Clinical trial NCT03003468
Conditions: Non-Small Cell Lung Cancer
Keywords: Anti-PD-1 Pembrolizumab Imprime PGG MK-3475
Sponsor: Lawrence Feldman, MD
Start date: 2017-07-11; Completion date: 2022-11-28
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, multi-institutional, single arm study with a dose escalation phase Ib cohort, followed by a phase II cohort of pembrolizumab and Imprime PGG. No randomization or blinding is involved.

Detailed description:
OUTLINE: This is a multi-center study.

The phase Ib dose escalation will evaluate the combination of pembrolizumab and Imprime PGG for subjects with metastatic non-small cell lung cancer (NSCLC) after progression on first-line platinum-based chemotherapy. The phase II trial will test whether addition of Imprime PGG to pembrolizumab will increase median progression-free survival (PFS) in second line therapy setting in NSCLC.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive

* Imprime PGG 2 mg/kg IV on Days 1, 8, 15 for Cycles 1-4
* Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16
* Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

Cohort 2 will consist of 3-6 patients who will receive

* Imprime PGG 4 mg/kg IV on Days 1, 8, 15 for Cycles 1-4
* Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16
* Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional three subjects will be enrolled at dose level 2. If all subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled into dose level 2 to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

Pembrolizumab will be given on Day 1 of each 21 day cycle after Imprime PGG, and the RP2D dose of Imprime PGG will be given on Days 1, 8 and 15 of each 21 day cycle. Treatment will continue up to 16 cycles, or until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes.

Life expectancy: of 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hepatic:

* total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 x ULN (except subject with Gilbert's Syndrome, who can have total bilirubin \< 3.0 mg/dl)
* aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
* alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases

Renal:

* Serum creatinine ≤ 3 mg/dL OR
* if serum creatinine \> 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min

Hematopoietic:

* hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start study
* and absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L
* and platelet count ≥ 100 × 10\^9/L

Coagulation:

* INR \< 1.5 × ULN OR
* for subjects receiving anticoagulant, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for subjects on warfarin should be in the therapeutic range. Low molecular weight heparin (LMWH) is allowed.

Arms: arm 1: Dose Escalation Cohort Cohort 1 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 of each 21 day cycle. Imprime PGG will be administered at 2mg/kg on Day 1,8, and 15 of cycles 1-4, and on Day 1 of cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.

Experimental: Arm A - Phase II Investigational Treatment The maximum safe dose of Imprime PGG in combination with pembrolizumab (as determined in the phase Ib cohort) will be given on Day 1,8, and 15 for cycles 1-4, and on Day 1 of cycles 5-16.

Cohort 2 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 and Imprime PGG at 4mg/kg on Day 1,8, and 15 for Cycles 1-4 and on Day 1 only for Cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.
Interventions: intervention 1: Imprime PGG intervention 2: MK-3475 intervention 3: Imprime PGG
Intervention descriptions: intervention 1: Arm A: Phase Ib Cohort 1: 2mg/kg IV; Arm A: Phase Ib Cohort 2: 4mg/kg IV intervention 2: 200mg IV intervention 3: Arm B: Phase II treatment: administered at the maximum safe dose of 2mg or 4 mg as established in the Phase Ib cohort study.

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 68 
 
A Phase Ib/II Study of Anti-PD-1 Antibody Pembrolizumab and Imprime PGG for  
Patients with Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy:   
Big Ten Cancer Research Consortium BTCRC-LUN15-017 
 
Sponsor Investigator 
Lawrence Feldman, MD  
University of Illinois at Chicago 
 
Co-Investigator  
Muhammad Furqan, MD 
University of Iowa 
 
Statistician 
Li Liu, PhD or designee 
Associate Professor of Biostatistics 
Division of Epidemiology and Biostatistics School of Public Health 
University of Illinois-Chicago 
 
Trial Supported by  
Merck Sharp & Dohme Corp. (MISP 53602) 
HiberCell Inc. 
 
Trial Management by 
BTCRC Administrative Headquarters at Hoosier Cancer Research Network 
7676 Interactive Way, Suite 120 
Indianapolis, IN 46278 
 
Investigational New Drug (IND) Application # 
131502 
 
 
Initial Protocol Version Date:  
20SEP2016 
 
Amendment Version Date: 
25JAN2017 
31MAR2017  
18JAN2018 
12APR2018 revised  
14MAR2019  
28MAY2019  
29OCT2020 (current) 


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PROTOCOL SIGNATURE PAGE  
 
A Phase Ib/ II Study of Anti-PD-1 Antibody Pembrolizumab and Imprime PGG for Patients with 
Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy:  
Big Ten Cancer Research Consortium BTCRC-LUN15-017 
 
VERSION DATE:  29OCT2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, or the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the individual. 
I will accept the monitor’s overseeing of the study. I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
 
 
       Date 
 
____________________________________ 
 Site Investigator Name (printed) 
 
____________________________________ 
 Site Investigator Title 
 
____________________________________ 
 Name of Facility 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO BTCRC ADMINISTRATIVE HEADQUARTERS  
 
 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to BTCRC Administrative Headquarters and keep a record 
for your files. 


