 
11 
13 
Every 8 weeksb 
Every 3 months until 
documentation of 
disease progression 
Every 3 months 
for up to 5 years 
or until date of 
death 
Timeline – Day(s) 
1a 
22 
36 
50 
64 
78 
92 
Up to 1 year 
Allowed Visit Window - Days 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±14 
Procedures 
Enrollment, stratification, and treatment 
allocatione 
X 
 
 
 
 
 
 
 
 
 
Record prior and concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for central laboratory chemistry 
laboratory testsf 
X 
X 
 
X 
X 
 
X 
 
 
 
Blood for central laboratory hematologyf 
X 
X 
 
X 
X 
 
X 
 
 
 
Urinalysisf 
X 
 
 
 
 
 
X 
 
 
 
Blood for anti-NY-ESO-1 plasma ELISAg 
X 
 
 
 
 
 
X 
 
 
 
Blood for immunity assessmentsg 
X 
 
 
 
 
 
X 
X 
 
 
Blood for circulating tumor genomicsh 
X 
 
 
 
 
 
X 
 
 
 
Pregnancy testi 
X 
 
 
 
 
 
X 
 
 
 
Vital sign measurementsj 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examinationk 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead electrocardiogram 
 
 
 
 
 
 
X 
 
 
 
Tumor imaging with response assessment by 
RECIST v1.1 (CT scan or MRI)l 
 
 
 
 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
 
 
QoL assessmentm 
X 
 
 
 
 
 
X 
X 
 
 
Report AEs and SAEsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Treatment Period 
Post-Treatment 
Periodc 
Long-term 
Follow-up Periodd 
Prime Phase 
Boost Phase 
Follow-up 
Follow-up 
Visit 
3 
4 
5 
6 
7 
8 
9 
10+ 
Timeline – Week(s) 
1 
3 
5 
7 
9 
11 
13 
Every 8 weeksb 
Every 3 months until 
documentation of 
disease progression 
Every 3 months 
for up to 5 years 
or until date of 
death 
Timeline – Day(s) 
1a 
22 
36 
50 
64 
78 
92 
Up to 1 year 
Allowed Visit Window - Days 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±14 
Study drug administration:  
Placebo (Arm A) 
LV305 (Arm B) 
X 
X 
 
X 
 
X 
 
 
 
 
Study drug administration:  
Placebo (Arm A) 
G305 (Arm B) 
 
 
X 
 
X 
 
X 
Xo 
 
 
Blood for LV305 persistencep  
 
 
 
 
 
 
X 
X 
X 
X 
Tumor biopsyq 
 
 
 
 
 
 
X 
 
 
 
Survival statusr 
 
 
 
 
 
 
 
 
X 
X 
AE = adverse event; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; IHC = immunohistochemistry; MRI = magnetic resonance 
imaging; NY-ESO-1 = New York esophageal squamous cell carcinoma-1; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event 
a Day 1 will occur within 28 days after the last dose of first-line systemic anti-cancer therapy or the last day of local regional therapy. Day 1 procedures must 
occur within 72 hours of randomization. 
b In the Boost Phase, tumor imaging will be performed every 8 weeks for 1 year or until investigator-determined progressive disease, using RECIST v1.1, is 
documented.   
c The Post-treatment period will begin at the end of treatment and will continue until investigator-determined progressive disease, using RECIST v1.1, is 
documented. If a subject has reached 12 months on study without disease progression, tumor imaging will be performed every 12 weeks ±7 days until disease 
progression. 
d The Long-term Follow-up period will begin at the time investigator-determined progressive disease (using RECIST v1.1) is documented and will continue for 
up to 5 years, until the date of death, or until sponsor notification of study closure.  
e The following information must be available at Day 1: subjects must have documented completion of first-line systemic anti-cancer therapy and must have 
received at least 4 to 8 cycles of therapy (or no more than 180 days of systemic anti-cancer therapy); results of IHC testing for the presence of NY-ESO-1 
(≥1% expression) must be available from the central laboratory; and the investigator-evaluated tumor response, using RECIST v1.1, to first-line systemic anti-
cancer therapy must be documented. 
 
 
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f 
During the study dosing period, all laboratory assessments are to be performed prior to dosing. Hematology and clinical chemistry samples will be shipped to 
the central laboratory for safety analyses, and will include: chemistry with liver function tests, lactate dehydrogenase, alkaline phosphatase, albumin, thyroid 
function, and hematology with complete blood count with differential. Urinalysis will be conducted at the central laboratories. All laboratory tests to be 
performed are listed in Table 4. 
g Blood for anti-NY-ESO-1 T cell assessments to be collected only for subjects on prior to dosing on Day 1 and Day 92 only at select US sites. Additional 
blood samples for immunity assessments will be drawn for any subject who has no evidence of tumor progression by RECIST v1.1 at 1 year at the same 
select US sites. 
h For circulating tumor genomics, please see lab manual. 
i 
For FCBP, serum and confirmation urine pregnancy testing will be performed by the local laboratory prior to dosing on Day 1; results must be negative. 
Serum pregnancy testing will be performed by the local laboratory prior to dosing on Day 92; results must be negative. Pregnancy testing will be performed 
more frequently as required per local regulatory authority. 
j 
Vital sign measurements will include body temperature, heart rate, respiratory rate, and resting systolic and diastolic blood pressure. On the day of each 
dosing, vital signs will be obtained no more than 60 minutes before dosing and 30 minutes after dosing (±10-minute window). 
k Once the Screening physical examination has been conducted, a simple symptom-directed physical examination should be performed for all subsequent visits. 
Measurements of body weight will be obtained at every visit. 
l 
Beginning in the Treatment period, imaging will be performed at 8-week intervals after Day 1 administration of the first dose of the study drug for up to 
1 year or until the time investigator-determined progressive disease, using RECIST v1.1, is documented. 
m QoL assessments will be conducted at the study site. In addition to the screening QoL assessment, the QoL assessment will be obtained on Day 1 prior to the 
first dose of study drug, at Day 92, and at 6 months and 12 months after Day 1. All subjects, regardless of their disease response status, will continue to have 
QoL assessments performed for 12 months after Day 1. 
n All AEs and SAEs will be collected until 30 days after administration of the last dose of the study drug. Information on any SAEs and new malignancies that 
come to the attention of the site staff that are considered at least possibly related to CMB305 will be collected until the time of last subject contact. 
o After Day 92, G305 or placebo will be given on Day 148 and at 8-week intervals as a boost for up to 1 year, or until unacceptable toxicity, or 
investigator-determined progressive disease, using RECIST v1.1, is documented, whichever occurs first. AEs will be reported at the subsequent visit and until 
at least 30 days after the last dose. 
p Peripheral blood will be collected at the following times after administration of the first dose of study drug on Day 1: no sooner than Day 92 (3 months) but 
up to 4 months; 6 months up to 9 months; and 1 year up to 15 months; and then yearly at no sooner than every 12 months but not more than 15 months up to 
the time of study closure. If all post-treatment assays are negative during the first year, then the yearly samples should be archived. Samples will be used for 
an assay to test for persistence of LV305. 
q The Day 92 biopsy may be obtained within ±2 weeks of Day 92, Day 365, and at time of progression event will be encouraged at the same selected US sites 
per footnote “g”.  
r 
Survival status will be obtained by any means, which includes, but is not limited to, public records where allowed per local authority, telephone contact, 
during an in-clinic visit, chart review, or via communicating with an individual (e.g., family, friend, referring health care provider) who is knowledgeable of 
the subject’s survival status. More frequent survival status updates may be obtained at the request of the sponsor. 
 
 
 
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3.2 
Rationale for Study Design and Control Group 
Synovial sarcoma is commonly grouped together with other STS subtypes, and while it 
constitutes a small subgroup of subjects within clinical studies, therapies for all types of STS are 
commonly used as the standard treatment for subjects with synovial sarcoma. Because STS 
comprises multiple tumor histologies (more than 50 histologic subtypes), patterns of care and 
respective clinical outcomes vary considerably by histologic subgroup (Van Tine 2016; 
Lee 2016; Reichardt 2014; Skafida 2017). No therapy has been approved specifically for 
treatment of subjects with synovial sarcoma. 
Currently available systemic anti-cancer therapies carry significant safety risks when used as 
single agents or even greater risk when administered in combination regimens. These safety risks 
include cardiotoxicity, myelosuppression, nausea/vomiting, and fatigue. The aforementioned 
toxicities can cause significant subject morbidity and may require hospitalization and/or the use 
of supportive care measures such as high-dose steroids, antibiotics, and transfusions (Lee 2016).  
Per NCCN, maintenance therapy refers to treating a subject with an anti-cancer therapy after 
maximal response to first-line induction therapy (NCCN). The goal of maintenance therapy 
should be to improve OS or subject QoL when compared with no treatment (Schilsky 2011). 
This should be an appropriate setting to study the efficacy of CMB305 in synovial sarcoma 
subjects. Though all subjects with advanced synovial sarcoma will inevitably progress, PFS 
following the initial response to first-line systemic anti-cancer therapy ranges from 6 to 8 months 
with up to two-thirds of subjects experiencing SD or a response (Judson 2014). Once maximum 
benefit has been achieved by therapy, treatment is often stopped, and subjects receive no therapy 
until subsequent progressive disease. Some of the subjects who were deemed unresectable prior 
to the first-line systemic anti-cancer therapy may undergo local regional therapy upon its 
completion. After such local regional control procedure, subjects will receive no therapy until 
progression.  
CMB305 has a well-tolerated safety profile compared with other active systemic anti-cancer 
therapies and should not increase cumulative toxicities due to systemic anti-cancer therapy when 
administered in the proposed maintenance setting, which makes CMB305 an attractive option for 
subjects. Further, use of CMB305 is well-tolerated and therefore not anticipated to impact the 
ability to administer subsequent lines of alternative therapies in subjects after disease 
progression.  
This phase 3 trial design in the maintenance setting, where no other options for treatment of 
synovial sarcoma are approved, will use a placebo in an effort to minimize bias. There are 
circumstances that justify the use of placebo, one of which is when there is no approved standard 
therapy (La Vaque 2001). Placebo controls are justified for “first-generation” drugs designed to 
fill a gap in the therapeutic armamentarium (Orentlicher 2001). The use of a placebo in a 
double-blind, randomized, controlled trial is the most rigorous test of treatment efficacy for 
evaluating a medical therapy (Castro 2007). Because there is no standard or approved therapy for 
subjects with synovial sarcoma who have no evidence of progression on first-line systemic 
 
 
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anti-cancer therapy, the use of a placebo in this trial is warranted. This trial will evaluate whether 
CMB305 active therapy is better than observation alone (i.e., placebo). 
Advantages for the use of placebo in the control arm of this trial include:  
• Lowers the risk of altering the natural history of a subject’s tumor progression so that 
there is a true comparator arm 
• Minimizes confounding factors and bias 
• Reduces the potential of study withdrawal 
The study will be stratified by response to first-line treatment to maintain balance between arms. 
The strata will allow for statistical impact of subjects who have received local regional therapy. 
In addition, subjects on the study are not forgoing any standard therapy, which minimizes risks 
and allows for blinded analysis of not only efficacy but also of QoL and the safety of CMB305. 
In summary, there remains a high unmet medical need for subjects with locally-advanced 
unresectable or metastatic synovial sarcoma who have no evidence of progression. Currently, 
there is no disease-specific therapy approved specifically for the indication of synovial sarcoma 
based on the underlying biology or subtype specific activity. Therapeutic options that are 
approved for the broader STS indication have limited efficacy in subjects with synovial sarcoma 
and are often associated with significant toxicities. Thus, there is a need for a novel approach on 
how to develop and evaluate a new targeted therapy that is safe for this ultra-rare subject 
population with a high unmet medical need. 
3.3 
Study Duration and Dates 
Subject participation is inclusive of the Pre-screening, Screening, Treatment, Post-treatment, and 
Long-term Follow-up periods.  
The Pre-screening period is up to 151 days (Day -180 to Day -29) and begins from the time the 
subject and/or their legally authorized representative sign the Pre-screening ICF/assent form to 
the time the Main Study ICF/assent form is signed. The Pre-screening period can start as early as 
the first dose of first-line systemic anti-cancer therapy. 
The duration of the Screening period is 28 days (Day -28 to Day -1) and begins on the date the 
subject and/or their legally authorized representative sign the Main Study ICF/assent form and 
ends at time of randomization. The screening window may be extended up to 56 days by the 
sponsor, if a patient is recovering from toxicity related to first line systemic anti-cancer therapy, 
or completing local regional therapy, or baseline imaging needs adjudication to determine 
eligibility.  
The Treatment period will begin on the day of randomization (Day 1), which is to be within 
28 days after the last dose of first-line systemic anti-cancer therapy or the last day of local 
regional therapy, if applicable, and will continue until investigator-determined radiographic PD 
 
 
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(using RECIST v1.1) is documented, the occurrence of unacceptable toxicity, or until 1 year 
after the first dose, whichever occurs first. All visits during the Treatment period will have a 
window of ±3 days from the day specified. 
The Post-treatment period (for subjects who discontinue study treatment for reasons other than 
disease progression) will begin at the end of treatment and will continue until 
investigator-determined PD (using RECIST v1.1) is documented. All visits during the 
Post-treatment period will have a window of ±7 days from the day specified. 
The Long-term Follow-up period will begin at the time investigator-determined PD (using 
RECIST v1.1) is documented and will continue for up to 5 years, until the date of death, or until 
sponsor notification of study closure. All visits during the Long-term Follow-up period will have 
a window of ±14 days from the day specified. 
4.0 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 248 subjects who have synovial sarcoma expressing NY-ESO-1 will be enrolled 
and randomly allocated in a 1:1 ratio to treatment with CMB305 or placebo. 
4.2 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study. 
1. 
Have documented histologic diagnosis of synovial sarcoma (may be confirmed by the 
presence of t(X;18) (p11:q11) translocation or B cell lymphoma 6 corepressor [BCOR] 
rearrangement) and have disease that is unresectable locally-advanced or metastatic prior 
to the start of first-line systemic anti-cancer therapy. Unresectable is defined as having 
evidence of positive surgical margins after resection of primary disease or a documented 
surgical consultation with assessment of an inability of resection to provide clear 
margins.  
2. 
Have IHC test results from tumor biopsy for NY-ESO-1 that are positive (≥1% 
expression). 
3. 
At the time of Pre-screening, subjects must be receiving a first-line anthracycline or 
ifosfamide-containing systemic anti-cancer therapy regimen (single agent ifosfamide, 
single agent anthracycline, combination anthracycline plus ifosfamide, or combination 
anthracycline plus olaratumab). Subjects must have received at least 4 cycles but no more 
than 8 cycles of therapy (or no more than 180 days of systemic anti-cancer therapy). 
Subjects who have received local regional therapy (surgical resection, radiotherapy, 
radiofrequency ablation, or cryotherapy) are eligible if they meet the following: 
a. Subjects whose disease converted to operable after completion of first-line 
chemotherapy are eligible, if local regional therapy (surgical resection, 
radiotherapy, radiofrequency ablation or cryotherapy) is completed within the 
 
