Clinical trial NCT02981303
Conditions: Advanced Melanoma Triple-Negative Breast Cancer
Sponsor: HiberCell, Inc.
Start date: 2017-02-22; Completion date: 2020-12-31
Enrollment: 64 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective: To determine the Overall Response Rate (ORR) to Imprime PGG + pembrolizumab in subjects with advanced melanoma or metastatic TNBC

Safety: To characterize the safety of Imprime PGG + pembrolizumab given in combination

Hypothesis: Restore (for melanoma) or enhance (for TNBC) sensitivity to checkpoint inhibitors (CPI) by appropriate and effective stimulation of the subject's innate and adaptive immune systems in those subjects who have failed 1st line therapy

The study will incorporate Simon's optimal 2-stage design with sample size fixed at 12 subjects each in Stage 1 for advanced melanoma and for Triple Negative Breast Cancer (TNBC) subjects. The safety criterion of ≤ 4 (or ≤ 33%) subjects with Grade 3/4 adverse events in Cycle 1 within either tumor type must be met in order to proceed to Stage 2. The starting dose is 4 mg/kg for Imprime PGG. In the event there are a total of \> 4 (or \> 33%) of subjects with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced to 2 mg/kg, and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of n=12 subjects. For the dose that meets the safety criterion in Stage 1, at least 1 response in melanoma subjects and 2 responses in TNBC subjects amongst the 12 subjects within each tumor type must be observed in order to proceed to Stage 2.

Stage 2 will enroll an additional 17 subjects with melanoma, and 30 subjects with TNBC. For the dose that meets the Stage 1 safety criterion, success will be declared if at least 4 amongst the total of up to 29 subjects with melanoma, and 13 amongst the total of up to 42 subjects with TNBC achieve an objective response.

Detailed description:

Arms: arm 1: Imprime PGG + Pembrolizumab arm 2: Imprime PGG + Pembrolizumab
Interventions: intervention 1: Imprime PGG intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Imprime PGG is a soluble, β-1,3/1,6 glucan isolated from the cell wall of a proprietary Saccharomyces cerevisiae yeast strain. Imprime PGG acts as a Pathogen-Associated Molecular Pattern (PAMP). Imprime will be administered at a dose of 4 mg/kg IV over a 2-hour infusion time on Days 1, 8 and 15 of each 3-week treatment cycle. intervention 2: Pembrolizumab is a humanized monoclonal antibody against the programmed death receptor-1 protein. Pembrolizumab will be given at a fixed dose of 200 mg IV over 30 minutes on Day 1 of each 3-week treatment cycle after the Imprime infusion.

Protocol documents:
Prot_ICF_002.pdf: 
Product:  Imprime PGG and Pembrolizumab  
1 
Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
 
SPONSOR:  Biothera Pharmaceuticals, Inc. 
 
TITLE:  A Multicenter, Open-label, Phase 2 Study of Imprime PGG and Pembrolizumab in 
Subjects With Advanced Melanoma Failing Front-line Treatment with Checkpoint Inhibitors 
(CPI) or Triple Negative Breast Cancer (TNBC) Failing Front-line Chemotherapy for 
Metastatic Disease 
 
 
 
 
 
 
Clinical Protocol BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 
 
 
Biothera 
 
10 August 2017, Version 2.0 
 
 
 
 
 


Product:  Imprime PGG and Pembrolizumab  
2 
Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
Table of Contents 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN.......................................................................................................... 8 
2.1 
Trial Design .............................................................................................................. 8 
2.2 
Trial Diagram ........................................................................................................... 9 
3.0 
OBJECTIVES and HYPOTHESIS ......................................................................... 10 
3.1 
Primary Objectives and Hypothesis ..................................................................... 10 
3.2 
Secondary Objectives ............................................................................................ 10 
3.3 
Exploratory Objectives .......................................................................................... 11 
4.0 
BACKGROUND and RATIONALE....................................................................... 11 
4.1 
Imprime PGG Background ................................................................................... 11 
4.1.1 Imprime PGG – Therapeutic Mechanism of Action ........................................... 11 
4.2 
Pembrolizumab Background ................................................................................ 16 
4.2.1 Pembrolizumab Pharmaceutical and Therapeutic Background .......................... 16 
4.2.2 Pembrolizumab Background and Clinical Trials ................................................ 18 
4.3 
Rationale ................................................................................................................. 18 
4.3.1 Rationale for the Trial and Selected Subject Population .................................... 18 
4.3.2 Rationale for Dose Selection/Regimen/Modification ......................................... 20 
4.3.3 Rationale for Endpoints ...................................................................................... 21 
5.0 
METHODOLOGY ................................................................................................... 23 
5.1 
Entry Criteria ......................................................................................................... 23 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 23 
5.1.2 Subject Inclusion Criteria.................................................................................... 24 
5.1.3 Subject Exclusion Criteria .................................................................................. 26 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
5.2 
Trial Treatments .................................................................................................... 28 
5.2.1 Dose Selection/Modification .............................................................................. 28 
5.2.2 Timing of Dose Administration .......................................................................... 34 
5.2.3 Trial Blinding/Masking ....................................................................................... 34 
5.3 
Randomization or Treatment Allocation ............................................................. 35 
5.4 
Stratification ........................................................................................................... 35 
5.5 
Numbers of Sites and Subjects and Study Duration .......................................... 35 
5.5.1 Number of Sites .................................................................................................. 35 
5.5.2 Number of Subjects ............................................................................................. 35 
5.5.3 Study Duration .................................................................................................... 35 
5.6 
Concomitant Medications/Vaccinations (Allowed and Prohibited) .................. 35 
5.6.1 Acceptable Concomitant Medications ................................................................ 36 
5.6.2 Prohibited Concomitant Medications.................................................................. 36 
5.6.3 Supportive Care Guidelines ................................................................................ 37 
5.7 
Diet/Activity/Other Considerations ...................................................................... 38 
5.7.1 Diet ...................................................................................................................... 38 
5.7.2 Contraception ...................................................................................................... 38 
5.7.3 Use in Pregnancy ................................................................................................ 39 
5.7.4 Use in Nursing Women ....................................................................................... 40 
5.8 
Subject Withdrawal/Discontinuation Criteria .................................................... 40 
5.8.1 Withdrawal/Discontinuation Criteria .................................................................. 40 
5.8.2 Discontinuation of Study Therapy After Complete Response ............................ 41 
5.9 
Subject Replacement Strategy .............................................................................. 41 
5.10 Clinical Criteria for Early Trial Termination .................................................... 41 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
6.0 
TRIAL FLOW CHART ........................................................................................... 43 
6.1 
Schedule of Assessments - Study Flow Chart ...................................................... 43 
7.0 
TRIAL PROCEDURES ........................................................................................... 48 
7.1 
Visit Windows ........................................................................................................ 48 
7.2 
Screening Period .................................................................................................... 48 
7.3 
Treatment Period (Treatment Cycles) ................................................................. 48 
7.3.1 Clinical Assessments and Procedures ................................................................. 49 
7.3.2 Tumor Response Criteria .................................................................................... 49 
7.3.3 Tumor Imaging ................................................................................................... 51 
7.3.4 RECIST Assessment of Disease ......................................................................... 52 
7.3.5 Tumor Biopsy Samples ....................................................................................... 52 
7.3.6 Physical Examination and Measurement of Vital Signs ..................................... 52 
7.3.7 Performance Status ............................................................................................. 53 
7.3.8 Clinical Safety Assessments ............................................................................... 53 
7.3.9 Planned DNA and RNA Analysis ....................................................................... 53 
7.3.10 Laboratory Assessments ..................................................................................... 53 
7.3.11 Pharmacokinetic Evaluations .............................................................................. 55 
7.3.12 Unscheduled Visits ............................................................................................. 55 
7.4 
Post-treatment Assessments .................................................................................. 55 
7.4.1 End of Treatment/End of Study Visit ................................................................. 55 
7.4.2 30-Day Safety Follow-up Visit (30-Day SFU) ................................................... 56 
7.4.3 Every 2-Month Overall Survival Monitoring ..................................................... 57 
8.0 
ADVERSE EVENTS (SERIOUS and NON-SERIOUS) ....................................... 57 
8.1 
Non-serious Adverse Events ................................................................................. 57 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
8.1.1 Definition of Adverse Event and Non-serious Adverse Event ........................... 57 
8.1.2 Reporting and Treating Non-serious Adverse Events......................................... 57 
8.2 
Serious Adverse Events ......................................................................................... 59 
8.2.1 Definition of Serious Adverse Event .................................................................. 59 
8.2.2 Reporting and Treating Serious Adverse Events ................................................ 59 
8.3 
Definition of an Overdose for This Protocol and Reporting of Overdose ........ 60 
8.4 
Reporting of Pregnancy and Lactation ................................................................ 61 
8.5 
Events of Clinical Interest ..................................................................................... 61 
9.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 62 
9.1 
Statistical Analysis Plan Summary ...................................................................... 62 
9.1.1 Hypothesis and Study Design ............................................................................. 62 
9.1.2 Sample Size ......................................................................................................... 63 
9.1.3 Efficacy Analyses ............................................................................................... 63 
9.1.4 Safety Analyses ................................................................................................... 64 
9.1.5 PK Analyses ........................................................................................................ 64 
9.1.6 Interim Analyses ................................................................................................. 64 
9.2 
Statistical Analysis Plan ........................................................................................ 64 
10.0 
LABELING, PACKAGING, STORAGE and RETURN of CLINICAL 
SUPPLIES ................................................................................................................. 65 
10.1 Investigational Product Identification and Description ..................................... 65 
10.1.1 Imprime PGG ...................................................................................................... 65 
10.1.2 Pembrolizumab ................................................................................................... 65 
10.2 Storage and Handling of Clinical Study Material .............................................. 66 
10.2.1 Storage and Handling of Imprime PGG .............................................................. 66 
10.2.2 Storage and Handling of Pembrolizumab ........................................................... 66 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
10.3 Preparation, Dosing Instructions, and Schedule................................................. 66 
10.4 Premedications ....................................................................................................... 67 
10.5 Preparation and Dosing Instructions for Imprime PGG ................................... 67 
10.6 Preparation and Dosing Instructions for Pembrolizumab ................................ 68 
11.0 
CLINICAL STUDY ADMINISTRATION............................................................. 68 
12.0 
INFORMED 
CONSENT 
and 
AUTHORIZATION 
for 
USE 
and 
DISCLOSURE of PROTECTED HEALTH INFORMATION ........................... 69 
12.1 Study Documentation ............................................................................................ 69 
12.1.1 Study Files .......................................................................................................... 69 
12.1.2 Case Report Forms and Source Documentation ................................................. 70 
12.1.3 Retention of Study Documents ........................................................................... 70 
12.2 Clinical Monitoring ................................................................................................ 71 
12.3 Confidentiality ........................................................................................................ 71 
12.3.1 Data ..................................................................................................................... 71 
12.3.2 Subject Anonymity ............................................................................................. 71 
12.3.3 Publication and Use of Information .................................................................... 71 
13.0 
LIST OF REFERENCES ......................................................................................... 73 
14.0 
APPENDICES ........................................................................................................... 78 
14.1 Imprime PGG 4 mg/kg and 2 mg/kg Preparation and Dosing Instructions .... 78 
14.2 Pembrolizumab (KEYTRUDA®) Package Insert and Summary of 
Product Characteristics [Annex I of the European Public Assessment 
Report (EPAR)] ..................................................................................................... 82 
14.3 ECOG Performance Status ................................................................................... 83 
14.4 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) .............. 84 
14.5 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 85 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
14.6 Immune Related Response Criteria (irRECIST) ................................................ 86 
 
 
 
List of Tables 
 
Table 1. Dose Modifications And Toxicity Management Guidelines For Immune-
Related AEs Associated With Pembrolizumab .......................................................... 31 
Table 2. Infusion Reaction Treatment Guidelines For Pembrolizumab ......................... 33 
Table 3. Laboratory Tests .................................................................................................... 54 
Table 4. Time And Events For Sparse PK Collection ....................................................... 55 
Table 5. Pembrolizumab Product Description ................................................................... 66 
Table 6. Target Imprime PGG Administration Values ..................................................... 68 
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
A Multicenter, Open-label, Phase 2 Study of Imprime PGG and 
Pembrolizumab in Subjects With Advanced Melanoma Failing Front-line 
Treatment with Checkpoint Inhibitors (CPI) or Triple Negative Breast 
Cancer (TNBC) Failing Front-line Chemotherapy for Metastatic Disease 
Trial Phase 
2 
Clinical Indication 
Advanced Melanoma and Triple Negative Breast Cancer 
Trial Type 
Multicenter, Simon’s 2-stage optimal design of Imprime PGG and 
pembrolizumab 
Type of control 
Historical control 
Route of administration 
Intravenous for both products 
Trial Blinding 
None 
Treatment Groups  
All subjects to receive Imprime PGG + pembrolizumab 
Number of trial subjects 
Up to N=94 in total (up to 41 with advanced melanoma, up to 53 with 
TNBC) 
Estimated duration of trial 
Approximately 3 years 
Duration of Participation 
Approximately 2 years for any individual subject 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
The study will incorporate Simon’s optimal 2-stage design with sample size fixed at 12 
subjects each in Stage 1 for advanced melanoma and for Triple Negative Breast Cancer 
(TNBC) subjects. The safety criterion of ≤ 4 (or ≤ 33%) subjects with Grade 3/4 adverse 
events in Cycle 1 within either tumor type must be met in order to proceed to Stage 2. The 
starting dose is 4 mg/kg for Imprime PGG. In the event there are a total of > 4 (or > 33%) of 
subjects with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced 
to 2 mg/kg, and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of 
n=12 subjects. For the dose that meets the safety criterion in Stage 1, at least 1 response in 
melanoma subjects and 1 response in TNBC subjects amongst the 12 subjects within each 
tumor type must be observed in order to proceed to Stage 2.   
Stage 2 will enroll an additional 17 subjects with melanoma, and 29 subjects with TNBC. For 
the dose that meets the Stage 1 safety criterion, success will be declared if at least 4 amongst 
the total of up to 29 subjects with melanoma, and 5 amongst the total of up to 41 subjects 
with TNBC achieve an objective response. 
The study population will be those having failed front-line therapy, defined as any treatment 
regimen or regimens used specifically in the treatment of metastatic disease. Refer to Section 
5.1 on Entry Criteria for the study-specific requirements. 
 
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
2.2 
Trial Diagram 
 
 
 
 
Screening for Advanced 
Melanoma Subjects 
Screening for TNBC Subjects 
Stage 1 
N=12 
Imprime PGG 4 mg/kg on 
D1, D8, D15 + 
Pembrolizumab 200 mg on 
D1 of 3-wk Cycle 
≤ 4 Subjects have C1 Grade 3/4 AEs? * 
Yes 
Study Ends 
in Advanced 
Melanoma 
Stage 1 
N=12 
Imprime PGG 4 mg/kg on 
D1, D8, D15 + 
Pembrolizumab 200 mg on 
D1 of 3-wk Cycle 
Stage 2 
N=17 
Imprime PGG 2 or 4 mg/kg 
on D1, D8, D15 + 
Pembrolizumab 200 mg on 
D1 of 3-wk Cycle 
Study 
Ends 
in TNBC
Stage 2 
N=29 
Imprime PGG 2 or 4 mg/kg 
on D1, D8, D15 + 
Pembrolizumab 200 mg on 
D1 of 3-wk Cycle 
Treatment Ends at: 
• 2 years 
• PD 
• Intolerable AE 
• Consent withdrawn 
Follow-up for survival ends 3 years after last subject’s 1st dose or at least 70% 
of subjects have died, whichever occurs earlier and Study Ends 
* ≤ 4 subjects or 33% of Stage 1 subjects does not include infusion reactions (from either study drug) which were 
subsequently controlled and reduced in Cycle 1 via ameliorating actions, and which did not recur in Cycle 2 
 Stage 1: Additional 
Cohort of N=12 
Imprime PGG 2 mg/kg 
on D1, D8, D15 + 
Pembrolizumab 200 mg 
on D1 of 3-wk Cycle 
No
Yes 
No 
Response in ≥ 1 Subject 
≤ 4 Subjects have C1 
Grade 3/4 AEs? * 
Response in ≥ 
1 Subject 
Study Ends 
in Advanced 
Melanoma
No
Yes 
No
Yes 
≤ 4 Subjects have C1 Grade 3/4 AEs? * 
No 
Yes 
 Stage 1: Additional 
Cohort of N=12 
Imprime PGG 2 mg/kg 
on D1, D8, D15 + 
Pembrolizumab 200 mg 
on D1 of 3-wk Cycle 
Response in ≥ 1 Subject 
≤ 4 Subjects have C1 
Grade 3/4 AEs? * 
No
Yes 
Response in ≥ 
1 Subject 
Study 
Ends 
in TNBC
No
Yes 
No
Yes 


Product:  Imprime PGG and Pembrolizumab  
10 
Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
3.0 OBJECTIVES AND HYPOTHESIS 
RECIST v1.1 criteria will be used for all applicable primary and secondary endpoints. 
Immune related response criteria (irRECIST) will be used for exploratory efficacy endpoints. 
3.1 
Primary Objectives and Hypothesis 
▪ Objective: To determine the Overall Response Rate (ORR) to Imprime PGG + 
pembrolizumab in subjects with advanced melanoma or metastatic TNBC 
▪ Safety: To characterize the safety of Imprime PGG + pembrolizumab given in 
combination 
 
Hypothesis:  Restore (for melanoma) or enhance (for TNBC) sensitivity to checkpoint 
inhibitors (CPI) by appropriate and effective stimulation of the subject’s innate and 
adaptive immune systems in those subjects who have failed front-line therapy 
 
Melanoma Subjects:  
• H0: ORR ≤ 5% 
• HA: ORR ≥ 23% 
TNBC Subjects:  
• H0: ORR ≤ 5% 
• HA: ORR ≥ 21% 
Rejection of the null hypothesis will require documenting at least 4 objective responses 
among the total of up to 29 subjects with melanoma (Stage 1 + Stage 2), and 5 objective 
responses among the total of up to 41 subjects with TNBC (Stage 1 + Stage 2). 
3.2 
Secondary Objectives 
Objectives:   
▪ To determine the time to response (TTR), complete response rate (CRR), and 
duration of overall response (DoR) in subjects with advanced melanoma or metastatic 
TNBC when treated with Imprime PGG in combination with pembrolizumab 
▪ To measure the Progression-Free Survival (PFS) and PFS rate at 6 months and 1 year 
in subjects with advanced melanoma or metastatic TNBC when treated with Imprime 
PGG in combination with pembrolizumab 
▪ To measure overall survival (OS) and OS rate at 1 year in subjects with advanced 
melanoma or metastatic TNBC when treated with Imprime PGG in combination with 
pembrolizumab  


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
▪ To profile pharmacokinetic (PK) data in subjects with advanced melanoma or 
metastatic TNBC when treated with Imprime PGG in combination with 
pembrolizumab 
 
3.3 
Exploratory Objectives 
Objectives:   
▪ Determine ORR and PFS based on irRECIST in subjects with advanced melanoma or 
metastatic TNBC when treated with Imprime PGG in combination with 
pembrolizumab 
▪ Correlate levels of baseline serum anti-β-glucan antibody (ABA) with objective 
response and treatment outcomes 
▪ Correlate changes in immune cell activation markers, such as CD86 expression in 
tumor biopsy samples* and in peripheral blood immune cells with objective response 
and treatment outcome 
▪ In tumor biopsies, correlate changes in the tumor immune microenvironment 
including TILs (Tumor-infiltrating Lymphocytes) and tumor-infiltrating myeloid cells 
with objective response and treatment outcome 
▪ Correlate PD-L1 expression in tumor biopsy samples (in tumor cells and myeloid 
cells) with objective response and treatment outcome 
*Information on 1 tumor biopsy sample is required and is as follows: (1) Historical 
(diagnostic) tumor biopsy official pathology report +/- archival biopsy sample. 
Additional biopsy samples, preferably obtained from the same localized region, are 
highly desirable when feasible at the following time points: (2) Before the first dose of 
study treatment, (3) After completion of Cycle 2 but before the start of Cycle 3 dosing, 
and (4) At the time of response or disease progression, or at the End of Study Visit (if no 
response) 
 
4.0 BACKGROUND AND RATIONALE 
4.1 
Imprime PGG Background 
4.1.1 Imprime PGG – Therapeutic Mechanism of Action 
Imprime PGG is a soluble, β-1,3/1,6 glucan isolated from the cell wall of a proprietary 
Saccharomyces cerevisiae yeast strain. Imprime PGG acts as a Pathogen-Associated 
Molecular Pattern (PAMP). PAMPs are critical, “non-self” signals efficiently and effectively 
recognized by the different lineages of the innate immune system- macrophages, monocytes, 
neutrophils and dendritic cells. As a PAMP, Imprime PGG enhances innate immune cell 
killing, counteracts immune suppression and, importantly, triggers the activation and 
maturation of antigen presenting cells (ie, macrophages and dendritic cells), enabling T cell 
expansion and activation.  


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
Non-clinical ex vivo studies using whole blood from healthy human volunteers have 
demonstrated that Imprime PGG treatment stimulates neutrophils to specifically recognize 
and kill antibody-decorated cancer cells via a remarkable burst in the generation of reactive 
oxygen species. Imprime PGG treatment also promotes the degranulation and the killing 
activity of Natural Killer (NK) cells directed against human cancer cells. M2 macrophages 
differentiated and isolated from Imprime PGG treated monocytes in human whole blood re-
polarize, reducing expression of M2-specific surface markers (eg, CD163) and increasing 
M1-state markers (eg, CD86, PD-L1). These repolarized M2 macrophages exhibit 
significantly enhanced capacity to recognize and phagocytose antibody-decorated human 
cancer cells. Furthermore, these Imprime PGG treated M2 macrophages actively stimulate 
the expansion of CD4 T cells and the production of the potent anti-tumor cytokine 
IFN. Monocyte-derived dendritic cells (MoDCs) from Imprime PGG treated whole blood 
show increased expression of activation and maturation markers (CD80, CD83, CD86, HLA-
DR), indicating these cells have matured into fully professional antigen presenting cells. In 
allogeneic Mixed Lymphocyte Reactions, these Imprime PGG-treated MoDCs can now 
instruct substantial CD4 and CD8 T cell expansion and increased IFN production. 
Collectively, these ex vivo studies suggest that Imprime PGG treatment drives the direct 
killing activity of innate immune effectors, re-polarizes the function of normally 
immunosuppressive M2 macrophages, and significantly enhances T cell priming, eliciting 
CD4 and CD8 T cell expansion and IFN production (Fraser et al, AACR 2016; Fulton et al, 
AACR 2016; Leonardo et al, AACR 2016; Jonas et al, AACR 2016). 
In multiple pre-clinical tumor models in vivo, Imprime PGG has been shown to enhance the 
efficacy of tumor-targeted antibodies (eg, cetuximab). This anti-tumor response absolutely 
requires GR1+ (myeloid) cells, complement, and CR3. Recent in vivo work in preclinical 
tumor models further highlights the capacity of Imprime PGG to enlist the full functionality 
of the innate immune system to drive an anti-tumor response. In xenografted human tumor 
models, IV administration of Imprime PGG in conjunction with anti-angiogenic monoclonal 
antibodies (bevacizumab and DC101- a murine anti-VEGFR2 antibody) enhances anti-tumor 
efficacy while re-polarizing the immune microenvironment – ie, enhancing M1 marker 
expression (iNOS, TNFα, CD86, PD-L1), decreasing M2 marker expression (Arg1, TGFβ, 
CD206) and promoting differentiation of Myeloid Derived Suppressor Cells (MDSCs) 
(Fraser et al, AACR 2016 A; Fraser et al, AACR 2016 B; Jonas et al, AACR 2016). In the 
B16 melanoma model, Imprime PGG synergizes with the tumor targeting anti-Trp1 antibody 
in immune-competent C57BL/6 mice to significantly reduce the number and size of lung 
metastases (Leonardo et al, AACR 2016). Finally, in immune-competent C57BL/6 mice, IV 
administered Imprime PGG triggers mobilization of neutrophils and monocytes into 
circulation and into secondary lymphoid organs. Imprime PGG also effectively binds 
dendritic cells, inducing increased surface expression of CD86 and MHC class II, suggesting 
enhanced antigen presentation capability. Consistent with these data, Imprime PGG treatment 
specifically and robustly enhanced expansion of adoptively transferred CD8 T cells (the Ova-
specific OT-1 cells) when co-injected with the model peptide antigen, Ova (Fulton et al, 
AACR 2016). 


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Confidential – Biothera Pharmaceuticals, Inc. 
 
These ex vivo and in vivo data demonstrate that Imprime PGG treatment prompts a shift from 
an immunosuppressive microenvironment typified by M2 macrophages, MDSCs and 
immature dendritic cells, to an immune microenvironment characterized by M1 
macrophages, differentiated MDSCs, and mature, activated dendritic cells. These data 
therefore suggest that Imprime PGG may enhance antigen presentation and cross-talk with T 
cells, thereby promoting the anti-tumor efficacy of checkpoint inhibitor therapy (eg, PD-1 
or PD-L1 antibodies). Indeed, in multiple preclinical tumor models in syngeneic, 
immunocompetent mice, Imprime PGG enhances the efficacy of both anti-PD-1 and anti-PD-
L1 antibody therapy. For instance, in the MC-38 tumor model, Imprime PGG treatment 
significantly expanded the percentage of mice remaining tumor-free from 33% (6/18) in mice 
treated with PD-L1 antibody alone, to 83% (14/17) in mice treated with Imprime PGG and 
PD-L1 antibody. Importantly, when re-challenged with MC-38 tumor cells injected on the 
opposite flank, all of these tumor-free mice remained tumor-free, whereas tumors readily 
established in age-matched, tumor naïve mice. These data suggest that Imprime PGG can 
boost the efficacy of checkpoint inhibitor therapy and further enhance immunologic memory 
(Fraser et al., AACR 2016 A and B). 
Collectively, these studies demonstrate that Imprime PGG acts as a PAMP to enlist the broad 
functionality of the innate immune system to enhance the anti-tumor efficacy of tumor-
targeting, anti-angiogenic, and immune checkpoint inhibitor monoclonal antibodies. Imprime 
PGG activates anti-cancer innate immune effector functions by triggering direct tumor killing 
by innate effector cells, overriding tumor-induced immunosuppression, and generating cross-
talk with the adaptive immune system via enhanced activation of the antigen presenting cells. 
In human serum, Imprime PGG forms an immune complex with anti-beta glucan antibodies 
(ABA), which activate the classical complement pathway, opsonizing the complex with 
complement. The opsonized Imprime PGG-ABA complex binds to FcγRIIa and complement 
receptor 3 (CR3), leading to subsequent modulation of innate immune effector cell functions 
(eg, IL-8 production) (Bose et al, Aug 2013; Qiu et al, 2014; Antonysamy et al, 2014; 
Keystone 2015). The formation of these immune complexes is necessary for Imprime PGG-
induced innate effector cell function. Immune cells from human subjects with insufficient 
ABA do not respond to Imprime PGG unless supplemented with exogenous ABA. 
Responsiveness to Imprime PGG-based immunotherapy is predicated on ABA levels in 
individual subjects. Accordingly, pre-treatment ABA levels may represent a plausible, 
minimally invasive biomarker to enrich for patients most likely to benefit from Imprime 
PGG-based immunotherapy (Chan et al, 2016). 
4.1.1.1 Imprime PGG in Healthy Volunteers 
4.1.1.1.1 Completed Studies 
Two Phase 1 studies in healthy subjects have evaluated single-dose, dose-escalations of 
Imprime PGG (doses of 0.5, 1, 2, 4 and 6 mg/kg; Study BIOBG-CL-001) and multiple-dose, 
dose-escalations of Imprime PGG (7 consecutive daily doses of 1, 2 and 4 mg/kg/day; Study 
BIOBG-CL-002).  
 


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Additionally, a Phase 1/2 study in healthy subjects evaluating co-administration of Imprime 
PGG (2 or 4 mg/kg) and granulocyte colony stimulating factor (G-CSF) for the mobilization 
of peripheral blood progenitor cells (PBPC) has been completed (Study BT-CL-PGG-
SCM0611 [SCM0611]). Results of these studies are summarized in Section 5 of the Imprime 
PGG Investigators Brochure. 
4.1.1.2 Imprime PGG in Cancer Patients 
To date, Biothera has collected data from 5 cancer studies in which Imprime PGG has been 
administered in combination with anti-tumor monoclonal antibodies (mAbs). Three of these 
clinical studies have been completed with study reports, 1 has been completed and is 
awaiting a final study report, and 1 has completed the treatment phase and is in the process of 
closing. 
4.1.1.2.1 Imprime PGG Completed Studies 
▪ Study BT-CL-PGG-CRC0713 [CRC0713] evaluated administration of Imprime PGG 
in combination with cetuximab (Erbitux®), with and without standard irinotecan 
therapy, in subjects with metastatic colorectal cancer (mCRC). The primary objective 
of this study was to determine safety and maximum tolerated dose of Imprime PGG; 
key secondary objectives were to determine tumor response rates (including complete 
response [CR], partial response [PR], stable disease [SD], and progressive disease 
[PD]), overall response rate (ORR), disease control rate (DCR), time to progression 
(TTP), and duration of tumor response; and to establish the pharmacokinetic (PK) 
profile in this setting. Subjects were enrolled into dose-escalating cohorts and dosed 
with either 2, 4, or 6 mg/kg Imprime PGG and a standard regimen of cetuximab either 
with concomitant irinotecan (Arm 1; 10 subjects) or without concomitant irinotecan 
(Arm 2; 22 subjects). Under a separate protocol, BT-CL-PGG-CRC0814 (CRC0814), 
tumor tissue samples from consenting subjects in this study were collected for KRAS 
gene status analysis. Complete safety and efficacy results of this study are 
summarized in Section 5 of the Imprime PGG Investigators Brochure. The results 
from the CRC0713 study (and associated CRC0814 protocol) formed the basis for the 
design of a Phase 3 study in KRAS wild type (WT) mCRC subjects that has 
completed the treatment phase (CRC1031 also known as PRIMUS). 
 
▪ Study BT-CL-PGG-CRC0821 [CRC0821] assessed 4 mg/kg Imprime PGG with a 
standard regimen of cetuximab in the treatment of subjects with Stage IV, KRAS-
mutated mCRC. The primary endpoint was ORR and key secondary endpoints 
included DCR, duration of response (DoR), TTP, PFS and OS. This study enrolled 18 
subjects who had failed previous oxaliplatin and irinotecan-containing therapies. 
Results from the 18 subjects enrolled in Stage 1 show that 1 (5.6%) subject had a PR, 
and SD was observed in 9 (50.0%) additional subjects (of these 9 subjects SD was 
confirmed in 3 and unconfirmed in 6 subjects), yielding a DCR of 55.6% (10 total 
subjects with a response of SD or better). The DoR was 4.2 months for the subject 
with a PR, while the median duration of SD for the total 9 subjects with SD was 2.8 
months (range: 0.4 – 7.2 months). In total, 13 (72.2%) subjects had documented 


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tumor progression. The median TTP was 2.7 months (range: 1.2-16.2 months). In 
total, 18 (100.0%) subjects had recurrence, progression, or death. The median PFS 
was 2.2 months (range: 1.2-16.2 months). In total, 16 (88.9%) subjects died. The 
median OS was 6.6 months (range: 1.9-23.1 months). These data compare favorably 
with historical responses of cetuximab monotherapy in KRAS mutated subjects where 
ORR, DCR, and median OS have been reported to be 0%-1%, 10%-30%, and 19-21 
weeks, respectively. Complete safety and efficacy results are reported in Section 5 of 
the Imprime PGG Investigators Brochure. 
 