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STUDY SYNOPSIS 
TITLE 
A Phase Ib/II Study of Anti-PD-1 Antibody Pembrolizumab and Imprime 
PGG for Patients with Metastatic Non-small Cell Lung Cancer After 
Progression on First-Line Therapy
PHASE  
Phase Ib/II 
OBJECTIVES 
Primary Objectives: 
Phase Ib Dose Escalation Cohort:  To establish the maximum tolerated dose 
(MTD) of Imprime PGG in combination with pembrolizumab for subjects with 
metastatic non-small cell lung cancer (NSCLC) after progression on first-line 
platinum-based chemotherapy.  
Phase II Study:  To estimate progression-free survival (PFS) using RECIST v1.1 
in subjects with metastatic NSCLC treated with Imprime PGG in combination 
with pembrolizumab after progression on first-line systemic therapy (either 
platinum-based chemotherapy with or without immune checkpoint inhibitor or 
immune checkpoint inhibitor as first line therapy) based on RECIST v1.1.  
Secondary Objectives for Phase Ib:  
 Characterize adverse effects (AEs) of Imprime PGG in combination with 
pembrolizumab in subjects with NSCLC who progressed after first-line 
platinum-based chemotherapy. 
 Estimate clinical benefit rate (CBR: complete response, partial response, or 
stable disease) measured by RECIST v1.1 of Imprime PGG in combination 
with pembrolizumab in subjects with NSCLC who progressed after first-line 
platinum-based chemotherapy.  
 Estimate Progression-Free Survival (PFS) and 6 month PFS using RECIST v1.1 
in subjects with NSCLC who progressed after first-line platinum-based 
chemotherapy when treated with Imprime PGG in combination with 
pembrolizumab.  
 Estimate overall survival (OS) and 1-year OS in subjects with NSCLC who 
progressed after first-line platinum-based chemotherapy when treated with 
Imprime PGG in combination with pembrolizumab.  
Secondary Objectives for Phase II:  
 Characterize adverse effects (AEs) of Imprime PGG in combination with 
pembrolizumab in subjects with NSCLC who progressed after first-line 
systemic therapy. 
 Estimate clinical benefit rate (CBR: complete response, partial response, or 
stable disease) of Imprime PGG in combination with pembrolizumab in 
subjects with NSCLC who progressed after first-line systemic therapy. 
 Estimate Progression-Free Survival (PFS) and 6 month PFS using RECIST v1.1 
in subjects with NSCLC when treated with Imprime PGG in combination with 
pembrolizumab who progressed after first-line systemic therapy.  
 Estimate overall survival (OS) and 1-year OS in subjects with NSCLC when 
treated with Imprime PGG in combination with pembrolizumab who progressed 
after first-line systemic therapy.  
Correlative Objectives for Phase Ib/II Study:  
 Correlate biomarkers on immune cell subsets (including, but not limited to 
monocytes, macrophages, granulocytes, and lymphocytes, and PD-L1) 
concentrations and localization (peri- vs. intratumoral) in archived diagnostic 
tumor tissue with PFS and CBR. 
 Correlate change in soluble PD-L1 levels pre-dose Cycles 2 and 3, relative to 


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baseline (i.e., pre-dose Day 1 of Cycle 1) level with PFS and CBR. 
 Correlate PD-L1 expression on circulating peripheral mononuclear cells from 
whole blood pre-dose Cycles 2 and 3, relative to baseline (i.e., pre-dose Day 1 of 
Cycle 1) level.  
 Correlate anti-β-glucan antibody (ABA) (IgM, IgG) levels with PFS and CBR. 
 Correlate proteomic immune classifiers at baseline with PFS and CBR. 
 Correlate FcRIIa polymorphism to PFS and CBR.
STUDY DESIGN 
Single arm study with dose escalation Phase Ib cohort followed by a Phase II 
cohort 
KEY INCLUSION 
CRITERIA  
1. Subjects with histologically or cytologically confirmed non-small cell lung 
cancer (NSCLC). 
2. Subjects with stage IV non-small cell lung cancer (NSCLC) as defined by 
American Joint Committee on Cancer (AJCC) 7th Edition.  Patients with 
locally advanced or recurrent disease who are candidates for systemic 
therapy are also allowed. 
3. Subjects without EGFR activating mutation (Exon 19 del, L858R) or ALK, 
ROS translocation if histology is adenocarcinoma. Subjects with an EGFR 
activating mutation or ALK translocation are eligible only after failing TKI 
therapy (such as gefitinib, erlotinib, or afatinib). Furthermore, if a T790M 
resistance mutation is found, the patient must have failed a 3rd generation 
TKI such as osimertinib. 
4. Phase Ib: Subjects who progressed after first-line platinum-based 
chemotherapy and who are candidates for second-line therapy. 
Phase II: Subjects who progressed after first-line systemic therapy (either 
platinum-based chemotherapy with or without immune checkpoint inhibitor 
or immune checkpoint inhibitor as first line therapy) who are candidates for 
second-line systemic therapy. Patients with early stage cancer will also be 
eligible if progression occurs: 
a. within 6 months of adjuvant chemotherapy after curative resection 
b. within 6 months of adjuvant chemotherapy after curative resection 
while on adjuvant immunotherapy, currently only available as part of 
a clinical trial 
c. within 6 months of curative surgery if chemotherapy is given in the 
neoadjuvant setting 
d. within 6 months of completion of chemoradiation (or 6 months from 
completion of consolidation chemotherapy if administered after 
concurrent chemoradiation) 
e. within 6 months of completion of chemoradiation or consolidation 
chemotherapy (if administered) while on consolidation 
immunotherapy, a setting for which durvalumab is FDA approved. 
Phase II: Subjects with an EGFR or ALK mutation who are no longer 
candidates for TKI therapy and have progressed on standard systemic 
therapy (either platinum-based chemotherapy with or without immune 
checkpoint inhibitor or immune checkpoint inhibitor as first line therapy). 
5. Phase II only: Measurable disease according to RECIST v1.1 (Section 8) 
obtained by imaging within 28 days prior to study registration.  
Phase Ib: subjects may enroll with or without measurable disease. 
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 