 
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180-day period from the date of the first dose of first-line systemic anti-cancer 
therapy. Please note that an extension of this 180-day period may be allowed per 
Section 3.3 of the protocol. 
b. Subjects whose disease remains inoperable after completion of radiotherapy are 
eligible if radiotherapy is completed within the 180-day period from the date of 
the first dose of first-line systemic anti-cancer therapy and there is no evidence of 
progressive disease prior to initiation of radiotherapy. Please note that an 
extension of this 180-day period may be allowed per Section 3.3 of the protocol. 
c. Subjects who have PD ≤6 months after date of last dose of adjuvant/neoadjuvant 
systemic anti-cancer therapy or date of last day of local regional therapy are not 
eligible. 
4. 
Must have documentation of no evidence of disease progression of the tumor during or 
after completion of first line systemic anti-cancer therapy as determined by the 
investigator using RECIST v1.1 guidelines. Subjects who have a tumor response of SD 
with evidence of ≥15% to 20% increase in tumor burden will be submitted for Central 
Review to adjudicate the investigator’s assessment of tumor response prior to 
randomization. Subjects with NED are eligible. 
5. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
6. 
Age ≥12 years. 
7. 
Have a life expectancy of at least 6 months, as determined by the investigator. 
8. 
If a female of child-bearing potential (FCBP), willing to undergo pregnancy testing and 
agree to use at least 1 highly-effective contraceptive method, such methods include 
combined estrogen and progesterone-containing hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal) or progesterone only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable), 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal 
occlusion, vasectomized partner or true sexual abstinence (when this is in line with the 
preferred and usual lifestyle of the subject, refraining from heterosexual intercourse 
during the entire period of risk associated with study treatments) during the dosing period 
and for 1 month (which is the duration of a menstruation cycle) after administration of 
the last dose of CMB305. More stringent contraception criteria should be followed if 
requested by local regulatory authorities.  
9. 
If male and sexually active with a FCBP, must be surgically sterile (i.e., vasectomy) or 
agree to use highly-effective contraception, such as latex condom, during the dosing 
period and for 3 months (which is the duration of a sperm cycle) after administration of 
the last dose of CMB305. More stringent contraception criteria should be followed if 
requested by local regulatory authorities. 
10. Have recovered from the toxic effects (except alopecia) to grade 2 or better from 
systemic anti-cancer therapy according the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 (or newer). 
 
 
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4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for the study. 
1. 
Have received the last dose of first-line systemic anti-cancer therapy or date of most 
recent local regional therapy >28 days prior to Day 1 (unless otherwise indicated in 
Section 3.3). 
2. 
Have received prior NY-ESO-1 therapy. 
3. 
Have received first-line systemic anti-cancer therapy with an agent other than an 
anthracycline-containing or ifosfamide-containing regimen (single agent anthracycline, 
single agent ifosfamide, combination anthracycline plus ifosfamide, or combination 
anthracycline plus olaratumab), or ifosfamide. 
4. 
Have received treatment with systemic immunomodulatory agents (including, but not 
limited to, interleukin-2) within 28 days prior to administration of the first dose of 
CMB305 (i.e., Day 1) or 5 half-lives of the drug, whichever occurs sooner. 
5. 
Have significant immunosuppression from: 
a. Concurrent, recent (≤21 days prior to administration of the first CMB305 dose 
[i.e., Day 1]), or anticipated need for chronic treatment with systemic 
immunosuppressive dose of corticosteroids (the use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor). The use of 
topical or inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is 
allowed. 
b. Other immunosuppressive medications (≤21 days prior to administration of the first 
CMB305 dose [i.e., Day 1]) including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) 
agents or conditions such as common variable hypogammaglobinemia. 
6. 
Have psychiatric, other medical illness, or any other condition that, in the opinion of the 
investigator, prevents compliance with the study procedures or the ability to provide valid 
informed consent (or assent for subjects 12 to <18 years of age). 
7. 
Have a history of uncontrolled autoimmune disease. Uncontrolled disease is defined as 
one requiring chronic supra-physiologic doses of systemic steroids or other forms of 
immunosuppression or that requires a recently increased or newly prescribed dose within 
28 days of Screening. 
8. 
Have a significant electrocardiogram (ECG) finding or cardiovascular disease, such as 
New York Heart Association cardiac disease (> Class II), myocardial infarction within 
the previous 3 months before administration of the first dose of CMB305 (i.e., Day 1), 
unstable arrhythmias, or unstable angina. 
 
 
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9. 
Have inadequate organ function as evidenced by: 
a. Marrow: 
i. Absolute neutrophil count (ANC) ≤1000/mm3 
ii. Platelets <75,000/mm3 
iii. Hemoglobin (Hgb) <8 g/dL 
iv. Lymphocytes ≤800/mm3. 
b. Hepatic: 
i. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0× the 
upper limit of normal (ULN) for subjects without liver metastases or ≥5× ULN 
for subjects with liver metastases 
ii. Total serum bilirubin >1.5× ULN (or direct bilirubin ≥1.5 ULN for subjects 
with total bilirubin levels <1.5× ULN). Subjects with Gilbert’s disease may be 
included if their total bilirubin is <3.0 mg/dL). 
c. Renal: 
i. Creatinine clearance <0.50 x LLN. 
d. For subjects not using blood thinners: 
i. Prothrombin time (PT) >1.5× ULN or international normalized ratio (INR) 
>1.5× ULN 
ii. Partial thromboplastin time (PTT) >1.5× ULN 
iii. Subjects using blood thinners must be able to modify their normal dosing 
regimen to allow for injections of investigational product. 
10. History of other cancer within 3 years (except for appropriately treated carcinoma in situ 
of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, localized prostate 
cancer treated with curative intent, ductal carcinoma in situ treated surgically with 
curative intent, or other cancers with a similar outcome). 
11. Evidence of active tuberculosis or recent (<1 week prior to first scheduled dosing on 
Day 1) clinically-significant infection requiring systemic therapy. (Prophylactic 
antibiotics [e.g., for prevention of a urinary tract infection or chronic obstructive 
pulmonary disease] are permitted.) 
 
 
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12. Evidence of active HepB, HepC, or HIV infection: 
a. Active HepB is defined as having a positive HepB surface antigen (HBsAg) test 
result at Screening. 
b. Subjects with past/resolved HepB infection (defined as having a negative HBsAg test 
and a positive antibody to HepB core antigen [anti-HBc] antibody test) are eligible. 
HepB viral DNA results must be negative in these subjects prior to the first scheduled 
dosing on Day 1.  
c. Subjects with test results positive for HepC antibody are eligible only if polymerase 
chain reaction (PCR) testing is negative for HepC viral RNA. 
d. Subjects who are HIV positive. 
13. Have had live, attenuated vaccine administered within 28 days prior to the first scheduled 
dosing on Day 1 or anticipate that such a live, attenuated vaccine will be required during 
the study. 
14. Have a history of brain metastasis. 
15. Have received cancer therapies, including chemotherapy, radiation, biologic or kinase 
inhibitors, granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage 
colony stimulating factor (GM-CSF) within 3 weeks prior to the first scheduled CMB305 
dosing. 
16. A FCBP who is pregnant, is planning to become pregnant, or is breast feeding; or a male 
who is sexually active with a FCBP who is planning to become pregnant. 
17. Hypersensitivity to any ingredient of either LV305 or G305. 
5.0 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
CMB305 
CMB305 is a novel DC-targeting active immunotherapy regimen that consists of in vivo 
immunization by sequential administration of 2 complementary products: LV305 (an immune 
priming component) and G305 (an immune-boosting component). LV305 is a DC-targeting viral 
vector that encodes the full-length gene of the NY-ESO-1 cancer testes antigen. G305 consists of 
the recombinant full-length NY-ESO-1 protein adjuvanted with the synthetic TLR4 agonist 
GLA. 
5.1.1.1 
LV305 
The LV305 product (priming component of the vaccine regimen) is a purified DC-tropic, 
replication-incompetent, integration-deficient, third-generation LV generated from our ZVex 
vector platform, which encodes the NY-ESO-1 cancer testes antigen. Like other third-generation 
 
 
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LVs, ZVex is devoid of all HIV 1-derived accessory proteins, except for Rev (regulator of 
expression of virion proteins [Lentivirus accessory protein]), and is encoded by a split genome 
with a deletion in the U3 region (ΔU3, for self-activation of the 3´LTR) (Dull 1998). The ΔU3 
deletion is a self-inactivating mutation that: (1) prevents transcription of the full-length vector 
genome from reversed transcribed double-stranded DNA vectors in the infected target cell 
(Miyoshi 1998), and (2) minimizes the risk of insertional activation that can occur when a 3´LTR 
can function as a promoter after integration. In addition, the ZVex vector platform has been 
pseudotyped with a modified Sindbis virus envelope protein (SINVar1) (Morizono 2010) to 
selectively target DCs. 
LV305 is formulated in Tris buffer containing 5% sucrose and 50 mM L-arginine at pH 7.5. The 
LV305 drug product is produced at the nominal concentration (product strength) of 1 × 1010 
vector genomes (vg)/mL, 1.4 mL per vial. 
5.1.1.2 
G305 
The G305 product (immune-boosting component of the vaccine regimen) is composed of the 
recombinant NY-ESO-1 protein admixed with GLA in a stable emulsion. G305 is supplied in a 
2-vial configuration. One vial contains the formulated NY-ESO-1 protein and the second vial 
contains the adjuvant, GLA-SE. 
5.1.1.2.1 
NY-ESO-1 
NY-ESO-1 is a protein of 182 amino acids, produced in Escherichia coli. The theoretical 
molecular weight of the recombinant NY-ESO-1 protein is 18,146.5 daltons. The amino acid 
sequence of NY-ESO-1 is: 
GPMQAEGRGT GGSTGDADGP GGPGIPDGPG GNAGGPGEAG ATGGRGPRGA 
GAARASGPGG GAPRGPHGGA ASGLNGCCRC GARGPESRLL EFYLAMPFAT 
PMEAELARRS LAQDAPPLPV PGVLLKEFTV SGNILTIRLT AADHRQLQLS 
ISSCLQQLSL LMWITQCFLP VFLAQPPSGQ RR 
The NY-ESO-1 drug product consists of 0.65 mL of purified, aseptically filtered NY-ESO-1 
drug substance (containing 0.5 mg/mL NY-ESO-1 protein, 50 mM glycine, 3 M urea [pH 9.0] 
and 0.05% polysorbate 20) in 2-mL vials. 
5.1.1.2.2 
GLA-SE 
GLA-SE is a fully synthetic TLR4 agonist (GLA) in an SE formulation comprising squalene 
(oil), glycerol, α-tocopherol (vitamin E), dimyristoylphosphatidylcholine (DMPC), surfactant 
(poloxamer) and ammonium phosphate buffer. GLA-SE is packaged in 3-mL single-use vials. 
The chemical structure of GLA is provided in Figure 2. 
 
 
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Figure 2 
GLA Structure 
 
 
5.1.2 
Placebo 
The matching placebo for CMB305 will include matching placebos for each component of the 
vaccine: 1 for LV305 and 2 for G305. 
5.1.2.1 
LV305 Placebo 
The matching placebo for LV305 will be normal saline. 
5.1.2.2 
G305 Placebo 
5.1.2.2.1 
NY-ESO-1 Placebo 
The matching placebo for the NY-ESO-1 component of G305 will be normal saline. 
5.1.2.2.2 
GLA-SE Placebo 
The matching placebo for the GLA-SE component of G305 will be the non-active SE. 
5.2 
Treatments Administered 
LV305 will be administered on Days 1, 22, 50, and 78. For each day of administration, the 
LV305 daily dose of 4× 1010 vg will be given as 4 separate 1-mL SC injections of 
1 x 1010 vg/mL administered preferably to a separate extremity (upper or lower limb [or stump if 
subject had prior resection]). If injection to a separate extremity is not feasible, then each SC 
injection should be at least 3 cm from the neighboring injection site of the same extremity. 
G305 is an admixture of NY-ESO-1 and GLA-SE described in the Pharmacy Manual. G305 will 
be administered via IM injection in the anterior upper thigh or deltoid region on Days 36, 64, and 
92, and then at 8-week intervals up to 1 year or until investigator-determined PD (using RECIST 
v1.1) is documented or unacceptable toxicity, whichever occurs first. The quantity of 
 
 
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recombinant NY-ESO-1 protein is fixed at 250 μg/dose, and the dose of GLA-SE will be 5 μg of 
GLA in a 2% oil-in-water emulsion. The limb or stump used for injection will be alternated with 
each treatment. 
Three placebos (fully matched to characteristics of LV305, the NY-ESO-1 protein, and GLA-SE) 
will be provided for this study and will be administered on the same schedule and by the same 
route as the corresponding experimental therapy components to ensure that the sponsor, site 
personnel (including pharmacist), and subjects remain blinded to study drug for the duration of 
the study. 
Matching placebo for LV305 will be administered by the same route and on the same days as 
LV305; matching placebos for G305 will be mixed per the Pharmacy Manual in the same 
manner as the product G305 and then administered by the same route and on the same days as 
G305. 
Full details on the administration of CMB305 and matching placebo will be provided in the 
Pharmacy Manual provided to study sites. 
5.3 
Selection and Timing of Dose for Each Subject 
The CMB305 or matching placebo dosing regimen is presented in Figure 3.  The proposed 
CMB305 regimen for this study consists of 4 × 1010 vg of LV305 (administered SC as 4 
injections of 1 × 1010 vg, with one injection preferably given to each upper arm and each upper 
leg at each visit) on Days 1 and 22. On Day 36 (2 weeks after Day 22) the boost, G305, will be 
administered. Thereafter, alternating doses of LV305 and G305 will be administered every 
2 weeks until Day 92. In total, 4 doses (16 SC injections) of LV305 and 3 doses (3 IM injections) 
of G305 will be administered through Day 92. G305 will then be administered IM at 8-week 
intervals for up to 1 year or until the time investigator-determined PD (using RECIST v1.1) is 
documented or unacceptable toxicity occurs, whichever occurs first. Details on the preparation 
and administration are provided in the Pharmacy Manual. 
Figure 3 
CMB305 or Matching Placebo Dosing Regimen 
 
IM = intramuscular; Q8W = every 8 weeks; SC = subcutaneous 
LV305 or matching placebo is administered as 4 separate 1-mL SC, each preferably administered in a separate upper 
or lower limb (or stump if the subject has had a resection), or administered at least 3 cm from the neighboring 
injection site if on the same limb/stump. G305 or matching placebo is administered IM. 
 