▪ Study BT-CL-PGG-LCA0822 [LCA0822] assessed 4 mg/kg Imprime PGG in 
combination with cetuximab and a standard regimen of carboplatin and paclitaxel 
therapy in first-line treatment of late stage (Stage IIIB or IV) NSCLC. The primary 
endpoint was ORR; secondary endpoints included DCR, OS, tumor response rates 
(CR, PR, and SD), DoR, TTP, safety of regimen, and PK profile. A total of 90 
subjects were enrolled. Of these, 59/60 subjects randomized into the Imprime PGG 
arm received this treatment (1/60 received no study treatment). Thirty (30) subjects 
were randomized into the control arm and of these, 29/30 received treatment (1/30 
received no study treatment). This study was closed on 04 November 2015 with final 
results available in November 2015. The addition of Imprime PGG (4mg/kg 
intravenous infusion) to weekly infusions of cetuximab in combination with 
carboplatin and paclitaxel chemotherapy administered Q3W in subjects with 
advanced NSCLC resulted in improved ORR, the primary endpoint of the study 
(36.6% in the Imprime PGG arm vs. 23.1% in the Control arm [p=0.2895] based on 
central and 47.8% vs. 23.1% [p=0.0468], respectively, based on investigator 
assessment). Of the secondary endpoints, results were (Imprime PGG vs. Control): 
median DoR of 4.4 vs. 4.1 months by central review and 3.8 vs. 4.7 months by 
investigator assessment; median TTP of 6.4 months vs. 6.0 months (p=0.6044) by 
central review and 4.3 vs. 4.4 months (p=0.7305) by investigator assessment; median 
OS of 11.7 months vs. 12.4 months (p= 0.8972). All available efficacy and safety 
results are reported in Section 5 of the Imprime PGG Investigators Brochure. 
 
▪ Study BT-CL-PGG-LCA0821 [LCA0821] assessed 4 mg/kg Imprime PGG in 
combination with a standard regimen of bevacizumab (Avastin®) and concomitant 
carboplatin and paclitaxel therapy in first-line treatment of late stage (Stage IIIB or 
IV) non-small cell lung cancer (NSCLC). The primary endpoint was ORR; secondary 
endpoints included DCR, OS, tumor response rates (CR, PR, and SD), DoR, TTP, 
PFS, TTR, safety of regimen, and PK profile. Ninety-two (92) subjects were 
randomized into the study. Of these, 59/61 randomized to the Imprime PGG arm 
received this treatment (2/61 received no study treatment). Thirty-one (31) were 
randomized to the control arm and of these, 30/31 received treatment (1/31 received 
no study treatment). This study was closed on 05 April 2016 with final results 
available in May 2016. Imprime PGG in combination with bevacizumab, carboplatin, 
and paclitaxel resulted in (Imprime PGG vs. Control): ORR of 60.4% vs. 43.5% 
(p=0.2096) based on independent central radiology review; median DoR of 10.3 vs. 
5.6 mo (p=0.9040); median TTP of 11.6 mo vs. 9.6 mo (p=0.5639); median OS of 


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16.1 mo vs. 11.6 mo (HR 0.66; p=0.1345). All available efficacy and safety results to 
date are summarized in Section 5 of the Imprime PGG Investigators Brochure. 
4.1.1.2.2 Study in Process of Closing (Treatment Phase Complete) 
▪ Study BT-CL-PGG-CRC1031 [CRC1031 also known as PRIMUS] is a randomized, 
international, multi-center, Phase 3 study evaluating the efficacy and safety of the 
combination of Imprime PGG and cetuximab versus cetuximab alone in subjects with 
recurrent or progressive KRAS WT mCRC. Enrollment of up to 795 subjects was 
planned for this study, with up to 530 subjects randomized to the Imprime PGG arm, 
and up to 265 subjects randomized to the cetuximab-only control arm. The primary 
endpoint for this study is OS and key secondary endpoints include PFS, rates of 
response (CR, PR, and ORR), safety, PK profile, and changes in quality of life. Due 
to changes in standard of care since initiation of the study, continuing enrollment has 
proven to be not feasible, and further enrollment was halted on 23 September 2015. 
Subjects enrolled or randomized as of 23 September 2015 completed screening, 
treatment, and/or survival monitoring per protocol. In total, 140 subjects have 
received Imprime PGG 4 mg/kg with the standard cetuximab regimen, and 77 
subjects have received the standard cetuximab without Imprime PGG regimen. While 
analysis of the data is ongoing, learnings from the biomarker assays have contributed 
to Biothera’s understanding of biomarkers (see Section 4.3.3.2 Biomarker Research).    
 
▪ Analysis of a Phase 1 study in healthy volunteers is currently ongoing. A total of 36 
subjects in 3 cohorts were treated with Imprime PGG at doses of 4 mg/kg and 2 
mg/kg. This study explored the immunopharmacodynamic characteristics of Imprime 
PGG through assessment of the following parameters: activation of blood leukocytes, 
concentrations of ABA, circulating opsonized immune complexes, concentrations of 
cytokines, total complement levels (CH50), polymorphism of FcγRII sequence, effect 
of prophylactic antihistamine/corticosteroid premedication on PD effects, and PK of 
serum Imprime PGG. In addition, kinetics of decay and recovery of 
pharmacodynamic responsiveness following Imprime PGG may be assessed, as well 
as the safety of Imprime PGG in symptomatology of adverse events, physical 
examination (if indicated), serum chemistry, changes in differential blood cell counts, 
blood coagulation parameters, urinalysis, and ECG. 
 
4.2 
Pembrolizumab Background 
Refer to the pembrolizumab (KEYTRUDA®) Investigators Brochure/approved labeling for 
detailed background information on pembrolizumab. 
4.2.1 Pembrolizumab Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis, 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and prognosis in 


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various malignancies (Mei 2014, Salgado 2014, Schatton 2014, Gooden 2011, Schreiber 
2011, Bremnes 2011, Talmadge 2011, Shirabe 2010, Nosho 2010, Bellati 2009, Oble 2009, 
Uppalari 2008, Dunn 2007). In particular, the presence of CD8+ T cells and the ratio of 
CD8+ effector T cells/FoxP3+ regulatory T cells seem to correlate with improved prognosis 
and long-term survival in many solid tumors (Nosho 2010, Chang 2014, Preston 2013, Yoon 
2012, Kim 2013, Mathai 2012, Liu 2011, Kirk 2010). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control (Pedoeem 2014). The normal function of PD-1, expressed on the cell surface 
of activated T cells under healthy conditions, is to down-modulate unwanted or excessive 
immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
Ig superfamily member related to CD28 and CTLA-4, which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). 
The structures of murine PD-1 alone (Zhang 2004) and in complex with its ligands were first 
resolved (Lazar-Molnar 2208, Lin 2008), and more recently the NMR-based structure of the 
human PD-1 extracellular region and analyses of its interactions with its ligands were also 
reported (Cheng 2013). PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a 
cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM), and an immunoreceptor tyrosine-based switch motif (ITSM). 
Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to 
the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules, such as CD3zeta, PKCθ and ZAP70, which are involved in the CD3 T cell 
signaling cascade (Sheppard 2004). The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from that of CTLA-4 (Ott 2013). PD-1 was shown to be 
expressed on activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T 
regs and Natural Killer cells (Yao 2014). Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T cells (Nishimura 1996), as well as subsets of 
macrophages (Huang 2009) and dendritic cells (Pena-Cruz 2010). The ligands for PD-1 (PD-
L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types (Keir 
2008). PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments (Karim 
2009). Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and short cytoplasmic regions with no known signaling 
motifs. Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the 
T cell receptor. PD-L2 is thought to control immune T cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T cell function in peripheral tissues. Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T cell inhibitor (Karim 2009, Taube 2012), which, via its 
interaction with the PD-1 receptor on tumor-specific T cells, plays a critical role in immune 
evasion by tumors (Sammamed 2014). As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in cancer (Topalian 2012). 


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4.2.2 Pembrolizumab Background and Clinical Trials 
Pembrolizumab [KEYTRUDA® (US)], a humanized monoclonal antibody against the 
programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the 
treatment of patients with cancer. Pembrolizumab is approved for treatment of patients with 
melanoma in several countries; in the US and EU it is approved for the treatment of patients 
with advanced (unresectable or metastatic) melanoma in adults. Pembrolizumab has also 
been approved for treatment of patients with NSCLC in several countries; the US and the 
European Commission have indicated it for either first-line treatment of patients with 
metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test, or 
for those patients with metastatic NSCLC whose tumors express PD-L1 as determined by an 
FDA-approved test and who have disease progression on or after platinum-containing 
chemotherapy. Patients with NSCLC and EGFR or ALK genomic tumor aberrations should 
also have disease progression on FDA-approved therapy for these aberrations prior to 
receiving pembrolizumab. In the United States, pembrolizumab was granted accelerated 
approval for the treatment of patients with recurrent or metastatic squamous cell carcinoma 
of the head and neck with disease progression on or after platinum-containing chemotherapy, 
and for patients locally advanced or metastatic urothelial carcinoma who are not eligible for 
cisplatin-containing chemotherapy. Pembrolizumb has also been approved for the treatment 
of Classical Hodgkin Lymphoma, for patients with locally advanced or metastatic urothelial 
carcinoma who have disease progression during or following platinum-containing 
chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy, and for colorectal cancer patients with a microsatellite instability-
high ( MSI-H) or a mismatch repair deficient (dMMR) biomarker following progression on a 
fluoropyrimidine, oxaliplatin, and irinotecan. Pembrolizumab is administered once every 3 
weeks (Q3W), and can be administered for up to 35 cycles. 
 
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in 
subjects with non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial 
cancer, gastric cancer, triple negative breast cancer, and Hodgkin’s Lymphoma as determined 
by response rate. Ongoing clinical trials are being conducted in these tumor types as well as a 
number of other advanced solid tumor indications and hematologic malignancies. For study 
details please refer to the Keytruda® (Pembrolizumab) Investigators Brochure. 
4.3 
Rationale 
4.3.1 Rationale for the Trial and Selected Subject Population 
With the approval and use of pembrolizumab in 1st line therapy for advanced melanoma, the 
options to continue deriving benefit from CPI treatment in 2nd line or further have been 
considerably limited if not eliminated altogether for patients with advanced melanoma. It is 
therefore of interest to explore whether sensitivity to CPI can be restored in 2nd line or further 
treatment by appropriate and effective stimulation of the patient’s innate and adaptive 
immune system. 


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Pembrolizumab has also demonstrated clinical activity in subjects with metastatic TNBC. 
Study KEYNOTE-012 enrolled subjects with a variety of solid tumors, including a cohort of 
32 subjects with metastatic or recurrent TNBC, an ECOG performance status of 0 or 1, and 
positive for PD-L1 expression. The median age was 50.5 years and most were heavily 
pretreated, in both the early and advanced settings (47% of subjects having received at least 3 
lines of therapy for metastatic disease and 25% at least 5). In the 27 subjects who were 
evaluable for response, ORR was 18.5%, including 1 CR. Stable disease and progressive 
disease were reported in approximately 26% and 48% of subjects, respectively. The median 
time to response (TTR) was 18 weeks, and the median PFS was 1.9 months. The median 
duration of SD was 17 weeks, while median OS was 11.2 months (Nanda et al., 2016).   
Study KEYNOTE-086 Cohort A enrolled a total of 170 subjects with centrally confirmed 
metastatic TNBC,  1 prior chemotherapy for metastatic disease, ECOG performance status 
of 0 or 1, and had pembrolizumab 200 mg every 3 weeks for up to 24 months. The median 
age was 54 years and 44% of subjects received at least 3 lines of therapy for metastatic 
disease. The ORR was 5% regardless of PD-L1 expression. Best overall response was 0.6% 
CR, 4% PR, and 21% SD. Median DOR was 6.3 months (range 1.2+ to 10.3+). Median PFS 
and OS were 2.0 moths (95% CI 1.9-2.0) and 8.9 months (95% CI 7.2-11.2) respectively 
(Adams et al., 2017). 
Though in KEYNOTE-012, 18.5% of the subjects with PD-L1+ TNBC experienced an 
objective response, further data from the Phase 2 KEYNOTE-086 study showed the ORR 
was approximately 5% regardless of PD-L1 expression. These data highlight the need for 
further improvements in pembrolizumab-based combination immunotherapy.   
Preclinical studies have now shown that Imprime PGG significantly enhances the anti-tumor 
efficacy of checkpoint inhibitor therapy in multiple, syngeneic (immune-competent) tumor 
models. This synergy likely reflects the mechanism of action for Imprime PGG - specifically, 
Imprime PGG-induced immune microenvironmental activation as well as the activation and 
maturation of professional antigen-presenting cells (dendritic cells). This synergy, and the 
mechanistic complementarity of pembrolizumab and Imprime PGG, provide compelling 
rationale for testing this combination clinically.  
Importantly, recent research has now revealed that Imprime PGG forms an immune complex 
with naturally occurring anti-β-glucan antibodies (ABA) and that this complex is necessary 
for Imprime induced immune activation and anti-tumor immune effects (Chan et al, 2016). 
Furthermore, evidence from Imprime PGG clinical trials suggests that IgG pretreatment ABA 
levels in peripheral blood may act as a predictive biomarker of clinical activity of Imprime 
PGG (company data on file).  In line with this evidence, subjects enrolled in this study will 
be required to have pre-specified ABA levels in peripheral blood. 
In this study, subjects with advanced melanoma or TNBC failing front line treatment with 
CPI (melanoma) or chemotherapy (TNBC), will receive combination therapy with 
pembrolizumab and Imprime PGG with the purpose of assessing whether a further response 
(melanoma) or an increased response (TNBC) can be obtained by adding Imprime PGG to 
pembrolizumab. An ORR of 23% in melanoma subjects and of 21% in TNBC subjects would 
be considered clinically significant and relevant findings in these patient populations.  


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4.3.2 Rationale for Dose Selection/Regimen/Modification  
The dose of 4 mg/kg of Imprime PGG administered IV over 2 hours is based on the results of 
the normal volunteer and oncology clinical studies in over 400 human subjects, including 
over 300 cancer subjects in combination with diverse monoclonal antibodies. A description 
of these studies and the study results is presented in Section 4.1.1.1 and Section 4.1.1.2. 
Additional details may be found in the Imprime PGG Investigators Brochure. 
The dose of 2 mg/kg of Imprime PGG administered IV over 2 hours is based on the results of 
the normal volunteer and oncology clinical studies BIOBG-CL-001, BIOBG-CL-002, BT-
CL-PGG-SCM0611, and BT-CL-PGG-CRC0713 in approximately 47 human subjects, 
including cancer subjects. A description of these studies and the study results is presented in 
the Imprime PGG Investigators Brochure. 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose 
recently approved in the United States and several other countries for treatment of melanoma 
subjects is 2 mg/kg Q3W. Information on the rationale for selecting 200 mg Q3W is 
summarized below. 
KEYNOTE-001 was an open-label Phase 1 study conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor activity of 
pembrolizumab when administered as monotherapy. The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) 
and dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with 
advanced solid tumors. All dose levels were well tolerated and no dose-limiting toxicities 
were observed. This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels. No maximum 
tolerated dose (MTD) has been identified. In addition, 2 randomized cohort evaluations of 
melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W 
have been completed, and 1 randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg 
Q2W has also been completed. The clinical efficacy and safety data demonstrate a lack of 
important differences in efficacy or safety profile across doses.  
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to 
provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W. Previously, 
a flat pembrolizumab exposure-response relationship for efficacy and safety has been found 
in subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. Exposures 
for 200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.   
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance 
and a limited volume of distribution. The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range established 


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in melanoma as associated with maximal clinical response. Pharmacokinetic properties of 
pembrolizumab, and specifically the weight-dependency in clearance and volume of 
distribution are consistent with no meaningful advantage to weight-based dosing relative to 
fixed dosing.    
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in PK exposures obtained at tested doses among 
tumor types. Thus the 200 mg Q3W fixed-dose regimen is considered an appropriate fixed 
dose for other tumor indications as well.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. The existing data suggest 
200 mg Q3W as the appropriate dose for pembrolizumab. 
4.3.3 Rationale for Endpoints 
The primary and secondary endpoints selected will allow for assessment of whether a further 
response (melanoma) or an increased response (TNBC) can be obtained by adding Imprime 
PGG to pembrolizumab. An ORR of 23% in the melanoma subjects and of 21% in the TNBC 
subjects would be considered clinically significant and relevant findings in these patient 
populations.   
This clinical study will also explore a number of translational research parameters and 
biomarkers germane to Imprime PGG and to the mechanisms of anti-tumor immunity.  
Specifically, evidence of myeloid cell activation at the tumor site, in peripheral blood 
(increase in CD86, PD-L1), in dendritic cell activation, and increased tumor lymphocyte 
infiltration (especially CD8+ T cells) in tumor biopsies will be measured. Their correlation 
with the observed clinical outcomes and their value at helping identify subgroups of interest 
will be assessed. It is expected that these cellular, immunological and biochemical 
parameters will inform on the factors at play in the response to therapy with pembrolizumab 
plus Imprime PGG, and help design and manage future studies of this combination. 
4.3.3.1 Endpoints 
Primary: 
The primary efficacy endpoint is ORR, which is defined as the proportion of subjects 
demonstrating complete response (CR) or partial response (PR) based on RECIST v1.1 
criteria. 
Safety endpoints include the incidence of adverse events, serious adverse events, laboratory 
safety tests (eg, hematology, clinical chemistry), and ECOG performance. 


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 Secondary: 
Measurement of the secondary endpoints is based on RECIST v1.1 criteria. 
▪ Time to response (TTR) is defined as time from first dose of study treatment (Study 
Day 1) to first response (CR or PR) 
▪ Complete response rate (CRR) is defined as the proportion of subjects demonstrating 
CR 
▪ Duration of response (DoR) is defined as the time from the first documented evidence 
of CR or PR until time of documented disease progression (PD) or death due to any 
cause, whichever is first  
o For responders who are lost to follow-up or who discontinue study before PD 
or death, DoR will be censored at the date of last radiological assessment  
▪ Progression-free survival (PFS) is defined as: 
o Time from Study Day 1 until PD or death due to any cause, whichever occurs 
first 
o For subjects who are lost to follow-up or who discontinue study before PD or 
death, PFS will be censored at the date of the last radiological assessment 
▪ Overall survival (OS) is defined as: 
o Time from date from Study Day 1 until date of death due to any cause 
o For subjects who have not died or who are lost to follow-up or withdrew 
consent, OS will be censored at the date of last contact 
▪ Pharmacokinetic profile 
 
Exploratory: 
▪ ORR, as defined by irRECIST  
▪ PFS, with date of PD as defined by irRECIST 
The following exploratory analyses will be conducted to examine the relationship between 
biomarker data and endpoints if the data warrants: 
 
▪ Analysis of ABA and endpoints  
▪ Analysis of change in the immune cell activation markers and endpoints 
▪ Analysis of change in the tumor immune microenvironment and endpoints  
 
4.3.3.2 Biomarker Research 
Mechanistically, Imprime acts as pathogen-associated molecular pattern (PAMP) directly 
activating innate immune effector cells and triggering a coordinated anti-cancer immune 
response. In ex vivo systems, using whole blood from healthy human subjects, Imprime- 
induced anti-cancer functionality is dependent on immune complex formation with naturally- 
occurring, anti-β glucan antibodies (ABA). The formation of Imprime:ABA complexes 
activates complement, primarily via the classical complement pathway, and is opsonized by 
iC3b. Immune complex binding depends upon Complement Receptor 3 and Fcγ Receptor IIa, 
eliciting phenotypic activation of, and enhanced chemokine production by, neutrophils and 


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monocytes, enabling these effector cells to kill antibody-opsonized tumor cells via the 
generation of reactive oxygen species and antibody-dependent cellular phagocytosis. 
Importantly, these innate immune cell changes are not evident in subjects with low ABA 
levels but could be rescued with exogenous ABA supplementation. Thus, pre-existing ABA 
are essential for Imprime-mediated anti-cancer immune activation (Chan et al, manuscript in 
preparation). These findings have also been corroborated in healthy subjects dosed in vivo 
with Imprime (ongoing findings from Study BT-CL-PGG-HHV1516). 
 
Analysis from a Biothera-sponsored randomized clinical study in colorectal cancer subjects 
in N=168 subjects (CRC1031 also known as PRIMUS) established a correlation between IgG 
ABA level and increased PFS and OS only in subjects treated with Imprime PGG. 
Exploration of ABA IgG cutoffs indicate that hazard ratios (HRs) for both PFS and OS are 
more favorable when ABA IgG > 20 mcg/mL. A similar relationship of this ABA IgG cutoff 
to OS was observed in study BT-CL-PGG-LCA0822 [LCA0822] which assessed Imprime 
PGG in combination with cetuximab and a standard regimen of carboplatin and paclitaxel 
therapy in first-line treatment of late stage (Stage IIIB or IV) NSCLC. In this study, ABA 
IgG levels > 23.4 mcg/mL showed an increased OS (HR=0.58, CI 0.3-1.13, p=0.105). 
Finally, in studies of healthy human volunteers dosed with Imprime PGG, the biological 
activities associated with Imprime PGG (complement activation, white blood cell 
mobilization, and cytokine production) were never observed in volunteers that had ABA IgG 
levels < 20 mcg/mL, whereas most of these activities were evident in volunteers with ABA 
IgG levels > 20 mcg/mL.   
Based on the above findings, only those subjects with serum IgG ABA levels ≥ 20 mcg/mL 
will be selected for treatment in this protocol. Analysis of ABA IgG levels in all cancer 
patients in trials where Imprime PGG has been dosed reveals an overall median ABA IgG 
level of 18.2 mcg/mL (ranging between median values of 14.3-23.0 mcg/mL depending on 
the trial). This indicates that at an ABA IgG value of 20 mcg/mL, the population will be 
approximately equally split by those above and below this value. Thus, for considerations of 
enrollment, it is expected that using an ABA IgG cutoff of 20 mcg/mL should include 
approximately 50% of subjects. Biothera has developed a technical-qualified manual, direct 
enzyme-linked immunosorbent assay (ELISA) to measure IgG ABA serum concentrations. 
The assay is in the process of being transferred to a College of American Pathologists (CAP)- 
accredited, Clinical Laboratory Improvement Amendment (CLIA)-environment laboratory.  
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Subjects with advanced melanoma or triple negative breast cancer failing front-line therapy 
for advanced disease. 


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5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have signed an informed document prior to any study-specific procedures or treatment  
2. Be ≥ 18 years of age at time of consent 
3. For Melanoma Subjects: Have histologically or cytologically confirmed diagnosis of 
unresectable Stage III or metastatic (Stage IV) melanoma not amenable to local therapy, 
and irrespective of PD-L1 status  
4.   For TNBC Subjects: Have histologically or cytologically confirmed diagnosis of 
metastatic (Stage IV) TNBC, and irrespective of PD-L1 status. TNBC is defined as 
negative immunohistochemistry (IHC) assays for Estrogen Receptor (ER), and 
Progesterone Receptor (PR), and HER2 negative (IHC 0 or 1+, or 2+ by IHC confirmed 
negative by FISH) 
5. Have documented objective radiographic or clinical disease progression: 
a. For Melanoma: After PD-1/PD-L1 +/- anti-CTLA-4 inhibitor therapy 
b. For TNBC: After 1 or more prior lines of chemotherapy for metastatic disease 
6. Have resolution of all previous treatment-related toxicities to Grade 1 severity or lower, 
except for stable sensory neuropathy (less than or equal to Grade 2) or alopecia. If subject 
received major surgery or radiation therapy of > 30 Gy, must have recovered from the 
toxicity and/or complications from the intervention. 
7.   Have at least one radiologically measurable lesion as per RECIST v1.1 defined as a lesion 
that is at least 10 mm in longest diameter or lymph node that is at least 15 mm in short 
axis imaged by CT scan or MRI and obtained by imaging within 28 days prior to start of 
study treatment. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
8. Have peripheral blood levels of IgG anti-β-glucan antibody (ABA) of ≥ 20 mcg/mL as 
determined by an ELISA test prior (within 90 days) to start of study treatment 
9.  Be willing to consider providing fresh tissue for biomarker analysis, and, based on the 
adequacy of the tissue sample quality, for assessment of biomarker status. Repeat 
samples may be required if adequate tissue is not provided. Newly obtained biopsy 
specimens are preferred to archived samples and formalin-fixed, paraffin-embedded 
block specimens are preferred to slides. 
Note:  Information on 1 tumor biopsy sample is mandatory and is as follows: (1) To 
determine eligibility, historical (diagnostic) tumor biopsy official pathology report 
+/- an archival sample. Additional biopsy samples, preferably obtained from the 
same localized region, are highly desirable when feasible at the following time 
points: (2) Sample before the first dose of study treatment, (3) Sample after 
completion of Cycle 2 but before the start of Cycle 3 dosing, and (4) Sample either 
at the time of response or at the End of Study Visit (if no response). 


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10. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Appendix 14.3) 
11. Have life expectancy of 3 months or greater as determined by the treating physician 
12. Have adequate organ function (all screening labs should be performed within 15 days 
prior to start of study treatment): 
a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN 
for subjects with total bilirubin levels > 1.5 x ULN 
b. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
c. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
13. Have adequate renal function within 15 days prior to start of study treatment as defined 
by the following criteria:  
Creatinine  1.5 x ULN and CrCl ≥ 30 ml/min per Cockcroft Gault formula:  
 
14. Have adequate hematologic function within 15 days prior to start of study treatment, 
defined as meeting all of the following criteria: 
a. Hemoglobin ≥ 9 g/dL (uncorrected by RBC transfusion) 
b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
c. Platelet count ≥ 100 × 109/L 
15. Have adequate coagulation functioning within 15 days prior to start of study treatment, 
defined by either of the following criteria:  
a. INR < 1.5 × ULN 
b. OR for subjects receiving warfarin or low molecular weight heparin (LMWH), 
the subjects must, in the Investigator’s opinion, be clinically stable with no 
evidence of active bleeding while receiving anticoagulant therapy. The INR for 
these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy. 
c. Activated Partial Thromboplastin Time (aPTT) < 1.5 × ULN unless subject is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
16. Female subjects of childbearing potential as defined in Section 5.7.2 must have a 
negative urine or serum pregnancy within 72 hours prior to receiving the first dose of 
study medication. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
17. If of childbearing potential as defined in Section 5.7.2, must be willing to use an adequate 


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method of contraception (see Section 5.7.2) from the first dose of study medication 
through 120 days after the last dose of study medication  
18. Be willing and have the ability to comply with scheduled visits (including geographical 
proximity), treatment plans, laboratory tests, and other study procedures 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has disease that is suitable for local therapy administered with curative intent  
2. Is currently participating or has received an investigational agent or used an 
investigational device within 4 weeks of the first dose of treatment 
3. Has a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment. The 
use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor. 
4. Has known history of active tuberculosis 
5. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
6. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected 
7. Has a history of clinically severe autoimmune disease, or history of organ transplant 
8. Has a history of ocular melanoma  
9. Has known hypersensitivity to baker’s yeast 
10. Had previous exposure to Betafectin® or Imprime PGG 
11. Has severe hypersensitivity ( Grade 3) to pembrolizumab and/or any of its excipients 
12. Had a prior anti-cancer monoclonal antibody (except immune CPI in the case of 
melanoma subjects) within 30 days prior to start of study treatment, or failure to recover 
to CTCAE Grade 1 or better from the adverse events of prior therapies  
13. Had within 2 weeks prior to Study Day 1, received prior chemotherapy, targeted small 
molecule therapy, or radiation therapy or who has not recovered from adverse events due 
to a previously administered agent or major surgery 
14. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF, or recombinant 
erythropoietin) within 4 weeks prior to Study Day 1 
15. Has known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 


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16. Has known active central nervous system metastases and/or carcinomatous meningitis. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least 4 weeks prior to the first dose of 
trial treatment and any neurologic symptoms have returned to baseline), have no evidence 
of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
trial treatment. This exception does not include carcinomatous meningitis, which is 
excluded regardless of clinical stability. 
17. Has active autoimmune disease requiring systemic treatment in the past 2 years (ie, with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteriod replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment. 
18. Has evidence of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
19.  Has a history of interstitial lung disease 
20.  Has an active infection requiring systemic therapy 
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject's participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator 
22. Has a clinically significant cardiovascular disease such as unstable angina, myocardial 
infarction, or acute coronary syndrome within ≤180 days prior to start of study treatment, 
symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 
cardiac disease as defined by the New York Heart Association Functional Classification 
23. Has a known psychiatric or substance abuse disorder(s) that would interfere with 
informed consent or cooperation with the requirements of the trial 
24. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment 
25. Has received: 
a. For Melanoma: Has received any prior oncolytic vaccine  
b. For TNBC: Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, 
or anti-PD-L2 agent 
26. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal 
flu vaccines that do not contain live virus are permitted. 
 


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5.2 
Trial Treatments 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
Please refer to Section 4.2.2. 
If Stage 1 proceeds without the need for any dose modification as described in Section 
5.2.1.2.1, Imprime PGG will be administered to all subjects at a dose of 4 mg/kg IV over a 2-
hour infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. Refer to 
Appendix 14.1 for further details. 
If enrollment into an additional cohort in Stage 1 is necessitated based on the dose 
modification requirements as described in Section 5.2.1.2.1, Imprime PGG will be 
administered to all subjects in the specified indication at a dose of 2 mg/kg IV over a 2-hour 
infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. Refer to Appendix 
14.1 for further details. 
Imprime PGG will always be administered first, followed 15-30 minutes later only on Day 1 
of each cycle by pembrolizumab administration. 
The pembrolizumab fixed dose of 200 mg will be administered IV over 30 minutes on Day 1 
of each 3-week treatment.  
5.2.1.2 Dose Modification  
5.2.1.2.1 Imprime PGG 
Each cycle will be 3 weeks in duration. The dose of Imprime PGG may be delayed or 
reduced as described below, due to the occurrence of infusion reactions or other adverse 
events. 
 
Per CTCAE guidelines, mild-to-moderate reactions (Grades 1 and 2) are characterized by 
flushing, rash, fever, rigors, chills, dyspnea, nausea, back pain, and mild hypotension. Severe 
reactions (Grades 3 and 4) are associated with bronchospasm and hypotension requiring 
treatment, cardiac dysfunction, anaphylaxis, abdominal cramping, and other symptoms. The 
preferred order for actions the Investigator may take to ameliorate infusion reactions are 
listed below: 
 
1. Premedication(s) 
Subjects may receive pre-treatment with standard anti-histamine medications before 
commencing dosing of study medications on each treatment day and, as needed, 
post-dose.  
 