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0, 1, or 2 within 28 days prior to study registration. 
7. Adequate hepatic function within 28 days prior to study registration defined 
as meeting all of the following criteria: 
a. total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ 
ULN for subjects with total bilirubin levels > 1.5 x ULN (except subject 
with Gilbert’s Syndrome, who must have total bilirubin < 3.0 mg/dl) 
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 
8. Adequate renal function within 28 days prior to study registration defined by 
either of the following criteria:  
a. serum creatinine ≤ 3 × ULN 
b. if serum creatinine > 3 × ULN, estimated glomerular filtration rate 
(GFR) ≥ 20 mL/min 
9. Adequate hematologic function within 28 days prior to study registration 
defined as meeting all of the following criteria: 
a. hemoglobin ≥ 9 g/dL; subjects requiring transfusion will be eligible to 
start study. 
b. absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
c. platelet count ≥ 100 × 109/L 
10. 
Adequate coagulation functioning within 28 days prior to study 
registration defined by either of the following criteria:  
a. INR < 1.5 × ULN 
b. for subjects receiving anticoagulation, 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 should be in therapeutic range. Low molecular weight heparin 
(LMWH) is allowed.
TREATMENT 
PLAN 
Phase Ib: Dosing will occur in 21-day cycles. Imprime PGG in this dose 
escalation study will be dosed at 2 mg/kg IV or 4 mg/kg IV on Day 1, 8, and 
15 of each 21 day cycle. On Day 1 of each cycle, pembrolizumab will be 
infused at 200 mg.  On Day 1 of each cycle, the Imprime PGG intravenous 
infusion is given first followed 15-30 minutes later by the pembrolizumab 
infusion. Imprime PGG will be administered as a 2-4 hour intravenous infusion 
(based on dose and on the subject’s weight). Pembrolizumab will be 
administered as a 30-minute intravenous infusion. Subsequent cycles beyond 
Cycle 1 must meet the criteria found in section 6.1. 
Phase II: Imprime PGG will be dosed at the dose established in Phase 1b (4 
mg/kg) on Day 1, 8, and 15 of each 21 day cycle for the first 4 cycles (12 
weeks) and on Day 1 for Cycles 5-16. On Day 1 of each cycle, pembrolizumab 
will be infused at 200 mg. On Day 1 of each cycle, the Imprime PGG 
intravenous infusion is given first followed 15-30 minutes later by the 
pembrolizumab infusion. Imprime PGG will be administered as a 2-4 hour 
intravenous infusion (based on dose and on the subject’s weight). 
Pembrolizumab will be administered as a 30-minute intravenous infusion. 
Subsequent cycles beyond Cycle 1 must meet the criteria found in section 6.1. 


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STATISTICAL 
CONSIDERATIONS 
Phase Ib: A standard “3+3” design will be used with maximum number of 
subjects accrued to be 12. 
Phase II: For this single arm Phase II study, study endpoint will be median 
PFS as assessed by the RECIST v1.1 criteria. 
The null hypothesis is that median PFS of combination drug is 3.2 months 
(equal to single agent pembrolizumab among subjects with a proportion score 
of 1 to 49%); the alternative hypothesis is that the PFS is 6.3 months (equal to 
single agent pembrolizumab among subjects with a proportion score of ≥ 
50%).  
With a total sample size of 24 the study will have 90% power to detect a 
difference of 3.1 months (i.e., 6.3 months versus 3.2 months), controlling for a 
two-sided type I error probability of 5%. The power analysis was conducted 
using the power calculation for one arm survival design proposed by 
Lawless39.  
Unevaluable subjects will be replaced. 
TOTAL NUMBER 
OF SUBJECTS  
Up to 36 (up to 12 in dose escalation phase and up to 24 in Phase II study)  
ESTIMATED 
ENROLLMENT 
PERIOD  
18 months 
ESTIMATED 
STUDY 
DURATION 
30 months 
 
 