Days: 1  
      22 
 
36  
   50 
    64 
 
78  
 
92  
 
Q8W up to 1 year 
LV305 or 
Placebo 
LV305 or 
Placebo 
LV305 or 
Placebo 
LV305 or 
Placebo
G305 or 
Placebo 
G305 or 
Placebo 
G305 or 
Placebo 
G305 or 
Placebo 
 
 
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5.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly allocated in a 1:1 ratio to receive placebo (Arm A) or CMB305 
(Arm B) according to a centrally randomized treatment schedule.  
An IRT system will use the following stratification factors at the time of randomization: 
• Disease status at screening: locally advanced unresectable (LAUR) vs metastatic 
• Tumor response during screening: stable disease (SD)/partial response (PR) vs complete 
response (CR)/no evidence of disease (NED)  
• Baseline presence of anti-NY-ESO-1 antibody (yes vs no) 
5.5 
Blinding 
The study subjects, investigators, study site personnel, including the pharmacist, safety 
laboratory personnel, central imaging readers, sponsor, and representatives of the sponsor 
involved in the conduct and/or management of the study will be blinded to treatment assignment.  
LV305 and its placebo will be identical in appearance; G305 and its placebos will be identical in 
appearance. 
All study treatments (CMB305 or placebo) will be labeled with the study number, a unique 
number, and any additional information required in accordance with government regulations. 
Further details will be contained in the Pharmacy Manual provided to study sites.  
The blind may be broken in case of a medical emergency when unblinding the treatment is 
necessary to manage the treatment of a subject.  The investigator has the ability to perform 
unblinding immediately according to emergency unblinding procedures. 
5.6 
Treatment Modification and Discontinuation 
There are no protocol allowed dose reductions or increases. 
5.6.1 
Treatment Interruptions 
If less than a full dose of a study treatment component (LV305 or G305) is administered (eg, less 
than the four (4) injections of LV305/placebo), document the injections that were administered 
and the reason the other injections were not administered.  The missed injections will not be 
administered at a later time. Treatment should resume according to the next scheduled dose and 
visit. 
 
 
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5.6.2 
Treatment Delay 
Administration of a study treatment component (LV305 or G305) will be delayed for the 
following adverse reactions: 
• A drug-related non-hematological toxicity ≥Grade 2, with the exception of toxicity listed 
under requirement of permanent discontinuation of study treatment; Grade 2 fatigue 
alone does not require the withholding of study treatment; 
• A drug-related hematological toxicity Grade 4. 
Study treatment will resume according to schedule if drug-related toxicity improves to ≤Grade 1 
within 4 weeks of onset. If Grade 2 toxicity stabilizes based on the investigator assessment 
(subject is asymptomatic and controlled), study treatment may resume after consultation with 
and approval by the Sponsor.  
5.6.3 
Treatment Discontinuation 
Permanent discontinuation of a study treatment component (LV305 or G305) responsible for an 
adverse event should be considered following discussion with the Sponsor if any of the following 
drug related adverse events are experienced: 
• Severe or life-threatening drug-related adverse events; 
• Grade 2 or above drug related adverse events which persist without improvement for 
>4 weeks. With Investigator and Sponsor agreement, subjects with a drug-related adverse 
event still at Grade 2 may continue in the study only if asymptomatic and controlled. 
For subjects who experience a recurrence of the same ≥Grade 3 drug-related adverse events with 
rechallenge of study treatment component (LV305 or G305), a consultation between the Sponsor 
and Investigator will occur to determine whether therapy with study treatment component 
responsible for the event should be discontinued. A subject who experiences the same drug-
related serious adverse events (SAE) of the same Grade or higher with rechallenge, therapy with 
study treatment component responsible for the event must be discontinued immediately. 
5.7 
Concomitant Therapy 
Except for excluded medications (Section 5.8), medications for symptoms and supportive 
management are permitted. During the study, if the use of any concomitant treatment becomes 
necessary (e.g., for treatment of an AE), the treatment must be recorded on the source document 
and eCRF, including the reason for treatment, name of the drug, dosage, route, and date of 
administration. All medications including prescription, over-the-counter (OTC), herbal, and 
other nutritional vitamins and/or supplements taken within 60 days of Day 1 will be recorded on 
the eCRF.  
 
 
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5.8 
Restrictions 
In addition to the restrictions specified in Section 4.3, Exclusion Criteria; subjects must comply 
with the following restrictions. 
5.8.1 
Prior Therapy 
Subjects cannot have received prior treatment with the following: 
• NY-ESO-1-directed immunotherapies 
Subjects must have received the last dose of first-line systemic anti-cancer therapy, or the last 
day of treatment with local regional therapy, if applicable, no more than 28 days prior to Day 1. 
The following are prohibited within 21 days prior to the first administration of CMB305 on 
Day 1 or 5 half-lives of the drug (whichever is sooner):  
• Any investigational agent or cancer therapy 
• Immunomodulatory agents (including, but not limited to, interleukin-2) 
The following are prohibited within 21 days prior to the first administration of CMB305 on 
Day 1: 
• Immunosuppressive medications, including but not limited to, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-TNF agents 
• Any systemic anti-cancer therapy or local regional therapy (surgical resection, 
radiotherapy, radiofrequency ablation, cryotherapy) 
5.8.2 
Prohibited Concomitant Therapy 
The following treatments will be prohibited from Day 1 through the end of treatment or until 
investigator-determined PD (using RECIST v1.1) is documented: 
• Any investigational drug other than LV305 or G305 is prohibited prior to documentation 
of investigator-determined PD (using RECIST v1.1).  
• Any chronic treatment with systemic immunosuppressive dose of corticosteroid at supra-
physiologic doses within 28 days prior to administration of the first dose on Day 1 
through the end of treatment or until investigator-determined PD (using RECIST v1.1) is 
documented. The use of physiologic doses of corticosteroids may be approved after 
consultation with the sponsor.  
• Other concurrent immunosuppressive medications such as methotrexate, cyclosporine, or 
azathioprine are prohibited prior to documentation of investigator-determined PD (using 
RECIST v1.1).  
• Concomitant systemic anti-cancer therapy prior to documentation of 
investigator-determined PD (using RECIST v1.1) is prohibited for symptomatic 
deterioration or for subjects with NED at time of study entry who develop a new 
malignant lesion.  
 
 
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• Any systemic anti-cancer therapy or local regional therapy (surgical resection, 
radiotherapy, radiofrequency ablation, cryotherapy) prior to documentation of 
investigator-determined PD (using RECIST v1.1), or documented symptomatic 
deterioration, or for subjects with NED at time of study entry who develop a new 
malignant lesion.  
5.9 
Treatment Compliance 
All doses of study drug will be administered under the supervision of the investigator or 
identified sub-investigator(s). Appropriate study personnel will maintain records of study drug 
receipt and dispensing. Any discrepancy regarding the dose administered and the reason for the 
discrepancy will be recorded in the eCRF. 
5.10 
Packaging and Labeling 
CMB305 and its matching placebos will be manufactured, packaged, and labeled according to 
Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP). 
5.11 
Storage and Accountability 
Full details on the storage of CMB305 and matching placebo will be provided in the Pharmacy 
Manual and on the investigational product label. 
LV305 drug product is stored at -90°C to -60°C. For G305, the NY-ESO-1 protein is stored at -
90°C to -60°C and GLA-SE is stored at 2°C to 8°C. 
Under no circumstances is it permitted to use study supplies for any purposes other than those 
specified in this protocol. 
The investigator or a medically qualified, authorized delegate will be provided with forms to 
enable accurate recording of all study doses at the study site at all times. The investigator, or 
designee, must sign a statement that he/she has received study drug supplies intended for the 
study. At any given time, the amount of study drug supplied, used, and unused at the study site 
must match. An accounting must be given of any discrepancies. 
 
 
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6.0 
STUDY PROCEDURES 
All study procedures detailed in Sections 6.1 to 6.3 will be performed at the time points 
stipulated in the schedule of events for the Pre-Screening and Screening periods (Table 1) and 
for the Treatment through Long-term Follow-up periods (Table 2). 
6.1 
Informed Consent or Assent 
All subjects and legal authorized representatives must provide written informed consent 
(if ≥18 years of age) or assent (if 12 to <18 years of age) at Pre-screening and Screening. 
Two informed consents/assents will be used.  
The Pre-screening ICF/assent form will allow for IHC testing of the tumor sample (fresh or 
archival) for the presence of NY-ESO-1, and review of the tumor images (CT or MRI) collected 
before and after administration of the first dose of first-line systemic anti-cancer therapy.  
The Main Study ICF/assent allows for participation in the study and must be signed before 
initiation of any Screening study-related procedures. Before the Main Study ICF/assent can be 
signed, results of IHC testing for the presence of NY-ESO-1 (≥1% expression) must be available 
from the central laboratory, and the investigator-evaluated tumor response (SD or better using 
RECIST v1.1) to first-line systemic anti-cancer therapy must be documented. 
Prior to any involvement in study-related activities, an institutional review board 
(IRB)/independent ethics committee (IEC)-approved written ICF/assent must be signed and 
dated by the subject and/or by the subject’s legally acceptable representative according to local 
regulations. Documentation of local regulations regarding what constitutes legally acceptable 
representation should be filed at the study site. A copy of the signed and dated ICF and any other 
required forms to meet local or country-specific regulations must be given to the subject and the 
legally acceptable representative. During the consent process, the person obtaining consent must 
inform the subject of all elements of the study. No protocol-specific procedures, including 
screening procedures, are to be performed until the subject has signed and dated an 
IRB/IEC-approved ICF/assent. The study begins with the signing and dating of the Main Study 
ICF/assent form. 
6.2 
Demographics and Medical History 
Subject demographic data such as age, sex, ethnicity (where legally allowed), and race will be 
obtained during Screening.  
The subject’s clinically significant and relevant medical history will be obtained at Screening. 
The medical history should include (but not be limited to) clinically significant and relevant 
medical history with following body systems: head, eyes, ears, nose, and throat (HEENT), 
neurologic and psychiatric, endocrine and metabolic, dermatological, cardiovascular, respiratory, 
gastrointestinal, genitourinary, musculoskeletal, hematologic, lymphatic, hepatic and renal, 
 
 
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immunological, and surgical history. Medical history data will be reviewed and updated, as 
appropriate, at Day 1. 
6.3 
Efficacy Assessments 
6.3.1 
Tumor Imaging and Response 
Subjects will have imaging performed at the time points stipulated in the schedule of events 
(Table 1 and Table 2).  
For individual subjects, the same imaging method should be used for all subsequent image 
collections throughout the study. The preferred method of imaging is via CT scan with 
intravenous (IV) contrast (MRI may also be considered as indicated). The slice thickness of 
images obtained at Pre-screening (i.e., after treatment with first-line systemic anti-cancer 
therapy), Screening, or while on study must be the same size or smaller than the slice thickness 
of the image obtained prior to administration of the first dose of first-line systemic anti-cancer 
therapy used to document all lesions present during staging of the synovial sarcoma. All images 
must include windows of the chest, abdomen, and pelvis. Brain images will be obtained if 
symptoms or signs suggest central nervous system involvement. Bone images will be obtained if 
symptoms, signs, or history suggest bone involvement by metastatic disease.  
All images will be evaluated by the investigator using RECIST v1.1 measurement criteria 
expressed as PR, CR, SD, or PD (see Appendix 1). 
Radiographic images (e.g., CT scan or MRI) will also be submitted to an IRC for storage and 
will be available for evaluation by a central reader, if requested by the sponsor. Subjects who 
have a tumor response of SD with evidence of >15% to 20% increase in tumor burden will be 
submitted for evaluation by a central reader for adjudication. 
The Radiology manual includes complete details for the collection, storage, and evaluation of 
images.  
6.3.1.1 
Imaging at Pre-screening 
For subjects to be eligible for study participation, the investigator must confirm no evidence of 
disease progression while the subject is receiving treatment with first-line systemic anti-cancer 
therapy for unresectable locally-advanced or metastatic disease. During the Pre-screening period, 
imaging will be performed per standard-of-care and all target and non-target lesions documented 
before initiating first-line systemic anti-cancer therapy using RECIST v1.1. The images obtained 
during Pre-screening will be compared with images obtained before the start of first-line 
systemic anti-cancer therapy, which should have been obtained no more than 60 days prior to 
administration of the first dose of first-line systemic anti-cancer therapy. For a subject who has 
no digital images available but has a documented response classification per RECIST v1.1, a 
radiologist’s report certifying no disease progression may be used in individual cases after prior 
approval by the sponsor.   
 