Premedications: 
▪ Cycle 1/Day 1: Pretreat with an H1 antagonist (eg, 50 mg of diphenhydramine IV) 


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▪ Subsequent cycles: Premedication is allowed for each Imprime PGG infusion, but 
if tolerated by the subject and if medically appropriate, reduced premedication 
doses from those administered at Cycle 1/Day 1 should be used 
2. Infusion Time Extension 
The infusion time should be lengthened from 2 hours to 4 hours and the infusion flow 
rate should be adjusted accordingly to 50% of the previous rate. 
3. Dose Reduction 
If a subject experiences an infusion reaction despite having been administered 
premedication and despite the infusion time being lengthened, the PI may re-challenge 
the subject at the next visit by dose reducing the Imprime PGG to 2 mg/kg. 
All attempts should be made to ameliorate Grade 3/4 infusion reactions by the Investigator 
following the 3 recommendations provided above sequentially.  
In Stage 1, any Grade 3/4 infusion reactions mitigated by these actions and either resolving 
or decreasing to Grade 1/2, if this mitigation occurs within Cycle 1 and the Grade 3/4 
infusion reaction does not recur in Cycle 2, will not be counted towards the total of > 4 or 
33% of Grade 3/4 adverse events which require halting the study in Stage 1 for each 
individual indication. Only Cycle 1 Grade 3/4 infusion reactions (or those which recur in 
Cycle 2) will be counted towards the total which would halt advancement to Stage 2. 
▪ In the event there are a total of > 4 or 33% of Grade 3/4 adverse events in Stage 1 
which were unable to be ameliorated by the sequential recommendations above, the 
dose of Imprime PGG will be reduced to 2 mg/kg.  
▪ Stage 1 will be repeated with an additional cohort of n=12 subjects at the reduced 
dose of 2 mg/kg. Toxicity at the dose of 2 mg/kg will be assessed in this additional 
Stage 1 cohort in the same manner as was done for the initial dose of 4 mg/kg, with 
the identical sequential recommendations for any observed infusion reactions.  
▪ Advancement to Stage 2 will be halted if there are > 4 or 33% of Grade 3/4 adverse 
reactions. Otherwise, subjects will proceed to Stage 2 with all subjects at the new, 
reduced dose of 2 mg/kg. 
Note that continuation onto Stage 2 requires a demonstration of at least 1 or 2 objective 
responses in subjects with melanoma or TNBC, respectively, in addition to meeting the 
adverse event requirements detailed above, at either Imprime PGG dose of 4 mg/kg or 2 
mg/kg. Please refer to the Trial Diagram in Section 2.2 for a schema of the study flow from 
start to end. 
In general, any Grade 4 non-infusion or non-hematological AE will lead to the withdrawal of 
the subject from treatment. A dosing delay of up to 3 weeks is allowed in case of Grade 3 
non-hematological AEs to reduce toxicity to baseline or Grade 0-1. Dose levels will be 
adjusted individually for each study drug. 


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5.2.1.2.2 Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These immune-related adverse events (irAEs) may occur 
shortly after the first dose or several months after the last dose of pembrolizumab treatment 
and may affect more than one body system simultaneously. Therefore, early recognition and 
initiation of treatment is critical to reduce complications. Based on existing clinical trial data, 
most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids, and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, or skin biopsy may be included as part of the 
evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided as per Table 1 below.  
 


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Table 1. Dose Modifications and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per 
day within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be 
controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.03) 
Action Taken to 
Pembrolizumab 
irAE Management with Corticosteroid 
and/or Other Therapies  
Monitor and Follow-up  
Pneumonitis  
Grade 2 
Withhold  
• 
Administer corticosteroids (initial dose of 
1-2mg/kg prednisone or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and symptoms of 
pneumonitis 
• 
Evaluate subjects with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• 
Administer corticosteroids (initial dose of 
1-2mg/kg prednisone or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and symptoms of 
enterocolitis (ie diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie peritoneal signs and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
• 
Subjects with diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT Elevation 
or Increased Bilirubin 
Grade 2 
Withhold 
• 
Administer corticosteroids (initial dose of 
0.5- 1 mg/kg prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• 
Administer corticosteroids (initial dose of 
1-2mg/kg prednisone or equivalent) 
followed by taper 


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Type 1 diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• 
Initiate insulin replacement therapy for 
subjects with T1DM  
• 
Administer anti-hyperglycemic in subjects 
with hyperglycemia  
 
• 
Monitor subjects for hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
 
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
Permanently 
discontinue  
Hyperthyroidism  
Grade 2 
Continue  
• 
Treat with non-selective beta-blockers (e.g. 
propranolol) or thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue 
Hypothyroidism 
Grade 2-4 
Continue  
• 
Initiate thyroid replacement hormones (e.g. 
levothyroxine or liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis and Renal 
Dysfunction 
Grade 2 
Withhold  
• 
Administer corticosteroids (prednisone 1-2 
mg/kg or equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
All Other immune-
related AEs 
Grade 3, or intolerable/ 
persistent Grade 2 
Withhold 
• 
Based on severity of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to confirm etiology or 
exclude other causes 
 
Grade 4 or recurrent 
Grade 3  
Permanently 
discontinue 
NOTES:  
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the Investigator or treating physician.   
2. 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is 
controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   


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Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reactions are provided in Table 2. 
 
Table 2. Infusion Reaction Treatment Guidelines for Pembrolizumab 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤ 24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further study 
drug treatment. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrines** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, refer to the Common Terminology Criteria for Adverse Events v4.03 (CTCAE) at http://ctep.cancer.gov 
 


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In Stage 1, any Grade 3/4 infusion reactions mitigated by these actions and either resolving 
or decreasing to Grade 1/2, if this mitigation occurs within Cycle 1 and the Grade 3/4 
infusion reaction does not recur in Cycle 2, will not be counted towards the total of > 4 or 
33% of Grade 3/4 adverse events which require halting the study in Stage 1 for each 
individual indication. Only Cycle 1 Grade 3/4 infusion reactions not controlled by the above 
measures (or those which recur in Cycle 2) will be counted towards the total which would 
halt advancement to Stage 2. 
Dose will be managed individually for each study drug. 
5.2.1.3 Dose Interruptions  
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should 
be documented in the subject's study record. 
 
5.2.2 Timing of Dose Administration 
If Stage 1 proceeds without the need for any dose modification as described in Section 
5.2.1.2.1, Imprime PGG will be administered to all subjects at a dose of 4 mg/kg IV over a 2-
hour infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. Refer to 
Appendix 14.1 for further details. 
If enrollment into an additional cohort in Stage 1 is necessitated based on the dose 
modification requirements as described in Section 5.2.1.2.1, Imprime PGG will be 
administered to all subjects in the specified indication at a dose of 2 mg/kg IV over a 2-hour 
infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. Refer to Appendix 
14.1 for further details. 
Imprime PGG must always be administered first, with a 15-30 minute window before the 
start of the pembrolizumab infusion. 
The pembrolizumab fixed dose of 200 mg will be administered IV over 30 minutes on Day 1 
of each 3-week treatment. Sites should make every effort to target infusion timing to be as 
close to 30 minutes as possible. However, given the variability of infusion pumps from site to 
site, a window between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 
minutes -5 min/+10 min).  
5.2.3 Trial Blinding/Masking 
Subjects in this study will not be blinded, as all subjects will receive identical treatment. 


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10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
5.3 
Randomization or Treatment Allocation 
Neither randomization nor treatment allocation is required in this study, as all subjects will 
receive identical treatment. 
5.4 
Stratification 
There will be no stratification in this study. 
5.5 
Numbers of Sites and Subjects and Study Duration 
5.5.1 Number of Sites 
It is anticipated there will be approximately 25 sites within the United States. Additional 
regions, countries, or sites may be added as needed. 
 
Sites that do not enroll subjects within 3 months of site initiation may be closed. 
5.5.2 Number of Subjects 
The individual patients in this clinical trial will be referred to as “subjects”. 
 
It is anticipated there will be approximately up to N=94 subjects in total, distributed in the 
following manner between melanoma and TNBC subjects: 
 
1. Up to N = 41 subjects with melanoma (up to 24 in total in Stage 1 and 17 in Stage 2) 
2. Up to N = 53 subjects with TNBC (up to 24 in total in Stage 1 and 29 in Stage 2) 
Please refer to Section 5.9 on Subject Replacement Strategy for further information on the 
replacement of subjects who do not complete the study. 
5.5.3 Study Duration 
Study duration for a subject may last approximately 3 years comprising of the following: 
▪ Screening: Up to 90 days 
▪ Treatment Phase: Up to 2 years 
▪ Survival Follow-up: Up to 1 year 
 
The actual study duration for any individual subject may be shorter or longer than what is 
listed above, depending on when the subject enrolled during the overall life of the study, and 
the subject’s individual situation.   
5.6 
Concomitant Medications/Vaccinations (Allowed and Prohibited) 
Subjects should be treated for any concurrent medical conditions at the discretion of the 
Investigator according to community standards of medical care. 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The Investigator should discuss any questions regarding this with the Sponsor. 
The final decision on any supportive therapy or vaccination rests with the Investigator and/or 
the subject's primary physician. However, the decision to continue the subject on trial therapy 
or vaccination schedule requires the mutual agreement of the Investigator, the Sponsor, and 
the subject. 
Other than Imprime PGG or pembrolizumab, any medication administered to the subject 
during any portion of the study after study treatment is initiated on Cycle 1/Day 1 is 
considered a concomitant medication and must be documented in the electronic Case Report 
Form (eCRF). This includes all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications and fluids. 
Medications administered during the Screening period should be recorded as prior 
medications on the eCRF. 
5.6.1 Acceptable Concomitant Medications 
Most concomitant medications, including pretreatment with anti-emetics, anti-diarrheals, and 
anti-histamines are permitted and may be administered at the Investigator’s discretion.  
 
5.6.2 Prohibited Concomitant Medications 
The Sponsor or designee should be notified in advance (or as soon as possible thereafter) of 
any instances in which prohibited therapies are administered. Continued participation of the 
subject will be at the discretion of the Sponsor. 
 
Medications or vaccinations contraindicated for use in combination with pembrolizumab 
include those listed in the exclusion criteria should not be administered. If there is a clinical 
indication for a medication or vaccination specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required. The Investigator should 
discuss any questions regarding this with the local Clinical Monitor. 
 
Following is a list of therapies subjects are prohibited from receiving at any point during this 
clinical study: 
 
▪ Antineoplastic systemic chemotherapy or biological therapy 
▪ Immunotherapy not specified in this protocol  
▪ Chemotherapy not specified in this protocol 
▪ Investigational agents other than pembrolizumab or Imprime PGG 
▪ Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with 
Sponsor. The subject must have clear measurable disease outside the radiated 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
field. Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS. 
▪ Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: Measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed. However, intranasal influenza vaccines (eg, Flu - 
Mist®) are live attenuated vaccines, and are not allowed. 
▪ Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Note:  Inhaled steroids are allowed for management of asthma 
 
In addition, no additional investigational agents are to be administered during the study. In 
the event a subject develops neutropenia, GCSF administration is allowed (to be 
administered per ASCO guidelines and/or the site’s standard of care). 
 
Subjects who have received palliative radiotherapy for pain will be assessed during the data 
analysis phase to determine if their data may be assessed with that of other subjects, or if 
their data should be truncated at the time of receiving the radiotherapy with data extrapolated 
for all remaining visits as the response assessment may be affected. 
There are no prohibited therapies Post-Treatment, however any such therapies must be 
recorded during the time the subject is being followed for OS. 
5.6.3 Supportive Care Guidelines 
Imprime PGG supportive care guidelines should follow the ASCO Clinical Practice 
Guidelines. 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below, along with the dose 
modification guidelines presented earlier in Section 5.2.1.2.2 in Table 1. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the Investigator determines the events to be related to pembrolizumab.  
Note:  If after the evaluation the event is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance. Refer to Section 5.2.1.2.2 for 
guidelines regarding dose modification and supportive care. 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
See Section 5.2.1.2.2 for treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
adverse event such as diarrhea, nausea or vomiting. 
 
5.7.2 Contraception 
It is unknown what the effects of Imprime PGG may be during a pregnancy.  
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they:  
(1) Are postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.)  
OR  
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening  
OR  
(3) Have a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) Practice abstinence† from heterosexual activity;  
OR  
(2) Use (or have their partner use) acceptable contraception during heterosexual 
activity.   


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
Acceptable methods of contraception are the following‡: 
▪ Single method (1 of the following is acceptable): 
• Intrauterine device (IUD) 
• Vasectomy of a female subject’s male partner  
• Contraceptive rod implanted into the skin 
▪ Combination method (requires use of 2 of the following): 
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• Cervical cap with spermicide (nulliparous women only)   
• Contraceptive sponge (nulliparous women only)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (eg, calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy. If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with either Imprime PGG or 
pembrolizumab, the subject will immediately be removed from the study. The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated.  
 
The outcome of the pregnancy will be reported to the Sponsor without delay and within 24 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
hours if the outcome is a serious adverse experience (eg, death, abortion, congenital anomaly, 
or other disabling or life-threatening complication to the mother or newborn). The study 
Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. 
 
5.7.4 Use in Nursing Women 
It is not known whether either Imprime PGG or pembrolizumab is excreted in human milk. 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment into the study. 
 
5.8 
Subject Withdrawal/Discontinuation Criteria 
5.8.1 Withdrawal/Discontinuation Criteria 
Subjects will be encouraged to complete the study; however, they may voluntarily withdraw 
at any time without prejudice to future care. The Investigator will provide a written report 
describing the reason for discontinuation. If a subject discontinues study drug, every effort 
should be made to complete the assessments scheduled to occur during the Post-Treatment 
Visit and survival follow-up period. The subject will continue to be followed until 
completion of the study. 
 
A subject may discontinue study drug for the following medical or administrative reasons: 
 
▪ Adverse event: If a subject suffers an AE that in the judgment of the Investigator, 
presents an unacceptable consequence or risk to the subject, the subject may be 
discontinued from study drug  
▪ Progressive Disease per irRECIST (see Section 7.3.2) 
▪ Subject decision: A subject may voluntarily discontinue from study drug at any time 
▪ Intercurrent illness: A subject may discontinue study drug if, in the judgment of the 
Investigator, the subject develops an intercurrent illness or complication that is not 
consistent with the protocol requirements or that, in any way, justifies withdrawal 
from the study drugs, or that requires treatment with a restricted medication. 
▪ Ineligibility to protocol entry criteria determined 
▪ Lost to follow-up 
▪ Administrative discontinuation: After consultation between the Investigator, the 
medical monitor, or the Sponsor when appropriate, a subject may be discontinued 
from study drug for the following administrative reasons: 
• Noncompliance (all occurrences of noncompliance must be documented on the 
appropriate eCRFs) 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
• Failure to receive study drug per protocol as defined in Section 5.2 Trial 
Treatments 
• Failure to comply with protocol requirements 
• Refusal of study drug administration (with reason documented) 
In all cases, when subjects discontinue study drug, reasonable efforts should be made to 
monitor the subject for AEs and to complete follow-up assessments following such 
discontinuation. These efforts should be documented on the appropriate eCRF. The subject 
will continue to be followed for survival for the duration of the study.  
 
If a subject withdraws consent for follow-up of survival, this must be documented, and no 
further efforts at contact will be attempted. 
5.8.2 Discontinuation of Study Therapy After Complete Response 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR, who have been treated for at least 24 weeks, and who had at least 2 treatments with 
study medications beyond the date when the initial CR was declared. Subjects who then 
experience radiographic disease progression may be eligible for up to 1 year of additional 
treatment with Imprime PGG + pembrolizumab at the discretion of the Investigator if:  
• No cancer treatment was administered since the last dose of pembrolizumab 
• The subject meets the safety parameters listed in the Inclusion/Exclusion criteria 
• The trial is open   
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Response or progression in this resumed course of therapy will not count 
towards the ORR of the primary endpoint in this trial. 
5.9 
Subject Replacement Strategy 
Subjects who discontinue the study treatment due to reasons other than progressive disease or 
treatment-related adverse events before the first post-baseline scan may be replaced. 
5.10 Clinical Criteria for Early Trial Termination 
If the Sponsor, Investigator, medical or safety monitor, or appropriate regulatory officials 
discover conditions arising during the study that indicate the study should be halted or the 
study site should be terminated, this action may be taken after appropriate consultation 
among the Sponsor, Investigator, regulatory, and medical and safety monitors.  
 
Conditions that may warrant early termination of the study include, but are not limited to, the 
following: 
 
▪ The discovery of an unexpected, serious, or unacceptable risk to enrolled subjects 


Product:  Imprime PGG and Pembrolizumab  
42 
Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
▪ A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
Other conditions that may also warrant termination of an individual study site include, but 
are not limited to, the following: 
 
▪ Failure of the Investigator to enroll subjects into the study at an acceptable rate 
▪ Failure of the Investigator to comply with pertinent regulations of appropriate 
regulatory authorities 
▪ Submission of knowingly false information from the research facility to the Sponsor, 
clinical research associate (CRA), medical and/or safety monitor(s), or appropriate 
regulatory authority 
▪ Insufficient adherence to protocol requirements 
Study termination and follow-up will be performed in compliance with the conditions set 
forth in the guideline provided by ICH for Technical Requirements for Registration of 
Pharmaceuticals for Human Use, Good Clinical Practice (ICH GCP): Consolidated Guideline 
(E6), Sections 4.12, 4.13, 5.20, and 5.21.  
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
6.0 TRIAL FLOW CHART 
6.1 
Schedule of Assessments - Study Flow Chart 
Cycle 
 
C1 
C2 
C3 
C4 
C5 
C6  
C7 
and 
QOC 
C8 and Q4C  
 
(C12, C16, C20, 
C24, C28, C32) 
C10 and Q4C  
 
(C14, C18, C22, 
C26, C30, C34) 
End of 
Treatment 
(EOT) 
 
Post-Treatment  
(up to 3 Years 
after Last 
Subject’s 1st 
Dose) 
Visit Week  
Screening 
(-30 to -1 
Days)* 
W1 
W4 
W7 
W10 
W13 
W16  
 
W19 
and 
Q6W 
W22 and Q12W  
 
(W34, W46, W58, 
W70, W82, W94) 
W28 and Q12W  
 
(W40, W52, W64, 
W76, W88, W100) 
 
30-
Day 
SFU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administrative 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Entry 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Medical Hx and 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures / 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AE Monitoring 
(Every Visit in Cycle) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of 
Pembrolizumab 
(D1 of Each Cycle) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Administration of 
Imprime PGG 
(D1, D8, D15 of 
Each Cycle) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
Medications 
(Every Visit in Cycle) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory 
Procedures / 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology**  
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
Cycle 
 
C1 
C2 
C3 
C4 
C5 
C6  
C7 
and 
QOC 
C8 and Q4C  
 
(C12, C16, C20, 
C24, C28, C32) 
C10 and Q4C  
 
(C14, C18, C22, 
C26, C30, C34) 
End of 
Treatment 
(EOT) 
 
Post-Treatment  
(up to 3 Years 
after Last 
Subject’s 1st 
Dose) 
Visit Week  
Screening 
(-30 to -1 
Days)* 
W1 
W4 
W7 
W10 
W13 
W16  
 
W19 
and 
Q6W 
W22 and Q12W  
 
(W34, W46, W58, 
W70, W82, W94) 
W28 and Q12W  
 
(W40, W52, W64, 
W76, W88, W100) 
 
30-
Day 
SFU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential 
(Pre-Imprime 
infusion and 4 Hr 
Post-SOI of Imprime: 
Q4C after C2, EOT)* 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
PBMC (Pre-Imprime 
infusion and EOI of 
Imprime: C1, C2, C6, 
EOT) 
 
X 
X 
 
 
 
X  
 
 
 
X 
 
 
RNA/DNA (Pre-
Imprime infusion and 
EOI of Pembro: Q4C 
after C2, EOT) 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
Serum Chemistry 
(QOC, EOT, SFU) 
X* 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Coagulation Tests 
X* 
  
 
 
 
 
 
 
 
 
 
 
 
Serum ABA (Pre-
Imprime Infusion and 
EOI of Imprime: Q4C 
after C6, EOT) 
X  
(within 90 
days) 
X 
X 
X 
X 
X 
X 
  
 
X 
X 
 
 
Serum Cytokines & 
Complement (Pre-
Imprime Infusion and 
EOI of Imprime: Q4C 
after C6, EOT) 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
PK (C1, C3 only) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan with 
Contrast or MRI 
(Q6W/QOC) 
X 
 
X 
(C2 
end) 
 
X  
(C4 
end) 
 
X  
(C6 
end) 
 
X  
(Cycle end) 
X  
(Cycle end) 
 
 
 
 
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
Cycle 
 
C1 
C2 
C3 
C4 
C5 
C6  
C7 
and 
QOC 
C8 and Q4C  
 
(C12, C16, C20, 
C24, C28, C32) 
C10 and Q4C  
 
(C14, C18, C22, 
C26, C30, C34) 
End of 
Treatment 
(EOT) 
 
Post-Treatment  
(up to 3 Years 
after Last 
Subject’s 1st 
Dose) 
Visit Week  
Screening 
(-30 to -1 
Days)* 
W1 
W4 
W7 
W10 
W13 
W16 
 
W19 
and 
Q6W 
W22 and Q12W  
 
(W34, W46, W58, 
W70, W82, W94) 
W28 and Q12W  
 
(W40, W52, W64, 
W76, W88, W100) 
 
30-
Day 
SFU 
 
Tumor Biopsies 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Biopsy  
(if feasible) 
(Sample 1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy before First 
Dose of Treatment  
(if feasible) 
(Sample 2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Biopsy after C2 
Complete but before 
C3 Dosing  
(if feasible) 
(Sample 3) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy at Time of 
Response or 
Progression, or EOT 
(if feasible) 
(Sample 4) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Long-Term Follow-
up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Monitoring  
(Up to 3 Years After 
Last Subject’s 1st 
Dose) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
*Screening window is 15 days before start of dosing for the following Inclusion Criteria: Organ, Renal, Hematologic, and Coagulation Functions 
 Serum Chemistry includes Thyroid Function Panel 
**Hematology results may be used without the need for an additional blood draw if Hematology is drawn within approximately 1 hour before start of Imprime 
PGG infusion 
Monthly pregnancy testing should be conducted as per local regulations where applicable. 


Product:  Imprime PGG and Pembrolizumab  
46 
Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
 


Product:  Imprime PGG and Pembrolizumab  
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
 
 
Note:  
C = Cycle 
W = Week 
D8 = Day 8 
D15 = Day 15 
EOI = End of Infusion of Imprime PGG (unless pembrolizumab has been specified) (Samples collected EOI should be within approximately 30 minutes 
after infusion ends) 
EOT = End of Treatment 
Pre-infusion = Before start of Imprime PGG infusion (Samples collected Pre-infusion should be within approximately 1 hour before start of infusion) 
SOI = Start of Infusion of Imprime PGG 
QOC = Every Other Cycle 
Q4C = Every 4th Cycle 
Q6W = Every 6 weeks 
Q12W = Every 12 weeks 
 
Cycle Assessments:  
 
▪ 
C1, C2, C3, C4, C5, C6, EOT, 30-Day SFU, and Post-Treatment are as indicated in the table above 
▪ 
C7, C9, C11, C13, C15, C17, C19, C21, C23, C25, C27, C29, C31, C33, and C35 have identical assessments 
▪ 
C8, C12, C16, C20, C24, C28, and C32 have identical assessments 
▪ 
C10, C14, C18, C22, C26, C30, and C34 have identical assessments  
 
 
 


Product:  Imprime PGG and Pembrolizumab 
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Protocol/Amendment No.:  BT-CL-PGG-MEL/BCA-1621 / 
MK3475 PN-545 / Amendment 001 
 
 
10 August 2017 
 
Confidential – Biothera Pharmaceuticals, Inc. 
 
7.0 TRIAL PROCEDURES 
Table 6.1, Schedule of Assessments – Study Flow Chart, summarizes the frequency and 
timing of study activities and assessments from Screening through the end of the study and 
Post-treatment Visits (30-Day Safety Follow-up (SFU) Visit and monitoring for overall 
survival). Visits should occur as scheduled in Table 6.1 to the extent possible. 
7.1 
Visit Windows 
All treatment visits should occur on the visit days specified in Table 6.1, Schedule of 
Assessments. However the following visit windows, while not desirable, are acceptable: 
 
▪ For study medication administration, a visit window of +/- 3 days 
 
▪ For hematology and chemistry laboratories, a visit window of - 3 days 
 
▪ For imaging, a visit window of +/-7 days (which should follow calendar days and not 
be adjusted for cycle delays) 
 
▪ For the End of Study Visit, a visit window of +3 days 
 
▪ For the 30-Day SFU Visit, a visit window of -7 days 
 
▪ For Every-2-Month Survival Monitoring, a visit window of +/- 7 days  
 
7.2 
Screening Period 
Prior to any study-specific assessments or Screening procedures, a written, signed ICF will 
be obtained from subjects. A copy of the signed ICF will be provided to the subject. 
 
A Screening examination should be performed between 1 and 30 days before the first day of 
treatment to determine study eligibility. Subjects who meet all entry criteria will be enrolled 
into the study.  
 
A Screen Failure Log must be maintained by the Investigator for all screened subjects. 
A subject may be re-screened an additional 2 times if entry criteria are not met, as long as 
this occurs within 90 days of the signing of the ICF. 
7.3 
Treatment Period (Treatment Cycles) 
Study Day 1 is defined as the day of the first dose of study medication. 
The study treatment period will be divided into treatment cycles. Each cycle will be 3 weeks 
in duration and defined by the frequency of pembrolizumab administration. During each 
cycle, subjects will dose weekly with Imprime PGG for all 3 weeks (Days 1, 8, and 15). 
Pembrolizumab will be dosed on D1 of each 3-week cycle. Subjects will be dosed until 


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disease progression or death or study termination or 2 years or until any of the criteria for 
study drug discontinuation are met (whichever occurs first). 
 
See Section 5.2.2 Timing of Dose Administration for the order in which the study 
medications must be administered. 
 
7.3.1 Clinical Assessments and Procedures 
7.3.2 Tumor Response Criteria 
Tumour response will be evaluated according to the RECIST v1.1 (see Appendix 14.5) 
(http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf) and clinical criteria 
(Eisenhauer et al, 2009). Disease progression will be defined as per RECIST version 1.1 
guidelines on radiological, clinical, or symptomatic progression.   
 
Evaluation of response by RECIST v1.1 criteria should be performed at baseline and then at 
6-week intervals beginning at Week 6. Immune-related response criteria (irRECIST) (see 
Appendix 14.6) may be used for clinical management of subjects, but will not be used for OR 
evaluation (other than as an exploratory endpoint). Therefore RECIST 1.1 will be adapted to 
account for the unique tumor response characteristics seen with immunotherapy treatment. 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.  Standard RECIST may not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab. 
Therefore, RECIST 1.1 will be used with the following adaptations: 
If radiologic imaging verifies initial PD, tumor assessment should be repeated ≥ 4 weeks 
later in order to confirm PD with the option of continuing treatment per the conditions stated 
below, while awaiting radiologic confirmation of progression.   
If repeat imaging shows < 20% or < 5 mm absolute increase in tumor burden compared to 
nadir, stable or improved previous new lesion (if identified as cause for initial PD), and 
stable/improved non-target disease (if identified as cause for initial PD), treatment may be 
continued / resumed.   
If repeat imaging confirms PD due to any of the scenarios listed below, subjects will be 
discontinued from study treatment*.   
In determining whether or not the tumor burden has increased or decreased, the Investigator 
should consider all target lesions as well as non-target lesions. 
Scenarios where PD is confirmed at repeat imaging: 
▪ Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 


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▪ Non-target disease resulting in initial PD is worse (qualitative) 
▪ New lesion resulting in initial PD is worse (qualitative) 
▪ Additional new lesion(s) since last evaluation 
 
In subjects who have initial evidence of radiological PD, it is at the discretion of the subject 
and the Investigator whether to continue a subject on study treatment until repeat imaging is 
obtained: 
 
▪ The subject must re-consent to the study, in order to continue receiving study medication 
in light of the radiological evidence of PD.  
▪ The Investigator’s clinical judgment decision regarding the subject continuing should be 
based on the subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  
 
Subjects may receive study treatment while waiting for confirmation of PD if they have re-
consented and are clinically stable as defined by the following criteria: 
 
▪ Absence of signs and symptoms indicating disease progression 
▪ No decline in ECOG performance status 
▪ Absence of rapid progression of disease 
▪ Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
When feasible, subjects should not be discontinued until PD has been confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease.  
*Note: If PD is confirmed but the subject is experiencing an extraordinary clinical benefit, 
contact Sponsor to discuss continuing treatment. 
 
All RECIST assessments (v1.1 or irRECIST) will be evaluated against the initial lesion 
measurement values from the baseline computed tomography (CT) scan or magnetic 
resonance imaging (MRI) obtained prior to the initiation of study treatment. Either CT or 
MRI is acceptable, but the same method must be used throughout the study for any individual 
subject. If MRIs are used, they must include images of the head, chest, abdomen, and pelvis.  
 


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7.3.3 Tumor Imaging 
Tumor imaging should be performed by CT (preferred). MRI should only be used when CT 
is contraindicated or for imaging in the brain, but the same imaging technique should be used 
in a subject throughout the trial. A CT scan is the more commonly used modality and is 
preferred for the majority of subjects. An MRI can be utilized if clinically appropriate.   
Imaging should include the chest, abdomen, and pelvis.  
For TNBC subjects, bone scans will also be utilized to assess osseous metastases.  
Additionally, X-ray evaluation will be obtained for symptomatic sites with negative bone 
scan evaluations. The sponsor should be notified of any supplemental imaging done to 
support a positive or negative bone scan. 
7.3.3.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of first 
dose of trial treatment. The Investigator must review screening images to confirm the subject 
has measurable disease per RECIST v1.1. 
Scans performed as part of routine clinical management are acceptable for use as initial 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
start of study treatment and viewed by the Investigator.   
7.3.3.2 On Study Tumor Imaging 
The first on study imaging assessment should be performed 6 weeks (±7 days) from the date 
of first dose of trial treatment. Subsequent tumor imaging should be performed every 6 
weeks (±7 days) or more frequently if clinically indicated. Imaging should not be delayed for 
delays in cycle starts or extension of study medication cycle intervals.   
Per RECIST v1.1, partial or complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan (ie 6 weeks later), 
whichever is clinically indicated.   
Continue to perform imaging until whichever of the following occurs first:  
▪ Disease progression 
▪ The start of new anti-cancer treatment 
▪ Withdrawal of consent 
▪ Death  
▪ End of the study 


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7.3.4 RECIST Assessment of Disease 
RECIST v1.1 will be applied by the Investigator as the primary measure for assessment of 
tumor response, date of disease progression, and as a basis for all protocol guidelines related 
to disease status.  
irRECIST will applied by the Investigator solely for clinical management of subjects, as 
described in Section 7.3.2 and in Appendix 14.6. 
7.3.5 Tumor Biopsy Samples 
Tumor biopsy information must be collected for this study as follows: 
 
1. An official diagnostic pathology report +/- archival tumor biopsy sample (in order to 
be eligible for the study) 
 
An additional 3 tumor biopsy samples, preferably obtained from the same localized region, 
are highly desirable when feasible and are as follows: 
 
2. Sample before the first dose of study treatment (which will also be used for PD-L1 
biomarker analysis) 
3. Sample after Cycle 2 is completed but before initiation of Cycle 3 dosing (which will 
also be used for PD-L1 biomarker analysis) 
4. Sample either at the time of response or at the End of Study Visit (if no response). 
Note that for Sample 2 and Sample 3, the following condition must be met: 
 
▪ The tumor tissue sample for PD-L1 biomarker analysis should be from a newly 
obtained core or excisional biopsy. Repeat samples may be required if adequate tissue 
is not provided. If submitting unstained cut slides, freshly cut slides should be 
submitted to the testing laboratory within 14 days from when the slides are cut. 
▪ Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and 
submitted to the testing laboratory within 14 days from site slide sectioning date, 
otherwise a new specimen will be requested.      
 