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INDEX 
SECTION                                                                                                                 
PAGE 
STUDY SYNOPSIS ................................................................................................................................ 3 
PHASE Ib SCHEMA .............................................................................................................................. 9 
PHASE II SCHEMA ............................................................................................................................ 10 
ABBREVIATIONS ............................................................................................................................... 11 
1. 
BACKGROUND AND RATIONALE ..................................................................................... 15 
1.1. 
Introduction ........................................................................................................................................ 15 
1.2. 
Study Rationale .................................................................................................................................. 20 
2. 
OBJECTIVES ............................................................................................................................... 20 
2.1. 
Phase Ib Objectives ........................................................................................................................... 20 
2.2. 
Phase II Objectives ............................................................................................................................ 21 
3. 
ELIGIBILITY CRITERIA ........................................................................................................ 22 
3.1. 
Inclusion Criteria ............................................................................................................................... 22 
3.2. 
Exclusion Criteria .............................................................................................................................. 23 
4. 
SUBJECT REGISTRATION .................................................................................................... 25 
5. 
OVERALL DESIGN AND TREATMENT PLAN ............................................................... 25 
5.1. 
Phase Ib Dose Escalation Study ..................................................................................................... 25 
5.2. 
Phase II Study .................................................................................................................................... 27 
5.3. 
Correlative Research (all phases) .................................................................................................. 27 
5.4. 
Imprime PGG Pre-medication ....................................................................................................... 27 
5.5. 
Drug Administration ........................................................................................................................ 28 
5.6. 
Supportive Care ................................................................................................................................. 29 
5.7. 
Concomitant Medications ................................................................................................................ 30 
5.8. 
Diet/Activity/Other Considerations ............................................................................................... 31 
6. 
DOSE DELAYS ............................................................................................................................ 33 
6.1. 
Start of a New Cycle .......................................................................................................................... 33 
6.2. 
Management of Allergic Reaction/ Hypersensitivity ................................................................ 33 
6.3. 
Other Adverse Event Guidelines ................................................................................................... 35 
6.4. 
Dose Modifications ............................................................................................................................ 35 
7. 
STUDY CALENDAR & EVALUATIONS [Cycle = 21 days] ............................................ 38 
7.1. 
Screening Evaluations ...................................................................................................................... 40 
7.2. 
On Treatment (±3) ............................................................................................................................. 40 
7.3. 
Off Treatment ..................................................................................................................................... 42 
8. 
CRITERIA FOR DISEASE EVALUATION ........................................................................ 43 
8.1. 
Definitions Associated with RECIST v. 1.1 ................................................................................. 43 
8.2. 
Response Criteria for Target Lesions ........................................................................................... 45 
8.3. 
Evaluation of Best Overall Response: ........................................................................................... 45 
8.4. 
Definitions for Response Evaluation –RECIST version 1.1 .................................................... 46 
9. 
BIOLOGICAL CORRELATIVES .......................................................................................... 47 
9.1. 
Correlate biomarkers on immune cell subset concentrations and localization in archived 
diagnostic tumor tissue with PFS and CBR (HiberCell). ....................................................................... 47 


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9.2. 
Evaluate PD-L1 from diagnostic tissue (Dako) .......................................................................... 47 
9.3. 
Correlate change in soluble PD-L1 level in serum with PFS and CBR (UIC). ................... 47 
9.4. 
Correlate PD-L1 expression on circulating PBMCs from whole blood (HiberCell) ......... 47 
9.5. 
Correlate ABA levels and FcRIIa polymorphism with PFS and CBR (HiberCell). ........ 48 
9.6. 
Correlate baseline proteomic immune classifiers with PFS and CBR. ................................ 48 
9.7. 
Banking of Leftover Biospecimens ................................................................................................ 48 
9.8. 
Banking Samples for Future Unspecified Research .................................................................. 48 
9.9. 
Confidentiality of Biospecimens ..................................................................................................... 48 
10. 
DRUG INFORMATION ........................................................................................................ 49 
10.1. 
Drug name: Imprime PGG: (Beta 1,3/1,6 glucan): ................................................................... 49 
10.2. 
Drug Name: Pembrolizumab (MK-3475 [Anti-PD-1 Antibody MK-3475]) ........................ 53 
11. 
ADVERSE EVENTS ............................................................................................................... 54 
11.1. 
Definitions of Adverse Events: ....................................................................................................... 54 
11.2. 
Adverse Event (AE) Reporting: ..................................................................................................... 56 
11.3. 
Definition and Reporting of a Pembrolizumab Overdose: ...................................................... 56 
11.4. 
Reporting of Pregnancy and Lactation: ....................................................................................... 56 
11.5. 
Definition and Reporting of Events of Clinical Interest (ECI): ............................................. 56 
11.6. 
Serious Adverse Events (SAEs) ...................................................................................................... 57 
11.7. 
BTCRC AHQ Responsibilities for Reporting SAEs to FDA ................................................... 58 
11.8. 
Sponsor-Investigator Responsibilities .......................................................................................... 58 
11.9. 
IND Safety Reports Unrelated to This Trial ............................................................................... 59 
12. 
STATISTICAL CONSIDERATIONS ................................................................................ 59 
12.1. 
Study Design: ...................................................................................................................................... 59 
12.2. 
Criteria for Stopping Study: ........................................................................................................... 59 
12.3. 
Sample Size: ........................................................................................................................................ 59 
12.4. 
Analysis of Primary Objectives/Aims ........................................................................................... 60 
12.5. 
Analysis of Secondary Endpoints: ................................................................................................. 60 
12.6. 
Analysis of Phase II Correlative Endpoints: ............................................................................... 61 
13. 
TRIAL MANAGEMENT ....................................................................................................... 62 
13.1. 
Data and Safety Monitoring Plan: ................................................................................................. 62 
13.2. 
University of Illinois Cancer Center Data Safety Monitoring Committee .......................... 62 
13.3. 
Data Quality Oversight Activities .................................................................................................. 62 
13.4. 
Compliance with Trial Registration and Results Posting Requirements ............................. 63 
14. 
DATA HANDLING AND RECORD KEEPING ............................................................. 63 
14.1. 
Data Management ............................................................................................................................. 63 
14.2. 
Case Report Forms and Submission:............................................................................................ 63 
14.3. 
Record Retention: .............................................................................................................................. 63 
14.4. 
Confidentiality .................................................................................................................................... 64 
15. 
ETHICS ...................................................................................................................................... 64 
15.1. 
Institutional Review Board (IRB) Approval ............................................................................... 64 
15.2. 
Ethical Conduct of the Study: ........................................................................................................ 64 
15.3. 
Informed Consent Process ............................................................................................................... 64 
16. 
REFERENCES ......................................................................................................................... 66 