 
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6.3.1.2 
Imaging at Screening  
During the Screening period, and before randomization, imaging (images will include all organ 
systems that had disease present prior to start of first-line systemic anti-cancer therapy) will be 
performed, and all target and non-target lesions that were documented during Pre-screening will 
be assessed by the investigator using RECIST v1.1 to determine the subject’s response to 
first-line systemic anti-cancer therapy. The images obtained at Screening will be compared with 
both images obtained at Pre-screening and images obtained before the start of first-line systemic 
anti-cancer therapy to ensure that no disease progression has occurred. Subjects who have a 
tumor response of SD with evidence of ≥15% to 20% increase in tumor burden will be submitted 
for central review to adjudicate the investigator’s assessment of tumor response prior to 
randomization. For individual subjects, the images obtained during the Screening period must 
have been collected using the same imaging method used for all images. Radiographic images at 
Screening (e.g., CT scan or MRI) will also be submitted to an IRC for storage and will be 
available for evaluation by a central reader, if requested by the sponsor. Details for the collection 
and evaluation of radiographic images are included in the Radiology Manual.  
6.3.1.3 
Imaging During Treatment to the Time of Disease Progression 
Tumor imaging assessments will be performed and evaluated every 8 weeks after Day 1 until 
investigator-determined PD (using RECIST v1.1) is documented. Disease progression will be 
assessed by the investigator using RECIST v1.1. For each subject, the images obtained during 
the Treatment period must have been collected using the same imaging method for all images 
during the Pre-screening and Screening periods. Subjects who have a global deterioration of 
health status that is attributed to progressive disease and leads to discontinuation of study 
treatment, but who are unable to provide radiographic evidence of disease progression 
(symptomatic deterioration), will be considered as having PD at the time of documented global 
deterioration of health for the purpose of determining PFS. Radiographic images (e.g., CT scan 
or MRI) will also be submitted to an IRC for storage and will be available for evaluation by a 
central reader, if requested by the sponsor. Details for the collection and evaluation of 
radiographic images are included in the Radiology Manual.  
6.3.2 
Immune Response Assessments 
Results for anti-NY-ESO-1 plasma antibody must be available for subject stratification at the 
time of randomization. In addition, at select US sites, pre- and post-treatment anti-NY-ESO-1 
plasma antibodies may be used for exploratory analyses.   
Pre- and post-treatment blood and tumor samples will be collected for exploratory analyses of 
potential biomarkers of CMB305 immunogenicity and clinical tumor response as shown in 
Table 3.  
Circulating tumor genomics will be collected for exploratory analyses of potential immune 
response effect on tumor growth. 
 
 
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Table 3 
At Select US Sites Only:  Immune Response Assessments 
Assessment 
Subjects/Timepoint 
Analysis 
Presence of T cell 
immunity at baseline  
(peripheral blood) 
Day 1 prior to dosing 
NY-ESO-1-specific T cells are detected in PBMC 
by ELISPOT (ex vivo or following 7-day in vitro 
stimulation). The assay is performed in 
quadruplicate.  
Positive response is defined as follows: 
• 
ex vivo ELISPOT: no less than 
15 IFNγ-secreting spots per well after 
background subtraction 
• 
in vitro stimulation ELISPOT: no less than 
50 spots per well after background subtraction 
Presence of antibody 
at baseline 
(peripheral blood) 
Screening  
NY-ESO-1 specific plasma antibodies that are 
detected by ELISA at a titer of ≥1:100 
Induction of antibody 
on treatment 
(peripheral blood) 
Day 92 
• 
NY-ESO-1 specific plasma antibodies that are 
detected by ELISA at a ≥4-fold increase in titer 
at Day 92 
or 
• 
Seroconversion of NY-ESO-1 specific plasma 
antibodies that are detected by ELISA at 92  
Induction of T cells 
on treatment 
(peripheral blood) 
Day 92 and only Day 
365 for subjects who 
have not yet progressed 
• 
Ratio of post-treatment to pre-treatment 
NY-ESO-1-specific T cell counts ≥2 
or  
• 
Post-treatment positive ELISPOT from 
pre-treatment negative baseline 
Intratumoral immune 
status at baseline and 
on treatment  
(tumor biopsy) 
Fresh biopsy either at 
Prescreening or 
Screening, Day 92, 
Day 365, and at time of 
progression event will 
be encouraged  
Ratio of post-treatment to pre-treatment 
NY-ESO-1-specific T cells within the tumor 
ELISA = enzyme-linked immunosorbent assay; ELISPOT = enzyme-linked immunospot;  
NY-ESO-1 = New York esophageal squamous cell carcinoma-1; PBMC = peripheral blood mononuclear cells 
 
Many exploratory analyses for potential biomarkers are being investigated, but the predictive 
value of such tests is not yet known. The data collected from these exploratory tests will help to 
define a set of biomarkers that might be used in future studies to help define the ability of 
CMB305 to stimulate anti-tumor immune responses and to help stratify subjects who might 
respond to these treatments. Exploratory blood tests may include functional assays of cytolytic 
T cells or other immune cells directed against autologous tumor cells or surrogate target cells, 
 
 
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modifications of current assays to detect anti-tumor cellular immunity, detection and/or analyses 
of circulating tumor cells, or analyses of other (not yet undefined) tumor markers and immune 
function. Screening and post-treatment cancer biopsy tissue may be collected at select study sites 
and only if tumor sites are accessible. These tumor samples will be examined for evidence of 
anti-tumor cellular immunity (e.g., CD8 T cell or natural killer cell infiltration, tumor necrosis) 
by IHC and for evidence of immune suppression within the tumor microenvironment. Samples 
may also be sent for gene expression analysis, T cell receptor expression, fluorescence-activated 
cell sorting analysis, and isolation of tumor-infiltrating lymphocytes. Any blood or tumor 
samples will only be used to examine the subject’s immune response, their cancer, or to help 
evaluate any potential toxicity arising in the study. The samples will not be examined for 
unrelated research or to examine unrelated genes or diseases. 
The following immune monitoring may be conducted: 
• Cellular immunogenicity by changes from baseline and over the course of the trial period 
in peripheral blood levels of NY-ESO-1 antigen specific T cells and T cell associated 
cytokine production 
• Cellular immunogenicity by changes from baseline and over the course of the trial period 
in peripheral blood levels of overall T cell effector and memory populations 
• Humoral immunogenicity as measured by changes from baseline and over the course of 
the trial period with anti-NY-ESO-1 antibodies and anti-LV antibodies 
Details for sample handling and assay performance will be provided in the Laboratory Manual 
provided to study sites. 
6.3.3 
Tumor Biopsy 
Biopsy samples will be collected as specified in the schedule of events (Table 1, Table 2) and in 
accordance with the site’s standard operating procedures. Details of biopsy collection are 
included in the Laboratory Manual. 
6.3.4 
ECOG 
ECOG scores will be obtained according to the schedule of events (Table 1, Table 2). The ECOG 
assessment tool is provided in Appendix 2. 
6.3.5 
QoL Assessment 
Quality of life will be assessed using a paper form completed by the subject according to the 
schedule of events (Table 1, Table 2) using the EuroQol 5-Dimension 5 Level (EQ-5D-5L). for 
subject ≥18 years of age as shown in Appendix 3. or using the EuroQol 5-Dimension Youth 
(EQ-5D-Y) for subjects 12 to <18 years of age as shown in Appendix 4. 
 
 
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6.4 
Safety Assessments 
The investigator is responsible for the appropriate medical care and safety of subjects who have 
entered this study. The investigator must notify the sponsor within 24 hours if any of the 
following events occurs: 
• Any grade 3 or higher event, regardless of relationship to the study drug(s) 
• Any event meeting the criteria for an SAE 
• Any medical event of interest (MEOI) (see Section 6.4.7.5) 
Safety assessments will include solicited and unsolicited symptoms, physical examination 
findings, vital signs, documentation of AEs, ECGs and/or echocardiogram as applicable, clinical 
laboratory evaluations, deviations or discontinuations attributed to AEs, concomitant medication 
use, and LV305 persistence.  
6.4.1 
Physical Examination 
A physical examination will be performed at Screening and should include an evaluation of 
organ systems, including, but not limited to, head and neck; chest and lungs; cardiac; 
gastrointestinal; neurologic; endocrine; and musculoskeletal and integument. Other organ 
systems should be evaluated as directed by medical history or current symptoms. At subsequent 
visits, limited, symptom-directed physical examinations should be performed. 
Measurements of weight and height will be recorded only at screening and weight at every visit. 
6.4.2 
Vital Signs 
Vital sign measurements will include systolic/diastolic blood pressure, respiratory rate, heart 
rate, and body temperature. On the day of each dosing, vital signs will be obtained before dosing 
and 30 minutes after dosing (±10-minute window). Blood pressure and heart rate will be 
measured no more than 60 minutes before the scheduled dosing. Vital signs should be performed 
before invasive procedures (e.g., blood sample collection). 
6.4.3 
Clinical Laboratory Tests 
6.4.3.1 
Laboratory Parameters 
Central laboratory parameters to be analyzed are shown in Table 4. Screening laboratory 
measurements will be used to determine study eligibility. Central laboratory measurements will 
be used for safety analyses and for other exploratory data analyses. Data on local laboratory tests 
may be collected for subjects experiencing adverse events upon sponsor notification. Sites will 
collect and analyze blood and urine samples at local laboratories based on their routine practice.  
 
 
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Table 4 
Clinical Laboratory Tests (Central Laboratory) 
Hematology 
Hematocrit (Hct); hemoglobin (Hgb); mean corpuscular hemoglobin (MCH); 
mean corpuscular hemoglobin concentration (MCHC); mean corpuscular 
volume (MCV); platelet count; red blood cell (RBC) count; white blood cell 
(WBC) count with differential; absolute neutrophil count (ANC); absolute 
lymphocyte count 
Serum Chemistry 
Albumin; alkaline phosphatase; alanine aminotransferase (ALT); aspartate 
aminotransferase (AST); total protein; blood urea nitrogen (BUN); calcium; 
carbon dioxide; chloride; creatinine; creatinine clearance; uric acid; gamma-
glutamyl transferase (GGT); glucose; lactate dehydrogenase (LDH); 
phosphorus; potassium; sodium; total bilirubin; direct bilirubin; thyroid 
stimulating hormone (TSH) (if TSH abnormal then T3, T4 to be evaluated) 
Coagulation 
Prothrombin time (PT); partial thromboplastin time (PTT); international 
normalized ratio (INR) 
Urinalysis 
Appearance; bilirubin; color; glucose; ketones; microscopic examination of 
sediment; nitrite; occult blood; pH; protein; specific gravity; urobilinogen 
Viral tests 
Hepatitis B (HepB), hepatitis C (HepC), or human immunodeficiency virus 
(HIV) infection 
 
6.4.3.2 
Sample Collection, Storage, and Shipping 
Complete details for sample collection, storage, and shipping to the central laboratory are 
included in the Laboratory Manual. 
6.4.4 
Electrocardiogram  
A standard 12-lead ECG will be obtained. Subjects should rest in the supine position before each 
12-lead ECG recording is started. The ECGs should be reviewed, signed, and dated by a 
qualified health care practitioner and any clinically important finding recorded on the ECG 
report and on the appropriate eCRF. The investigator is responsible for providing the 
interpretation of all ECGs.  
6.4.5 
Concomitant Medication Use 
Concomitant treatment is permitted if the medication is not expected to interfere with the 
evaluation of safety or efficacy of the study drug. During the study, if the use of any concomitant 
treatment becomes necessary (e.g., for treatment or prophylaxis of an AE), the treatment must be 
recorded on the eCRF, including the reason for treatment, generic name of the drug, dosage, 
route, and date of administration. Restricted and prohibited concomitant medication use is 
presented in Section 5.8. 
 
 
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The use of concomitant medications will be recorded from Day 1 through the end of the 
Treatment period or until the time of disease progression. Details of concomitant medication use 
should include the name, dose, route of administration, and indication. 
6.4.6 
LV305 Persistence 
Peripheral blood will be collected at Screening and at the following timepoints after 
administration of the first dose of study drug on Day 1: no sooner than Day 92 (3 months) up to 
4 months; from 6 months up to 9 months; and from 1 year up to 15 months; and then yearly at no 
sooner than every 12 months but not more than 15 months until study closure. If all 
post-treatment assays are negative during the first year, then the yearly samples should be 
archived. Samples will be used for an assay to test for persistence of LV305. 
6.4.7 
Adverse Events Assessments 
All subjects who receive at least 1 study injection or another study-related procedure will be 
considered evaluable for safety. This includes any untoward signs (including abnormal 
laboratory findings) or symptoms experienced by the subject from the time of enrollment until 
30 days post administration of the last dose of the study drug (i.e., CMB305). Safety will be 
evaluated for all treated subjects using the NCI-CTCAE v.4.03 or newer. Safety assessments will 
be based on medical review of both solicited and spontaneously reported AEs, including 
symptoms, physical examination findings, vital signs, laboratory findings, ECGs, and treatment 
discontinuations due to AEs. The nature, severity, and frequency of AEs will be monitored on an 
ongoing basis for risk assessment and to determine if risk management interventions are 
warranted (e.g., expedited notification of safety findings to investigators, IRBs/IECs, or 
regulators; update of Investigator’s Brochure and ICF risks and re-consenting study subjects; 
revision of safety monitoring procedures; revision of eligibility criteria or other study 
procedures).  
6.4.7.1 
Adverse Event Collection Period 
All enrolled subjects will have periodic assessment of clinical and laboratory AEs. All AEs, 
SAEs, and MEOIs will be collected until at least 30 days after administration of the last dose of 
the study drug (i.e., CMB305). MEOIs, immune-mediated events and secondary malignancies 
(regardless of causality) to be reported through 90 days following last IP dose/cessation of 
treatment or 30 days after initiation of new anti-cancer therapy, whichever is earlier, need to be 
reported to the Sponsor within 24 hours of event in the same manner as outlined for SAEs. All 
SAEs and new malignancies that come to the attention of the site staff and are considered at least 
possibly related to CMB305 will be collected until the time of last subject contact. AEs are to be 
reported 30 days after last dose of study drug if possibly related to CMB305/blinded IP, unless 
they fall in category above. 
 