7.3.6 Physical Examination and Measurement of Vital Signs 
Vital signs will be measured on all subjects at Screening. 
Subjects will undergo a complete physical examination (including observable tumor 
measurements) at the Screening and at the End of Study Visits.  
Weight will be taken at Screening, on Day 1 of every 3-week treatment cycle before study 
drug is administered, and at the End of Study Visit. 


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7.3.7 Performance Status 
Performance status will be measured using the ECOG performance status scale (see 
Appendix 14.3). It is recommended, whenever that the subject be assessed by the same 
person throughout the study.  
Performance status will be assessed at Screening, on Day 1 of every 3-week treatment cycle 
before study drug is administered, at the End of Study visit, and at the 30-Day Safety Follow-
up (SFU) visit. 
7.3.8 Clinical Safety Assessments 
The NCI CTC-AE version 4.03 will be used to evaluate the clinical safety of the treatment in 
this study. Subjects will be assessed for AEs at each clinical visit and as necessary 
throughout the study.  
 
7.3.9 Planned DNA and RNA Analysis  
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study. 
In addition to studying variation across the human genome, RNA expression profiles may be 
investigated. 
7.3.10 Laboratory Assessments 
Laboratory safety assessments will be performed at the timepoints specified in Section 6.1 
Schedule of Assessments. All laboratory testing will be conducted via local laboratories. 
Normal ranges for the study laboratory parameters must be supplied to Biothera before study 
start by each investigational site.  
 
Samples for PBMC, RNA, DNA, Serum ABA, Serum Cytokines, Serum Complement and 
inflammation markers, and potentially other serum proteins, will be collected by the central 
laboratory for conduct of the assays. 
 
Please refer to Table 3 below for the analytes to be collected in this study:  
 
 


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Table 3. Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal 
results noted)  
PK 
Absolute Neutrophil Count 
Carbon Dioxide ‡ (CO2 or biocarbonate) 
Urine pregnancy test † 
PBMC 
 
Uric Acid 
 
Serum ABA 
 
Calcium 
 
Serum Cytokines 
 
Chloride 
 
RNA 
 
Glucose 
 
PD-L1 
 
Phosphorus 
 
DNA 
 
Potassium   
 
Serum complement and inflammation 
markers 
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is elevated 
above ULN) 
 
  
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Thyroid Function Panel 
 
 
 
• Total triiodothyronine (T3) or (FT3) 
 
 
 
• Free thyroxine (FT4) 
 
 
 
• Thyroid stimulating hormone (TSH) 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 


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7.3.11 Pharmacokinetic Evaluations 
Samples for sparse PK will be taken at specified times (please refer to Table 4) for all 
subjects on Cycle 1/Day 1 and on Cycle 3/Day 1.   
 
See Section 5.2.2 Timing of Dose Administration for the order in which the study 
medications must be administered. 
 
Table 4. Time and Events for Sparse PK Collection 
Time (Hours)  
All Subjects 
 
 
Cycle 1/Day 1 
Cycle 3/Day 1 
 
 
 
Imprime PGG Infusion 
 
 
Pre-dose 
X 
X 
0 
 
 
1.5 hrs (±30 min) post end of 
Imprime infusion 
X 
X 
 
 
 
Pembrolizumab Infusion 
 
 
Pre-dose 
X 
X 
0 
 
 
3 hrs (±30 min) post end of 
pembrolizumab infusion 
X 
X 
 
7.3.12 Unscheduled Visits 
Additional visits may be scheduled per the Investigator discretion if the subject’s medical 
condition warrants, ensuring his/her safety and well-being. Any additional visits, 
examinations, or procedures must be documented. 
7.4 
Post-treatment Assessments 
7.4.1 End of Treatment/End of Study Visit 
Study drug will be discontinued upon disease progression, development of study withdrawal 
criteria, duration of 2 years in the study, or study closure. Subjects deriving clinical benefit 
from the administration of Imprime PGG + pembrolizumab and who have completed 2 years 
of study treatment may be candidates for continued treatment after discussion between the 
subject, Investigator, and Sponsor. 


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The End of Treatment Visit (EOT) should occur as soon as possible after the end of the cycle 
in which the last administration of study drug occurred (window of +3 days). During this 
visit, the following assessments will occur: 
▪ ECOG Performance Status Score 
▪ Physical examination 
▪ Weight 
▪ Adverse events recording 
▪ Concomitant medications recording 
▪ Hematology 
▪ CBC/Differential*  
▪ RNA/DNA* 
▪ Chemistry 
▪ Serum ABA* 
▪ Serum cytokines, serum complement, and inflammation markers* 
▪ If feasible, the fourth and final biopsy sample (unless it was collected earlier at time of 
response or progression) 
 
* Only collected once (instead of at both Pre-infusion and Post-infusion as at other visits as 
no study medication is administered at this visit) 
 
7.4.2 30-Day Safety Follow-up Visit (30-Day SFU) 
The 30-Day SFU visit will occur within 4 weeks (window of -7 days) of study drug dosing 
being stopped. During this visit, the following assessments will occur: 
 
▪ ECOG Performance Status Score 
▪ Pregnancy test for women of childbearing potential 
▪ Adverse event recording 
▪ Concomitant medications recording 
▪ Hematology 
▪ Chemistry 
 


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7.4.3 Every 2-Month Overall Survival Monitoring 
Upon completion of the 30-Day SFU visit, subjects will be monitored on an every 2-month 
visit schedule for survival until death or until study completion. Study completion is defined 
as the death of at least 70% of subjects or 3 years after the last subject’s first dose, whichever 
occurs earlier.  
Only survival status and start of any new anti-cancer therapy will be collected during this 
period.  
Subjects who discontinue study drug without evidence of PD per RECIST v1.1 will have CT 
scans or MRI every 6 weeks during the survival-monitoring period to determine disease 
status until PD. 
8.0 ADVERSE EVENTS (SERIOUS AND NON-SERIOUS) 
8.1 
Non-serious Adverse Events 
8.1.1 Definition of Adverse Event and Non-serious Adverse Event 
The following definition of adverse event will be used for the study: 
 
Any untoward medical occurrence in a study subject administered a 
pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to medicinal (investigational) 
product.  
 
This definition includes any abnormalities or anomalies that were not seen at baseline or 
which worsened during the course of the study, if present at baseline. Disease progression, 
and events caused by disease progression, will be considered an efficacy endpoint and should 
not be reported as an AE, even if the event results in hospitalization. Therefore progression 
of the cancer under study is not considered an adverse event. 
 
A “non-serious” AE is any event that does not meet the definition of “serious adverse event” 
(SAE) as presented in Section 8.2 below. 
 
8.1.2 Reporting and Treating Non-serious Adverse Events 
It is the responsibility of the Investigator to perform regular assessments for AEs. Subjects 
will be regularly queried about the occurrence of any AEs and will be monitored throughout 
the study for reactions to study drug and/or study procedures. The Investigator and clinical 
staff will record all AEs, whether volunteered by or elicited from the subject, at anytime 


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during a subject’s participation in the study. All events occurring prior to the first dosing will 
be recorded on the Medical History eCRF, except an SAE leading to exclusion from the trial 
or as a result of a protocol-specified intervention as described in Section 8.2.2, will be 
recorded on the Adverse Event eCRF. All AEs occurring at any time after the initiation of the 
first dose of study drug up to 30 days following the last dose of study drug will be recorded 
on the Adverse Event eCRF. Adverse events will be recorded according to the CTCAE v4.03 
(Appendix 14.4). Adverse events meeting the definition of SAE require additional reporting 
as described in the following section. 
 
All subjects experiencing an AE will be evaluated by the Investigator and monitored until 
resolution of the event or until the Investigator deems the event clinically stable and/or at an 
acceptable level. Unless the event requires hospitalization (SAE), medical treatment will be 
provided to the subjects at the unit, and treatment medication and/or medical procedures will 
preferably be provided under the guidance of the treating-Investigator’s clinical discretion. 
All AEs, including clinically significant laboratory abnormalities, will be followed until 
resolution. Serious adverse events require special reporting in addition to documentation in 
the eCRF as described in the section on Serious Adverse Events. 
 
It is the Investigator’s responsibility to provide his/her assessment of the relationship of the 
event to the study drug and the severity of the event using the following scales: 
▪ Relationship 
• No (unrelated, not related, no relation) – The time course between the 
administration of study drug and the occurrence or worsening of the AE rules 
out a causal relationship and another cause (concomitant drugs, therapies, 
complications, etc.) is suspected 
• Yes – The time course between the administration of study drug and the 
occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified 
▪ Severity 
The severity of all AEs should be graded according to the CTCAE v4.03. These criteria 
can be found at http://ctep.cancer.gov/reporting/ctc.html. For those AEs not listed in the 
CTCAE, the following grading system should be employed:  
▪ Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but 
easily tolerated and no interference with subject’s daily activities 
▪ Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with 
subject’s usual activities, but still acceptable 
▪ Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause 
considerable interference with the subject’s daily activities, unacceptable 


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▪ Life-threatening (CTCAE Grade 4): Life-threatening of disabling adverse event 
▪ Death (CTCAE Grade 5):  Death-related adverse event. See CTCAE Guidelines 
for assigning Grade 5. 
8.2 
Serious Adverse Events 
8.2.1 Definition of Serious Adverse Event 
The following definition of SAE applies for the study: 
 
An SAE is defined as any AE occurring at any dose that results in any of the 
following outcomes:  
▪ Death 
▪ Life-threatening AE 
▪ Inpatient hospitalization or prolongation of existing hospitalization 
▪ Persistent or significant disability/incapacity 
▪ Congenital anomaly/birth defect  
Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. A life-threatening AE is any AE that places the subject or 
subjects, in the view of the Investigator, at immediate risk of death from the 
reaction as it occurred (eg, it does not include a reaction that, had it occurred 
in a more severe form, might have caused death). 
 
In addition to the above criteria, adverse events meeting either of the below criteria, although 
not serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs 
in order to meet certain local requirements. 
Therefore, the following events are considered serious by the Sponsor for collection 
purposes: 
▪ Is a new cancer (that is not a condition of the study) 
▪ Is associated with an overdose 
 
8.2.2 Reporting and Treating Serious Adverse Events 
An AE that is serious (SAE) requires additional detailed reports and follow-up. The content 
of these detailed reports must address the Investigator’s estimate of causality and must 
provide the information specified in the SAE Report Form and International Conference on 
Harmonisation (ICH) guidelines, in so far as is possible.  
 


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For the time period beginning when the consent form is signed until treatment enrollment, 
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
discontinuation of usual therapy, diet, or a procedure. 
For the time period beginning at treatment enrollment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under study, 
whether or not related to the Sponsor's products, must be reported within 24 hours to the 
Sponsor. 
Additionally, any serious adverse event, considered by an Investigator who is a qualified 
physician to be related to the Sponsor's products that is brought to the attention of the 
Investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph, also must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome. 
 
Following is the safety contact information for reporting serious adverse events worldwide: 
 
Safety Contact Information 
SAE Hotline: +01 609.531.0476  
Facsimile: +01 609.531.0154 
E-mail: safety.biothera@apcerpharma.com 
 
The Investigator will be requested to supply detailed information regarding the event. All 
serious and unexpected AEs/SAEs must also be reported to the reviewing IEC/IRB as per 
specific requirements and a copy of that report must be retained at the investigative site and 
filed in the Investigator Site File. 
 
Death due to any cause occurring 30 days after the last dose of study drug during the 
survival-monitoring period will not be reported as an adverse event. Disease progression will 
not be reported as an AE/SAE. 
 
Each Investigator is responsible for reporting adverse events observed with concomitant 
medications per his/her region’s respective regulatory guidelines. 
8.3 
Definition of an Overdose for This Protocol and Reporting of Overdose 
For purposes of this trial, an Imprime PGG overdose will be defined as any Imprime PGG 
dose > 6 mg/kg (50% increase).  


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For purposes of this trial, a pembrolizumab overdose will be defined as any pembrolizumab 
dose ≥ 1000 mg (5 times the dose).  
 
There have been no known reports of overdose of Imprime PGG. No specific information is 
available on the treatment of overdose of either Imprime PGG or pembrolizumab. In the 
event of overdose, study medication should be discontinued and the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
All reports of overdose with and without an adverse event must be reported within 24 hours 
of the Investigator’s knowledge of the event to the Sponsor.  
 
8.4 
Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
Investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.  
Pregnancies and lactations that occur after the consent form is signed but before treatment 
enrollment must be reported by the Investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, or a procedure.   
Pregnancies and lactations that occur from the time of treatment enrollment through 120 days 
following cessation of Sponsor’s products, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
Investigator. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious adverse events. If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within one (1) working day of the Investigator becoming aware 
of the event. 
8.5 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment enrollment, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure. 


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For the time period beginning at treatment enrollment through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s products, 
must be reported within 24 hours to the Sponsor. 
Events of clinical interest for this trial include: 
1. Overdose of Sponsor's products, as defined in Section 8.3 Definition of an 
Overdose for This Protocol and Reporting of Overdose, that is not associated with 
clinical symptoms or abnormal laboratory results  
2. Elevated AST or ALT laboratory value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin laboratory value ≥ 2X the 
ULN and at the same time, an alkaline phosphatase laboratory value < 2X the 
ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. * 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
 
All ECIs should be reported to the sponsor within 24 hours of the Investigator’s knowledge 
of the event. 
 
9.0 STATISTICAL ANALYSIS PLAN 
9.1 
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized below.  
 
9.1.1 Hypothesis and Study Design 
The study design is based on hypothesis testing of the ORR for pembrolizumab + Imprime 
PGG. For melanoma subjects, the null hypothesis is ORR ≤ 5%, versus the alternative 
hypothesis of ORR ≥ 23%; for the TNBC subjects, the null hypothesis is ORR ≤ 5% 
(ORR=5% in KEYNOTE-086), and the alternative hypothesis is ORR ≥ 21%. Hypotheses 
testing will be conducted using a one-sided type I error of 0.05. 
     
The study will incorporate Simon’s optimal 2-stage design with sample size fixed at 12 
subjects in Stage 1 (for melanoma, Simon’s optimal 2-stage design has 12 subjects at Stage 
1; for TNBC, a modified Simon’s 2-stage design with the sample size fixed at 12 at Stage 1 
is used). The safety criterion of ≤ 4 (or ≤ 33%) subjects with Grade 3/4 adverse events in 
Cycle 1 within either tumor type must be met in order to proceed to Stage 2. The starting 
dose is 4 mg/kg for Imprime PGG. In the event there are a total of > 4 (or > 33%) of subjects 
with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced to 2 
mg/kg, and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of n=12 
subjects. For the dose that meets the safety criterion in Stage 1, at least 1 response in 


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melanoma subjects and 1 response in TNBC subjects amongst the 12 subjects within each 
tumor type must be observed in order to proceed to Stage 2. The probabilities of early 
termination at Stage 1 for not achieving such responses are 0.54 and 0.54 if the null 
hypothesis is observed for melanoma and TNBC subjects, respectively. Stage 2 will enroll an 
additional 17 subjects with melanoma and 29 subjects with TNBC. 
 
For the dose that meets the safety criterion in Stage 1, rejection of the null hypothesis will 
require documenting at least 4 objective responses among the total of up to 29 subjects with 
melanoma and 5 objective responses among the total of up to 41 subjects with TNBC.  
 
The above designs correspond to a type I error 0.05 and power of 90% for both melanoma 
and TNBC. The PASS 14 Power Analysis and Sample Size System statistical software was 
used for the study design calculation. 
 
9.1.2 Sample Size 
The planned sample size for melanoma is up to 41 subjects with up to 24 subjects for Stage 1 
and 17 subjects for Stage 2; the planned sample size for TNBC is up to 53 subjects with up to 
24 subjects for Stage 1 and 29 subjects for Stage 2. 
 
9.1.3 Efficacy Analyses 
Efficacy analysis will be conducted separately for each tumor type. The primary efficacy 
endpoint is ORR, and the secondary efficacy endpoints include PFS, TTR, CRR, DoR and 
OS. The primary efficacy population will include all evaluable subjects who receive at least 
one dose of study treatment, have measurable disease at baseline per RECIST v1.1, and have 
at least one post-baseline scan or discontinue study treatment as a result of progressive 
disease, death, or a treatment-related adverse event before the first post-baseline scan.  
Hypotheses testing of ORR will be conducted among evaluable subjects at the dose which 
meets the safety criterion in Stage 1. Among the 12 evaluable subjects in Stage 1, at least 1 
objective response in melanoma subjects would be needed to proceed to Stage 2 for 
melanoma; and at least 1 objective response in TNBC subjects would be needed to proceed 
to Stage 2 for TNBC. If there are at least 4 objective responses among the total of 29 
evaluable subjects with melanoma and/or at least 5 objective responses among the total of 41 
evaluable subjects with TNBC, the null hypothesis will be rejected for melanoma and/or 
TNBC and the study will be declared a success.  
 
The point estimate along with the exact 95% confidence interval will be computed for ORR 
and CRR. PFS and OS will be summarized descriptively and graphically using the Kaplan-
Meier method. The Kaplan-Meier estimate for the median, first, and third quartiles will be 
determined along with 95% confidence intervals (CIs). The Brookmeyer-Crowley method 
will be used for the CI calculations. For the subset of subjects who have a CR or PR, TTR 
and DoR will be summarized similarly using the Kaplan-Meier method. The Kaplan-Meier 


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estimate of PFS rate at the landmark times of 6 months and 1 year, and the OS rates at the 
landmark time of 1 year will be calculated.  
Exploratory analyses may be conducted using iRECIST. 
9.1.4 Safety Analyses 
Safety analysis will be conducted separately for each tumor type. All subjects who receive at 
least 1 dose of study treatment will be included in the safety analysis. Adverse events by 
maximum toxicity grade will be summarized with frequency/proportion of total subjects by 
system organ class and preferred term. Separate summaries will be provided for all adverse 
events, drug-related adverse events, serious adverse events, and adverse events leading to 
discontinuation of study treatments. The incidence of deaths and the primary cause of death 
will be summarized. Hematology and clinical chemistry data will be summarized by worst-
case toxicity grade shift from baseline. The results of other safety measurements (eg, ECOG 
performance status) will also be summarized. 
9.1.5 PK Analyses 
The PK analyses will be based on the PK population. The PK concentration data will be 
listed and summarized by planned visit/time.  
9.1.6 Interim Analyses 
One interim analysis will be conducted at the end of Stage 1 for each tumor type. For the 
dose which meets the safety criterion in Stage 1, if at least 1 objective response among 12 
evaluable melanoma subjects is not observed, the melanoma cohort will be terminated; if at 
least 1 objective response among 12 TNBC evaluable subjects are not observed, the TNBC 
cohort will be terminated. Early stopping at the interim analysis will only occur for futility, 
not efficacy. Adverse events including ≥ Grade 3 events will be summarized at the time of 
the interim analysis.   
9.2 
Statistical Analysis Plan 
A detailed Statistical Analysis Plan will be developed as a separate document for this 
protocol. 


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10.0  LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
10.1 Investigational Product Identification and Description 
10.1.1 Imprime PGG 
Imprime PGG will be provided by Biothera as a preservative-free, sterile, formulation in 20 
or 50-mL clear borosilicate vials. Each vial will contain active ingredient at a nominal 
concentration of 1.0 mg/mL in 140 mM sodium chloride, 11 mM sodium citrate, at pH of 5.0 
to 7.5. Vials are filled to a target volume of 21.2 or 52.0 mL respectively, to ensure a 
deliverable amount of 20 or 50 mL respectively. The active ingredient under investigation is 
β(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β(1,3)-D-glucopyranose (PGG beta glucan) 
derived from a proprietary, nonrecombinant strain of Saccharomyces cerevisiae and has an 
average molecular weight of 120,000 to 205,000 Daltons. The vehicle used to dilute Imprime 
PGG is 0.9% sodium chloride for injection. Each individual clinical study site will supply its 
own vehicle.   
 
Imprime PGG will be individually labeled in accordance with local regulations. A label will 
be affixed to the vial with the following information.  
 
Protocol: BT-CL-PGG-XXXXXXX 
Imprime PGG Injection (i.v.) 
50mL (1mg/mL), Lot#: xxxxx 
Expiry: 
50mg solution, dilute, infuse as 
directed 
Store at 20ºC - 25ºC- Do not freeze 
Biothera, Eagan, MN 55121 USA 
Caution: New drug- Limited by 
Federal (or United States) law to 
investigational use 
Protocol: BT-CL-PGG-XXXXXXX 
Imprime PGG Injection 
50mL (1mg/mL), Lot#: xxxxx 
Subject number: _____________ 
Site/Investigator: ____________ 
Date dispensed: _____________ 
Dispensed by: _______________ 
Biothera, Eagan, MN 55121 USA 
Investigator: ________________ 
  
10.1.2 Pembrolizumab 
For a complete description of pembrolizumab, please refer to the pembrolizumab regional 
prescribing guidelines (see Appendix 14.2). 
 
In summary, pembrolizumab for injection is a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials. Each vial is reconstituted and diluted for intravenous 
infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is 
formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). It may 
contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5. 
 


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Pembrolizumab will be provided by the Sponsor as summarized in Table 5.  
Table 5. Pembrolizumab Product Description 
Product Name and Potency 
 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
10.2 Storage and Handling of Clinical Study Material 
10.2.1 Storage and Handling of Imprime PGG 
Imprime PGG vials will be provided to the investigative site. Vials must be stored at 
controlled room temperature that encompasses the usual and customary working environment 
of 20ºC - 25ºC upon arrival at the site. A packing list will be included with the shipment of 
clinical study material. Upon receipt of study drug, the site will inspect the shipment for any 
damage, and compare contents against the packing list. The site will acknowledge receipt of 
the shipment and note any discrepancies or damages. Lot numbers and vial counts should be 
entered into the EDC. 
 
10.2.2 Storage and Handling of Pembrolizumab 
Please refer to the pembrolizumab regional prescribing guidelines for a comprehensive 
discussion on the storage and handling of pembrolizumab (see Appendix 14.2). 
 
10.3 Preparation, Dosing Instructions, and Schedule 
The clinical study site’s pharmacist or the study Investigator will be responsible for the 
preparation of all study medications: Imprime PGG and pembrolizumab. All subjects will 
receive Imprime PGG prior to pembrolizumab. The compounds should be administered 
consecutively, at least 15 minutes apart (but no more than 30 minutes).  
 
Instructions for the proper mixing and administration of Imprime PGG can be found in 
Appendix 14.1 on Imprime PGG Preparation and Dosing Instructions. A low protein binding 
0.22-micrometer inline filter should be utilized during administration of Imprime PGG.  
 
Instructions for the proper mixing and administration of pembrolizumab can be found in the 
regional prescribing guidelines for pembrolizumab. 
 
Other drugs should not be added to the infusion mixtures, and IV lines should be flushed as 
per standard practice between infusions. Care should be taken to avoid extravasation at the 
infusion site. The infusion site should be monitored frequently for signs of inflammation.  


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The dosing schedule is presented in Table 6.1 in the Schedule of Assessments. 
10.4 Premedications 
Each cycle will be 3 weeks in duration. During this time, subjects may receive pre-treatment 
with standard anti-histamine medications before commencing dosing of study medications on 
each treatment day and, as needed, post-dose.  
 
Premedications: 
• Cycle 1/Day 1: Pretreat with an H1 antagonist (eg, 50 mg of diphenhydramine IV). 
• Subsequent cycles: Premedication is allowed for each Imprime PGG infusion, but if 
tolerated by the subject, reduced premedication doses from those administered at 
Cycle 1/Day 1 should be used. 
10.5 Preparation and Dosing Instructions for Imprime PGG 
Refer to Appendix 14.1 for complete instructions on the preparation and administration of 
Imprime PGG. 
 
Imprime PGG is to be administered via IV infusion through a low protein binding 0.22-
micrometer in-line filter; an infusion pump should be used to assure accurate and consistent 
dosing. Imprime PGG should not be administered as an intravenous push or bolus. Table 6 
below on Target Imprime PGG Administration Values describes recommended 
concentration, dilution volume, and administration time. Dependent upon actual total body 
weight on Cycle 1/Day 1, the concentration of the final diluted solution and the rate of 
infusion may be outside of the values in Table 6, but should not exceed 0.8 mg/mL or 4.2 
ml/min respectively. Site standard guidelines should be utilized for any re-calculations of 
study medication based on weight change. 


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Table 6. Target Imprime PGG Administration Values 
Subject Weight 
(kg) 
Dose Level 
(mg/kg) 
Total Infusion 
Volume 
(mL) 
Infusion 
Time 
(hours) 
Rate of Infusion 
(mL/min) 
75 
4 
500 
2 
4.2 
75 to 150 
4 
750 
3 
4.2 
150 
4 
1000 
4 
4.2 
 
 
 
 
 
75 
2 
500 
2 
4.2 
75 to 150 
2 
750 
3 
4.2 
150 
2 
1000 
4 
4.2 
 
Note: Concentration and rate calculations are based upon an average weight of 75 kg and are approximate; 
actual values will differ among subjects based upon total body weight and may therefore be outside of the 
ranges presented above in Table 6. 
 
Please refer to Section 5.2.1.2.1 for instructions on handling infusion reactions related to the 
administration of Imprime PGG. 
 
10.6 Preparation and Dosing Instructions for Pembrolizumab 
Subjects will receive pembrolizumab at a dose of 200 mg IV on D1 of every 3-week cycle.   
 
The lyophilized powder for pembrolizumab should be reconstituted and prepared per the 
pembrolizumab package insert (see Appendix 14.2). 
 
Pembrolizumab should be administered on D1 of each 3-week cycle intravenously over 30 
minutes.  
 
Please refer to Section 5.2.1.2.2 for instructions on handling infusion reactions related to the 
administration of pembrolizumab. 
 
Please refer to the pembrolizumab regional prescribing guidelines for complete instructions 
on the preparation, storage, handling, administration, and toxicity of pembrolizumab. 
11.0 CLINICAL STUDY ADMINISTRATION 
This research will be carried out in accordance with ICH Guidelines, GCP, and with 
applicable local regulatory requirements. A subject’s voluntary signing of the informed 
consent is a required precondition to participating in the study.  
 


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The Investigator is responsible for ensuring that the clinical study is conducted in accordance 
with the principles above, the protocol, and other applicable requirements of the governing 
regulatory body. 
12.0 INFORMED CONSENT AND AUTHORIZATION FOR USE AND 
DISCLOSURE OF PROTECTED HEALTH INFORMATION 
Written informed consent, authorization of use, and disclosure of personal health information 
must be obtained from each subject (or the subject’s legal representative) prior to performing 
any study-related procedures. Prior to signing the informed consent, the study must be 
thoroughly explained to the subject (or legal representative) and the subject must be given the 
opportunity to ask questions. Included in the explanation must be the aims and methods of 
the study, anticipated benefits, potential hazards, and any anticipated possible discomfort. It 
must be explained to the subjects that they are free not to participate in the study and that if 
they do decide to participate, they may elect to withdraw at anytime without prejudice to 
future care. Subjects will also be told of any available treatment alternatives.  
 
Subjects will be told that competent authorities and authorized personnel may examine their 
records, but that their personal data will be kept strictly confidential and will not be made 
publicly available, nor will it be used for reasons other than those outlined in the informed 
consent. The subject’s dated signature on the IRB/IEC-approved form constitutes consent. If 
a subject and/or his/her legal representative are unable to read, an impartial witness must be 
present during the entire informed consent discussion and the signature of the witness must 
be on the informed consent. The informed consent presented to the subject must be in his/her 
primary language and must have been IRB/IEC-approved.  
 
One copy of the signed informed consent document and authorization will be given to the 
subject and the Investigator will retain another. The informed consent document and 
authorization, which is prepared by the Investigator, must have been reviewed and approved 
by the Sponsor, the Investigator’s IRB/IEC, and privacy board, as applicable, prior to the 
initiation of the study. The consent document must contain the 20 elements of informed 
consent described in ICH E6 Section 4.8. The site shall document the informed consent 
process. 
 
12.1 Study Documentation  
12.1.1 Study Files 
Documentation concerning Investigator data, IRB/IEC data, and clinical laboratory data, as 
well as the signed protocol page and a blank copy of the IRB/IEC-approved informed 
consent document and authorization are required before study unit initiation. Copies of these 
documents as well as supplemental information, such as the Investigators Brochure, 
Responsibilities and Obligations of Investigators and Sponsor, and final protocol, including 
any amendments, will be kept on-site in a special study file. This file also will contain the 


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Statement of Investigator Forms (or other forms required by the governing regulatory 
agency) and curricula vitae for the principal Investigator(s) and each Subinvestigator, subject 
accountability records, drug accountability (receipt/dispensing) records, Sponsor or 
Sponsor’s representative/Investigator correspondence, IRB/IEC correspondence, changes to 
the protocol, information regarding monitoring activities, biological samples records, and 
SAE/Safety reports. 
 
12.1.2 Case Report Forms and Source Documentation 
Source documents are the records maintained at the clinical research center that represent the 
first written (handwritten or electronic) record of subject information. Source documents 
include signed informed consent forms, written progress notes, laboratory reports, ECG 
tracings, etc. All source documents must be maintained at the clinical research center. 
Handwritten source documents should be recorded in blue or black ink. Any corrections to 
these handwritten source documents should be made by a single line drawn through the 
entry, adding the correct information, initialing and dating by the person making the change, 
and (preferably) indicating why the change was required. 
 
Electronic case report forms will be used for this study. The Investigator will ensure that all 
data are entered promptly, completely, accurately and conform to source documents, in 
accordance with specific instructions accompanying the eCRFs, designed specifically for this 
study and supplied by the Sponsor or Sponsor’s representative. 
 
Data will be recorded at the investigational site and reviewed by the Sponsor (or Sponsor’s 
representative)-assigned clinical research associate (CRA) during monitoring visits. The 
eCRFs will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for and when each casebook has been reviewed and signed by the 
Investigator, indicating his/her assurance of the accuracy of all recorded data. 
12.1.3 Retention of Study Documents 
Regulatory agencies require retention of study records for 7 years (or longer as required by 
specific countries regulatory agencies) following the termination of all clinical activities with 
the study drug or 7 years (or longer as required by specific countries regulatory agencies) 
following approval of the product for marketing. Since Investigators may not be aware of the 
date when a product is approved or withdrawn, all study-related records, including all source 
documents and all case report forms must be maintained for at least 10 years (or longer if 
requested by the Sponsor). The Sponsor will notify the Investigator when records may be 
destroyed or transferred. The Investigator must notify the Sponsor if the records are to be 
moved to an alternate storage site. 
 