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PHASE Ib SCHEMA 
 
The primary objective of the phase Ib study is to establish the maximum tolerated dose of Imprime PGG in 
combination with Pembrolizumab for subjects with metastatic non-small cell lung cancer after progression 
on first-line platinum-based chemotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Cohort 
# of Subjects 
Imprime PGG 
(mg/kg) 
Pembrolizumab 
(mg) 
1 
3-6 
2
200
2 
3-6 
4
200
 
 
Imprime PGG 

Days 1, 8, 15  
Pembrolizumab 

Day 1 
(cycle = 21 days)
CR, PR or SD 
Follow for progression and 
survival for 5 years (±2 months) 
from start of treatment. 
Disease Assessment every 2 cycles 
If at least SD after Cycle 7, may assess every 3 cycles 
Progression or significant toxicity 
Continue treatment  
up to 16 cycles. 
Discontinue treatment. 
Subjects with metastatic non-small cell lung cancer who have progressed 
on first-line platinum-based chemotherapy.  


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PHASE II SCHEMA 
 
The primary objective of the Phase II Study is to estimate Progression-Free Survival (PFS) using RECIST 
v1.1 in subjects with metastatic non-small cell lung cancer treated with Imprime PGG in combination with 
pembrolizumab after progression on first-line systemic therapy (either platinum-based chemotherapy with 
or without immune checkpoint inhibitor or immune checkpoint inhibitor as first line therapy).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be treated with pembrolizumab at a 200 mg dose and the recommended phase II dose of 
Imprime PGG.  
 
Imprime PGG 

Days 1, 8, 15 for Cycles 1-4 

Day 1 only for Cycles 5-16  
Pembrolizumab 

Day 1 
(cycle = 21 days)
CR, PR or SD 
Follow for progression and 
survival for 5 years (±2 months) 
from start of treatment. 
Disease Assessment every 2 cycles 
If at least SD after Cycle 7, may assess every 3 cycles 
Progression or significant toxicity 
Continue treatment  
up to 16 cycles. 
Discontinue treatment. 
Subjects with metastatic non-small cell lung cancer who have progressed on 
first-line systemic therapy (either platinum-based chemotherapy with or 
without immune checkpoint inhibitor or immune checkpoint inhibitor as first 
line therapy) who are candidates for second-line systemic therapy. 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
ABA 
Anti-beta-glucan antibody 
AE 
adverse event 
AHQ 
Administrative Headquarters 
ANC 
absolute neutrophil count 
Anti-PD-1 antibody 
anti-programmed death 1 antibody 
Anti-PD-L1 antibody 
anti-programmed death-ligand 1 antibody 
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASCO 
American society of clinical oncology 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic event 
BCG 
Bacillus Calmette–Guérin 
BMP 
basic metabolic panel 
BOR 
best overall response 
BTCRC 
Big Ten Cancer Research Consortium 
C1D1 
Cycle 1 day 1 
CA 
cancer antigen 
CBC 
complete blood cell count 
CBR 
clinical benefit rate 
CI 
Confidence interval 
CIK 
cytokine-induced killer 
CLM 
Correlative Laboratory Manual 
cm 
Centimeter 
CNS 
Central nervous system 
CR 
complete response 
CR3  
Complement receptor 3 
CR3-DCC 
Complement Receptor3-dependent cell mediated cytotoxicity 
CT 
computed tomography 
CTC 
cytotoxic T cell 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTLA4 
cytotoxic T-lymphocyte-associated antigen 4 


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dL 
Deciliter 
DLT 
dose-limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
Estimated Glomerular Filtration Rate 
EGFR 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FDG PET/CT 
fluorine 18 fluorodeoxyglucose positron emission tomography/ 
computed tomography
HBsAg 
Hepatitis B surface antigen 
HCl 
Hydrochloric acid 
Hgb 
Hemoglobin 
HepC 
Hepatitis C 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hr 
Hour 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IND 
Investigational New Drug 
INR 
international normalized ratio 
I/O 
input/output 
IRB 
Institutional Review Board 
irAEs 
Immune related adverse events 
irBOR 
Immune related best overall response 
irCR 
Immune related complete response 
irECI 
Immune related event of clinical interest 
irPD 
Immune related progressive disease 
irPR 
Immune related partial response 
irPD 
Immune related progressive disease 