 
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6.4.7.2 
Adverse Event Reporting 
All SAEs that are unexpected and considered possibly, probably, or definitely related to study 
drug by the investigator or sponsor will be reported to the Food and Drug Administration (FDA), 
applicable regulatory agencies, and IRB/IEC in accordance with the requirements in 21 Code of 
Federal Regulations (CFR) §312.32 and International Conference on Harmonization 
(ICH) guidelines. 
At each study visit (including unscheduled visits), the investigator, or designee, will determine 
whether any AEs have occurred. Each AE will be reported in the subject’s medical record and on 
the AE eCRF page and classified according to the criteria in Section 6.4.7.4, Section 6.4.7.6, and 
Section 6.4.7.7. If known, the diagnosis should be recorded, in preference to the listing of 
individual signs and symptoms. Any pre-existing conditions that are detected as part of the initial 
screening procedures will be reported in the medical history and not as an AE. However, 
pre-existing conditions that worsen after enrollment should be reported as an AE.  
Adverse events will be reported to the FDA and applicable regulatory authorities in accordance 
with the requirements outlined in 21 CFR §312.32 and ICH guidelines. Progression of cancer is 
not considered an AE unless it is considered to be drug-related by the investigator. Deaths due to 
cancer progression will not be reported as expedited events. The investigator will continue to 
monitor the subject until any new, changed, or worsened AE resolves, returns to baseline, or 
until the investigator and IMDZ agree that follow-up is no longer necessary. AEs must be 
followed until resolution whenever possible. 
6.4.7.3 
Serious Adverse Event Reporting 
If an SAE occurs, IMDZ will be notified within 24 hours of awareness of the event by the 
investigator. In particular, if the SAE is fatal or life-threatening, IMDZ must be notified 
immediately, irrespective of the extent of available AE information. In the rare event that the 
investigator or designee does not become aware of the occurrence of an SAE immediately, the 
investigator or designee must report the event within 24 hours of their awareness and document 
the time of when his/her first awareness occurred. For all SAEs, the investigator or designee is 
obligated to pursue and provide information to IMDZ in accordance with the time frames for 
reporting specified above. In addition, an investigator may be requested to obtain specific 
additional follow-up information in an expedited fashion. This information may be more detailed 
than that captured on the AE case report form. In general, this will include a description of the 
AE in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of causality.  
New SAEs experienced by subjects during the Screening period (pre-study treatment) will be 
reported to IMDZ if the events are considered related to study procedures. New SAEs 
determined to be related to study tests or procedures (not including cancer-related events) and 
any hospitalizations determined to be related to study tests or procedures that are experienced by 
subjects from the time of signing the Main Study ICF/assent form until Day 1 (start of CMB305 
 
 
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treatment) will be noted on the SAE form and eCRF. From Day 1 until 30 days after 
administration of the last dose of the investigational product (i.e., CMB305), any new SAE will 
be noted on the SAE form and eCRF. After that point, any AE that comes to the attention of the 
site staff that may be causally related to study drug, i.e., CMB305, (i.e., there is a reasonable 
possibility that the event may have been caused by the drug) will be reported to IMDZ. 
SAEs will be monitored until they have resolved, returned to baseline, or they are not clinically 
significant, stable, or do not require additional follow-up, as judged by the investigator and 
IMDZ. 
STUDY CONTACT FOR REPORTING 
SERIOUS ADVERSE EVENTS 
Vendor: 
Everest Clinical Research, Corp. 
Telephone: 
 (office) or 
 (mobile) 
Email: 
SAE forms must be completed electronically in the EDC clinical database. 
Back-up SAE report forms or supplemental information is to be emailed to: 
 
 
6.4.7.4 
Medical Event of Interest Reporting 
Selected non-serious AEs, as described in Section 6.4.7.5, are classified as MEOIs and must be 
recorded as such on the AE CRF and reported to the sponsor via electronic media or on the paper 
MEOI Report Form. MEOIs that are identified from the date of first dose through 90 days 
following cessation of treatment, or 30 days after the initiation of a new anti-cancer therapy, 
whichever is earlier, need to be reported to the sponsor within 24 hours of the event in the same 
manner as outlined for SAEs (see Section 6.4.7.3). 
Subjects should be assessed for the occurrence of possible MEOIs before administration of each 
dose of study treatment. Laboratory results should be evaluated, and subjects should be asked 
about any signs and symptoms experienced that are suggestive of an immune-related event. If 
laboratory test results or symptoms indicate possible immune-related MEOIs, then additional 
testing should be performed to rule out other etiologic causes. If no other cause is found, then the 
MEOI will be considered to be immune-related. 
6.4.7.5 
Definitions of Adverse Event 
Adverse Event (AE)—Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product, medical treatment, or procedure, and which does 
not necessarily have to have a causal relationship with this regimen. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, medical 
 
 
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treatment, or procedure whether or not considered possibly, probably, or definitely related to the 
medicinal product. Progression of cancer is not considered an AE unless it is considered to be 
drug-related by the investigator. 
Treatment-Emergent Adverse Event (TEAE)—Any AE that occurs, or an existing condition 
that worsens in severity, after administration of the first dose of the study drug. 
Medical Event of Interest (MEOI)—Selected non-serious AEs are classified as MEOIs. The 
following treatment-emergent immune-mediated event is an MEOI for CMB305: 
• Pneumonitis 
As NY-ESO-1 is only detected in certain testicular cells in healthy individuals (Gnjatic 2006), 
the following male genitourinary-related events are MEOIs for CMB305: 
• Prostatic pain 
• Groin pain 
• Testicular pain 
• Epididymo-orchitis 
MEOIs for this study include the following: 
• An overdose of the sponsor’s investigational product that is not associated with clinical 
symptoms or abnormal laboratory results 
• Results from protocol-specified or unscheduled laboratory results showing simultaneous:  
o Increased ALT and/or AST ≥3× ULN, 
o Increased serum total bilirubin ≥2× ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase) and 
o No other reason can be found to explain the combination of increased 
aminotransferase enzymes and total bilirubin, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of causing the observed 
injury. 
Note: These criteria are based upon available regulatory guidance documents. 
The purpose of these criteria is to specify a threshold of abnormal hepatic test results 
that may require an additional evaluation for an underlying etiology. The site 
guidance for assessment and follow-up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent). 
During study conduct, additional new MEOIs may be identified by the Sponsor based on their 
clinical and laboratory features and understanding of underlying pathophysiology of the adverse 
events and will need to be reported as such. Such events may include dermatologic, endocrine, 
neurologic, gastrointestinal, respiratory and musculoskeletal toxicities, which are possibly 
 
 
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immune-mediated and possibly related to the study drug mechanism of action. Such adverse 
events may be delayed and wide ranging in terms of organs affected and severity. 
Unexpected Adverse Event—An AE is “unexpected” when its nature (specificity), severity, or 
frequency are not consistent with the known or foreseeable risk of AE associated with the 
research procedures described in the protocol, Main Study ICF/assent form, or the Investigator 
Brochure. 
Serious Adverse Event (SAE)—Any AE that results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
Note: Hospitalizations not to be reported as SAEs include admissions for planned 
medical/surgical procedure (such as scheduled tumor excision or debulking surgery) or 
routine health assessment requiring admission for baseline/trending of health status 
documentation (e.g., routine colonoscopy) or admission for social purposes such as lack 
of housing, economic inadequacy, caregiver respite, or family circumstances. 
• A persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
• Is a medically important condition that is judged by a health care professional as serious 
The term “life-threatening” refers to an event in which the subject was at risk of death at the time 
of the event, and it does not refer to an event that hypothetically might have caused death if it 
were more severe.  
Disability refers to a substantial disruption of a person’s ability to conduct normal life function.  
• Medical and scientific judgment will be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the outcomes listed in the 
definition above. These may also be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; or blood 
dyscrasias or convulsions that do not result in hospitalization. For reporting in this study, 
any suspected transmission of an infectious agent via an investigational medicinal 
product is considered a serious adverse event.  
When there is doubt regarding an AE meeting the criteria for an SAE, the investigator should 
default to reporting the AE as an SAE.  
There are special circumstances in which an SAE reporting form is used to communicate 
important clinical trial safety observations that may not constitute an SAE.  
 
 
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• Pregnancy: Although pregnancy is not considered an SAE and is instead a normal human 
experience, all pregnancies reported in female subjects occurring in the month before or 
month after or occurring in female partners of male subjects in the month before or 
3 months after for the last investigational injection must be reported to sponsor. 
• Overdose: An overdose is defined as the accidental or intentional administration of any 
dose of a product that is considered both excessive and medically important. For 
reporting purposes, an overdose will be considered, regardless of adverse outcome, as an 
important medical event. All cases of overdose must be reported immediately to the 
sponsor. 
6.4.7.6 
Adverse Event Severity 
All AEs will be evaluated according to the NCI-CTCAE v4.03 (2010) or newer 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) 
For AEs not listed in this reference scale, severity will be assessed by the investigator according 
to the criteria in Table 5. 
Table 5 
Adverse Event Severity Assessment 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
Grade 2 (Moderate) 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADLb 
Grade 4 (Life threatening) 
Life-threatening consequences; urgent intervention indicated 
Grade 5 (Death) 
Death related to AE 
ADL = activities of daily living; AE = adverse event 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
Changes in the severity of an AE should be documented to enable an assessment of the duration 
of the event at each level of intensity. Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
6.4.7.7 
Relationship 
The investigator will report his or her interpretation of the relationship between an AE and the 
study treatment on the basis of their clinical judgment and the definitions in Table 6. 
 
 
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Table 6 
Assessment of Relationship 
Definitely related 
AEs clearly attributable to study regimen administration  
Probably related 
AEs for which there is a reasonable possibility of causal association to 
study regimen  
Possibly related 
AEs for which there is confounding by comorbidities, medications or 
other considerations but for which it is not unreasonable that the AE 
may have been caused by study regimen. Note that it is not 
appropriate to invoke “you can’t rule it out.” 
Not related 
AEs that are considered clearly not causally related to study regimen, 
or for which there is a clear alternative explanation 
AE = adverse event 
 
If there is any question whether or not an AE is possibly, probably, or definitely related, the 
investigator should default to conservatism in categorization. Similarly, the investigator should 
default to conservatism by calling an AE an SAE if there is doubt regarding the serious nature of 
an AE, if it meets one of the definitions described above.  
6.4.7.8 
Clinical Laboratory Adverse Events 
Clinically significant laboratory test results, in the opinion of the investigator, will be considered 
AEs and will be reported as shown in Section 6.4.7.  
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 
changes in laboratory values within the normal range will require similar judgment. An abnormal 
laboratory value that is not already associated with an AE is to be recorded as an AE only if any 
one of the following criteria is met: 
• An action on the study drug is made as a result of the abnormality 
• Intervention for management of the abnormality is required 
• At the discretion of the investigator should the abnormality be deemed clinically 
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6.4.8 
Pregnancy 
Sexually-active men and FCBP must use a highly effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. Before enrolling FCBP in 
this clinical trial, all FCBP must be advised of the importance of avoiding pregnancy during trial 
participation and for 30 days after the last dose of study drug administration and the potential 
risk factors for an unintentional pregnancy. Male subjects must be advised of the importance of 
their female partners avoiding pregnancy during the male subject’s participation and for 
3 months after the last dose of the study drug. All subjects (men and women) must sign an ICF 
documenting this discussion.  
All FCBP must have a negative pregnancy test within 2 weeks prior to the study regimen 
initiation. If the pregnancy test is positive, the subject must not be enrolled in the study.  
In addition, all FCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
If following initiation of study dosing, it is subsequently discovered that a trial subject is 
pregnant or may have been pregnant within 1 month before or 4 months after, study regimens 
will be permanently discontinued, and the subject will be followed as possible by the investigator 
or designated health care professional to determine pregnancy outcomes for both mother and 
baby. If a male subject enrolled in study has a female sexual partner who becomes pregnant after 
initiation of the study, then the study subject should be asked by the investigator (or designated 
health care professional) for permission to approach his pregnant partner to follow-up to 
determine outcomes for both mother and baby. 
6.4.9 
HIV Screening Assessment 
As part of study eligibility, subjects are required to have a negative HIV screening test at 
baseline. LV305 is an engineered lentivirus vector and is therefore derived from HIV. It is not 
known if treatment with LV305 will result in seroconversion of subjects to positive with HIV 
screening. Vectors derived from lentiviruses share some, but not all, of the proteins that are 
recognized in several screening blood tests for HIV. Secondary confirmatory assays such as 
Western Blot will demonstrate that the normal complement of HIV proteins is not present 
(unless, of course, the subject has developed true HIV infection). The informed consent 
document informs subjects regarding the possibility of positive HIV screening test after study 
treatment. Subjects enrolled in the study will be provided with a card from the study sponsor 
describing the possibility of a screening test becoming positive and the importance of 
confirmatory testing. In the event a study subject should have a screening HIV test performed 
and it returns a positive result, the site should inform and consult IMDZ for recommendations on 
the most appropriate confirmatory test to use. 
 