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12.2 Clinical Monitoring 
An authorized CRA will visit the site prior to initiation and at periodic intervals to review the 
study records (including ICFs, inventory of study drug, and eCRFs), and assess compliance 
with the study protocol. The monitor(s) will also visit at conclusion of the study to help 
resolve any remaining data queries and close out all record keeping. 
 
It is the responsibility of the Investigator to make sure all necessary source documentation 
and records are available to the CRA during his/her visit and to provide a suitable space for 
the CRA to review these documents. Additionally, the Investigator must also be available as 
needed during the monitoring visit. It is the CRA’s responsibility to arrange the visits with 
the unit in advance and to notify the unit of the documentation that he/she will need during 
the visit. If the situation warrants, and at the request of the Sponsor, an interim monitoring 
visit may be made without pre-notification to the unit.  
 
All findings resulting from monitoring visits will be documented and shared with the 
Investigator and Sponsor via follow-up letters and monitoring reports. As much as possible, 
issues/discrepancies should be resolved during the monitoring visits, but those remaining at 
the end of the visit will be followed through until resolution. 
 
12.3 Confidentiality 
12.3.1 Data 
All information regarding the nature of the proposed investigation provided by the Sponsor 
or CRA to the Investigator (with the exception of information required by law or regulations 
to be disclosed to the IRB/IEC, the subject, or the appropriate regulatory authority) must be 
kept in confidence by the Investigator. 
 
12.3.2 Subject Anonymity 
The anonymity of participating subjects must be maintained. Subjects’ initials and an 
assigned subject number (only) will appear on any document submitted to the Sponsor or 
Sponsor-designated clinical research organization (CRO). Documents that will not be 
submitted to the CRO and that identify the subject (eg, the signed ICF) must be maintained in 
strict confidence by the Investigator, except to the extent necessary to allow auditing by the 
appropriate regulatory authority, the CRA, or Sponsor representatives. 
 
12.3.3 Publication and Use of Information 
All information concerning Imprime PGG, Sponsor’s patent applications, formulas, operating 
procedures, manufacturing processes, and scientific data supplied by the Sponsor and not 
previously published is considered confidential and remains the sole property of Biothera. 


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The Investigator agrees to use this information only to conduct this study and not to use it for 
other purposes without prior written consent from Biothera. 
 
The Investigator understands information developed in the clinical study will be used by the 
Sponsor or its designee in connection with the continued development of Imprime PGG and 
thus may be disclosed to other Investigators, regulatory authorities, or groups at the 
Sponsor’s discretion. The Investigator is obligated to provide to the Sponsor all data 
generated from this study. 
 
Any publication or other public presentation of data from this study is at the sole discretion 
of the Sponsor and requires Sponsor review and written approval. Authorship of any 
publications resulting from this study will be determined on the basis of the Uniform 
Requirement for Manuscripts Submitted to Biomedical Journals (International Committee of 
Medical Journal Editors), which states: 
 
▪ Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of 
the version to be published.  Authors should meet conditions 1, 2, and 3. 
 
▪ When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
 
▪ Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
▪ All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
▪ Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
Please refer to the full publication guidelines at http://www.icmje.org/. 
Requests for review of material for publications must be made to the Sponsor at least 30 days 
prior to any applicable submission deadline. Further, upon request, such submission shall be 
deferred for an additional period not exceeding 90 days to enable the Sponsor to protect its 
right in maintaining the confidentiality of proprietary information. 
 


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13.0 LIST OF REFERENCES 
Adams S, Schmid P, Rugo H, et al. Phase 2 Study of Pembrolizumab Monotherapy for 
Previously Treated Metastatic Triple-Negative Breast Cancer (mTNBC): KEYNOTE-086 
Cohort A. J Clin Oncol 35, 2017 (suppl; abstr 1008).  
 
Antonysamy MA, Bose N, Chan AS, et al, Endogenous Anti-Β-Glucan Antibodies, A 
Potential Predictive Biomarker For The Efficacy Of Soluble Yeast -1,3/1,6 Glucan 
(Imprime PGG®) Immunotherapy In Cancer Patients. J Immunol. 2014;May 1;192:73.9. 
 
Bellati, F., et al, Immunology of gynecologic neoplasms: analysis of the prognostic 
significance of the immune status. Curr Cancer Drug Targets, 2009. 9(4): p. 541-65. 
 
Bose N, Chan AS, Guerrero F, Maristany CM, Qiu X, Walsh RM, Ertelt KE, Jonas AB, 
Gorden KB, Dudney CM, Wurst LR, Danielson ME, Elmasry N, Magee AS, Patchen ML, 
Vasilakos JP. Binding of Soluble Yeast β-Glucan to Human Neutrophils and Monocytes is 
Complement-Dependent. Front Immunol. 2013 Aug 12;4:230. 
 
Bremnes, R.M., et al, The role of tumor-infiltrating immune cells and chronic inflammation 
at the tumor site on cancer development, progression, and prognosis: emphasis on non-small 
cell lung cancer. J Thorac Oncol, 2011. 6(4): p. 824-33. 
 
Chan AS, Bose N., et al. Imprime PGG-mediated Anti-cancer Immune Activation Requires 
Immune Complex Formation. Submitted, J Clin Invest, June 2016. 
 
Chang, W.J, et al, Inflammation-related factors predicting prognosis of gastric cancer. 
World J Gastroenterol, 2014. 20(16): p. 4586-96. 
 
Cheng, X., et al, Structure and interactions of the human programmed cell death 1 receptor. 
J Biol Chem, 2013. 288(17): p. 11771-85. 
 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8 
 
Dunn, G.P., I.F. Dunn, and W.T. Curry, Focus on TILs: Prognostic significance of tumor 
infiltrating lymphocytes in human glioma. Cancer Immun, 2007. 7: p. 12. 
Fraser K, Ottoson N, Qiu X, Chan AS, Jonas A, Kangas T, Graff J, Bose N. Imprime PGG 
synergizes with anti-angiogenic antibodies to repolarize the immune microenvironment, 
suppressing xenograft tumor growth in vivo (poster). Meeting of the American Association 
for Cancer Research; 2016 Apr 16–20; New Orleans (LA): AACR; 2016. Abstract nr 3280. 
(A). 
Fraser K, Chan AS, Fulton R, Leonardo S, Jonas A, Qiu X, Ottoson N, Kangas T, Gordon K, 
Graff J, Bose N. Imprime PGG triggers PD-L1 expression on tumor and myeloid cells and 


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prevents tumor establishment in combination with αPD-L1 treatment in vivo (poster). 
Meeting of the American Association for Cancer Research; 2016 Apr 16–20; New Orleans 
(LA): AACR; 2016. Abstract nr 2335. (B). 
Fulton R, Leonardo S, Jonas A, Fraser K, Chan AS, Ottoson N, Danielson M, Bose N, Graff 
J, Gorden K. Imprime PGG, a β-glucan PAMP (pathogen-associated molecular pattern), 
effectively elicits in vivo maturation of antigen presenting cells in mice and humans, 
suggesting potential synergy with checkpoint inhibitor therapy (poster). Meeting of the 
American Association for Cancer Research; 2016 Apr 16–20; New Orleans (LA): AACR; 
2016. Abstract nr 089. 
Gooden, M.J, et al, The prognostic influence of tumour-infiltrating lymphocytes in cancer: a 
systematic review with meta-analysis. Br J Cancer, 2011. 105(1): p. 93-103. 
 
Huang, X., et al, PD-1 expression by macrophages plays a pathologic role in altering 
microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S 
A, 2009. 106(15): p. 6303-8. 
 
Imprime PGG Investigators Brochure, Version 11, 2015. 
 
Jonas A, Chan AS, Ottoson N, Qiu X, Fraser K, Kangas T, Fulton R, Rathmann B, Graff J, 
Bose N. Imprime PGG drives adaptive immune resistance within the tumor 
microenvironment by modulating the myeloid compartment and enhances the efficacy of anti-
PD1 antibody in vivo (poster). Meeting of the American Association for Cancer Research; 
2016 Apr 16–20; New Orleans (LA): AACR; 2016. Abstract nr 087. 
Karim, R., et al, Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration 
and survival of patients with cervical carcinoma. Clin Cancer Res, 2009. 15(20): p. 6341-7. 
Keir, M.E., et al, PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008. 
26: p. 677-704. 
Keystone Symposium: Dendritic cells and macrophages reunited. March 8-13 2015, Quebec, 
Canada. Fc poster. 
 
Keytruda® (Pembrolizumab) US Prescribing Information (USPI), Revised December 2015 
 
Kim, S.T., et al, Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in 
patients with early breast cancer. Am J Clin Oncol, 2013. 36(3): p. 224-31. 
 
Kirk, R., Risk factors. CD8+:FOXP3+ cell ratio is a novel survival marker for colorectal 
cancer. Nat Rev Clin Oncol, 2010. 7(6): p. 299. 


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Lazar-Molnar, E., et al, Crystal structure of the complex between programmed death-1 (PD-
1) and its ligand PD-L2. Proc Natl Acad Sci U S A, 2008. 105(30): p. 10483-8. 
Leonardo S, Fulton R, Fraser K, Harrison B, Kangas T, Jonas A, Chan AS, Ottoson N, 
Yokoyama Y, Bose N, Gorden K, Graf J. Imprime PGG, a β-glucan PAMP (pathogen-
associated molecular pattern) activates the direct killing functions of innate immune cells in 
concert with tumor targeting antibodies (poster). Meeting of the American Association for 
Cancer Research; 2016 Apr 16–20; New Orleans (LA): AACR; 2016. Abstract nr 080. 
Li B, Allendorf DJ, Hansen R, Marroquin J, Ding C, Cramer DE, et al. Yeast beta-glucan 
amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-
phosphatidylinositol 3-kinase pathway. J Immunol. 2006;177:1661-9. 
 
Li B, Allendorf DJ, Hanson R, Marroquin J, Cramer DE, Harris CL, et al. Combined yeast β-
glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil 
chemotaxis via regulation of decay accelerating factor CD55. Cancer Res. 2007;67:7421-30. 
 
Lin, D.Y., et al, The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of 
antibodies and T cell receptors. Proc Natl Acad Sci U S A, 2008. 105(8): p. 3011-6. 
 
Liu, F., et al, CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation 
to breast cancer survival and molecular subtypes. Breast Cancer Res Treat, 2011. 130(2): p. 
645-55. 
 
Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of 
oncogenic BRAF in metastatic melanoma. J Clin Oncol 29(10):1239-46, 2011. 
 
Mathai, A.M., et al, Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic 
features and clinical outcomes of hepatocellular carcinoma. Am J Surg Pathol, 2012. 36(7): 
p. 980-6. 
 
Mei, Z., et al, Tumour-infiltrating inflammation and prognosis in colorectal cancer: 
systematic review and meta-analysis. Br J Cancer, 2014. 110(6): p. 1595-605. 
 
Nanda R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: 
Phase Ib KEYNOTE-012 Study – J. Clin. Oncol., published online before print, May 2, 2016, 
doi: 10.1200/JCO.2015.64.8931.  
Nishimura, H., et al, Developmentally regulated expression of the PD-1 protein on the 
surface of double-negative (CD4-CD8-) thymocytes. Int Immunol, 1996. 8(5): p. 773-80. 
 
Nosho, K., et al, Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, 
and prognosis: cohort study and literature review. J Pathol, 2010. 222(4): p. 350-66. 
 


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Oble, D.A., et al, Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in 
human melanoma. Cancer Immun, 2009. 9: p. 3. 
 
Ott, P.A., F.S. Hodi, and C. Robert, CTLA-4 and PD-1/PD-L1 blockade: new 
immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin 
Cancer Res, 2013. 19(19): p. 5300-9. 
 
Pena-Cruz, V., et al, PD-1 on immature and PD-1 ligands on migratory human Langerhans 
cells regulate antigen-presenting cell activity. J Invest Dermatol, 2010. 130(9): p. 2222-30. 
Pedoeem, A., et al, Programmed death-1 pathway in cancer and autoimmunity. Clin 
Immunol, 2014. 153(1): p. 145-52. 
 
Preston, C.C., et al, The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T 
cells correlate with poor clinical outcome in human serous ovarian cancer. PLoS One, 2013. 
8(11): p. e80063. 
 
Qiu X, Chan AS, Jonas AB, Walsh RM, Grossman WJ, and Bose N. Serum levels of natural 
anti-beta glucan antibodies correlate to binding and immunomodulatory functions of yeast-
derived beta glucan: a potential predictive biomarker in cancer immunotherapy? Keystone 
Symposium on Inflammation, Infection & Cancer, Whistler, Canada, March 2014. 
 
Salgado, R., et al, Harmonization of the evaluation of tumor infiltrating lymphocytes (TILs) 
in breast cancer: recommendations by an international TILs-working group 2014. Ann 
Oncol, 2014. 
 
Sanmamed, M.F. and L. Chen, Inducible expression of B7-H1 (PD-L1) and its selective role 
in tumor site immune modulation. Cancer J, 2014. 20(4): p. 256-61. 
 
Schatton, T., et al, Tumor-infiltrating lymphocytes and their significance in melanoma 
prognosis. Methods Mol Biol, 2014. 1102: p. 287-324. 
 
Schreiber, R.D., L.J. Old, and M.J. Smyth, Cancer immunoediting: integrating immunity's 
roles in cancer suppression and promotion. Science, 2011. 331(6024): p. 1565-70. 
 
Sheppard, K.A., et al, PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004. 
574(1-3): p. 37-41. 
 
Shirabe, K., et al, Tumor-infiltrating lymphocytes and hepatocellular carcinoma: pathology 
and clinical management. Int J Clin Oncol, 2010. 15(6): p. 552-8. 
 


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Taube, J.M., et al, Colocalization of inflammatory response with B7-h1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci 
Transl Med, 2012. 4(127): p. 127ra37. 
 
Topalian, S.L., C.G. Drake, and D.M. Pardoll, Targeting the PD-1/B7-H1(PD-L1) pathway 
to activate anti-tumor immunity. Curr Opin Immunol, 2012. 24(2): p. 207-12. 
 
Qi C, Cai Y, Gunn L, Ding C, Li B, Kloecker G, et al. Differential pathways regulating 
innate and adaptive antitumor immune responses by particulate and soluble yeast-derived 
beta-glucans. Blood. 2011;117:6825-36. 
 
Qiu X, Chan AS, Jonas AB, Walsh RM, Grossman WJ, and Bose N. Serum levels of natural 
anti-beta glucan antibodies correlate to binding and immunomodulatory functions of yeast-
derived beta glucan: a potential predictive biomarker in cancer immunotherapy? Keystone 
Symposium on Inflammation, Infection & Cancer, Whistler, Canada, March 2014. 
 
Talmadge, J.E., Immune cell infiltration of primary and metastatic lesions: mechanisms and 
clinical impact. Semin Cancer Biol, 2011. 21(2): p. 131-8. 
Uppaluri, R., G.P. Dunn, and J.S. Lewis, Jr., Focus on TILs: prognostic significance of tumor 
infiltrating lymphocytes in head and neck cancers. Cancer Immun, 2008. 8: p. 16. 
Yao, S. and L. Chen, PD-1 as an immune modulatory receptor. Cancer J, 2014. 20(4): p. 
262-4. 
Yoon, H.H., et al, Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T 
lymphocyte density in human colon carcinomas. PLoS One, 2012. 7(8): p. e42274. 
Zent CS, Call TG, Bowen DA, et al. Early treatment of high risk chronic lymphocytic 
leukemia with alemtuzumab, rituximab and poly-(1,6)-beta-glucotriosyl-(1,3)-beta-
glucopyranose beta-glucan is well tolerated and achieves high complete remission rates. 
Leuk Lymphoma 56(8):2373-8, 2015. 
Zhang, X., et al, Structural and functional analysis of the costimulatory receptor 
programmed death-1. Immunity, 2004. 20(3): p. 337-47. 
 


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14.0 APPENDICES 
14.1 Imprime PGG 4 mg/kg and 2 mg/kg Preparation and Dosing Instructions 
Table 14. 1. Imprime PGG Injection Preparation and Dose Levels 
Subject Weight 
(kg) 
Dose Level 
(mg/kg) 
Total Infusion 
Volume 
(mL) 
Infusion Time 
(hours) 
Rate of Infusion 
(mL/min) 
75 
4 
500 
2 
4.2 
75 to 150 
4 
750 
3 
4.2 
150 
4 
1000 
4 
4.2 
 
 
 
 
 
75 
2 
500 
2 
4.2 
75 to 150 
2 
750 
3 
4.2 
150 
2 
1000 
4 
4.2 
 
Imprime PGG Injection is supplied in 20 mL or 50 mL vials containing 20 mg or 50 mg respectively 
of Imprime PGG (1.0 mg/mL). Imprime PGG Injection should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and container permit. The solution 
in the vial should be clear and colorless however it may contain a small amount of visible, white, 
amorphous particulates (precipitate). Imprime PGG is reconstituted in an appropriate volume of 0.9% 
sodium chloride injection, USP or equivalent normal saline infusion bags for administration by IV 
infusion through a low protein binding 0.22-micrometer in-line filter; an infusion pump should be 
used to assure accurate and consistent dosing. Do not administer Imprime PGG as an intravenous 
push or bolus. Table 14.1 describes total infusion volumes, administration times, and rate of infusion 
for the study dose. Do not exceed an infusion rate of 4.2 ml/min. Total storage time of Imprime PGG 
diluted in the IV bag, inclusive of administration, cannot exceed 8 hours at room temperature or 24 
hours at 2-8o C.  
 
The Imprime PGG infusion should be prepared as follows for a dose of 4 mg/kg: 
 
1. Determine the Imprime PGG dose/dose volume needed 
A. Example (For weight 75 kg): 
• Subject weighs 70 kg, 70 x 4 mg/kg = a total Imprime PGG dose of 280 mg  
• At the Imprime PGG vial concentration of 1mg/mL = 280 mL of Imprime PGG 
• Subject who weighs 70 kg should receive 280 mg, 280 mL of Imprime PGG prepared as 
described further in Steps 2 – 6 below.  
 
B. Example (For weight 75 kg, up to 150 kg): 
• Subject weighs 100 kg, 100 x 4 mg/kg = a total Imprime PGG dose of 400 mg  
• At the Imprime PGG vial concentration of 1mg/mL = 400 mL of Imprime PGG 
• Subject who weighs 100 kg should receive 400 mg, 400 mL of Imprime PGG prepared as 
described further in Steps 2 – 6 below. 
 
C. Example (For weight 150 kg): 
• Subject weighs 160 kg, 160 x 4 mg/kg = a total Imprime PGG dose of 640 mg  


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• At the Imprime PGG vial concentration of 1mg/mL = 640 mL of Imprime PGG 
• Subject who weighs 160 kg should receive 640 mg, 640 mL of Imprime PGG prepared as 
described further in Steps 2 – 6 below.  
 
2. Determine the required infusion size bag of 0.9% NS from the table above based on 
subject’s weight. Withdraw a volume of the 0.9% NS equal to the calculated Imprime PGG 
dose volume (from Step 1) and discard the withdrawn NS solution. 
A. Example (For weight 75 kg): 
• Since subject weighs 70 kg, a 500 mL 0.9% NS bag should be used. Withdraw and discard 
280 mL of NS from the 500 mL NS bag.  
 
B. Example (For weight 75 kg, up to 150 kg): 
• Since subject weighs 100 kg, a 750 mL 0.9% NS bag should be used. Withdraw and discard 
400 mL of NS from the 750 mL NS bag.  
 
C. Example (For weight 150 kg): 
• Since subject weighs 160 kg, a 1000 mL 0.9% NS bag should be used. Withdraw and discard 
640 mL of NS from the 1000 mL NS bag. 
 
3. Withdraw the calculated Imprime PGG dose volume from the Imprime PGG vials (from 
Step 1). 
A. Example (For weight 75 kg): 
• For a subject weighing 70 kg, withdraw the required 280 mg (280 mL) from the Imprime 
PGG vials, and inject the Imprime PGG into the NS bag and mix gently.  
 
B. Example (For weight 75 kg, up to 150 kg): 
• For a subject weighing 100 kg, withdraw the required 400 mg (400 mL) from the Imprime 
PGG vials, and inject the Imprime PGG into the NS bag and mix gently.  
 
C. Example (For weight 150 kg): 
• For a subject weighing 160 kg, withdraw the required 640 mg (640 mL) from the Imprime 
PGG vials, and inject the Imprime PGG into the NS bag and mix gently.  
 
4. Label bag appropriately.  
 
5. Attach appropriate IV tubing and using an infusion pump infuse at the rate determined by 
the total infusion volume/infusion time described above. 
A. Example (For weight 75 kg): 
• Since subject’s weight was 70 kg, a 500 mL total fluid volume was calculated. The length of 
infusion will be 2 hours at a rate of 4.2 mL/min 
 
B. Example (For weight 75 kg, up to 150 kg): 
• Since subject’s weight was 100 kg, a 750 mL total fluid volume was calculated. The length of 
infusion will be 3 hours at a rate of 4.2 mL/min 
 


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C. Example (For weight 150 kg): 
• Since subject’s weight was 160 kg, a 1000 mL total fluid volume was calculated. The length 
of infusion will be 4 hours at a rate of 4.2 mL/min 
 
6. When infusion is complete, flush tubing with additional NS to ensure complete dosing. 
 
 
 
The Imprime PGG infusion should be prepared as follows for a dose of 2 mg/kg: 
 
1. Determine the Imprime PGG dose/dose volume needed 
A. Example (For weight <75 kg):  
• 
Subject weighs 70 kg, 70 x 2 mg/kg = a total Imprime PGG dose of 140 mg. At the 
Imprime PGG vial concentration of 1mg/mL = 140 mLs of Imprime PGG. Imprime is 
supplied in 50 mL vials = 3 50-mL vials needed, and prepared as described further in 
Steps 2 – 6 below. 
 
B. Example (For weight >75 kg, up to ≤150 kg):  
• 
Subject weighs 100 kg, 100 x 2 mg/kg = a total Imprime PGG dose of 200 mg. At the 
Imprime PGG vial concentration of 1mg/mL= 200 mLs of Imprime PGG. Imprime PGG 
is supplied in 50 mL vials = 4 50-mL vials needed, and prepared as described further in 
Steps 2 – 6 below. 
 
C. Example C (For weight >150 kg):  
• 
Subject weighs 160 kg, 160 x 2 mg/kg = a total Imprime PGG dose of 320 mg. At the 
Imprime PGG vial concentration of 1mg/mL = 320 mLs of Imprime PGG. Imprime PGG 
is supplied in 50 mL vials = 7 50-mL vials needed, and prepared as described further in 
Steps 2 – 6 below. 
 
2. Determine the required infusion size bag of 0.9% NS from the table above based on the 
subject’s weight. Withdraw a volume of the 0.9% NS equal to the calculated Imprime 
PGG dose volume (from Step 1) and discard the withdrawn NS solution. 
A. Example (For weight <75 kg):  
• 
Since subject weighs 70 kg, a 500 mL 0.9% NS bag should be used. Withdraw and 
discard 140 mLs of NS from the 500 mL NS bag. 
 
B. Example (For weight >75 kg, up to ≤150 kg):  
• 
Since subject weighs 100 kg, a 750 mL 0.9% NS bag should be used. Withdraw and 
discard 200 mLs of NS from the 750 mL NS bag. 
 
C. Example (For weight >150 kg):  
• 
Since subject weighs 160 kg, a 1000 mL 0.9% NS bag should be used. Withdraw and 
discard 320 mLs of NS from the 1000 mL NS bag. 
 
 
 


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3. Withdraw the calculated Imprime PGG dose volume from the Imprime PGG vials (from 
Step 1). 
A. Example (For weight <75 kg):  
• 
From a total of 3 50-mL vials of Imprime PGG, withdraw the required 140 mg (140 mLs) 
and inject the Imprime PGG into the NS bag and mix gently. 
 
B. Example (For weight >75 kg, up to ≤150 kg):  
• 
From a total of 4 50-mL vials of Imprime PGG, withdraw the required 200 mg (200 mLs) 
and inject the Imprime PGG into the NS bag and mix gently. 
 
C. Example (For weight >150 kg):  
• 
From a total of 7 50-mL vials of Imprime PGG, withdraw the required 320 mg (320 mLs) 
and inject the Imprime PGG into the NS bag and mix gently. 
 
4. Label bag appropriately. 
5. Attach a low protein binding 0.22-micrometer in-line filter to appropriate i.v. tubing, and 
using an infusion pump infuse at the rate determined by the total infusion 
volume/infusion time described: 
A. Example (For weight <75 kg):  
• 
Since subject’s weight was 70 kg, a 500 mL total fluid volume was calculated. The length 
of infusion will be 2 hours at a rate of 4.2 mL/min 
 
B. Example (For weight >75 kg, up to ≤150 kg):  
• 
Since subject’s weight was 100 kg, a 750 mL total fluid volume was calculated. The 
length of infusion will be 3 hours at a rate of 4.2 mL/min 
 
C. Example (For weight >150 kg):  
• 
Since subject’s weight was 160 kg, a 1000 mL total fluid volume was calculated. The 
length of infusion will be 4 hours at a rate of 4.2 mL/min 
 
6. When infusion is complete, flush tubing with additional NS to ensure complete dosing. 
 
 
 
 
 


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14.2 Pembrolizumab (KEYTRUDA®) Package Insert and Summary of Product 
Characteristics [Annex I of the European Public Assessment Report (EPAR)] 
 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 
 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003820/WC500190990.pdf 
 
 
 


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14.3 ECOG Performance Status 
These scales and criteria are used by doctors and researchers to assess how a subject's disease 
is progressing, assess how the disease affects the daily living abilities of the subject, and 
determine appropriate treatment and prognosis. They are included here for health care 
professionals to access. 
 
ECOG PERFORMANCE STATUS* 
 
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 
* As published in Am. J. Clin. Oncol. 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, 
please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair.  
 
Source:  www.ecog.org/general/perf_stat.html 
 
 


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14.4 Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
 
http://www.oncology.tv/SymptomManagement/NationalCancerInstituteUpdatesCTCAEtov4
03.aspx 
 
 
 


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14.5 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf 
 
 
 
 


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14.6 Immune Related Response Criteria (irRECIST) 
 
Table 14.6 Imaging and Treatment after First Radiologic Evidence of PD 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic evidence 
of PD by RECIST 1.1  
Repeat imaging 
at > 4 weeks at 
site to confirm 
PD 
May continue study 
treatment at the 
local site 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST. 
Repeat imaging at > 4 
weeks to confirm PD 
per physician discretion 
only 
Discontinue 
treatment 
Repeat tumor imaging 
confirms PD by 
irRECIST at the local 
site 
No additional 
imaging required 
Discontinue 
treatment (exception 
is possible upon 
consultation with 
sponsor) 
No additional imaging 
required 
N/A 
Repeat tumor imaging 
shows SD, PR or CR 
by irRECIST by the 
local site 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study 
treatment at the 
local site 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next 
tumor image should 
occur according to 
the every 6 week (±7 
days) imaging 
schedule 
 
If tumor imaging shows initial disease progression, the Investigator may elect to continue 
treatment, repeat imaging ≥ 4 weeks later and assess tumor response or confirmed 
progression per irRECIST (see Section 7.3.2 and Table 14.6 above). 
irRECIST is RECIST 1.1 adapted as described in the Table 14.6 to account for the unique 
tumor response seen with immunotherapeutic drugs. irRECIST may be used by the 
Investigator to assess tumor response and progression, and make treatment decisions. This 
data will be collected in the clinical database.  
▪ In determining whether or not the tumor burden has increased or decreased, the 
Investigator should consider all target lesions as well as non-target lesions. Subjects who 


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are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation.   
▪ For a clinically stable subject with first radiologic evidence of PD by RECIST 1.1 (ie, 
unconfirmed progression of disease), it is at the discretion of the Investigator to 
continue treating the subject per the protocol until PD is confirmed at least 28 days from 
the date of the scan first suggesting PD. If radiologic progression is confirmed by 
subsequent scan, then the subject will be discontinued from study treatment. If radiologic 
progression is not confirmed by irRECIST per the Investigator, then the subjects may 
continue on treatment and follow the regular imaging schedule intervals until PD is 
confirmed at a later timepoint by the Investigator.  
o NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 
weeks apart demonstrating PD) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden 
at the confirmatory tumor imaging, an exception to continue treatment may be 
considered following consultation with the Sponsor. In this case, if treatment is 
continued, tumor imaging should continue to be performed following the intervals 
as outlined in Section 6.1 Schedule of Assessments - Study Flow Chart. 
▪ Any subject deemed clinically unstable should be discontinued from study treatment at 
first radiologic evidence of PD, and is not required to have repeat imaging for PD 
confirmation. 
▪ In subjects who discontinue study treatment without documented PD, every effort should 
be made to continue monitoring disease status by tumor imaging using the same imaging 
schedule used while on treatment (every 6 weeks ± 7 days), until (1) the start of new anti-
cancer treatment, (2) PD, (3) death, or (4) the end of the study, whichever occurs first. 
 
 


Biothera - BT-CL-PGG-MEL/BCA-1621 /  
MK3475 PN-545/Amendment 001 
 
 
Page 1 of 20 
Version 1.5   
05 October 2017 
INFORMED CONSENT 
 
 
TITLE: 
A Multicenter, Open-label, Phase 2 Study of Imprime PGG and 
Pembrolizumab in Subjects With Advanced Melanoma Failing 
Front-line Treatment with Checkpoint Inhibitors (CPI) or Triple 
Negative Breast Cancer (TNBC) Failing Front-line Chemotherapy 
for Metastatic Disease 
 
PROTOCOL NO.: 
BT-CL-PGG-MEL/BCA-1621/MK3475 PN-545/Amendment 001 
 
WIRB® Protocol #20162506 
 
SPONSOR: 
Biothera Pharmaceuticals, Inc. 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Name 
 
Phone number (24-hour number required) 
 
 
Introduction 
 
You have been asked to participate in a research study. In order to decide whether you agree to 
be part of this research study, you should read this informed consent, which describes how the 
study will be done and the possible risks and benefits. 
 
Please take your time to make your decision about taking part. You may discuss your decision 
with your friends and family or your healthcare team. If you have any questions, you can ask 
your study doctor for more explanation. 
 
If you agree to take part in this study, you will be asked to sign this form. You will be given a 
copy to keep. If you do not sign this form, you cannot take part in this study. 
 
You are being asked to take part in this study because you have either: 
 
▪ 
Metastatic Triple-Negative Breast Cancer (TNBC) and you have gotten worse after 
treatment with chemotherapy 
 
or 
 
▪ 
Advanced (unresectable [cannot be removed surgically] Stage III or Stage IV) melanoma 
and you have gotten worse after treatment with a type of medication called a “checkpoint 
inhibitor” 
 
Why is this study being done? 