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IUD 
Intra uterine device 
IV 
Intravenous 
IVRS 
Interactive voice response system 
kg 
Kilogram 
LAK 
lymphocyte-activated killer 
lb 
Pound 
LDH 
lactate dehydrogenase 
LMWH 
low-molecular-weight heparin 
mCRC 
metastatic colorectal cancer 
MDSC 
myeloid-derived suppressor cell 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm3 
cubic millimeters 
MRI 
Magnetic resonance imaging 
MTD 
maximum tolerated dose 
MTV 
metabolic tumor volume 
N/A 
Not applicable 
NaOH 
Sodium hydroxide 
NCI 
National Cancer Institute 
NDC 
National Drug Code 
NK Cells 
Natural Killer Cells 
NS 
Normal saline 
NSAID 
Non steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
PD 
Progressive disease 
PD-1 
programmed death 1 
PD-L1 
programmed death ligand 1 
PD-L2 
programmed death ligand 2 
PET-CT 
positron emission tomography/ computed tomography 
PFS 
progression-free survival 
PT 
Prothrombin time 
PK 
Pharmacokinetics 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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RP2D 
Recommend phase 2 dose 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
RR 
response rate 
SAE 
serious adverse event 
SPD 
sum of the products of the two largest perpendicular diameters 
SD 
stable disease 
T3 
Triiodothyronine 
T4 
Free thyroxine  
TAA 
tumor-associated antigen 
TAM 
tumor-associated macrophage 
TNF 
Tumor Necrosis Factor 
TIL 
tumor-infiltrating lymphocyte 
TKI 
tyrosine kinase inhibitor 
TSA 
tyramide signal amplification 
TSH 
Thyroid stimulating hormone 
UI-Health 
University of Illinois Health 
ULN 
upper limit of normal 
UPIRSO 
unanticipated problems involving risk to subjects or others 
US 
United States 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WOCP 
women of childbearing potential 
wt 
Weight 


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1. BACKGROUND AND RATIONALE  
1.1. Introduction 
Lung cancer is one of the most commonly diagnosed cancers worldwide with 1.8 million cases that 
account for 13.0% of the total.  It is also one of the leading causes of death worldwide accounting for 
1.6 million or 19.4% of all cancer related deaths.1 Historically, one management algorithm was 
applied to all patients with non-small cell lung cancer (NSCLC). A platinum agent combined with 
pemetrexed (for nonsquamous), paclitaxel, docetaxel, vinorelbine, or gemcitabine was recommended 
for first-line chemotherapy. 
 
More recently (May 10, 2017) the U.S. Food and Drug Administration (FDA) approved the immune 
checkpoint inhibitor (as described below) pembrolizumab in combination with pemetrexed and 
carboplatin for the treatment of patients with previously untreated metastatic non-squamous non-
small cell lung cancer (NSCLC).2 Just prior to that time (October 24, 2016) the FDA approved 
pembrolizumab as monotherapy for second-line therapy in patients with metastatic NSCLC whose 
tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as 
determined by an FDA-approved test.3 
 
Second-line chemotherapy at the time of disease progression could include docetaxel, or pemetrexed 
and erlotinib was recommended as second/third-line therapy.4 Commonly used 2nd line therapy for 
NSCLC creates median overall survival (OS) and progression free survival (PFS) of 7.5 (95% 
confidence interval [CI]: 6.6–8.4) and 4.1 (95% CI: 3.7–4.5) months, respectively, in community 
setting.5 Single docetaxel use results in 7.5% partial response rate (RR),6 pemetrexed use in 9.1% 
RR,7 and erlotinib use in 8.9% RR.8   These low survival and RR rates clearly indicate the need to 
develop more effective therapies for NSCLC after disease progression following first line therapy. 
 
There are now at least 3 immune checkpoint inhibitors that are approved in the second-line setting: 
nivolumab,9,10 pembrolizumab,11 and atezolizumab.12 Of note, nivolumab and atezolizumab are 
approved in this setting regardless of the degree of PD-L1 expression while PDL-1 expression >1% 
is required in the case of pembrolizumab. 
 
1.1.1. The Programmed Death 1 (PD-1) Receptor, Its Ligand PD-L1, and a Novel 
Immunotherapy  
An increasing body of evidence, both from lab based animal models and from clinical 
epidemiology, suggests that the immune system can operate as a significant barrier to tumor 
formation and progression. One of the hallmarks of cancer is its ability to evade immune 
destruction.13 The Programmed death 1 (PD-1) receptor is expressed on activated T- and B-
cells.14 Its major ligand, programmed death ligand 1 (PD-L1) (B7-H1) is typically expressed 
on a subset of macrophages, but can be induced by inflammatory cytokines in a variety of 
tissue types, including tumor cells.15-19 When activated T-cells expressing PD-1 encounter PD-
L1, T-cell effector functions are diminished. PD-1 also binds programmed death ligand 2 (PD-
L2) (B7-DC), which is expressed selectively on macrophages and dendritic cells.19-21 These 
unique expression patterns suggest that PD-L1 promotes self-tolerance in peripheral tissues, 
while PD-L2 may function in lymphoid organs, although the role of PD-L2 in 
immunomodulation is not as well understood.22 Multiple tumor types have been shown to 
express PD-L1 and PD-L2, effectively co-opting a native tolerance mechanism.23-26 It has been 
postulated that antibodies that block the interaction between PD-1 and PD-L1 in tumor tissue 
may preferentially unleash the cytotoxic function of tumor-specific T cells with fewer 