 
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6.4.10 
Immune-mediated Events 
While available data do not provide evidence of a causal relationship between CMB305 and the 
occurrence of immune-related events, a potential for such events exists because of the 
mechanism of action of CMB305. Investigators should promptly identify signs and symptoms of 
AEs representing an immunologic etiology and provide appropriate treatment. If an MEOI that is 
considered grade 2 or higher (with the exception of alopecia or vitiligo) occurs, subsequent doses 
of CMB305 should be withheld. CMB305 dosing should resume only after consultation with the 
sponsor. 
The occurrence of any immune-mediated event will be evaluated by the data monitoring 
committee (DMC). 
The immune-mediated event of pneumonitis will be captured as an MEOI; procedures for 
reporting MEOIs are provided in Section 6.4.7.4. 
6.5 
Removal of Subjects from the Trial or Study Drug 
Unless consent is withdrawn and the subject is unwilling to continue with safety follow-up, the 
subject is lost to follow-up, or the study is terminated, all efforts should be made to continue 
tumor and quality of life assessments as well as safety monitoring of all subjects.  
Subjects who withdraw prior to the end of the study should be followed for new AEs for at least 
until 30 days after their last dose of study drug, i.e., CMB305. If the subject withdraws 
prematurely and is unwilling to continue safety follow-up, any subsequent SAE that may be 
causally related to study drug (i.e., CMB305) that comes to the attention of the site staff should 
be reported to IMDZ. 
Information for long-term survival status should be obtained by any means, which includes, but 
is not limited to, public records where allowed by local authority, telephone contact, during an 
in-clinic visit, chart review, or via communicating with an individual (e.g., family, friend, 
referring health care provider) who is knowledgeable of the subject’s survival status. More 
frequent survival status updates may be obtained at the request of the sponsor. 
6.5.1 
Removal from Trial 
While subjects will be encouraged to continue participation in the study for safety follow-up, 
subjects MUST be discontinued from the study for the following reasons: 
1. Pregnancy within 1 month before or 4 months after study regimen administration 
(NOTE: All FCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant [e.g., missed or late menstrual period] at any time during 
study participation.) 
2. Termination of the study for safety 
 
 
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3. Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
4. Other 
6.5.2 
Removal from Study Drug 
While subjects will be encouraged to continue participation in the study for safety and survival 
follow-up, subjects MUST be discontinued from receiving further study drug for the following 
reason: 
• 
Progressive disease by RECIST v1.1 criteria 
• 
Withdrawal of informed consent from study treatment  
o Subject will continue to be followed for imaging and quality-of-life assessment 
• 
Any clinical AE that meets treatment discontinuation criteria in section 5.6 or any other 
reason that, in the opinion of the investigator, indicates that continued dosing on the study 
is not in the best interest of the subject 
o Subject will continue to be followed for imaging and quality-of-life assessment 
Subjects will be permitted to continue study drug if the RECIST v1.1 criteria for PD are met 
provided they meet all the following criteria: 
• Evidence of clinical benefit as assessed by the investigator 
• Absence of symptoms and signs (including worsening of laboratory values) indicating 
unequivocal progression of disease 
• No decline in ECOG performance status that can be attributed to disease progression 
• Absence of tumor growth at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
• Subjects for whom approved therapies exist must provide written consent to acknowledge 
deferring these treatment options in favor of continuing study treatment at the time of 
initial apparent progression. Study treatment will be discontinued upon commencement 
of subsequent systemic anti-tumor therapy. 
No unblinding will be permitted for subjects who continue study treatment beyond progression. 
6.6 
Appropriateness of Measurements 
The measurements of efficacy and safety in this study are standard measurements widely used 
and generally recognized as reliable, accurate, and relevant. The safety measurements evaluated 
in this study are those used in most clinical studies, including the assessment of AEs.  
 
 
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7.0 
PLANNED STATISTICAL METHODS 
7.1 
Determination of Sample Size 
A total of 248 subjects will be randomly assigned in a 1:1 ratio such that 124 subjects will be 
included in each of the 2 treatment arms. The study is powered at 90% with 179 death events 
required to detect a HR of 0.59, which corresponds to a 41% reduction in the risk of death, and 
an approximately 69% increase in median survival compared with a placebo median survival of 
20 months, and uses a 1-sided log-rank test, with an alpha of 0.0125, a 1:1 randomization ratio, 
and an interim OS non-binding futility analysis with boundary of HR = 1.0 at 67% of 
information time (120 death events from the 179 required death events for the final OS analysis). 
A total of 248 subjects will yield the 179 events required, under the assumption of 24 months for 
enrollment (25% of subjects enrolled in the first year and 75% of subjects enrolled in the second 
year) plus 42 additional months of follow-up.  
With 141 PFS events, the study is powered at 90% to detect a HR of 0.55, which corresponds to 
a 45% reduction in the risk of PFS events (either disease progression or death), and an 
approximately 82% increase in median PFS compared with a placebo median PFS of 4 months, 
and uses a 1-sided log-rank test, with an alpha of 0.0125, and a 1:1 randomization ratio. 
7.2 
Analysis Sets  
For the purpose of statistical analysis, there are 3 analysis sets: Intent-to-Treat set (ITT), Efficacy 
Evaluable set (EE), and Safety set. 
• The ITT set consists of all subjects randomized. All analyses of this set will be based on 
the randomized treatment arm to which the subjects are assigned. Efficacy analyses 
performed in the ITT set will be considered to be the primary indicator of efficacy. 
• The EE set consists of all subjects without major protocol violations, who have received 
at least 1 dose of study drug, and have the baseline and at least 1 post-baseline tumor 
assessments available. The EE set will be analyzed according to the treatment received. 
Efficacy analyses performed in the EE set will be considered to be supportive. 
• The Safety set consists of all subjects taking any amount of study drug. The Safety set is 
the primary set for safety analyses including AEs and clinical laboratory data. Study 
treatment exposure also will be summarized using the Safety set. Efficacy analyses 
performed in the Safety set will be considered to be supportive. 
7.3 
Demographics and Baseline Characteristics 
Subject disposition and characteristics including demographics, disease duration and stage at 
Screening, and relevant medical history will be summarized for the purpose of characterizing the 
subject population by treatment arm and establishing baseline comparability of the randomized 
treatment arms. 
 
 
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7.4 
Primary Endpoints  
• PFS, defined as the time from randomization to the investigator-determined (using 
RECIST v1.1) date of disease progression or death 
• OS, as the time from randomization to the date of death 
7.5 
Secondary Endpoints  
• TTNT 
• DMFS 
• ORR, defined by RECIST v1.1 
• Safety and tolerability 
• QoL, using the EQ-5D-5L for subjects ≥18 years of age or using the EQ-5D-Y for 
subjects 12 to <18 years of age 
7.6 
Exploratory Assessments or Analyses 
• Intratumoral and peripheral blood anti-NY-ESO-1 immune changes 
7.7 
Efficacy Analysis 
7.7.1 
Primary Efficacy Analyses: 
The 2 primary efficacy endpoints of PFS and OS will be compared between CMB305 and 
placebo. Overall survival is defined as the time from randomization to the date of death.  
Progression-free survival by investigator’s assessment is defined as the time from randomization 
to the investigator-determined (using RECIST v1.1) date of disease progression or death. 
Radiographic images will be collected and assessed using RECIST v1.1 until the time the subject 
begins a new line of treatment.  
For the purpose of PFS analysis, any one of the following events, whichever occurs first, will be 
used: 
• Disease progression per RECIST v1.1 (See Appendix 1 Table 7 [Eisenhauer 2009]) 
• Symptomatic deterioration (global health deterioration) as described by RECIST v1.1  
• For subjects with NED at time of randomization, any new malignant lesion that occurs 
after randomization per RECIST v1.1 (See Appendix 1 Table 8) 
Otherwise, subjects who do not have disease progression or have not died will be censored at the 
date when the last tumor imaging assessment determines a lack of progression. If a subject 
begins a new anti-cancer therapy or has radiotherapy, surgery, or other local regional therapy at a 
lesion site prior to documented progression, the subject will be censored at the last assessment 
where the subject was documented as progression free prior to the intervention. For subjects with 
NED at study entry, the appearance of a new malignant lesion as per RECIST v1.1 is defined as 
an event of progression for the purpose of PFS analysis. Subjects with 2 or more missing 
 
 
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response assessments (except for subjects with symptomatic deterioration) prior to a visit with 
documented progression (or death) will be censored at the last visit where the subject was 
documented to be progression free. PFS, by investigator’s assessment, will be the primary PFS 
analysis. PFS by independent radiological review will be the supportive analysis.  
The null hypothesis of no difference in OS/PFS between CMB305 and placebo, will be tested 
using a stratified log-rank test stratified by: disease status at screening (locally advanced 
unresectable versus metastatic), tumor response during screening (PR/SD versus CR/ NED), and 
by baseline presence of anti-NY-ESO-1 antibody (yes versus no)). 
The null hypothesis will be rejected, and it will be concluded that OS/PFS on CMB305 is 
superior to that on placebo in subjects with synovial sarcoma if the 1-sided p value at the final 
analysis for the stratified log-rank test is less than the pre-specified alpha of 0.0125 as discussed 
in Section 7.10, Multiplicity. The associated HR and its 2-sided 97.5% and 95% CI will be 
provided using the stratified Cox proportional hazard model. The Kaplan-Meier curve will 
summarize OS/PFS graphically by treatment arm. Tabular summaries of the Kaplan-Meier 
curves, including the median, will be provided by treatment. The 1-year and 18-month OS/PFS 
rate will be provided by treatment. The final PFS analysis will be conducted when a total of 
141 PFS events occur. The final OS analysis will be conducted when a total of 179 deaths occur.  
A pre-planned sensitivity analysis will be performed based on the number of cycles and type of 
prior therapy (neoadjuvant/adjuvant chemotherapy and surgery and/or radiotherapy). 
7.7.2 
Secondary Efficacy Analyses: 
The secondary efficacy endpoints of TTNT, DMFS, ORR and QoL using the EQ-5D-5L or 
EQ-5D-Y will be compared between treatment arms. 
The secondary efficacy endpoints will only be evaluated if at least one of the primary efficacy 
endpoints demonstrates superiority for CMB305 over placebo. Furthermore, to control the 
overall family-wise type I error rate at 1-sided α = 0.025 for the secondary efficacy endpoints, 
the secondary efficacy endpoint of TTNT will be tested first at 1-sided alpha of 0.025. DMFS 
will be tested at 1-sided alpha of 0.025 only if TTNT shows significant improvement. 
7.7.2.1 
Time to Next Treatment 
Time to next treatment is defined as the time from randomization to start of post-study treatment 
anti-cancer therapy. Subjects who do not start post-study treatment anti-cancer therapy will be 
censored at their last known date of being alive. TTNT will be analyzed using the same methods 
described for OS/PFS. In the event that the percent of subjects with competing events in either 
arm exceeds 3%, the cumulative incidence estimates, and Gray’s test will be the main TTNT 
comparison between the treatment arms.   
 
 
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7.7.2.2 
Distant Metastasis-Free Survival 
Distant metastasis-free survival is defined as the time from randomization to evidence of a new 
distant metastasis not documented at time of randomization. DMFS will be analyzed using the 
same methods described for OS/PFS. In the event that the percent of subjects with competing 
events in either arm exceeds 3%, the cumulative incidence estimates, and Gray’s test will be the 
main DMFS comparison between the treatment arms. 
7.7.2.3 
Other Secondary Efficacy Endpoints 
ORR defined by RECIST v1.1 will be summarized by the number and percent of subjects who 
achieve a CR or PR based on the investigator’s assessment. ORR will be compared between 
treatment arms using a logistic regression. 
QoL (EQ-5D-5L or EQ-5D-Y) scores will be compared between the treatment arms using a 
mixed model. 
7.8 
Safety Analysis 
Safety will be assessed primarily based on reported AEs. A TEAE is an AE with an onset on or 
after the initiation of study treatment, or a pre-existing condition that worsens after initiation of 
study treatment (i.e., increase in severity). Medical events of interest, immune-mediated events, 
and AEs that occur more than 30 days after the last dose, and that are deemed as related to the 
study drug, will be included as TEAEs. TEAEs occurring from the time of the first dose through 
30 days after the last dose of the study drug and medical events of interest, immune-mediated 
events and related AEs will be summarized. All AEs will be coded using the Medical Dictionary 
for Regulatory Affairs® (MedDRA v20.0 or newer). TEAEs will be tabulated by system organ 
class, preferred term, by treatment, and will be further categorized by NCI-CTCAE (v4.03 or 
newer) grade, and by relationship to the study drug. Clinically significant laboratory 
abnormalities, as measured by either the local or central laboratory, will be reported as AEs. The 
incidence for each AE will be provided as the total number of subjects that experience the AE, as 
well as the percentage of the population that this represents. If an AE is reported more than once 
during treatment for a given subject, the worst grade of severity and the most conservative 
relationship will be presented in the summary tables. 
AEs will also be listed for individual subjects, along with information regarding onset, duration, 
grade, relationship to the study drug, and outcome. AEs that lead to withdrawal from the study 
treatment will be listed and summarized. Tabulations and listings of SAEs and deaths also will 
be generated. 
Treatment exposure will be provided by treatment arm. The number of CMB305 or placebo 
injections, duration of exposure, and number of subjects with dose reductions/interruptions will 
be summarized by treatment arm based on the Safety set. 
 
 
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Laboratory values measured by the central laboratory will be used in the analysis of laboratory 
toxicities and will be defined based on universal normal ranges and NCI-CTCAE, Version 4.03 
or newer. The number and percentage of subjects will be summarized by grade using the most 
severe grade by treatment arm. Clinically significant changes in laboratory values will be 
summarized by treatment arm. Laboratory values will be listed, with grade 3 or 4 values flagged. 
All concomitant medications and prior medications will be coded to therapeutic drug classes and 
generic drug names using the World Health Organization (WHO) Drug Classification. The 
incidence of prior and concomitant medication usage will be summarized by treatment arm, by 
therapeutic drug class, and generic drug names. 
7.9 
Exploratory Analysis 
The baseline anti-NY-ESO-1 immune response and histologic and molecular changes in 
peripheral blood and tumor tissue and their association with clinical outcomes will be explored. 
In addition, a relationship between an induced anti-NY-ESO-1 immune response as well as 
tumor tissue changes during study treatment and clinical outcomes will be evaluated using 
peripheral blood and tumor tissue biopsies collected during study treatment at select sites. 
7.10 
Multiplicity 
The study is to be conducted with PFS and OS as 2 primary endpoints with the goal of 
a regulatory approval based on PFS or OS. The overall type I error probability is specified to be 
1-sided 0.025 with success for either of the 2 primary endpoints defining study success using the 
Bonferroni method to specify that each endpoint will be evaluated using a type I error probability 
of 1-sided 0.0125 in order to protect the overall type I error. 
7.11 
Data Monitoring Committee and Interim Analysis 
A data monitoring committee will be established with the responsibility of safeguarding the 
interest of study subjects and maintaining the overall integrity of the study. The DMC will 
review safety data periodically during the study as described under Section 8.17 (Data 
Monitoring Committee) of this protocol and will evaluate the results of final PFS analysis and a 
planned interim OS analysis to assess futility with the possibility of a recommendation for 
stopping the study early because of futility. The OS non-binding futility boundary is set to be 
HR = 1.0. It will be conducted at 67% of information time (120th death event from the 179 
required death events for final OS analysis). If deemed necessary by the DMC, unblinded data 
may be reviewed on a case-by-case basis. The sponsor will remain blinded to study treatment 
until either 1 of the 2 primary endpoints is met or until the study has been stopped early. Details 
of DMC function will be governed by a DMC Charter developed by the sponsor and accepted by 
DMC members. 
 