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The purpose of this study is to find out good and/or bad effects of the investigational drug, 
Imprime PGG, when given together with pembrolizumab which is also known as “Keytruda®” (a 
type of “checkpoint inhibitor”) in the treatment of your type of cancer. An investigational drug is 
one that is not approved by the United States Food and Drug Administration (FDA). Imprime 
PGG is a glucan. Glucans are molecules that are not normally present in your body. Imprime 
PGG when given with pembrolizumab may help the immune system to fight your type of cancer. 
Pembrolizumab is already approved by the FDA when given alone for the treatment of 
advanced metastatic melanoma, but not for TNBC. The combination of these drugs used in this 
study is also investigational. 
 
Biothera is the sponsor supporting this study and is responsible for the manufacturing of 
Imprime PGG. 
 
Pembrolizumab is manufactured by Merck. 
 
The term “study drug” or “study medication” will be used throughout this document to refer to 
both Imprime PGG and pembrolizumab. 
 
How many people will take part in the study? 
 
The goal of the research study is for up to 94 people (up to 41 who have melanoma and up to 
53 who have TNBC) to participate throughout the United States. 
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
 
Before you begin the study 
 
You will have the following exams, tests, or procedures to find out if you can be in the study - 
this is called the screening period. These exams, tests, or procedures may be part of your 
regular cancer care and may be done even if you do not join the study. If you have had some of 
them recently (within days before the start of the treatment on this study), they may or may not 
need to be repeated. This will be up to your study doctor. These screening tests and procedures 
include the following: 
 
▪ 
You will be asked to sign this consent form before any screening tests can be performed. 
▪ 
If you are a female who is able to have children, a urine or blood pregnancy test will be 
done.  You will not be allowed to enter the study if you are pregnant, or if you are breast-
feeding. 
▪ 
You will be asked about your past and present medical history including information about 
you, and medications (prescription, over the counter, and herbal) you are currently taking or 
have recently taken and the reason that you took them. 
▪ 
Your performance status will be done which is a general assessment (questions) of how 
your cancer is affecting your daily life, and how well you can carry out daily activities. 
▪ 
A physical examination including measurement of your vital signs (heart rate, breathing rate, 
blood pressure), weight, and height will be done. 
▪ 
Blood samples (approximately 18 mL or about 3 and a half teaspoons) and a urine sample 
will be collected for routine tests. 
▪ 
A screening blood sample (5 ml or 1 teaspoon) will also be collected to see if certain 
antibodies and proteins are present in your blood prior to your participation in the research 


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study; if you have previously been pre-screened with this blood test, you will not need to 
repeat it. Additional blood samples (5 ml or 1 teaspoon) will be collected during the study to 
see the effects of the study drug on your body. 
▪ 
An electrocardiogram (ECG) will be done to check the rhythm (tracing of the electrical 
activity) of your heart. 
▪ 
A computed tomography (CT) scan with contrast (you will be injected with a dye prior to the 
procedure to make the organs and tissues that are being scanned more visible) or magnetic 
resonance imaging (MRI) of the head, chest, abdomen, and pelvis are required within 
28 days of starting study drug. CT or MRI only needs to be performed if it hasn’t been done 
within the required time period. If your study doctor believes your cancer has spread to your 
bones, you may be asked to have a bone scan. A bone scan is a diagnostic procedure used 
to evaluate abnormalities involving bones and joints. 
▪ 
The pathology report describing your cancer upon initial diagnosis, and if available, a 
section of your archived cancer biopsy (which was taken from you in the past when you 
were first diagnosed with cancer), will be provided to the study researchers. 
 
During the Study 
 
Everyone in this study will get the same treatment of Imprime PGG in combination with 
pembrolizumab. 
 
If the exams, tests, and procedures completed for the screening period show that you can be in 
the study, the study doctor feels it is safe for you to do so, and you choose to take part, you will 
be receiving Imprime PGG + pembrolizumab. 
 
Treatment will occur in 3-week cycles. 
 
Each cycle begins immediately after the end of the previous cycle so treatment continues 
without any gaps in the cycles for as long as you are receiving study drug. 
 
Imprime PGG and pembrolizumab are both given through a needle in a vein as an intravenous 
(IV) line or through a previously surgically inserted venous access line, also known as a Port or 
PICC line. 
 
You may receive medications before receiving the study medications, and these medications 
are called “pre-treatment”. This pre-treatment is given to help your body tolerate the study 
medications better, and help to decrease the chance of an allergic type reaction. An anti-
histamine drug (for example, Benadryl or equivalent) or other drugs which your doctor feels may 
help you will be given before administration of the study drug. You will then receive the Imprime 
PGG over a 2-4 hour period depending on your weight. After the Imprime PGG administration is 
completed, you will wait 15-30 minutes, (a rest period) and then receive the pembrolizumab 
over approximately 30 minutes. 
 
You will need to be in the clinic for about 3 hours for each visit for all but 2 visits. 
 
During 2 visits (Day 1 of Cycle 1 and Day 1 of Cycle 3) when extra blood samples will be drawn 
for a pharmacokinetic (“PK”) analysis, you will need to stay in the clinic about 6 hours total. This 
includes your treatment time and 3 hour wait period to draw the PK blood work. 
 


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To find out how you are doing, the following tests and procedures will be done while you are on 
the study: 
 
Tumor Biopsies 
 
You will be asked if you are willing to undergo three procedures to provide the study 
researchers with biopsy samples of your cancer tumor. You need not agree to having these 
procedures done, but it will be very helpful to the study researchers in order to better 
understand how to help other people with your same disease. Even if you agree at the start of 
the study to undergo these procedures, you are free to change your mind for any reason and 
decline, without any negative consequences to you from your doctor or any of the research 
staff. 
 
If any written documents or reports about the sample are also sent with your biopsy sample(s), 
your name and medical records number will be removed from them.  
 
The biopsies will be collected at the following timepoints: 
 
1. Before Beginning Day 1 of Week 1 (First Cycle) 
2. After Finishing Cycle 2 But Before Beginning Day 1 of Cycle 3 
3. At Time of Response or End of Study Visit (just one of these times) 
 
 
I agree to these optional biopsies 
 
I do not agree to these optional biopsies 
 
 
Day 1 (All Cycles) 
 
▪ 
A general assessment performance status (questions) of how your cancer is affecting 
your daily life and how well you can carry out daily activities will be done. 
▪ 
Your weight (which is important to determine your correct dose of study medication) will 
be measured. 
▪ 
You will be asked about your health, and any adverse events (any symptoms good or 
bad that you felt during the week after you received the study medications that are new 
or different for you than you normally feel) and any new medications or changes to 
medications you have taken. 
▪ 
Blood samples will be collected for both routine tests and study-specific tests, unless 
these tests were performed less than 3 days prior to Day 1. The results of your blood 
tests will be reviewed by the study doctor prior to study drug administration. Therefore, 
this may require a separate visit each week for the blood draw prior to your treatment 
day, which can be scheduled up to 3 days prior to your treatment day, in order to allow 
for testing and processing of the blood sample. 
▪ 
The maximum amount of blood taken on any one day will be on the first day of the study 
when 84 mL (or about 17 teaspoons) will be collected (this includes PK samples listed 
below). On all other first days of subsequent cycles, the amount will vary from 3 mL (a 
little over half a teaspoon) to 54 mL (about 11 teaspoons). The site staff have been given 
a chart showing exactly how much blood will be collected for which tests at every visit. 


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▪ 
Part of the blood sample collected will include 20 mL (about 4 teaspoons) to see if 
certain antibodies and proteins are present in your blood and to see the effects of the 
study drug on your body. 
▪ 
You will receive Imprime PGG first and then pembrolizumab. 
 
Day 8 and Day 15 (All Cycles) 
 
• 
You will receive an infusion of Imprime PGG. 
• 
You will be asked about your health, and any adverse events (any symptoms good or 
bad that you felt during the week after you received the study medications that are 
different from you normally feel) and any new medications or changes to medications 
you have taken. 
 
Cycle 1 and Cycle 3 Only (Week 1 and Week 7) 
 
▪ 
Blood samples will be collected for pharmacokinetic (PK) testing. PK testing measures 
the amount of study drug that is circulating in the blood. You will spend additional time in 
the clinic for the study staff to collect the blood samples after the study drug 
administration. A total of 4 blood samples will be drawn, with the last one being about 6 
hours after you start getting your first study drug infusion. A total of 20 mL (about 4 
teaspoons) will be taken for this PK testing. 
 
Every Other Cycle (Every 6 Weeks) 
 
▪ 
In addition to the blood samples discussed earlier, a CT scan with contrast, or MRI scan 
of the head, chest, abdomen and pelvis, will be done. If necessary, a bone scan will be 
done. 
 
These tests and procedures may be part of regular cancer care. However, these tests and 
procedures may be done more often because you are in this study or because your study doctor 
feels it is necessary. 
 
End of Treatment Visit 
 
Within 3 days after the end of the cycle in which you received your last dose of study 
medication, the following tests and procedures will be performed: 
 
▪ 
A general assessment performance status (questions) of how your cancer is affecting 
your daily life and how well you can carry out daily activities will be done. 
▪ 
A physical examination will be done and your weight will be measured. 
▪ 
You will be asked about your health, and any adverse events (any symptoms good or 
bad that you felt during the week after you received the study medications that are new 
or different for you than you normally feel) and any new medications or changes to 
medications you have taken. 
▪ 
A voluntary procedure to provide the study researchers with a biopsy sample of your 
cancer tumor, as discussed in detail earlier. 
▪ 
Blood samples for routine tests and study-specific test totaling about 39 mL (about 8 
teaspoons). 
 


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Post-Treatment Visit 
 
Approximately 4 weeks after your last dose of study medication, the following tests and 
procedures will be performed: 
 
▪ 
If you are a female who can have children, a urine or blood pregnancy test will be done. 
▪ 
A general assessment performance status (questions) of how your cancer is affecting 
your daily life and how well you can carry out daily activities will be done. 
▪ 
You will be asked about your health, and any adverse events (any symptoms good or 
bad that you felt during the week after you received the study medications that are new 
or different for you than you normally feel) and any new medications or changes to 
medications you have taken. 
▪ 
Blood samples for routine tests and study-specific test totaling 23 mL (a little over 
4.5 teaspoons). 
 
Follow-up After Completion of the Post-treatment Visit 
 
The study staff will call you every 2 months after your last study visit in the office to ask about 
any further treatment you may have received or are currently receiving for your cancer. You 
may be asked to have a CT with contrast or MRI scans every 6 weeks to monitor your cancer. 
This follow-up will end once the whole study finishes for everyone, which is expected to be 
approximately 3 years after the last patient who enrolled in this study took his/her first dose of 
study medication. 
 
How long will I be in the study? 
 
You will receive Imprime PGG + pembrolizumab in 3-week cycles. The 3-week cycles will 
continue until you have received treatment in the study for 2 years, until your cancer shows 
signs of progression, or you experience unacceptable toxicities, whichever occurs first. 
 
Sometimes with checkpoint inhibitors such as pembrolizumab, your cancer may temporarily get 
worse (or show signs of progression) because the drug is helping your body to fight the cancer 
cells. This is sometimes called an “immune response”. If your doctor thinks this is happening to 
you, he/she will discuss with you the option to stay on the same study treatment you are on and 
check the size and number of your tumor(s) within about 4 weeks by taking an additional MRI or 
CT scan. During this time, your doctor will monitor your health carefully. 
 
If this does happen, your doctor will review your treatment options with you before continuing 
study treatment, and will explain your treatment plan. If you decide to remain in the study, you 
will sign below, which means you understand your doctor thinks the study medications are 
helping you to fight your cancer, even though it looks like your cancer is getting worse. You 
agree to allow your doctor to continue treating you with the same study medications until your 
doctor knows the results of the additional MRI or CT scan. Your doctor will then review your 
results with you and if your cancer is improving, you will remain on the study. But if your cancer 
stays the same or has become even worse, your participation in the study will end. 
 
Statement of Professional Obtaining Consent 
 


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I have fully explained what may be happening with the research participant’s response to the 
study medications. In my judgment, there was sufficient access to information, including risks 
and benefits to make an informed decision. 
 
 
Date:  
 
 
 
Signature of Person Obtaining Consent:  
 
 
 
Printed Name of Person Obtaining Consent:  
 
 
After the last study visit in the office, study staff will call you every 2 months up until 3 years 
have passed since the last patient’s first dose of study medication, and the study staff will ask 
about any additional cancer treatment you have received. 
 
If you stop receiving study medication because you have achieved a Complete Response, and 
then your cancer recurs, you may be able to go back onto the study medication as long as the 
study is still ongoing. 
 
It is possible that your study doctor or the sponsor will decide to end your participation in the study 
without your consent for any reason. Reasons for doing so include the following: 
 
▪ If your study doctor does not think it is best for you to continue 
▪ If your condition gets worse 
▪ If you have serious side effects 
▪ If you develop a serious illness, even if it is not related to your taking part in the study 
▪ New information becomes available that shows this study in not the best option for you 
▪ If you become pregnant, or you are nursing during this study 
▪ If the entire study is discontinued 
▪ If you are unable or are unwilling to follow the instructions for taking part in the study 
▪ If you no longer meet the requirements for the study 
 
Biothera, the FDA, an Institutional Review Board (IRB), an Ethics Committee, or other 
regulatory agencies may decide to stop the study before the study is done and without warning. 
If this happens to you, your study doctor will assist you with the plans for your continued care as 
appropriate. 
 
What side effects or risks can I expect from being in the study? 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
for side effects. However, doctors don’t know all the side effects that may happen. Side effects 
may be mild or very serious. Your health care team may give you medicines to help lessen side 
effects. Side effects may go away soon after you stop taking Imprime PGG and/or 
pembrolizumab. In some cases, side effects can be serious, long lasting, or may never go away. 
There is also a risk of death. You should talk to your study doctor about any side effects that 
you have while taking part in the study. 
 


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As with any new substance like Imprime PGG, new, previously unknown side effects may also 
occur. 
 
This section uses symbols to describe the frequency of side effect occurrences. The following is 
included as a key to help you understand these symbols: 
 
Symbol Meaning 
<  
less than 
≤  
less than or equal to 
>  
greater than 
≥  
greater than or equal to  
 
Imprime PGG 
 
Common side effects seen in > 5% of patients treated with Imprime PGG in the 
healthy volunteer studies of Imprime PGG, when it was given as a single agent 
without premedication include the following: 
 
• 
Shortness of breath 
• 
headache 
• 
tingling sensations 
• 
rash 
• 
nausea 
• 
flushing (reddening of the face) 
• 
red eyes 
• 
blurred vision 
• 
fatigue 
• 
low red blood cell count 
• 
dizziness 
• 
numbness 
• 
bruising 
• 
sweating 
• 
itching 
• 
sore throat 
• 
chest discomfort 
• 
chills 
• 
pain at injection site 
• 
incidental back injury 
• 
laceration or scratch 
• 
fast heart-beat 
• 
upper respiratory infection 
• 
low white blood cell count 
• 
joint aches or stiffness 
 
Common side effects seen in more than 5% of subjects who received Imprime 
PGG in the healthy volunteer studies of Imprime PGG, when it was given in 
combination with filgrastim (Neupogen®): 


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• 
Abdominal (stomach) pain 
• 
nausea 
• 
chest discomfort 
• 
chest pain 
• 
chills 
• 
injection site irritation 
• 
injection site pain 
• 
pain 
• 
joint aches 
• 
back pain 
• 
musculoskeletal (muscles and bones in the body) pain 
• 
pain in arms or legs 
• 
dizziness 
• 
headache 
• 
shortness of breath 
• 
rash 
• 
hives 
 
There were a few severe side effects which included: 
 
• 
stomach pain 
• 
hypersensitivity 
• 
low blood pressure 
• 
rapid heartbeat 
• 
injection site pain and injection site swelling 
 
Imprime PGG has been studied in patients with advanced cancer. The patients in these studies 
were also taking several other medications (eg antibodies, chemotherapy) to treat the cancer, in 
combination with Imprime PGG. The side effects seen in these studies have been similar to the 
side effects expected to be seen in patients that take these other medications (eg antibodies, 
chemotherapy). 
 
In previous studies with another drug substance (Betafectin®) that contained the same active 
ingredient (PGG Beta Glucan) as Imprime PGG, other observed side effects included 
inflammation of the joints and eyes, permanent liver damage, fever, and dilation of blood 
vessels were observed. The side effects of Imprime PGG may be similar to those seen with 
Betafectin®. 
 
Pembrolizumab 
 
What is known about this study drug? 
 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your type of 
cancer. 
 
Pembrolizumab works by helping your immune system to fight your cancer. 


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However, pembrolizumab can also cause your immune system to attack normal organs and 
tissues in your body and can affect the way they work, which can result in side effects that may 
become serious or life-threatening, and in some cases, may lead to death. 
 
What side effects could the study drug cause? 
 
VERY COMMON. SOME MAY BE SERIOUS (i.e. causing hospitalization, life-
threatening or where noted, may cause death) 
 
Out of 100 people who receive pembrolizumab, 20 or more people may have the 
following:  
 
▪ 
Itching of the skin 
▪ 
Loose or watery stools 
▪ 
Cough 
 
COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, 
or where noted, may cause death)  
 
Out of 100 people who receive pembrolizumab, at least 5 but less than 20 people 
may have the following: 
 
▪ 
Joint pain  
▪ 
Rash 
▪ 
Fever 
▪ 
Back pain 
▪ 
Pain in your belly 
▪ 
Loss of skin color 
▪ 
Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have 
infrequent or hard stools 
▪ 
Low levels of salt in the blood that may cause you to feel tired, confused, have a 
headache, muscle cramps and /or feel sick to your stomach 
 
UNCOMMON, SOME MAY BE SERIOUS (i.e. cause hospitalization, life-
threatening, or where noted, may cause death) 
 
Out of 100 people who receive pembrolizumab, at least 1 but less than 5 people 
may have the following: 
 
▪ 
Inflammation of the lungs so you may feel short of breath and cough. Sometimes this 
might lead to death 
▪ 
Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools 
▪ 
Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, 
feel short of breath at the time of receiving your infusion (IV) or just after, or pain at the 
site of infusion 


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▪ 
Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus 
▪ 
Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (i.e. peeling, itching and redness) could also be 
widespread throughout your body. More severe skin reactions may involve the inside of 
your mouth, the surface of your eye and genital areas, and/or may cause the top layer of 
your skin to peel from all over your body which can cause severe infection. These 
severe conditions can sometimes lead to death. 
 
RARE, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or 
where noted, may cause death) 
 
Out of 100 people who receive pembrolizumab, less than 1 person may have the 
following:  
▪ 
Inflammation of the nerves that may cause pain, weakness or tingling in your hands and 
feet, and may spread to your legs, arms and upper body leading to severe muscle 
weakness and possible temporary paralysis 
▪ 
Inflammation of the muscles so you may feel weak or have pain in the muscles 
▪ 
Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so 
you may have severe pain in the top part of your belly that may move to your back, feel 
sick to your stomach, and vomiting that gets worse when you eat 
▪ 
Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to light, 
eye pain, see floaters or have headaches 
▪ 
Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, have a pain in the right side of your belly, yellow 
eyes and skin, and dark urine 
▪ 
Inflammation of the pituitary gland (a gland in the head), which may cause you to feel 
sick to your stomach or have headaches, changes in your behavior, double vision, few to 
no menstrual cycles, weakness, vomiting and dizziness or fainting 
▪ 
Adrenal glands (glands on top of the kidneys) that may not make enough hormone, 
which could cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle 
and belly aches, nausea, vomiting, loose or watery stools, fever, salt craving, and 
sometimes darkening of the skin like a suntan 
▪ 
Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling 
thirstier than usual, frequent urination and weight loss. You are likely to need regular 
insulin shots.  
▪ 
Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain 
▪ 
Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath and swelling of the legs. You may experience a fast or irregular heartbeat that 
may cause dizziness or fainting. Sometimes this condition can lead to death. 
▪ 
Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. 
This condition may lead to change in your heart rate, blood pressure, body temperature, 
and the rate at which food is converted into energy.  
▪ 
A condition that may make you feel weak and tired and might have drooping of the 
eyelids, blurred or double vision, difficulty swallowing, slurred speech, weakness in your 
arms and legs, or difficulty breathing 


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▪ 
The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs 
▪ 
Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty 
speaking, weakness or loss of movement in some parts of your body, and loss of 
consciousness 
 
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in 
which a person receives blood-forming stem cells from a donor), you may experience graft 
versus host disease (GvHD), which may include diarrhea, skin rashes, and liver damage, after 
receiving pembrolizumab. Sometimes this condition can lead to death. 
 
Patients with multiple myeloma who were treated with pembrolizumab in combination with either 
pomalidomide or lenalidomide (drugs related to thalidomide which affect the body’s immune 
system) and dexamethasone (a steroid) had an increased number of serious side effects and 
deaths as compared to patients who received only dexamethasone and either pomalidomide or 
lenalidomide. 
 
To date, there have been no studies conducted using a combination of Imprime PGG and 
pembrolizumab. Therefore, it is not known what types of side effects might be observed or 
which you might experience with this combination. 
 
Due to the unknown effects of the study medication, you should be aware that the consumption 
of alcohol or the taking of any drugs or medication (with or without prescription or illegal ones), 
other than the study medications, at any time during the study without the consent of the study 
doctor or site staff might cause serious or even life-threatening reactions. Both new and current 
drugs can have unknown side effects, some of which might be serious. 
 
0.9% Normal Saline (Sodium Chloride): 
 
Infusion of normal saline can result in infusion site swelling, tenderness, redness, or infiltration 
(normal saline leaking into the tissue around the vein). More serious side effects may include 
increased heart rate, fever, rash, joint pain or shortness of breath. 
 
Diphenhydramine (Antihistamine): 
 
Diphenhydramine is used to treat symptoms of allergies such as runny nose, sneezing and itchy 
eyes, nose or throat. It is also used as a sleep aid or to decrease motion sickness. More 
common side effects include drowsiness, dry mouth (nose and throat), dizziness, nausea, 
headache, tightening of the chest and loss of appetite. More serious side effects may include 
change in vision, decrease or trouble urinating or trouble breathing. 
 
Infusion Site Reaction: 
 
It is possible to have what is called an infusion site reaction following an intravenous (IV) 
infusion (medication given through a needle in a vein). Symptoms of an infusion site reaction 
may include, pain, redness, burning sensation, and itching sensation. You may experience 
inflammation or infection at the infusion site. If you experience any of these report it to the clinic 
staff. The infusion site will be monitored throughout the study. 
 


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Allergic Reaction: 
 
It is possible to have what is called an allergic (or hypersensitivity) reaction during or soon after 
the administration of any investigational or non-investigational medicine. Some subjects have 
experienced difficulty breathing, wheezing, hives or swelling around the vein where the needle 
was placed, face, mouth, lips, gums, tongue, or neck. If you have any allergies that you are 
aware of, you should tell the study doctor before agreeing to take part in this study. Since 
Imprime PGG is investigational when taken alone or in combination with other medications, 
there may be other risks that are unknown. 
 
All drugs have a potential risk of an allergic reaction, which if not treated promptly, could 
become life threatening. If you experience any such symptoms, you should get medical help 
and contact the study doctor right away. 
 
Risks and possible discomforts you might experience from the study procedures 
include: 
 
Blood draws: Temporary discomfort from the needle in your arm, bruising, bleeding, and 
swelling at the needle insertion site or vein [phlebitis], and infection. Standard medical care will 
be taken to avoid these complications. 
 
ECG: The risks from an ECG can include skin irritation and a rash from the gel that is used or 
from wearing or removing the patches. 
 
CT Scan Risks: In this study, you will be exposed to some radiation from the CT scans. The 
amount of radiation you will get is like the amount from other x-ray exams routinely used in 
medicine.  Public policy is to keep exposure levels as low as possible. 
 
Contrast dye may be used, which has a small possibility of a severe allergic reaction and kidney 
problems. 
 
MRI Scan risk: You may have risks from MRI if you have metallic objects in your body. You 
may also become anxious from lying in a tight space without moving. 
 
Other Risks: 
 
Since Imprime PGG is investigational, there may be other risks that are unknown. For your own 
safety and for the safety of other subjects in the study, you must inform the study doctor or 
study staff about any side effects or other health problems you experience during the study. 
Other medicines or supplements could cause side effects if you use them while you are 
receiving Imprime PGG. Because of this, you must tell the study doctor or a member of the 
study staff about all of your past and present illnesses and allergies. You must also tell them 
about all drugs, vitamins, supplements, and medicines you are taking. 
 
It is important that you report all symptoms and side effects that you experience as soon as they 
occur, whether or not you think they are caused by the study drug. The phone numbers for the 
study team are on the first page of this document. 
 


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REPRODUCTION RISKS 
 
Pregnancy Related Risks / Use of Birth Control Females 
 
The effects of Imprime PGG on pregnancy, an unborn baby, or a nursing child are not known. If 
you are currently pregnant, planning to become pregnant, or are breastfeeding a child, you 
should not take part in this study. 
 
All females who are able to get pregnant and males whose partners are able to get pregnant 
and who are sexually active are required to use an acceptable form of contraception (birth 
control) during the study and continue contraception for 120 days after the last dose of study 
drug. Highly effective methods of contraception are those that, alone or in combination, result in 
a failure rate of less than 1% when used consistently and correctly. The study doctor will instruct 
you in correct use of your selected birth control method and review with you at each visit your 
responsibility to use your selected birth control method consistently and correctly. 
 
The following are highly effective methods of acceptable birth control: 
 
▪ 
Abstinence (refraining from intercourse for the required study period) 
▪ 
Correctly placed copper containing intrauterine device (IUD). 
▪ 
Contraceptive rod implanted into the skin 
▪ 
Male sterilization of subject or female subjects’ partner with confirmed absence of sperm 
in the post-vasectomy ejaculate. 
▪ 
Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label). 
 
Use of 2 of the following: 
 
▪ 
Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
▪ 
Cervical cap with spermicide 
▪ 
Contraceptive sponge 
▪ 
Male condom or female condom (cannot be used together) 
▪ 
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill, contraceptive skin patch, vaginal contraceptive ring, or subcutaneous (under the 
skin) contraceptive injection 
 
Discuss any other forms of birth control with your study doctor to see if they are acceptable. 
 
Birth control methods, even when used consistently and correctly, are not perfect. If you 
become pregnant or want to stop your required birth control while you are in the study, you 
should tell the study doctor immediately. You will be withdrawn from the study if you discontinue 
birth control or you become pregnant. 
 
Males 
 
The effects of Imprime PGG on sperm or a pregnancy are not known. If you are planning to 
father a child you should not join this study. If you and your partner are physically able to have 
children and you are sexually active, you must use an acceptable form of the birth control from 
the methods listed above consistently and correctly beginning with the first infusion of the study 
drug and at least 120 days after the last injection of the study drug. The study doctor will discuss 


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with you the permitted methods of birth control for this study and will help you select birth control 
that is appropriate for you. The study doctor will instruct you in correct use of your selected birth 
control method and review with you at each visit your responsibility to use your selected birth 
control method consistently and correctly. 
 
Pregnancy Follow Up 
 
If you become pregnant during the study or within at least 120 days, after the last infusion of the 
study drug, please tell the study doctor immediately. Please also tell the doctor who will be 
taking care of you during the pregnancy that you took part in this study. The study doctor will 
ask if you or your pregnancy doctor are willing to provide updates on the progress of the 
pregnancy and its outcome. If you agree, this information will be provided to the study sponsor 
for safety monitoring follow-up. 
 
What if New Information Becomes Available? 
 
The study doctor will tell you in a timely manner of any information learned during the course of 
the study that might cause you to change your mind about taking part in the study. You may 
contact the study doctor at any time after your participation ends to find out if any new 
information about this study has become available. 
 
As with any new substance, new and/or previously unknown side effects may also occur with 
the use of Imprime PGG. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not help your cancer. The information learned from this 
study may help doctors learn more about the combination of Imprime PGG and pembrolizumab 
as a treatment for people with cancer such as yours. This information could help future cancer 
patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
 
▪ 
Getting treatment or care for your cancer with a different cancer drug without being in a 
study 
o If you have advanced melanoma, the following is a list of other medication options 
available to you (in alphabetical order): 
▪ 
Aldesleukin for metastatic melanoma 
▪ 
Cobimetinib in combination with vemurafenib for BRAF-mutated unresectable 
or metastatic melanoma (BRAF is a protein which is involved in sending 
signals in cells and cell growth, and a mutation in BRAF can increase the 
growth and spread of cancer cells) 
▪ 
Dabrafenib for BRAF-mutated unresectable or metastatic melanoma 
▪ 
Dacarbazine for metastatic melanoma 
▪ 
Ipilimumab for adjuvant treatment after surgical removal of melanoma at high 
risk of recurrence OR for unresectable or metastatic melanoma 


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▪ 
Nivolumab used with Ipilimumab for BRAF-unmutated unresectable or 
metastatic melanoma OR alone in refractory melanoma after treatment with 
Ipilimumab or BRAF inhibitor if BRAF-mutated tumor 
▪ 
Peginterferon Alfa-2b for melanoma spread to lymph nodes after surgical 
removal of skin melanoma 
▪ 
Pembrolizumab for unresectable or metastatic melanoma (if you decide to 
participate in this study, you will receive pembrolizumab + Imprime PGG) 
▪ 
Talimogene Laherparepvec for local injection into recurrent melanoma of the 
skin or lymph nodes that are unresectable 
▪ 
Trametinib for BRAF-mutated unresectable or metastatic melanoma 
▪ 
Vemurafenib for BRAF-mutated unresectable or metastatic melanoma 
▪ 
Taking part in another study 
▪ 
Getting no treatment 
▪ 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible. 
 
Talk to your doctor about all of your choices before you decide if you will take part in this study. 
There may be new treatments your doctor can tell you about, which were not yet approved at 
the time this Informed Consent Form was written. 
 
What are my responsibilities if I decide to participate? 
 
If you decide that you want to participate in the study, you will be asked to come to all of your 
scheduled study visits, to follow the study doctor’s directions, and to inform the study staff about 
any new medications you are taking and how you have been feeling. 
 
Will my medical information be kept private? 
 
Every effort will be made to keep your study records private. It is the responsibility of the study 
staff to make sure that your research records are protected. If information from this study is 
used in any reports or publications, your name and anything else that could identify you will not 
be used. The study staff will review your records and require access to your medical 
information. 
 
Other organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
 
▪ 
The National Cancer Institute (NCI) and other government regulatory agencies like the US 
Food and Drug Administration (FDA) 
▪ 
Biothera the study sponsor, Merck (manufacturer of pembrolizumab), and representatives 
working on behalf of the sponsor 
▪ 
Regulatory agencies in other countries 
▪ 
Western Institutional Review Board® (WIRB®) 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 


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What are the costs of taking part in this study? 
 