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systematic toxic effects than those that are seen with other immune checkpoint inhibitors, such 
as anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies.27  
 
Two large, dose-escalation, phase 1 clinical trials evaluating the safety of the anti–PD-1 
antibody nivolumab (formerly known as BMS936558) and the anti–PD-L1 antibody 
BMS936559 showed significant antitumor activity in subjects with advanced melanoma, lung 
carcinoma, and renal cell carcinoma, among other cancers, thus validating the PD-1–PD-L1 
axis as a therapeutic target.28-30 Most tumor responses were durable beyond 1 year.29,30 Toxic 
effects were generally of low grade. Especially relevant to this protocol, cumulative response 
rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients).30 
 
A recent randomized, open-label, phase 3, international study comparing nivolumab to 
docetaxel in patients with advanced squamous-cell non–small-cell lung cancer who had disease 
progression during or after first-line chemotherapy showed that OS, PFS and RR were 
significantly better with nivolumab than docetaxel. The median overall survival was 9.2 
months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% 
CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with 
docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the OS rate was 42% 
(95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The RR 
was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median PFS was 3.5 
months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease 
progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). Treatment-related adverse events of grade 
3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of 
those in the docetaxel group.31 
 
Pembrolizumab (formerly known as MK-3475) is a highly selective, humanized monoclonal 
IgG4–kappa isotype antibody against PD-1 that can disrupt the engagement of PD-1 with its 
ligands and impede inhibitory signals in T Cells, with resultant tumor recognition by cytotoxic 
T cells. The anti-tumor activity, side effects and safety of pembrolizumab in patients with 
advanced non-small-cell lung cancer was studied as part of the large, international, Phase 1 
KEYNOTE-001 trial. The KEYNOTE-001 trial supported the approval by the U. S. Food and 
Drug Administration (FDA) of pembrolizumab for the treatment of 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. In this trial 495 patients 
received intravenous (IV) pembrolizumab at a dose of either 2mg or 10mg per kilogram of 
body weight every 3 weeks or 10 mg per kilogram every 2 weeks over a 30-minute period. The 
overall RR was 19.4% (95% CI 16.0-23.2), which included a response rate of 18.0% (95% CI, 
14.4 to 22.2) in 394 previously treated patients and 24.8% (95% CI 16.7 to 34.3) in the 101 
previously untreated patients. The best overall response was stable disease in 21.8% of 
patients. The RR was similar regardless of dose, schedule and histologic analysis. The median 
duration of response was 12.5 months (range 1.0 to 23.3) in all patients, 10.4 months (range, 
1.0 to 10.4) in previously treated patients and 23.3 months (range, 1.0 to 23.3) in previously 
untreated patients. Median PFS was 3.7 months (95% CI, 2.9 to 4.1) for all the patients, 3.0 
months (95% CI, 2.2 to 4.0) for previously treated patients, and 6.0 months (95% CI, 4.1 to 
8.6) for previously untreated patients. Median OS was 12.0 months (95% CI, 9.3 to 14.7) for 
all the patients, 9.3 months (95% CI, 8.4 to 12.4) for previously treated patients, and 16.2 
months (95% CI, 16.2 to not reached) for previously untreated patients.32 Treatment-related 
adverse events occurred in 351 patients (70.9%), with no clear difference according to dose or 


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schedule. The most common treatment-related adverse events were fatigue, pruritus, and 
decreased appetite. Adverse events of grade 3 or higher were reported in 47 of 495 patients 
(9.5%). The only treatment-related adverse events of an inflammatory or immune-mediated 
nature that occurred in more than 2% of patients were infusion-related reactions (in 15 patients 
[3.0%]), hypothyroidism (in 34 patients [6.9%]), and pneumonitis (in 18 patients [3.6%]). One 
infusion reaction led to treatment discontinuation. All the patients with hypothyroidism were 
successfully treated with medical therapy. Pneumonitis of grade 3 or greater was observed in 
9 patients (1.8%), including 1 (0.2%) who died.32 This study showed durable responses and 
acceptable tolerance and toxicity profile of pembrolizumab in patients with non-small-cell lung 
cancer, previously treated as well as untreated patients. It echoed findings from melanoma 
studies that efficacy and side-effect profile was not significantly different between patients 
receiving the dose of 10 mg per kilogram every 2 weeks and those receiving 10 mg per 
kilogram every 3 weeks.  
 