 
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8.0 
ADMINISTRATIVE CONSIDERATIONS 
8.1 
List of Personnel and Organizations Responsible for Conduct of the Study 
A list of personnel and organizations responsible for the conduct of the study will be provided to 
the study sites as part of the Investigator Study File (or equivalent). This list will be updated by 
the IMDZ or its authorized representatives and provided to study sites on as-needed basis. 
8.2 
Trial Sponsor: 
Immune Design Corp. (IMDZ) 
1616 Eastlake Ave. E, Suite 310 
Seattle, WA 98102 USA 
8.3 
Sponsor’s Medical Monitor: 
 
Immune Design Corp. (IMDZ) 
601 Gateway Blvd., Suite 250 
South San Francisco, CA 94080 USA 
Office: 
 
Email: 
 
8.4 
Clinical Trial Agreement 
This study will be conducted under a Clinical Trial Agreement between IMDZ (or its authorized 
representatives) and the respective institutions representing the study sites. Any financial support 
given to the study sites will be detailed in the Clinical Trial Agreement. The Clinical Trial 
Agreement, which must be signed before the start of any study related procedures, will clearly 
delineate the responsibilities and obligations of the investigator and the sponsor (or its authorized 
representatives), and will form the contractual basis upon which the study will be conducted. 
8.5 
Financial Disclosure by the Investigator 
Prior to study initiation, the investigator and any subinvestigator(s) directly involved in the 
treatment or evaluation of study subjects at each study site will disclose to IMDZ (or its 
authorized representatives) any relevant financial or proprietary interests in either the study 
product or the sponsor company. The appropriate disclosure form(s) will be provided by the 
sponsor (or its authorized representatives) for this purpose. Any relevant updates to the financial 
disclosure information that occur during the conduct of the study, or during one year after 
completion of the study, will be provided by the investigator and subinvestigator(s) to the 
sponsor (or its authorized representatives). All financial disclosure information provided by the 
investigator and subinvestigator(s) will be submitted to appropriate competent authorities 
according to the applicable regulatory requirements. 
 
 
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8.6 
Clinical Study Registration and Results Disclosure 
IMDZ will provide the relevant study protocol information in a public database 
(ClinicalTrials.gov) before or at commencement of the study, as required by the 2007 FDA 
Amendments Act. IMDZ (or its authorized representatives) may also provide study information 
for inclusion in national registries according to local regulatory requirements. 
If a potential subject contacts the sponsor (or its authorized representatives) regarding 
participation in the study, the investigator agrees that the sponsor (or its authorized 
representatives) may forward the relevant study site and contact details to the subject. Based on 
the inclusion and exclusion criteria for the study, the investigator will assess the suitability of the 
subject for enrollment into the study. Results of this study will be disclosed according to the 
relevant regulatory requirements. All publications in peer-reviewed medical journals resulting 
from this study will be listed in the original study protocol registration record on 
ClinicalTrials.gov. 
8.7 
Institutional Review Board or Independent Ethics Committee Approval 
The protocol and the ICFs and assents must have the approval of a properly constituted IRB/IEC 
responsible for approving clinical studies. The signed IRB/IEC approval letter must specify the 
date of protocol and ICF approval and identify the documents approved including the 
investigator's name, the protocol version, date, and title. Any subject materials or advertisements 
used to recruit volunteers should also be reviewed and approved by the IRB/IEC.  
Study drug supplies will not be shipped to the site until a signed approval letter from the 
IRB/IEC has been received as well as approval from the local competent authority(ies) and a 
clinical trial agreement has been signed by IMDZ or its authorized representative and the clinical 
site. 
8.8 
Ethical Conduct of the Study 
All investigators on the protocol must have received formal training in the ethical conduct of 
human research. The study will be conducted in accordance with the ethical principles that have 
their origins in the Declaration of Helsinki. All eCRFs, compliance with the protocol, 
compliance with GCP, and compliance with FDA regulations will be monitored by an IMDZ 
monitor or designee as outlined in the study’s Clinical Monitoring Plan Document. 
8.9 
Subject Information, Consent, and Assent 
As specified in ICH, GCP and the US 21 CFR Section 50.25, the informed consent discussion 
must emphasize that participation in the study is voluntary and that subjects have the right to 
withdraw their consent at any time without giving a reason and without any disadvantage for 
their subsequent care. 
 
 
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Written informed consent or assent must be obtained from the subject prior to performing any 
study-related procedures, including Pre-screening or Screening assessments. The investigator or 
investigator’s designee will provide background information on the study, including the benefits 
and risks of the investigative regimen. The investigator or investigator’s designee will also 
encourage the prospective subject to ask questions about the study and will provide the 
prospective subject with sufficient opportunity to consider whether or not to participate.  
Verification of the signed ICF or assent will be recorded in the subject’s eCRF. The original 
signed ICFs and assents will be filed with the subject’s records and/or in the Investigator Study 
File (or equivalent). A copy of the signed consent or assent must also be provided to the subject, 
and, if the subject is under 18 years of age, to the subject’s legal guardian. 
The subject ICF and assent templates that have been provided for this study may be revised by 
an investigator or an IRB/IEC based on the local requirements. However, all changes requested 
by an investigator or an IRB/IEC, even those that are not substantial and/or do not affect the 
rights, safety or welfare of a subject, must be approved by IMDZ or its designee. 
The subject ICF and assent must be revised whenever important new information becomes 
available that may be relevant to the subject’s consent. Any revision of these documents must be 
approved by the IEC/IRB before they can be used in the study. Subjects must be informed in a 
timely manner if new information becomes available that may be relevant to their willingness to 
continue participation in the study. The communication of this information should be 
documented by having all parties concerned sign and personally date the revised ICF or assent. 
8.9.1 
Assent for Subjects Under the Age of Consent (Pediatric Subjects) 
For all subjects who are under the age of consent (i.e., pediatric subjects under 18 years of age); 
the written informed consent of a legally acceptable representative is required. Pediatric subjects 
who can understand the nature, scope, and possible consequences of the study must also give 
their assent in writing via the assent document, as appropriate, and per local or institutional 
requirements. 
8.10 
Subject Confidentiality 
All study documents, including the study protocol and eCRFs, are the confidential property of 
IMDZ and should be treated as such. 
All subjects screened for the study will be documented in a screening log in compliance with the 
requirements of individual study sites. Subjects not enrolled into the study will be documented as 
such in the screening log together with the reason for not having been enrolled.  
The investigator will maintain a personal list of subject names and subject numbers (Subject 
Identification List) for participants in the study to enable records to be identified at a later date. 
These records should be retained in a confidential manner for the duration stipulated by 
applicable regulatory requirements. Subject names shall not be revealed to IMDZ or its 
 
 
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authorized representative. Only the subject identifier will be recorded in the eCRF, and if the 
subject’s name appears on any other document, it must be redacted and replaced with the subject 
identifier before a copy of the document is supplied to IMDZ or its authorized representatives. 
Clinical sites will comply with local laws regarding anonymization of subject identifiers, as 
required. In the event of accidental communication of subject names or other inappropriate 
identifying information, immediate steps to redact the information from all study files will be 
implemented, with appropriate documentation in the subject study file. 
The ICF will include a statement that all study findings, irrespective of the medium on which 
they are stored, will be handled in strictest confidence in accordance with applicable data 
protection laws (e.g., the European Data Protection Directive [95/46/EC] and the US Health 
Insurance Portability and Accountability Act [HIPAA]), and will be evaluated by the sponsor 
and/or a competent regulatory authority in an anonymized form. The subjects are also to be 
informed that their medical records may be audited or inspected by qualified delegates from the 
sponsor or a competent regulatory authority. The subject’s written consent authorizing direct 
access to his medical records, and computer processing and publishing of his anonymous 
personal data, must be obtained prior to participation in the study. 
8.11 
Quality Control and Assurance 
IMDZ performs quality assurance checks on all clinical studies that it sponsors. Before the 
enrollment of any subject in this study, IMDZ (or its authorized representative) and the 
investigator will review the protocol, the Investigator Brochure, the eCRFs and instructions for 
completing them, the procedure for obtaining informed consent or assent, and the procedure for 
reporting AEs/SAEs. Site monitoring visits will be performed by IMDZ (or its authorized 
representative) on a regular basis pursuant to its monitoring plan. During these visits, 
information recorded on the eCRFs will be verified against source documents. After the eCRFs 
are received by IMDZ (or its authorized representative), they will be reviewed for safety 
information, legibility, completeness, accuracy, and logical consistency. The data will be entered 
into a database. Additional computer programs that identify selected protocol deviations, out-of-
range data, and other data errors may be used to help monitor the study. As necessary, requests 
for clarification or correction will be sent to the investigator.  
Data entered in the eCRF will be source verified for accuracy and completeness. In addition, 
protocol compliance and compliance with FDA regulations and ICH GCP guidelines will be 
verified. 
8.12 
Study Files and Materials 
Before the start of any study-related procedures, all essential documents specified by ICH GCP 
and other applicable regulations must be available in the relevant files maintained by IMDZ (or 
its authorized representatives) and the investigator. An Investigator Study File prepared by the 
sponsor (or its authorized representatives), containing all applicable documents for use at the 
study site, will be made available to the investigator before the start of the study. A list of 
 
 
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personnel and organizations responsible for conduct of the study as well as the list of 
investigators will be included in the Investigator Study File. The respective files will be kept and 
updated by the sponsor (or its authorized representatives) and the investigator, as applicable. 
All study documentation and materials maintained in the Investigator Study File at the study site 
must be available for inspection by the sponsor’s study monitor (or its authorized 
representatives) to determine that all required documentation is present and correct (see 
Section 8.15).  
The study may be audited or inspected by an authorized representative from IMDZ or a 
competent regulatory authority (see Section 8.15). 
8.13 
Monitoring of the Study 
The investigator at each site will allow the sponsor’s study monitor (or its authorized 
representatives) reasonable access to the eCRFs and direct access to related source documents 
for monitoring purposes as frequently as the sponsor deems necessary. These documents include 
records of tests performed as a requirement for participating in the study as well as other medical 
records required to confirm information contained in the eCRF, such as past medical history and 
secondary diagnoses. 
Before each monitoring visit, the investigator (or its authorized representatives) should record all 
data generated since the last monitoring visit in the eCRF. The investigator and other relevant 
personnel at each study site will be expected to cooperate with the sponsor’s study monitor to 
assist in providing any missing information. 
The study monitor will require access to the Investigator Study File to ensure completeness of all 
documentation required for the study. The study monitor will ensure that the investigator at each 
site has been provided with adequate means for organization and filing of study documentation. 
The date on which the study monitor (or its authorized representatives) visits the study site will 
be recorded in the Site Visit Log. During monitoring visits, the study site’s coordinator (if 
applicable) and the investigator should be available, the source documentation should be 
accessible, and a suitable environment should be provided for the study monitor to review study 
related documentation. 
The main objectives of monitoring visits conducted by the study monitor include: 
• 
Resolution of any problems 
• 
Examination of all study documentation for completion, adherence to the study protocol, 
and possible AEs 
• 
Clarification of inconsistencies or missing data 
• 
Verification of study data against source documents 
• 
Checks that investigator obligations have been fulfilled 
 
 
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• 
Review of ICFs and dates of consent/assent 
• 
Inspection of drug product with respect to storage, labeling, and documentation 
• 
Drug accountability 
After each subject’s visit to the study site, the investigator (or its authorized representatives) will 
ensure that all data have been entered into the eCRF correctly and in a timely manner, after 
which the investigator will sign the eCRF. 
8.14 
Protocol Amendments 
A “substantial” amendment of a study protocol is any written description of change(s) to, or 
formal clarification of, a study protocol that may have a significant impact on the safety or 
physical or mental integrity of subjects, the scientific value of the study, the conduct or 
management of the study, or the quality or safety of any drug product used in the study. 
The IRB/IEC must approve all substantial protocol amendments prior to their implementation. 
If required by applicable local regulatory requirements, the local regulatory authority must also 
approve all substantial protocol amendments prior to their implementation. 
A “non-substantial” amendment of a study protocol includes minor corrections or clarifications 
that have no significant impact on the way the study is to be conducted and has no effect on the 
safety of participating subjects (e.g., change in study monitor, contact details). If required by 
applicable local regulatory requirements, the IRB/IEC, and/or the local regulatory authority 
should be notified of all non-substantial protocol amendments. The substantial and 
non-substantial protocol amendments will be integrated into an updated study protocol at the 
discretion of the sponsor if the changes to the original study protocol are numerous, or if required 
by applicable regulatory requirements. 
8.15 
Audits and Inspections 
The study may be audited or inspected by authorized representatives from IMDZ or a competent 
regulatory authority. In the event of an audit by the sponsor, the investigator must make all 
study-related documentation available to the auditor(s). Regulatory authorities may request 
access to all study related documentation, including source documents, for inspection and 
copying in keeping with applicable regulations. The sponsor will immediately notify the 
investigator (or vice versa) of an upcoming audit or inspection. 
If an audit or inspection occurs, the investigator and relevant personnel at the study site must 
allocate sufficient time to discuss the findings and any relevant issues. 
8.16 
Electronic Case Report Forms and Study Records 
The investigator is responsible for maintaining adequate and accurate medical records from 
which information will be transferred into the study electronic data capture (EDC) system. The 
eCRFs should be completed by a trained study team member at the investigative site. 
 