The sponsor will provide Imprime PGG and pembrolizumab at no cost to you or your health 
insurance. You and/or your health plan/insurance company will be charged for the costs of 
treating your cancer including the costs of the: 
 
▪ 
Imaging scans 
▪ 
Doctor visits 
▪ 
Regular tests of blood to test your health 
 
You/your insurance will NOT be charged for the following: 
 
▪ 
Blood tests for research purposes only 
▪ 
ECGs required for research purposes only 
▪ 
Tests on your tumor for research purposes only 
 
Some health plans will not pay the costs for taking part in studies. Taking part in this study may 
or may not cost your insurance company more than the cost of getting regular cancer treatment. 
Check with your health plan or insurance company to find out what they will pay for. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
If, during the study, Imprime PGG becomes approved for use in your cancer, you and/or your 
health plan may have to pay for drug needed to complete this study. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your doctor if you feel that you have been injured because of taking 
part in this study. They will treat you or refer you for treatment. If, during the course of the study, 
you experience any injury as a direct result of the administration of study drug, the sponsor 
agrees to pay all medical expenses necessary to treat such injury (1) to the extent you are not 
otherwise reimbursed by medical insurance, a government program, or a third party, and (2) 
provided you have followed the directions of the study doctor. 
 
You will not be financially compensated for your participation in this trial beyond what may be 
provided for time and travel. Payment for such things as lost wages, expenses other than 
medical care, or pain and suffering is not available. 
 
To help avoid injury, it is very important to follow all study directions. By signing and dating this 
form, you have not waived any of the legal rights to pursue a claim through the legal system, 
which you would have otherwise, if you were not a participant in a drug research study. 
 
Is my participation voluntary? 


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Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care. You can still get your 
medical care from our institution. 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions, complaints, or concerns you have about 
this study or if at any time you feel you have had a research-related injury or reaction to the 
study drugs. 
 
If you have any questions about your rights as a research subject or if you have questions, 
concerns, or complaints about the research, please contact: 
 
 
Western Institutional Review Board® (WIRB®) 
 
1019 39th Avenue SE Suite 120 
 
Puyallup, Washington  98374-2115 
 
Telephone:  1-800-562-4789 or 360-252-2500 
 
E-mail: Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 
About Using Tissue and Blood Specimens for Research 
 
You have had a biopsy (or surgery) of your cancer tumor(s) in the past to see if you have 
cancer. Your doctor removed some body tissue to do some pathology tests (tests and 
examination of your cancer tissue under a microscope). The results of these tests (the 
pathology report) confirmed that you have cancer. You will need to provide permission for this 
pathology tissue to be further examined for use this study. 
 
You will need to provide permission for your pathology tissue sample to be sent to a central 
testing facility for this study. It may be tested for biomarkers (a substance that can be measured 
which is indicative of your disease). Additional biomarkers may be evaluated as new information 
becomes available from research studies. These results will become part of the study record. All 
possible measures will be used to protect your privacy and confidentiality, such as the use of a 
study number specific to you in place of your name on the results. Any unused tumor tissue 
samples will be returned to your study doctor 6 months after the study has ended, or sooner 
should you request them earlier. There will also be 3 additional tumor biopsy samples that we 
would like to collect. You will need to provide permission for these samples to be collected. 
 


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As described earlier, an additional blood sample (20 mL or approximately 1.5 tablespoons) will 
also be collected at the timepoints specified previously in this document. The blood will be 
tested for markers that may be associated with side effects or response to therapy, and to learn 
more about the immune system and cancer. 
 
Statement of Professional Obtaining Consent 
 
I have fully explained this research study to the research participant. In my judgment, there was 
sufficient access to information, including risks and benefits to make an informed decision. 
 
 
Date:  
 
 
 
Signature of Person Obtaining Consent:  
 
 
 
Printed Name of Person Obtaining Consent:  
 
 
Research Participant Statement 
 
I have read this Informed Consent. I have had the opportunity to discuss this study with my 
family or any trusted friends, as I desired. I have had the opportunity to discuss this study with 
the consenting professional and all my questions have been answered to my satisfaction. I 
understand that my participation is voluntary. I understand the purpose, risks, and benefits of 
the research study. I agree to take part in this study. 
 
 
Date:  
 
 
 
Patient Signature:  
 
 
 
Patient Printed Name:  
 
 
 
The following section is only to be used after a discussion about continuing on treatment 
after possible pseudo-disease progression. 
 
Research Participant Statement to Continue Research Participation 
 
I have read the section of the Informed Consent about why my cancer may be improving even 
though the results look worse. I have had the opportunity to discuss this result with my family or 
any trusted friends, as I desired. I have had the opportunity to discuss this situation with the 
consenting professional and all my questions have been answered to my satisfaction. I 
understand that my participation is voluntary. I understand the purpose, risks, and benefits of 
continuing in this research study. I agree to continue taking part in this study. 
 
 


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Date:  
 
 
 
Patient Signature:  
 
 
 
Patient Printed Name:  
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol: BT-CL-PGG-MEL/BCA-1621/MK3475 PN-545 
 
 
A Multicenter, Open-label, Phase 2 Study of Imprime PGG and Pembrolizumab in 
Subjects with Advanced Melanoma Failing Front-line Treatment with Checkpoint 
Inhibitors (CPI) or Triple Negative Breast Cancer (TNBC) Failing Front-line 
Chemotherapy for Metastatic Disease 
 
 
 
 
 
Version 1.3 
 
May 20, 2019 
 
 
 
 
Biothera Pharmaceuticals, Inc. 
3388 Mike Collins Drive, Suite A 
Eagan, MN 55121 
 
 
 
 
CONFIDENTIAL STATEMENT 
 
The information in this document contains intellectual property, trade secrets and commercial 
information that are privileged and/or confidential and may not be disclosed without prior written 
consent or as required by applicable laws and regulations. Persons to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further disclosed by 
them. 




Page i 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................... 1 
2 
STUDY OBJECTIVES ................................................................................................................... 1 
2.1 
Primary Objective ...................................................................................................................... 1 
2.2 
Secondary Objectives ................................................................................................................. 1 
2.3 
Exploratory Objectives .............................................................................................................. 2 
3 
END POINTS .................................................................................................................................. 2 
3.1 
Primary ...................................................................................................................................... 2 
3.2 
Secondary .................................................................................................................................. 2 
3.3 
Exploratory ................................................................................................................................ 3 
4 
STUDY DESIGN ............................................................................................................................. 3 
5 
PLANNED ANALYSES ................................................................................................................. 4 
5.1 
Interim Analyses ........................................................................................................................ 4 
5.2 
Primary Analyses ....................................................................................................................... 4 
5.3 
Final Analysis ............................................................................................................................ 4 
6 
ANALYSIS POPULATIONS ........................................................................................................ 4 
7 
TREATMENT COMPARISONS .................................................................................................. 5 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................................... 5 
8.1 
Multicenter Study ...................................................................................................................... 6 
8.2 
Examination of Subgroups ........................................................................................................ 6 
9 
DATA HANDLING CONVENTIONS ......................................................................................... 7 
9.1 
Premature Withdrawal and Missing Data .................................................................................. 7 
9.1.1 
Missing Data in Objective Response .................................................................................. 7 
9.1.2 
Missing Data in Adverse Event .......................................................................................... 7 
9.2 
Derived and Transformed Data ................................................................................................. 7 
9.2.1 
Reference Dates .................................................................................................................. 7 
9.2.2 
Duration and Elapsed Time ................................................................................................ 7 
9.3 
Imputation of Partial Dates ........................................................................................................ 8 
9.4 
Baseline Definition .................................................................................................................... 8 
9.5 
Multiple Assessments ................................................................................................................ 8 
10 STUDY POPULATION ................................................................................................................. 8 
10.1 
Disposition of Subjects .............................................................................................................. 9 
10.2 
Protocol Deviations ................................................................................................................... 9 
10.3 
Demographic and Baseline Characteristics ............................................................................... 9 
10.4 
Concomitant Medications ........................................................................................................ 10 


Page ii 
10.5 
Post Study Treatment Cancer Therapies ................................................................................. 10 
11 EFFICACY ANALYSIS ............................................................................................................... 10 
11.1 
Primary Efficacy Analysis ....................................................................................................... 10 
11.2 
Secondary Efficacy Analysis ................................................................................................... 13 
11.2.1 
Time to Response ............................................................................................................. 13 
11.2.2 
Complete Response Rate .................................................................................................. 13 
11.2.3 
Duration of Response ....................................................................................................... 13 
11.2.4 
Progression Free Survival ................................................................................................ 14 
11.2.5 
Overall Survival ............................................................................................................... 15 
11.3 
Exploratory Efficacy Analysis Based on irRECIST ............................................................... 15 
11.3.1 
ORR Based on irRECIST ................................................................................................. 16 
11.3.2. PFS Based on irRECIST ......................................................................................................... 16 
11.4 
Exploratory Efficacy Analysis Based on Biomarker Data ...................................................... 17 
12 SAFETY ANALYSIS .................................................................................................................... 17 
12.1 
Study Treatment Administration ............................................................................................. 18 
12.2 
Adverse Events ........................................................................................................................ 18 
12.3 
Serious Adverse Events ........................................................................................................... 19 
12.4 
Adverse Events Leading to Study Discontinuation and Dose Modification ........................... 20 
12.5 
Deaths ...................................................................................................................................... 20 
12.6 
Pregnancies .............................................................................................................................. 20 
12.7 
Clinical Laboratory Evaluations .............................................................................................. 20 
12.8 
Vital Signs ............................................................................................................................... 21 
12.9 
Electrocardiograms .................................................................................................................. 21 
12.10 ECOG Performance Status ...................................................................................................... 21 
12.11 Physical Examination .............................................................................................................. 21 
13 PHARMACOKINETICS ............................................................................................................. 22 
14 BIOMARKER ANALYSIS .......................................................................................................... 22 
15 DATA DISPLAY SPECIFICATIONS ........................................................................................ 22 
 
 
 


Page 1 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is to describe in detail the statistical analyses to be conducted 
for the protocol BT-CL-PGG-MEL/BCA-1621/MK3475 PN-545. This is a Phase 2 study of 
Imprime PGG and pembrolizumab in subjects with advanced melanoma failing front-line treatment 
with checkpoint inhibitors or triple negative breast cancer failing front-line chemotherapy for 
metastatic disease. All decisions regarding the interim, primary and final analyses will be made 
prior to the database freeze of the study data. 
For further information on the study design, see Protocol BT-CL-PGG-MEL/BCA- 1621/MK3475 
PN-545 version 2.0, dated 10August 2017. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
§ Objective: To determine the Overall Response Rate (ORR) to Imprime PGG + pembrolizumab in 
subjects with advanced melanoma or metastatic triple negative breast cancer (TNBC) 
§ Safety: To characterize the safety of Imprime PGG + pembrolizumab given in combination 
 
Hypothesis: Restore (for melanoma) or enhance (for TNBC) sensitivity to checkpoint inhibitors 
(CPI) by appropriate and effective stimulation of the subject’s innate and adaptive immune systems 
in those subjects who have failed front line therapy 
Melanoma Subjects: 
• H0: ORR ≤ 5% 
• HA: ORR ≥ 23% 
TNBC Subjects: 
• H0: ORR ≤ 5% 
• HA: ORR ≥ 21% 
 
Rejection of the null hypothesis will require documenting at least 4 objective responses among the 
total of up to 29 subjects with melanoma (Stage 1 + Stage 2), and 5 objective responses among the 
total of up to 41 subjects with TNBC (Stage 1 + Stage 2). 
RECIST v1.1 criteria will be used for all applicable primary and secondary endpoints. Immune 
related response criteria (irRECIST) will be used for exploratory efficacy endpoints.  
2.2 
Secondary Objectives 
1. To determine the time to response (TTR), complete response rate (CRR), and duration of 
overall response (DoR) in subjects with advanced melanoma or metastatic TNBC when 
treated with Imprime PGG in combination with pembrolizumab 
2. To measure the Progression-Free Survival (PFS) and PFS rate at 6 months and 1 year in 
subjects with advanced melanoma or metastatic TNBC when treated with Imprime PGG in 
combination with pembrolizumab 
3. To measure overall survival (OS) and OS rate at 1 year in subjects with advanced melanoma 
or metastatic TNBC when treated with Imprime PGG in combination with pembrolizumab 


Page 2 
4. To profile pharmacokinetic (PK) data in subjects with advanced melanoma or metastatic 
TNBC when treated with Imprime PGG in combination with pembrolizumab 
2.3 
Exploratory Objectives 
1. Determine ORR and PFS based on irRECIST in subjects with advanced melanoma or 
metastatic TNBC when treated with Imprime PGG in combination with pembrolizumab 
2. Correlate levels of baseline serum anti-β-glucan antibody (ABA) with objective response and 
treatment outcomes 
3. Correlate changes in immune cell activation markers, such as CD86 expression in tumor 
biopsy samples and in peripheral blood immune cells with objective response and treatment 
outcome 
4. In tumor biopsies, correlate changes in the tumor immune microenvironment including TILs 
(Tumor-infiltrating Lymphocytes) and tumor-infiltrating myeloid cells with objective 
response and treatment outcome 
5. Correlate PD-L1 expression in tumor biopsy samples (in tumor cells and myeloid cells) with 
objective response and treatment outcome 
3 
END POINTS 
3.1 
Primary 
The primary efficacy endpoint is ORR, which is defined as the proportion of subjects 
demonstrating complete response (CR) or partial response (PR) based on RECIST v1.1 criteria. 
Safety endpoints include the incidence of adverse events, serious adverse events, laboratory safety 
tests (hematology, clinical chemistry, and urinalysis), and ECOG performance. 
3.2 
Secondary 
Measurement of the secondary endpoints is based on RECIST v1.1 criteria. 
§ Time to response (TTR) is defined as time from first dose of study treatment (Study Day1) to 
first response (CR or PR) 
§ Complete response rate (CRR) is defined as the proportion of subjects demonstrating CR 
§ Duration of response (DoR) is defined as the time from the first documented evidence of CR 
or PR until time of documented disease progression (PD) or death due to any cause, whichever 
is first 
o For responders who are lost to follow-up or who discontinue study before PD or 
death, DoR will be censored at the date of last radiological assessment 
§ Progression-free survival (PFS) is defined as: 
o Time from Study Day 1 until PD or death due to any cause, whichever occurs first 
o For subjects who are lost to follow-up or who discontinue study before PD or death, 
PFS will be censored at the date of the last radiological assessment 
§ Overall survival (OS) is defined as: 
o Time from Study Day 1 until date of death due to any cause 
o For subjects who have not died or who are lost to follow-up or withdrew consent, OS 
will be censored at the date of last contact 
§ Pharmacokinetic profile 


Page 3 
3.3 
Exploratory 
§ ORR, as defined by irRECIST 
§ PFS, with date of PD as defined by irRECIST 
The following exploratory analyses will be conducted to examine the relationship between 
biomarker data and endpoints if the data warrants: 
§ Analysis of ABA and endpoints 
§ Analysis of change in the immune cell activation markers and endpoints 
§ Analysis of change in the tumor immune microenvironment and endpoints 
4 
STUDY DESIGN 
This is a Phase 2 study of Imprime PGG and pembrolizumab in subjects with advanced melanoma 
failing front-line treatment with checkpoint inhibitors or TNBC failing front-line chemotherapy for 
metastatic disease. 
The study design is based on hypothesis testing of the ORR for pembrolizumab + Imprime PGG. 
For melanoma subjects, the null hypothesis is ORR ≤ 5%, versus the alternative hypothesis of ORR 
≥ 23%; for the TNBC subjects, the null hypothesis is ORR ≤ 5% (ORR=5% in KEYNOTE-086), 
and the alternative hypothesis is ORR ≥ 21%. Hypotheses testing will be conducted using a one-
sided type I error of 0.05. 
The study will incorporate Simon’s optimal 2-stage design with sample size fixed at 12 subjects 
each in Stage 1 for advanced melanoma and for TNBC subjects. The safety criterion of ≤ 4 (or ≤ 
33%) subjects with Grade 3/4 adverse events in Cycle 1 within either tumor type must be met in 
order to proceed to Stage 2 (Grade 3/4 infusion reactions which occur during Cycle 1 that either 
resolve or decrease to Grade 1/ 2 and recur in Cycle 2, will not be counted towards the total of > 4). 
The starting dose is 4 mg/kg for Imprime PGG. In the event there are a total of > 4 (or > 33%) of 
subjects with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced to 2 
mg/kg, and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of n=12 
subjects. For the dose that meets the safety criterion in Stage 1, at least 1 response in melanoma 
subjects and 1 response in TNBC subjects amongst the 12 subjects within each tumor type must be 
observed in order to proceed to Stage 2. Stage 2 will enroll an additional 17 subjects with 
melanoma, and 29 subjects with TNBC. For the dose that meets the Stage 1 safety criterion, 
success will be declared if at least 4 amongst the total of up to 29 subjects with melanoma, and 5 
amongst the total of up to 41 subjects with TNBC achieve an objective response. The above design 
corresponds to a type I error 0.05 and power of 90% for both melanoma and TNBC. 
The dosing schedule and the study assessments are presented in the schedule of assessment in the 
protocol. 


Page 4 
All subjects will receive Imprime PGG and pembrolizumab. Imprime PGG will be administered IV 
at a dose of 4 mg/kg over a 2-hour infusion time period on Day 1, Day 8, and Day 15 of each 3-
week cycle for subjects at stage 1. If Stage 1 proceeds without safety concerns necessitating a 
second cohort at 2 mg/kg, Imprime PGG will be administered to the Stage 2 subjects at a dose of 4 
mg/kg IV over a 2-hour infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. If 
enrollment into an additional cohort for 2 mg/kg in Stage 1 is required and dosing proceeds to 
Stage 2, Imprime PGG will be administered in Stage 2 at a dose of 2 mg/kg IV over a 2-hour 
infusion time period on Day 1, Day 8, and Day 15 of each 3-week cycle. The pembrolizumab fixed 
dose of 200 mg will be administered IV over 30 minutes on Day 1 of each 3-week treatment. 
Subjects will be dosed until disease progression, death, 2 years of treatment or study completion, 
whichever occurs first. After treatment discontinuation, subjects will be monitored every 2 months 
for survival until death or study completion. Study completion is defined as the death of at least 
70% of subjects or 3 years after the last subject’s first dose, whichever occurs earlier. 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR, 
who have been treated for at least 24 weeks, and who had at least 2 treatments with study 
medications beyond the date when the initial CR was declared. Subjects who then experience 
radiographic disease progression may be eligible for up to 1 year of additional treatment with 
Imprime PGG + pembrolizumab at the discretion of the Investigator if: 
• No cancer treatment was administered since the last dose of pembrolizumab 
• The subject meets the safety parameters listed in the Inclusion/Exclusion criteria 
• The trial is open 
 
Subjects will resume therapy at the same dose and schedule at the time of initial discontinuation. 
Response or progression in this resumed course of therapy will not count towards the ORR of the 
primary endpoint in this trial. 
5 
PLANNED ANALYSES 
5.1 
Interim Analyses 
An informal interim analysis was conducted at the end of Stage 1 to assess the safety criterion for 
each tumor type and confirm the dose of Imprime PGG before continuing enrollment in Stage 2. 
Overall response rate based on RECIST 1.1 and adverse events including Grade 3/4 adverse events 
were considered for decision-making. Safety data will be summarized periodically throughout the 
study as part of ongoing safety review. 
5.2 
Primary Analyses 
The primary analyses for the melanoma and TNBC subjects will be conducted when all subjects 
have completed the treatment phase of the study. All data will be included in the primary analyses 
and each tumor type will be analyzed separately. 
5.3 
Final Analysis 
The final analysis will be conducted after study completion. Study completion is defined as the 
death of at least 70% of subjects or 3 years after the last subject’s first dose, whichever occurs 
earlier. Overall survival data will be included in the final analysis. 
6 
ANALYSIS POPULATIONS 


Page 5 
The ABA pre-screening population will comprise all subjects who have been pre-screened for 
ABA test only (who have signed the ABA informed consent form but not the full informed consent 
form). 
The Screening population will comprise all subjects who have been screened for the study (who 
have signed the full informed consent form). 
The All Treated population will comprise all subjects in the Screening population who receive at 
least one dose of study treatment. The All Treated population will be the primary population for the 
baseline characteristics and safety analysis and the secondary population for the efficacy analysis. 
The Evaluable population will comprise all subjects in the All Treated population who 1) have 
measurable disease at baseline per RECIST 1.1, AND 2) have at least one post-baseline 
radiological disease assessment, or discontinue study treatment as a result of progressive disease, 
death, or a treatment-related adverse event before the first post-baseline radiological disease 
assessment. The Evaluable population will be the primary population for the efficacy analysis. 
The Per-Protocol population will comprise all subjects in the All Treated population who do not 
have any important protocol deviations (IPD) as defined in the study IPD list. The Per- Protocol 
population will be the tertiary population for the efficacy analysis. 
In the Screening population, subjects who do not meet eligibility criteria will be defined as screen 
failures, and subjects who meet all eligibility criteria but do not receive any study treatment will be 
defined as non-treated subjects. The Screening population will comprise of All Treated subjects, 
non-treated subjects, and screen failure subjects. 
Limited data will be collected for the ABA pre-screening population and the non-treated subjects 
and screen failure subjects in the Screening population. Summaries of these data may be produced: 
• ABA Pre-screening population: ABA level at screening, demography, inclusion/exclusion, 
adverse event (if any), concomitant medication (if any) and death data will be collected; 
• Screen failure subjects: ABA level at screening, demography, inclusion/exclusion, adverse 
event (if any), concomitant medication (if any) and death data will be collected; 
• Non-treated subjects: ABA level at screening, all other data that are planned to be collected 
at screening for All Treated subjects, adverse event (if any), concomitant medication (if 
any), death (if any) and end of study record will be collected. 
7 
TREATMENT COMPARISONS 
As this is a single arm study for each tumor type, the primary endpoint ORR is compared against 
the historical control ORR as defined in the null hypothesis. The primary objective will be achieved 
through a test of the hypotheses evaluating ORR in the Evaluable population using a one-sided 
alpha level of 0.05. 
8 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Clinical Data Interchange Standard Consortium (CDISC) Study Data Tabulation Model (SDTM) 
and Analysis Data Model (ADaM) will be used for the primary and final data analyses. 


Page 6 
Data analysis will be conducted separately for the melanoma and the TNBC tumor types. 
Summary tables/figures will be provided separately for the melanoma and the TNBC tumor type, 
and all summary tables will be produced by dose level (if there are >1 dose levels for a tumor type). 
Listings will be provided with both tumor types being included in one listing, and all listings will 
be sorted by cancer type (melanoma then TNBC), site ID, subject ID, and then by visit date and 
time. 
All analyses will be performed using SAS® Version 9.4 or higher. Continuous variables will be 
summarized with number of subjects (n), mean, median, standard deviation, minimum and 
maximum, and categorical variables will be summarized with frequency counts and percentages. 
In the event that the study is prematurely discontinued, all available data will be listed and a review 
will be carried out by the study team to assess which statistical analyses are still considered 
appropriate. 
Deviations from the planned analyses in the SAP will be identified in the study report. 
8.1 
Multicenter Study 
It is anticipated that subject accrual will be spread thinly across sites and summaries of data by site 
would be unlikely to be informative, therefore the data from all participating sites will be pooled 
prior to the analysis. 
8.2 
Examination of Subgroups 
The following subgroups may be explored in the efficacy analysis for the melanoma subjects if the 
subgroups are large enough to result in meaningful analyses: 
• IgG anti-β-glucan antibody (higher vs lower at baseline) 
• Previous anti-CTLA-4 inhibitor (ipilimumab) treatment (Yes vs No) 
• PD-L1 expression (if sample analyses are run) 
• Number of prior systemic regimens for metastatic disease 
• ECOG performance (0 vs 1) 
• BRAF V600 mutation 
• Prior BRAF or MEK inhibitor 
• LDH level (normal vs elevated at baseline) 
• Liver metastasis (Yes vs No at baseline) 
 
The following subgroups may be explored in the efficacy analysis for the TNBC subjects if the 
subgroups are large enough to result in meaningful analyses: 
• IgG anti-β-glucan antibody (higher vs lower at baseline) 
• PD-L1 expression (if sample analyses are run) 
• Number of prior systemic regimens for metastatic disease 
• Prior hormone therapy (Yes vs No; number of regimens) 
• ECOG performance status (0 vs 1) 
• LDH level (Normal vs elevated at baseline) 
• Liver metastasis (Yes vs No at baseline) 
 


Page 7 
Additional subgroups may be explored for efficacy data analysis if needed. 
9 
DATA HANDLING CONVENTIONS 
9.1 
Premature Withdrawal and Missing Data 
For all subjects, all data up to the time of completion of study participation will be included in the 
analysis, regardless of duration of treatment or follow-up. 
Missing data occurs when any requested data is not provided leading to blank field on the 
collection instrument. These data will be indicated by a dash in the subject listing displays. 
Answers such as “Not applicable” and “Not evaluable” are not considered to be missing data and 
should be displayed as such. 
9.1.1 Missing Data in Objective Response 
When determining the percentage of responders (CR or PR), subjects with unknown or not 
evaluable or missing best overall response will be assumed to be non-responders, and will be 
included in the denominator when calculating the percentage. 
9.1.2 Missing Data in Adverse Event 
Subjects with missing data with regard to the designation of treatment relationship for adverse 
events and serious adverse events will have the worst-case assumed to impute the relationship: if 
relationship to study treatment is missing it will be assumed to be “Yes”. 
9.2 
Derived and Transformed Data 
The following sections provide a general description of the derived and transformed variables that 
are used to describe and analyze the data. 
9.2.1 Reference Dates 
The reference date for age is the date of informed consent form signed. 
The efficacy and safety reference date are the date of the first dose of study treatment, and will be 
used to calculate the study day for study measurements/assessments and baseline characteristics 
(such as time since the most recent recurrence or progression). If the date of interest occurs on or 
after the reference date, then the study day will be calculated as (date of interest - reference date 
+ 1). If the date of interest occurs before the reference date, then the study days will be calculated 
as (date of interest – reference date). 
9.2.2 Duration and Elapsed Time 
Durations (e.g., the duration of an adverse event, duration on study treatment, etc.) are calculated as 
the stop date minus the start date plus one. 
For elapsed time (e.g., the time since most recent recurrence or progression), if the reference date is 
on or after the event date, then the elapsed time is calculated as the reference date minus the event 
date + 1. 
When reporting OS and PFS in months, divide the number of days by 30.4375; to report in weeks 
divide the number of days by 7; to report in years divide the number of days by 365.25. The "year" 
used in these algorithms is 365.25 days long, and the "month" is one-twelfth of that year. 


Page 8 
9.3 
Imputation of Partial Dates 
Partial dates in selected datasets as specified below will be imputed. Imputed partial dates will not 
be used to derive the study day, duration (e.g., duration of adverse events), or elapsed time 
variables. However, imputed dates may be used as temporary variables for the purpose of sorting 
data in the listings. In addition, partial dates may be imputed for ‘slotting’ data to specific study 
time periods. Imputed dates will not be displayed in the listings. 
The partial date will be included in the dataset with the imputed date and a flag variable to indicate 
the level of imputation. The flag variable can contain the values: blank and 'D'. 
Blank: indicates that no imputation is done 
D='Day': indicates that the day portion of the date is imputed 
Start dates for the new anti-cancer therapy after the study treatment discontinuation will be 
temporarily imputed in order to define the event and censoring rules for PFS and duration of 
response. Dates will only be imputed when a month and year are available but the day is missing. 
The following rules will be used to impute the date when partial start dates are present on the post-
treatment new anti-cancer therapy dataset: 
Table 1: Rules for Imputation of Partial Dates 
Dataset 
Date 
Missing Element Rule 
Anti-Cancer 
Therapy 
Start Date day, 
month, 
and year 
No Imputation for completely missing dates 
day, month 
No imputation for missing day and month 
day 
If the partial date falls in the same month as the last dose of the 
study treatment, then assign to earlier of (date of last dose of 
study treatment+1, last day of month). 
 
If the partial date falls in the same month as the subject’s last 
radiological disease assessment and the subject’s last 
assessment is PD, then assign to earlier of (date of PD+1, last 
day of month). 
 
If both rules above apply, then assign to the later of the 2 dates. 
 
If the partial date falls in the months after the month of last dose 
of study treatment or last radiological assessment of PD, impute 
the missing day to the first day of the month. 
 
9.4 
Baseline Definition 
Baseline will be defined as the most recent, non-missing value prior to or on the day of the first 
dose of study treatment (prior to first dose). 
9.5 
Multiple Assessments 
For any summary by visit, all data will be reported according to the scheduled visit date for which 
it is reported (that is, no visit windows will be applied during dataset creation). Data from the 
unscheduled visit will only be included in the summary that report worst-case or best-case post-
baseline. All data from the scheduled visits and the unscheduled visits will be included in the 
listings. 
10 STUDY POPULATION 


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Unless stated otherwise, all tables and listings in this section will be produced using the All Treated 
population. Summary tables for study population data will be provided separately for the melanoma 
and the TNBC tumor subjects, and all summary tables will be produced by dose level (if there are 
>1 dose levels). Listings will be provided with both tumor types being included in the listing, and 
all listings will be sorted by tumor type (melanoma then TNBC), center, subject ID, and then by 
visit date and time. 
The list of displays for the study population data is shown in Section 15.1. 
10.1 Disposition of Subjects 
A summary of the number of subjects in the All Treated, Evaluable and Per-Protocol populations as 
well as the subgroups of subjects as defined in Section 8.2 will be provided. A listing of subjects 
excluded from the Evaluable and Per-Protocol population will be provided. 
Using the ALL Treated population, summary of study treatment status will be provided for each 
drug. This display will show the number and percentage of subjects who are still receiving study 
treatment or who have discontinued study treatment, and a summary of reasons for study treatment 
discontinuation. A listing of study drug discontinuation will be generated for each study drug. The 
listing will include the date of last dose for each study drug, and reasons for study drug 
discontinuation. 
A summary of subject end of study status will be provided. This display will show the number and 
percentage of subjects who have died or are alive at time of study discontinuation, and reason for 
study discontinuation. A listing of subject end of study status will be provided for the ALL Treated 
population. 
If there are subjects who have discontinued study treatment after complete response and then re- 
entered the study to continue study treatment after meeting protocol specified criteria, a listing of 
disease characteristics at time of re-entry will be provided for these subjects. 
10.2 Protocol Deviations 
All important protocol deviations including inclusion/exclusion criteria deviations and other 
deviations will be summarized and listed. A separate summary and listing will be provided for the 
inclusion/exclusion criteria deviations. 
For the efficacy and safety analysis based on the All Treated population, deviations will not impact 
analyses nor result in subject exclusion from the All Treated population. 
10.3 Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, and baseline weight) will be 
summarized for the All Treated, Evaluable and Per-Protocol populations. Age and weight will be 
summarized using the mean, standard deviation, minimum, median, and maximum. The count and 
percentage will be computed for sex, race and ethnicity. Listing of demographic characteristics will 
be provided for the melanoma and TNBC subjects in the ALL Treated population. Listing of 
demography data also will be provided for the screen failure and non- treated subjects in the 
Screening population and the ABA Pre-screening population. 