 
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An eCRF will be provided for each subject. No data will be recorded directly on the eCRF 
without additional source documentation. Data/corrections entered will be signed or initialed by 
the study personnel undertaking that procedure.  
Only complete eCRFs, reviewed and signed by the investigator indicating his/her assurance of 
the accuracy of all recorded data, will be accepted. It is expected that the investigator and his/her 
staff will cooperate with the monitoring team and provide any missing data in a timely manner. 
Information on the eCRF will be verifiable to source documents. Other records that will be 
considered source documents include, but are not limited to, hospital records, clinic charts, 
radiographic data, laboratory reports, and pathology reports. Copies of source documents that 
should be sent to IMDZ or its authorized representative, if requested, include hospital or clinic 
records, radiographic data, laboratory reports, pathology reports, operative summaries, and 
discharge reports. Other source documents may include hospital discharge summaries, if 
available, or information in lieu of a discharge summary, such as discharge orders or progress 
notes; any relevant notes pertaining to AEs, additional surgical procedures, or deaths and autopsy 
reports. Any documentation sent from the site should be redacted to exclude subject identifying 
information. 
8.17 
Data Monitoring Committee 
A DMC will be established to provide independent review of safety data and to assure that the 
risk to subjects is minimized, in addition to the 2 interim efficacy analyses described under 
Section 7.11 (Data Monitoring Committee and Interim Analysis) of this protocol. The DMC will 
review all related and unexpected (i.e., expedited) SAEs as individual cases arise and will 
perform periodic reviews of all AEs, laboratory results, and subject discontinuations. If deemed 
necessary by the DMC, unblinded data may be reviewed on a case-by-case basis. 
Safety data will be collected and monitored on an ongoing basis throughout the study. IMDZ will 
summarize all available safety and laboratory data on all subjects at regular intervals 
(approximately every 3 months for the first 50 subjects, then approximately every 6 months) 
during the study, as specified in the DMC charter. IMDZ and the DMC will conduct separate 
reviews of these data for any safety trends that might impact the treatment of subjects.  
The DMC may convene on an ad-hoc basis to evaluate any urgent safety issues. Upon request, 
the DMC will be granted access to any available data pertinent to the issues under evaluation. An 
independent DMC Service Group will provide cumulative data, as specified in the DMC charter, 
to the DMC for review, including clinical laboratory values, AEs, SAEs, MEOIs, and subject 
discontinuations. 
 
 
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8.18 
Protocol Compliance 
The investigator must conduct the study in compliance with this study protocol as agreed to by 
the sponsor and approved by the regional competent regulatory authority(ies) and IRB/IEC, per 
local requirements.  
The investigator should not implement any deviation from, or changes to, the study protocol 
without agreement by IMDZ (or its authorized representatives) and documented approval or 
favorable opinion from the IRB/IEC of an amendment to the study protocol. Exceptions include 
only cases of medical emergency to address immediate hazards to study subjects. No protocol 
waivers will be granted by the sponsor. 
In the event of a medical emergency, the investigator at each site may institute any medical 
procedures deemed appropriate to address an immediate hazard to a subject without prior 
IEC/IRB approval or favorable opinion. As soon as possible, the implemented deviation and 
reason for the deviation should be submitted to: 
• IMDZ (or its authorized representatives) for agreement 
• The IRB/IEC for review and approval or favorable opinion (if required) 
• The applicable competent regulatory authority (if required) 
Details of the procedure for implementing study protocol amendments are available in 
Section 8.14. 
At the earliest opportunity, the investigator (or its authorized representatives) must inform IMDZ 
(or its authorized representatives) about any notable protocol deviations and explain any 
deviation from the approved study protocol in the eCRF and/or in the Protocol Deviation Log, if 
applicable. 
8.19 
Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with IMDZ. It is the responsibility of IMDZ to inform the investigator/institution as to when 
these documents no longer need to be retained. 
8.20 
Clinical Study Report 
After completion of the study, a clinical study report covering clinical and statistical aspects of 
the study will be prepared by IMDZ (or its authorized representatives) in consultation with the 
lead investigators. As required by the applicable regulatory requirements, the clinical study 
 
 
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report will be signed by the sponsor’s responsible medical officer as well as the lead 
investigators (if applicable). 
Progress reports and/or a summary of the clinical study report will be provided to the IRB/IEC 
and competent regulatory authorities in accordance with applicable requirements. 
8.21 
Publication and Disclosure Policy 
The rights and obligations of investigators and the sponsor concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the Clinical Trial Agreement for the study (see Section 8.4). 
It is expected that the results of this study will be published in a peer-reviewed journal. 
A publication plan for the primary results will be discussed with the investigators and established 
before the start of the trial. IMDZ will have 30 days from the date of receipt for review and shall 
have the right to request that publication be delayed for up to an additional 30 days in order to 
ensure that the sponsor’s confidential and proprietary data, in addition to the sponsor’s 
intellectual property rights, are protected. Any manuscripts reporting the results of this clinical 
trial must be provided to the sponsor by the principal investigator for review and comment prior 
to submission for publication. Abstracts, press releases, and other media presentations must also 
be forwarded to the sponsor prior to release. No publication, manuscript, or other form of public 
disclosure shall contain any of the sponsor’s confidential/ proprietary information. Co-authorship 
of subsequent publications with IMDZ personnel will be discussed and mutually agreed upon 
before submission of a manuscript to a publisher. 
 
 
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9.0 
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Butler NS, Nolz JC, and Harty JT. Immunologic considerations for generating memory 
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Castro M. Placebo versus best-available therapy control group in Clinical trials for 
pharmacologic therapies: which is better? Proc Am Thorac Soc. 2007;4;570–573. 
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Davis L, Janeway K, Weiss A, e. al. Clinical trial enrollment of adolescents and young 
adults with sarcoma. Cancer. 2017; 123(18): 3434-3440. 
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Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, e. al. A third-generation lentivirus 
vector with a conditional packaging system. Journal of Virology. 1998;(Nov)p. 8463–
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APPENDIX 1: 
DETERMINATION OF TUMOR RESPONSE 
Tumor response will be determined using RECIST v1.1 (Table 7) for subjects who enroll in the 
study with evidence of target and/or non-target lesions (Eisenhauer 2009). For subjects with 
NED at study entry RECIST v1.1 will be used such that the appearance of any new malignant 
lesion will be defined as PD, and no new lesions will be defined as SD as outlined in Table 8. 
Subjects with symptomatic deterioration will be documented as having had an event of PD as of 
the date the symptomatic deterioration was determined by the investigator. 
Table 7 
Time Point Response: Subjects with Target (+/- non-target) Disease 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Non-evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR – completed response; PR = partial response; SD = stable disease; PD = progressive disease;  
NE = inevaluable 
 
Table 8 
Disease Response Assessment on Study for Subjects with no Evidence of 
Disease at Study Day 1 
Baseline 
Post Day 1 Response Assessment 
Overall 
Response 
Target lesion 
Non-Target 
lesion 
Target lesion 
Non-Target 
lesion 
New Lesions 
 
Absent 
Absent 
Any 
Any 
New 
PD 
Absent 
Absent 
Absent 
Absent 
None 
SD 
PD = progressive disease; SD = stable disease 
 
 
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APPENDIX 2: 
ECOG 
ECOG PERFORMANCE STATUSa 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
a As published in American Journal of Clinical Oncology:  Oken MM, Creech RH, Tormey DC, Horton J, Davis 
TE, McFadden ET, Carbone PP: Toxicity and Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. 
 
 
 
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APPENDIX 3: 
EUROQOL 5-DIMENSION 5-LEVEL 
For subjects ≥18 years of age: 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf 
 
 
 
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APPENDIX 4: 
EUROQOL 5-DIMENSION-YOUTH 
For subjects 12 to <18 years of age: 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-Y_User_Guide_v1.0_2014.pdf 
 
 
 
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APPENDIX 5: 
Study Flow Diagrams for Subjects Receiving 4-cycles, 6-cycles and 8-cycles of First-line Systemic 
Anti-Cancer Therapy or Local Regional Therapy. 
 
Figure 4 
Study Flow Diagram for Subjects Receiving 4-Cycles of First-Line Systemic Anti-Cancer Therapy 
 
 
Imaging (CT/MRI) performed every 8 weeks until investigator-assessed 
disease progression (using RECIST v1.1) is documented 
Day 92 
G305  
or  
Placebo 
 
Pre-screening Period 
Screening Period 
(28 days) 
Imaging (CT/MRI) 
scan is performed 
within 60 days before 
administration of the 
first dose of first-line 
systemic anti-cancer 
therapy 
Cycle 1, Day 1 
First-line systemic 
anti-cancer 
Cycle 2 
Cycle 3 
Day of Last Dose 
Cycle 4 
1. Sign Pre-screening ICF/assent 
2. Obtain CT/MRI after 2-3 cycles of first-line 
systemic anti-cancer therapy for 
investigator-assessed tumor response (using 
RECIST v1.1) 
3. Determine NY-ESO-1 status 
 
Exclude subject if: 
1. Progressive disease 
2. NY-ESO-1 status negative 
Subject is eligible if: 
1. Subject has stable disease, partial 
response, or complete response 
2. NY-ESO-1 status positive 
Sign 
Screening 
ICF / 
assent 
Day 50 
LV305 
or 
Placebo 
Day 36 
G305  
or 
Placebo 
Day 1 
LV305  
or 
Placebo 
Within 
28 days of 
last dose of 
first-line 
therapy 
Day 22 
LV305 
or 
Placebo 
Day 64 
G305  
or  
Placebo 
Day 78 
LV305 
or 
Placebo 
Treatment Period 
Post-treatment 
& Long-term 
Follow-up 
(up to 5 years) 
Boost G305 
or Placebo 
every 
8 weeks for 
up to 1 year 
 
 
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Figure 5 
Study Flow Diagram for Subjects Receiving 6-Cycles of First-Line Systemic Anti-Cancer Therapy 
 
 
Imaging (CT/MRI) performed every 8 weeks until investigator-assessed 
disease progression (using RECIST v1.1) is documented 
Day 92 
G305  
or 
Placebo 
 
Pre-screening Period 
Screening Period 
(28 days) 
Imaging (CT/MRI) 
scan is performed 
within 60 days before 
administration of the 
first dose of first-line 
systemic anti-cancer 
therapy 
Cycle 1, 
Day 1 
First-line 
systemic 
anti-cancer 
therapy 
Cycle 2 
Cycle 3 
Cycle 4, Day 1 
 
1. Sign Pre-screening ICF/assent 
2. Obtain CT/MRI after 2-4 cycles of first-line 
systemic anti-cancer therapy for investigator-
assessed tumor response (using RECIST 
v1.1) 
3. Determine NY-ESO-1 status 
 
Exclude subject if: 
1.
Progressive disease 
2.
NY-ESO-1 status negative 
Subject is eligible if: 
1.
Subject has stable disease, partial 
response, or complete response 
2.
NY-ESO-1 status positive 
Sign 
Screening 
ICF / 
assent 
Day 50 
LV305 
or 
Placebo 
Day 36 
G305 
 or 
Placebo 
Day 1 
LV305  
or  
Placebo 
Within 
28 days 
of last 
dose of 
first-line 
therapy 
Day 22 
LV305 
or 
Placebo 
Day 64 
G305  
or 
Placebo 
Day 78 
LV305 
or 
Placebo
Treatment Period 
Post-treatment 
& Long-term 
Follow-up 
(up to 5 years) 
Cycle 5 
Day of Last 
Dose Cycle 6 
Boost G305 
or Placebo 
every 
8 weeks for 
up to 1 year 
 
 
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Figure 6 
Study Flow Diagram for Subjects Receiving 8-Cycles of First-Line Systemic Anti-Cancer Therapy 
 
 
Imaging (CT/MRI) performed every 8 weeks until investigator-assessed 
disease progression (using RECIST v1.1) is documented 
Day 92 
G305  
or 
 placebo 
 
Pre-screening Period 
Screening Period 
(28 days) 
Imaging (CT/MRI) 
scan is performed 
within 60 days before 
administration of the 
first dose of first-line 
systemic anti-cancer 
therapy 
Cycle 1, 
Day 1 
First-line 
systemic 
anti-cancer 
therapy 
Cycle 2 
Cycle 3 
Cycle 4, Day 1 
 
1. Sign Pre-screening ICF/assent 
2. Obtain CT/MRI after 2-6 cycles of first-line 
systemic anti-cancer therapy for investigator-
assessed tumor response (using RECIST 
v1.1) 
3. Determine NY-ESO-1 status 
 
Exclude subject if: 
1.
Progressive disease 
2.
NY-ESO-1 status negative 
Subject is eligible if: 
1.
Subject has stable disease, partial 
response, or complete response 
2.
NY-ESO-1 status positive 
Sign 
Screening 
ICF / 
assent 
Day 50 
LV305 
or 
Placebo
Day 36 
G305  
or  
Placebo 
Day 1 
LV305 or 
Placebo  
Within 
28 days of 
last dose of 
first-line 
therapy 
Day 22 
LV305 
or 
Placebo 
Day 64 
G305  
or  
Placebo 
Day 78 
LV305 
or 
Placebo 
Treatment Period 
Post-treatment 
& Long-term 
Follow-up 
(up to 5 years) 
Day of Last Dose 
Cycle 8 
Boost G305 
or Placebo 
every 
8 weeks for 
up to 1 year 
 
 
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Figure 7 
Study Flow Diagram for Subjects Receiving Local Regional Therapy 
 
Imaging (CT/MRI) performed every 8 weeks until investigator-assessed 
disease progression (using RECIST v1.1) is documented 
Day 92 
G305  
or 
Placebo 
 
Pre-screening Period 
Screening Period 
(28 days) 
Imaging (CT/MRI) 
scan is performed 
within 60 days before 
administration of the 
first dose of first-line 
systemic anti-cancer 
therapy 
Cycle 1, 
Day 1 
First-line 
systemic 
anti-cancer 
therapy 
Cycle 2 
Cycle 3 
Cycles 4-8 
 
1. Sign Pre-screening ICF/assent 
2. Obtain CT/MRI after 2-3 cycles of first-line 
systemic anti-cancer therapy for investigator-
assessed tumor response (using RECIST 
v1.1) 
3. Determine NY-ESO-1 status 
Exclude subject if: 
1.
Progressive disease 
2.
NY-ESO-1 status negative 
Subject is eligible if: 
1.
Subject has stable disease, partial 
response, or complete response 
2.
NY-ESO-1 status positive 
Sign 
Screening 
ICF /  
assent 
Day 50 
LV305 
or 
Placebo 
Day 36 
G305  
or 
Placebo 
Day 1 
LV305 
or 
Placebo 
Within 
28 days of 
last dose 
of first-
line 
therapy 
Day 22 
LV305 
or 
Placebo 
Day 64 
G305  
or 
Placebo 
Day 78 
LV305 
or 
Placebo 
Treatment Period 
Post-treatment 
& Long-term 
Follow-up 
(up to 5 years) 
Date of resection or 
last day of local 
regional (eg.XRT) 
Boost G305 
or Placebo 
every 
8 weeks for 
up to 1 year 
 
 
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