Page 10 
Cancer history and characteristics including date of initial diagnosis, date of the first presentation 
with distant metastatic disease, date of the most recent disease progression, stage at enrollment, M 
stage, N stage and overall staging, and BRAF V600 mutation status and C-kit mutation status for 
melanoma subjects and inflammatory breast cancer status for TNBC subjects will be listed. 
Summary of cancer history and disease characteristics will be provided for the All Treated, 
Evaluable and Per-protocol population. 
Prior cancer therapy will be listed for each subject. A summary of the number of prior anti- cancer 
therapy regimens for advanced or metastatic disease will be produced for the All Treated, 
Evaluable and Per-protocol population. Prior therapy regimens with intent as palliative or 
maintenance will be reviewed by clinical team to determine if these regimes are for metastatic 
disease. 
Medical history will be listed. 
10.4 Concomitant Medications 
Prior and concomitant medications including pre-medication will be coded using the WHO Drug 
dictionary. Prior medications include medications that were taken prior to the first dose of the study 
drug. Any medication used on or after the first dose of study drug during the course of the study 
will be considered a concomitant medication. Pre-medications include medications that are taken 
prior to study drug infusion such as standard anti-histamine medications. Concomitant medications 
will be summarized by anatomic therapeutic chemical classification (ATC) level 1 and preferred 
term. Pre-medication will be summarized by preferred term. 
Listing of prior and concomitant medications will be provided for the melanoma and TNBC 
subjects in the All Treated population. A separate listing of pre-medications will be provided for 
the All Treated population. 
10.5 Post Study Treatment Cancer Therapies 
Post study treatment cancer therapy along with start date will be listed. 
11 EFFICACY ANALYSIS 
The primary efficacy population will be the Evaluable population, the secondary efficacy 
populations will be the All Treated, and the tertiary efficacy population will be the PP population. 
Efficacy data will be summarized separately for each tumor type. Listings of efficacy data will 
include both tumor types. Unless stated otherwise, all listings in this section will be produced using 
the All Treated population. 
The definition efficacy endpoints are based on US Food and Drug Administration Guidance for 
Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 2007. 
The list of displays for efficacy analysis is shown in Section 15.2. 
11.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the overall response rate (ORR), which is defined as the 
proportion of subjects demonstrating complete response (CR) or partial response (PR) based on 
RECIST1.1. 


Page 11 
The evaluation of response based on RECIST 1.1 will be performed at baseline and then at 6- week 
intervals beginning at week 6. The best response is the best response recorded from the start of 
study treatment until the first disease progression based on RECIST1.1 or start of new cancer 
therapy, whichever occurs earlier. The best response will be determined programmatically based on 
the investigator’s assessment of response at each time point, using the following rules: 
Table 1 
Best Overall Response When Confirmation of Complete Response and Partial Response is Required 
Overall Response 
First Timepoint 
Overall Response 
Subsequent 
Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration was met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration was met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration was met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration was met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration was met, otherwise, NE 
NE 
NE 
NE 
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should 
be changed to PR and the best response is PR. 
CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable disease. 
Note: the minimum criteria for SD is the interval of 5 weeks (35 days). 
 
As further clarification: 
• 
To be assigned CR or PR as the best response, it must be confirmed no less than 4 weeks 
(28 days) from the time of the initial CR or PR; 
• 
If a best response of CR or PR cannot be established, stable disease (SD) can be assigned 
as a best response if the SD assessment is at least 5 weeks [35 days] after the first dose of 
study treatment (Note: a minimum interval of 5 weeks was chosen because tumor imaging 
is scheduled every 6 weeks +/- 1 week). 
• 
If the CR is not confirmed, and a best response of PR can not be established, then the best 
response will be SD if the CR, PR, or SD assessment is at least 5 weeks after the first 
dose of study treatment. 
• 
If the PR is not confirmed, and a best response of CR can not be established, then the best 
response will be SD if the CR, PR or SD assessment is at least 5 weeks after the first dose 
of study treatment. 


Page 12 
• 
If the CR or PR is not confirmed, and the assessment date does not meet SD criteria (a 
minimum interval of 5 weeks after the first dose of study treatment), then the best 
response will depend on the subsequent assessments: if an assessment of PD follows CR 
or PR, then the best response will be PD; if subjects are lost to follow up after only one 
CR or PR assessment, then the best response will be considered as NE.  
• 
If the SD assessment is less than 5 weeks after the first dose of study treatment and a best 
response of CR and PR could not be established, the best response will depend on the 
subsequent assessments: if an assessment of PD follows the SD, then the best response 
will be PD; if subjects are lost to follow up after the SD assessment, then the best response 
will be considered as NE. 
• 
PD is considered the best response when PD is documented and a best response of CR, 
PR, or SD could not be established. Clinical progression alone in the absence of 
radiological confirmation is not a progression event in this analysis. 
• 
NE is considered the best response when PD has not been documented and a best response 
of CR, PR, or SD could not be established. 
 
Specifically, overall response rate = (number of subjects with a best response of confirmed CR or 
PR) divided by the total number of subjects in the corresponding analysis population; complete 
response rate (CRR) = (number of subjects with a best response of confirmed CR) divided by the 
total number of subjects in the corresponding analysis population; and disease control rate (DCR) 
= (number of subjects with a best response of confirmed CR, confirmed PR or SD) divided by the 
total number of subjects in the corresponding analysis population. Subjects with not evaluable, 
unknown or missing best response will be treated as non-responders, i.e. they will be included in 
the denominator when calculating the percentage. 
For all assessments after the baseline visit, if tumor imaging for the target lesion, non-target lesion 
and new lesion are done in different dates for a scan visit, the date of response will be assigned as 
following: 
• If the overall response is CR/PR, the date of CR/PR response will be the latest date; 
• If the overall response is SD, the date of SD response will be the latest date; 
• If the overall response is PD, the date of PD response will be the earliest date among the 
new lesion, PD for target lesion or PD for non-target lesion; 
 
The best response will be summarized for the Evaluable, All Treated and Per-Protocol populations. 
In the summary, the ORR, CRR and DCR along with the number (%) of subjects with the best 
overall response of CR, PR, SD, PD, and NE will be included, and an exact 95% confidence 
interval will be computed for the ORR, CRR, and DCR. Summary of ORR will also be provided 
for each subgroup as defined in Section 8.2. A summary of DCR at ≥24 weeks may also be 
presented. 
For target lesions, sum of lesion diameters (SLD) will be calculated as the sum of shortest axes for 
lymph node target lesions and longest diameters for solid tumor target lesions at each visit. For 
target lesions lesion for which lesion diameter is missing and reported as too small to be measured, 
the lesion diameter will be set as 5mm for the SLD calculation. New lesions will NOT be included 
in the target lesion SLD calculation. 


Page 13 
A summary of disease burden at baseline will be produced for the Evaluable, All Treated and Per-
Protocol population, which will include measurable disease status, SLD for target lesions, and 
location of disease at specific sites. 
The maximum percent reduction from the baseline SLD will be plotted for the Evaluable and All 
Treated population. The maximum percent reduction is defined as the maximum reduction from the 
baseline SLD until the first disease progression or start of new anti-cancer therapy, whichever 
occurs earlier. In the plot of maximum reduction from baseline SLD, horizontal lines at 30% and 
20% will be provided. 
Listings of assessment based on RECIST 1.1 will be provided for the ALL Treated population. 
Listing of response will include the target lesion response along with SLD percent change from 
baseline and SLD percent change from nadir, non-target lesion response, new lesion and overall 
response at each visit, and the best overall response for each subject. For each post-baseline visits, 
the nadir SLD for target lesions is defined as the smallest SLD among all prior visits (this includes 
baseline visit). 
Target lesion assessments and non-target lesion assessments will be listed separately. Clinical 
progression based on investigator assessment will also be listed. 
11.2 Secondary Efficacy Analysis 
Secondary efficacy endpoints include the time to response, CRR, DoR, PFS and OS. 
11.2.1 Time to Response 
For the subset of subjects who show a confirmed CR or PR (RECIST 1.1), time to response is 
defined as time from the date of the first dose to the first response (the CR/PR prior to the 
confirmation). The Kaplan-Meier method will be used to summarize time to response descriptively 
and graphically. The median and the first and third quartiles will be presented, along with 
approximate 95% confidence intervals. Brookmeyer-Crowley method will be used for the 
confidence interval calculation. Time to response will also be summarized descriptively by planned 
assessment times (week 6, week 12, etc.). Time to response will be summarized for the Evaluable, 
All Treated and PP population, respectively. The Kaplan-Meier Plot of time to response will be 
provided for the Evaluable population. 
11.2.2 Complete Response Rate 
Complete response rate analysis is described in section 11.1. 
11.2.3 Duration of Response 
For the subset of subjects who show a confirmed CR or PR (RECIST 1.1), DoR is defined as the 
time from the first documented evidence of CR or PR (the response prior to the confirmation) until 
the time of documented disease progression or death due to any cause, whichever occurs earlier. 
Disease progression will be based on radiological assessments RECIST 1.1. Subjects who do not 
meet the RECIST 1.1 criteria for progression or die will be censored. Censoring rules for this 
analysis will follow those of the PFS based on radiological assessment as defined in Section 11.2.4. 


Page 14 
The Kaplan-Meier method will be used to summarize DoR descriptively and graphically. The 
Kaplan-Meier estimate for the median, first and third quartiles will be determined along with 95% 
confidence intervals (CI). The Brookmeyer-Crowley method will be used for confidence interval 
calculation. Summary of DoR will be provided for the Evaluable, All Treated and PP population, 
respectively. The Kaplan-Meier Plot of DoR will be provided for the Evaluable and All Treated 
population. Listing of DoR will be provided for the All Treated population. 
11.2.4 Progression Free Survival 
Progression-free survival is defined as the time from the date of the first dose until the first 
progressive disease or death due to any causes whichever occurs first. PFS based on radiological 
assessment RECIST 1.1 is defined as the time from the first dose until the earlier date of 
radiological PD based on investigator radiological assessment (RECIST 1.1) or death; and PFS 
based on radiological RECIST 1.1 and clinical assessment is defined as the time from the first dose 
until the earliest date of PD based on radiological assessment (RECIST 1.1), PD based on clinical 
assessment, or death. For subjects who have neither progressed nor died, PFS will be censored at 
the date of the last adequate assessment of CR, PR or SD before the start of new anti-cancer 
therapy. 
PFS will be analyzed with censoring for the extended loss to follow-up to account for two or more 
missed radiological assessments before PFS events (PD or death). Specifically, if there are two or 
more scheduled assessments that are missing or not evaluable followed by PD or death, PFS will be 
censored at the last adequate assessment of CR, PR or SD prior to the PD or death. In this study, 
the radiological assessment scheduled is every 6 weeks. If the time difference between the PD or 
death and the last adequate assessment of CR, PR or SD is more than 2 times scheduled time plus 
14-day window, the PFS will be censored at the last adequate assessment prior to the PD or death. 
For example, a window of 98 days (12 weeks + 14 days window) will be used to determine 
whether there is an extended loss to follow-up. 
For subjects who receive post-treatment new anti-cancer therapy, the following rules will apply: 
• If an anti-cancer therapy is started without documented disease progression or is started prior 
to documented disease progression, then PFS will be censored at the date of the last adequate 
assessment of CR, PR or SD that is no later than the date of initiation of anti-cancer therapy 
(i.e. if an assessment occurs on the same day as the start of new anti-cancer therapy, the 
assessment will be used as it will be assumed that the assessment occurred prior to the 
administration of new anti-cancer therapy). 
• If a subject has only a baseline visit or does not have any adequate assessment of CR, PR, 
SD or PD that is no later than the date of initiation of anti-cancer therapy, PFS will be 
censored at the date of the first dose. 
 
A summary of the assignments for event and censoring dates for PFS are specified in the following 
Table 3. 
Table 2: Assignments for Event and Censoring Dates for PFS Analysis 
Situation 
Date of Event (PD/Death) or Censoring 
Outcome 
No (or inadequate) baseline tumor assessments and the 
subject has not died (if the subject has died follow the rules 
for death indicted at the bottom of the table) 
Date of the first dose 
Censored 


Page 15 
Situation 
Date of Event (PD/Death) or Censoring 
Outcome 
No adequate post-baseline assessments of CR, PR, SD or 
PD, and the subject has not died (if the subject has died 
follow the rules for death indicted at the bottom of the 
table) 
Date of the first dose 
Censored 
Progression 
documented 
before death 
or 
without death 
Date of assessment of progression 
Event 
No progression (or death) 
Date of last adequate assessment of CR, PR 
or SD (on or prior to starting new anti-cancer 
therapy) 
Censored 
New anti-cancer  treatment starting prior to documented 
disease progression 
Date of last adequate assessment of CR, PR 
or SD (on or prior to starting new anti-cancer 
therapy) 
Censored 
Death before assessment of PD or before any adequate 
assessment of response 
Date of death 
Event 
PD or death after missing one scheduled assessment 
Date of PD or death 
Event 
PD or death after missing two or more scheduled 
assessments 
Date of last adequate assessment of response 
of CR, PR or SD (prior to the missed 
assessments) 
Censored 
 
The primary analysis of PFS will be based on the radiological assessment, and the sensitivity 
analysis of PFS will be based on the radiological and clinical assessment. The PFS based on 
radiological assessment and PFS based on the radiological and clinical assessment will be 
summarized descriptively using the Kaplan-Meier method for the Evaluable, All Treated and PP 
populations. The Kaplan-Meier estimate for the median, first and third quartiles will be determined 
along with 95% confidence intervals (CI). The Brookmeyer-Crowley method will be used for the 
conference interval calculation. The Kaplan-Meier estimate of PFS rate at landmark times 
including but not limited to 3, 6, 9 and 12 months will be summarized. The Kaplan-Meier Plot of 
PFS will be provided for the Evaluable and All Treated population. Listing of PFS will be provided 
for the All Treated population. 
11.2.5 Overall Survival 
The overall survival is defined as the time from the date of the first dose until the date of death due 
to any causes. For subjects who have not died or who are lost to follow-up or withdraw consent, OS 
will be censored at the date of the last contact. 
The overall survival will be summarized descriptively using the Kaplan-Meier method for the 
Evaluable, All Treated and PP populations. The Kaplan-Meier estimate for the median, first and 
third quartiles will be determined along with 95% confidence intervals (CI). The Brookmeyer- 
Crowley method will be used for the confidence interval calculation. The Kaplan-Meier estimate of 
OS rate at landmark times including but not limited to 3, 6, 9, 12, 18, and 24 months will be 
summarized. The overall survival will also be summarized by status of post study treatment new 
anti-cancer therapy (Yes or No) for the All Treated population. The Kaplan-Meier Plot of OS will 
be provided for the Evaluable and All Treated population. Listing of OS will be provided using the 
All Treated population. 
11.3 Exploratory Efficacy Analysis Based on irRECIST 
Exploratory efficacy analysis based on irRECIST may be run, including but not limited to  analysis 
of ORR and PFS based on irRECIST. The irRECIST will be performed to confirm PD once PD is 
determined based on the RECIST 1.1. The following are scenarios where PD is confirmed based on 
irRECIST: 


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• Target lesions resulting in initial PD remains ≥ 20% and at least 5 mm absolute increase 
compared to nadir sum of lesion diameters 
• New PD due to target lesions sum of lesion diameters ≥ 20% and at least 5 mm absolute 
increase compared to nadir 
• Non-target lesions resulting in initial PD is worse (qualitative) 
• New unequivocal PD of non-target lesions 
• New lesion resulting in initial PD is worse (qualitative) 
• Additional new lesion(s) since last evaluation 
 
The PD confirmation status based on irRECIST will be collected in the CRF. 
 
11.3.1 ORR Based on irRECIST 
The best response based on irRECIST is the best response recorded from the start of study treatment 
until the disease progression (the PD per RECIST1.1 or the PD confirmed by irRECIST, whichever 
is later) or start of new anti-cancer therapy, whichever occurs earlier. The best response will be 
determined programmatically in the same way as the best response based on RECIST 1.1 (Section 
11.1) except the following:   
 
• 
Confirmed PD is considered the best response when PD is documented and confirmed by irRECIST and 
a best response of CR, PR, or SD could not be established before documentation of PD. Clinical 
progression alone in the absence of radiological confirmation is not a progression event in this analysis.   
 
• 
Unconfirmed PD is considered the best response when PD is documented but not confirmed and a best 
response of CR, PR, or SD could not be established before documentation of PD. Unconfirmed PD will 
be further categorized as PD with further assessment but not confirmed by irRECIST vs PD without 
further assessment to confirm.  
 
The best response based on irRECIST will be summarized for the Evaluable, All Treated and Per-
Protocol populations. Calculation of ORR and CRR based on irRECIST are the same as those based 
on RECIST 1.1 in Section 11.1.  In the summary, ORR, CRR, DCR, the number (%) of subjects 
with the best overall response of CR, PR, SD, confirmation PD, unconfirmed PD, and NE will be 
included, and an exact 95% confidence interval will be computed for the rates of ORR, CRR and 
DCR.  
 
Listing of PD based on RECIST 1.1 and whether PD is confirmed by irRECIST at next visit will be 
provided.  
 
11.3.2. PFS Based on irRECIST 
Progression-free survival based on irRECIST is defined as the time from the date of the first dose 
until the PD or death due to any cause, whichever occurs first. The determination of PD as PFS 
event will be as following: 


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• For subjects with confirmed PD, the first PD (prior to the confirmation) that is confirmed by 
irRECIST will be the PFS event; 
• For subjects with PD but not confirmed by irRECIST and no further disease assessment after 
the last unconfirmed PD, the last unconfirmed PD will be the PFS event. 
 
For subjects who have neither progressed nor died, PFS will be censored at the date of the last 
adequate assessment of CR, PR or SD on/prior to the start of new anti-cancer systemic therapy and 
before missed visits (if 2 or more scheduled assessments are missed). Assignment of event and 
censoring date is similar with those of the PFS based on radiological assessment RECIST 1.1 (as 
defined in Section 11.2.4) with the exception that PD is determined differently for subjects with 
confirmed PD and subjects with unconfirmed PD as stated above. 
The PFS based on irRECIST will be summarized descriptively and graphically using the Kaplan- 
Meier method for the Evaluable, All Treated and PP populations. The Kaplan-Meier estimate for 
the median, first and third quartiles will be determined along with 95% confidence intervals. The 
Brookmeyer-Crowley method will be used for the conference interval calculation. The Kaplan- 
Meier estimate of PFS rate at landmark times including but not limited to 3, 6 and 12 months will 
be summarized. The Kaplan-Meier Plot of PFS will be provided for the Evaluable and All Treated 
population. Listing of PFS based on irRECIST will be provided for the All Treated population. 
 
11.4 Exploratory Efficacy Analysis Based on Biomarker Data 
Exploratory efficacy analysis will be conducted with the biomarker data including, but not limited 
to the following: 
• Correlate levels of baseline serum anti-β-glucan antibody (ABA) with objective response 
and treatment outcomes; 
• Correlate changes in immune cell activation markers with objective response and treatment 
outcome; 
• In tumor biopsies, correlate changes in the tumor immune microenvironment including 
TILs (Tumor-infiltrating Lymphocytes) and tumor-infiltrating myeloid cells with objective 
response and treatment outcome; and/or 
• Correlate PD-L1 expression in tumor biopsy samples (in tumor cells and myeloid cells) 
with objective response and treatment outcome. 
 
Due to the exploratory nature of the analysis, the list of tables and figures for the efficacy analysis 
with biomarker data will be determined after conducting the analysis. 
12 SAFETY ANALYSIS 
Safety measurements include adverse events, serious adverse events, death, ECOG performance 
status, laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis), vital signs, 
physical examination, and ECG measurements. Unless stated otherwise, all safety analyses will be 
based on the All Treated population, and will be conducted separately for each tumor type. Listings 
of safety data will include both tumor types. 


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12.1 Study Treatment Administration 
A listing of the individual Imprime PGG infusion data will be provided. The individual Imprime 
infusion data will include the date of administration, start and end time of infusion, total infusion 
time, actual dose (2 mg/kg or 4 mg/kg), total dose based on weight (actual dose times body 
weight), total dose received, total infusion volume, infusion rate (volume infused per minute), pre-
medication status, details about infusion interruption (including interrupted time, restarted time, 
total interrupted time, and reason for infusion not restarted after interruption), any dose 
modifications including dose delayed/interrupted, and dose reduced, and reasons for dose 
modifications. 
A listing of the individual pembrolizumab infusion data will be provided. The individual 
pembrolizumab data will include the date of administration, actual dose (200mg), actual dose 
received, total infusion volume, start and end time of administration, total infusion time, pre-
medication status, details about infusion interruption (including interrupted time, restarted time, 
total interrupted time, and reason for infusion not restarted after interruption), and dose 
delay/interruption along with reasons. 
Summary of cycles/days on study treatment and number of doses received will be provided for 
Imprime PGG and pembrolizumab infusion. Cycles and days on study treatment are defined as the 
number of cycles or days from the first dose of any study drugs until the last dose of any study 
drugs. As subjects may discontinue study treatment at any day of last cycle, receiving at least one 
dose of any study drug in the last cycle will be counted as one cycle for the calculation of cycles on 
study treatment. 
Dose modifications including dose delayed/interrupted, dose reduced (Imprime PGG only), 
infusion rate reduced (Imprime PGG only) will be summarized. For each type of dose modification, 
the number of subjects with dose modification, total number of dose modifications and reasons for 
dose modifications will be summarized, in which the total number of dose modifications is 
calculated across all subjects with dose modifications. For example, if a subject has two dose 
delay/interruptions for Imprime PGG, then this subject will be counted 2 times while calculating 
the total number of dose delay/interruptions. For reasons of dose modifications, the total number of 
dose modification events will be used as denominator for the percent calculation. 
12.2 Adverse Events 
All subjects will be assessed regularly for the potential occurrence of adverse events (AEs) from 
the date of informed consent to 30 days after the last dose of study drug. The incidence of 
treatment-emergent AEs (TEAEs) will be summarized and tabulated using MedDRA (version 
18.1), by System Organ Class (SOC) and Preferred Term (PT). A TEAE is defined as an AE that 
first occurs or worsens in severity on or after the first dose of any study drug and within 30 days 
after the last dose of any study drug. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
(Version 4.03) will be used to grade both clinical and laboratory AEs. A subject with several 
occurrences of the same AE will be counted once and classified by the most severe occurrence. 
AEs with missing severity ratings will be classified as having unknown severity. 


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An overview summary of AEs will be produced, which will include counts and percentages of 
subjects with any AEs and Grade III/IV AEs, AEs and Grade III/IV AEs related to study treatment, 
SAEs, SAEs related to study treatment, fatal SAEs, infusion reactions, AEs leading to dose 
delayed, dose reduced, and dose withdrawn for Imprime PGG, AEs leading to dose delayed and 
dose withdrawn for pembrolizumab, and AEs leading to study treatment discontinuation. AEs 
related to study treatment will be further categorized as AEs related to Imprime PGG and/or 
pembrolizumab, Imprime PGG only, pembrolizumab only, and both Imprime PGG and 
pembrolizumab. 
A treatment-related AE is defined as an AE for which the investigator classifies the relationship to 
study treatment as “Yes”. A worst-case scenario approach will be taken to handle missing data, i.e. 
AEs related to study treatment will include events with the relationship to study treatment as ‘YES’ 
or missing. Adverse event data will be reviewed periodically to identify infusion reactions, new 
cancers, and events related to pembrolizumab overdose (>=1000mg). 
The AE summary tables will use the following algorithms for counting subjects: 
• 
Preferred term rows: each subject is counted once within each unique preferred term at 
the maximum grade. For example, if a subject has two headaches, the subject is counted 
only once under the preferred term “Headache”. Subjects experiencing the same AE 
preferred term several times with different grades will only be counted once with the 
maximum grade. 
• 
System Organ Class (SOC) rows: each subject is counted only once at the maximum 
grade at each SOC level although they may have several different preferred term events 
within the same SOC. 
• 
Any event row: each subject with at least one AE will be counted only once at the 
maximum grade of all AEs he/she experiences. 
All AEs and study treatment related AEs will be summarized by maximum toxicity grade, SOC and 
preferred term. Infusion reactions will be summarized similarly. In addition, AEs will be 
summarized by SOC and preferred term for the following time periods: 0-3, 3-6, 6-12 and >12 
months. 
A summary of non-serious AEs that occurred in strictly 5% of subjects or above will be provided 
(no rounding for the percentage will be used in terms of 5% threshold, e.g., event with 4.9% 
incidence rate will not be included in this table). 
The listing of all AEs and Grade III/IV will be provided. Separate listing of infusion reaction, 
adverse events of new cancer (that is not a condition of the study) and adverse event associated 
with pembrolizumab overdose as determined by clinical team review will also be provided. 
Listing of AEs (if any) may be provided for the screen failure or non-treated subjects in the 
Screening population and the subjects in the ABA Pre-screening population. 
12.3 Serious Adverse Events 
Serious adverse events will be summarized similarly as AEs. A treatment related SAE is defined as 
an AE for which the investigator classifies the relationship to study drug as “Yes”. A worst- case 
scenario approach will be taken to handle missing data, i.e. SAEs related to study treatment will 
include events with the relationship to study treatment as ‘YES’ or missing. 


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For serious adverse events, the treatment-emergent time period begins at treatment enrollment 
through 90 days following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier. 
Supportive listings with subject-level details will be generated for fatal and all SAEs separately. 
12.4 Adverse Events Leading to Study Discontinuation and Dose Modification 
Adverse events leading to study discontinuation, Imprime PGG dose modification (dose 
withdrawn, dose reduced and dose interrupted), and pembrolizumab dose modification (dose 
withdrawn and dose interrupted) will be summarized. 
Listing of AEs leading to study discontinuation, Imprime PGG dose modifications and 
pembrolizumab dose modifications will be provided. 
12.5 Deaths 
All deaths will be summarized based on the number and percentage of subjects. This summary will 
classify subjects by time of death relative to the last dose of study treatment (>30 days or £ 30 
days) and primary cause of death. A supportive listing will be generated to provide subject- specific 
details for subjects who died and the reason for death. 
12.6 Pregnancies 
A listing of pregnancy test results will be provided. 
12.7 Clinical Laboratory Evaluations 
The assessment of laboratory toxicities includes hematology safety, timed completed blood count 
(CBC) with differential, clinical chemistry, coagulation and urinalysis. Laboratory toxicity grades 
will be reported using the CTCAE v4.03. 
• Hematology safety: Hemoglobin (HGB), hematocrit (HCT), platelet count, erythrocytes, 
and leukocytes, with differential including absolute neutrophils, monocytes, lymphocytes, 
eosinophils, and basophils. Hematology sample will be collected at pre-Imprime infusion. 
Hematocrit, red blood cell count, monocytes, eosinophils, and basophils are not graded by 
CTCAE v4.03. Lymphocyte count and hemoglobin are graded by CTCAE 4.03 for both 
increase and decrease directions. 
• Timed CBC with differential is the same set of tests as for hematology safety but collected 
pre-Imprime PGG infusion and 4 hours post start of Imprime infusion on the selected visit 
days. 
• Clinical Chemistry: Albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin (if total bilirubin 
is elevated above ULN), lactate dehydrogenase (LDH), carbon dioxide (if considered 
standard of care in the region), uric acid (urate), calcium, chloride, creatinine, glucose, 
phosphorus, potassium, sodium, magnesium, total protein, blood urea nitrogen, and thyroid 
function including total triiodothyronine (T3), free triiodothyronine (FT3), free thyroxine 
(FT4), thyroid stimulating hormone (TSH), and creatinine clearance. For sodium, 
potassium, calcium, glucose, and magnesium there will be bi- directional parameters (hyper 
and hypo) created, and the tests will be graded by CTCAE v4.03 in both directions. 
Chloride, direct bilirubin, LDH, carbon dioxide, blood urea nitrogen, T3, FT3, FT4, TSH, 
and total protein are not graded by CTCAE v4.03. 


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• Coagulation: Prothrombin time (PT), international normalized ratio (INR), and activated 
partial prothrombin time (aPTT) at screening. 
• Urinalysis: Blood, glucose, protein, specific gravity, and microscopic exam including 
bacteria, RBC and WBC (if abnormal results noted) 
 
The individual subject level data will be listed for hematology safety, timed CBC with differential, 
clinical chemistry, coagulation, and urinalysis/microscopic data. The listing of hematology tests 
will include the data from hematology safety and timed CBC data with differential. For the listing 
of hematology and clinical chemistry, the baseline value will be specified for each subject. 
The normal ranges from each site will be used to identify values that are out of normal range. 
Standard units will be used to report lab test results for hematology safety, timed CBC and clinical 
chemistry. The list of standard units for each lab test will be determined by the study team. 
A separate listing of liver function tests (ALP, AST, ALT, total and direct bilirubin) will be 
provided for subjects who have the following clinical event of interest: 
• Elevated AST or ALT value that is ≥ 3 x upper limit of normal range (ULN) and elevated 
total bilirubin value being ≥ 2 x ULN, and at the same time, alkaline phosphatase <2 x 
ULN.   
For each test of timed CBC with differential, the following will be summarized using mean, 
median, standard deviation, minimum and maximum: 
• Assessment value at the pre-Imprime infusion and 4-hour post start of Imprime infusion 
for each visit; 
• The 4-hour post start of Imprime infusion change from pre-Imprime infusion for each visit; 
• Change from baseline at pre-Imprime infusion and 4-hour post start of Imprime infusion 
for each visit, and baseline is defined as pre-infusion on Cycle 1 Day 1. 
Summaries of hematology (including hematology safety and timed CBC) and clinical chemistry 
toxicity grade shift from baseline will be provided for all graded laboratory tests for the worst- case 
post-baseline. The determination of the worst-case post-baseline will take into account both the 
planned and unscheduled assessments. 
12.8 Vital Signs 
Vital signs data (blood pressure, heart rate, respiration rate and temperature) will be listed for each 
subject. Body weight and change from baseline will be listed. 
12.9 Electrocardiograms 
The 12-lead Electrocardiogram (ECG) measurement will be listed for each subject. 
12.10 ECOG Performance Status 
The ECOG performance score shift from baseline will be produced for the worst-case post- 
baseline. The ECOG performance status values will be listed. Baseline value for each subject will 
be specified in the listing. 
12.11 Physical Examination 
Physical examination data will be listed. 


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13 PHARMACOKINETICS 
The PK concentration data analysis will be described in a separate PK analysis plan and data will 
be analyzed separately, independent of the data analysis conducted under this SAP. 
14 BIOMARKER ANALYSIS 
The ABA values assessed at screening will be summarized for the All Treated, Screening, and 
possibly the ABA Pre-screening population. Listing of ABA will be provided separately for the All 
Treated subjects and possibly for the screen failure and non-treated subjects in the Screening 
population and subjects in the ABA Pre-screening population. 
Data analysis for all other biomarker data will be described in a separate biomarker analysis plan(s) 
and data will be analyzed separately, independent of the data analysis conducted under this SAP. 
15 DATA DISPLAY SPECIFICATIONS 
All analyses will be performed using SAS® Version 9.2 or higher. Continuous variables will be 
summarized with the number of subjects (n), mean, median, standard deviation, minimum and 
maximum; and categorical variables will be summarized with frequency counts and percentages. 
For summary statistics, mean and median will be displayed to one more decimal place than the 
original value and dispersion statistics (e.g. standard deviation) will have two more decimal places 
than the original value. P-values will be reported to four (4) decimal places and those less than 
0.0001 will be reported as <.0001. When no data are available for a listing, summary table, or 
graph, the text "No Data to Report" will be printed in the body of the statistical reporting display.