In a recent multicenter study of 135 subjects with advanced melanoma, treatment with MK-
3475 was demonstrated to have a high rate of sustained tumor regression with mainly grade 1 
or 2 toxicities, and a very low incidence of grade 3 or 4 toxicities.33 Selection of 200 mg as the 
appropriate dose for a switch to fixed dosing is based on simulation results indicating that 200 
mg will provide exposures that are reasonably consistent with those obtained with 2 mg/kg 
dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response.  A population PK 
model, which characterized the influence of body weight and other patient covariates on 
exposure, has been developed using available data from 476 subjects from PN001. The 
distribution of exposures from the 200 mg fixed dose are predicted to overlap considerably to 
those obtained with the 2mg/kg dose, with some tendency for individual values to range 
slightly higher with the 200 mg fixed dose. The slight increase in PK variability predicted for 
the fixed dose relative to weight-based dosing is not expected to be important clinically given 
that the range of individual exposures is well contained within the range of exposures shown 
in the melanoma and NSCLC studies of 2 and 10 mg/kg to provide similar efficacy and safety.  
The population PK evaluation revealed that there was no significant impact of tumor burden 
on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different tumor types and 
indication settings. 
 
1.1.2. Imprime PGG: A Novel Potentiator of Checkpoint Inhibitor Therapy 
 
Preclinical Mechanism of Action 
Imprime PGG is a 1,3/1,6  glucan isolated from the cell wall of a proprietary strain of the 
yeast Saccharomyces cerevisiae and is in development for the treatment of cancer in concert 
with anti-cancer therapeutic antibodies, anti-angiogenics and checkpoint inhibitors. 
 
Imprime PGG is administered intravenously and is bound by naturally occurring anti- glucan 
antibodies (ABA) (IgG, IgM) which can then activate complement resulting in the 
opsonization of the Imprime-ABA complex. This immune complex can then bind directly to 
innate immune effector cells (macrophages, monocytes, neutrophils) via complement receptor 
3 and FcgRIIa (CD32a) and possibly the dectin receptor. Levels of ABA vary in the human 
population. In healthy human volunteer studies, binding of the Imprime PGG immune complex 
correlates with higher ABA levels, in particular IgG ABA. These IgG ABA are predominantly 


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of the IgG2a subtype and interact specifically with the IgG receptor FcgRIIa (CD32a). There 
are two genetic variants of FcgRIIa – a high binding and a low binding variant- encoded by 
either the HIS131 or Arg131 alleles, respectively. Imprime PGG binding to, and subsequent 
activation of, innate immune effector cells is thereby influenced by the levels of ABA and by 
the affinity of the FcgRIIa. Patients with higher ABA and/ or the high-binding FcgRIIa allele 
may therefore have the highest likelihood of responding to Imprime PGG- based therapy. A 
fully qualified ELISA for ABA has been developed. A genetic analysis for the single 
nucleotide polymorphism at codon 131 has also been developed. Both are being assessed as 
possible patient selection or stratification markers.34,35 
 
Preclinical mechanistic work has revealed that Imprime PGG acts therapeutically 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. As a PAMP, Imprime PGG enhances innate immune 
cell killing, macrophage re-polarization and, importantly, the maturation and activation of 
professional antigen presenting cells (i.e. dendritic cells). Accordingly, both ex vivo research 
in human whole blood and in vivo tumor studies in immunocompetent mice have indicated that 
Imprime PGG treatment may drive enhanced antigen presentation and cross-talk with T cells, 
thereby enhancing the efficacy of checkpoint inhibitor therapy. In the syngeneic tumor model 
MC-38, 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 to 83% (14/17) in 
mice treated with the combination of 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 while age-matched, tumor-naïve mice developed tumors. These 
data provide compelling preclinical evidence that Imprime PGG treatment expanded the 
percent of mice effectively treated with this checkpoint inhibitor and fostered immunologic 
memory.34 
 
Furthermore, recent work presented at the 2015 American Association for Cancer Research36 
showed that Imprime PGG can modulate PD-L1 expression.  Monocytes derived from human 
whole blood treated with Imprime PGG or vehicle were cultured in media with appropriate 
cytokines to foster differentiation of macrophages or dendritic cells. Imprime PGG increased 
the expression of PD-L1 and production of interferon in both macrophages and dendritic cells. 
When incubated with cell lines from numerous cancer types, including NSCLC, breast, 
pancreatic, and colon, PD-L1 expression was substantially unregulated on NSCLC, pancreatic 
and breast cancer cell lines. 
 
Collectively, these preclinical mechanistic studies indicate that Imprime PGG acts as a PAMP 
to enlist the full functionality of the innate immune system, to generate cross-talk with the 
adaptive immune system via enhanced antigen presentation and thereby to boost the anti-tumor 
efficacy of checkpoint inhibitors. 
 
Clinical Experience to Date   
Clinical benefit of Imprime PGG in NSCLC was demonstrated when Imprime PGG was added 
to carboplatin, paclitaxel, and cetuximab in a Phase 2 study of 90 patients with previously 
untreated stage IIIb/IV NSCLC. Patients received cetuximab without or with Imprime PGG 4 
mg/kg (2:1 randomization) on Days 1, 8, 15 of each 3-week treatment cycle with carboplatin 
and paclitaxel on Day 2 of each treatment cycle for the first 4 to 6 cycles.  If patients achieved 


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radiographic stability or response they received cetuximab or cetuximab/Imprime PGG 
maintenance treatment. Among all evaluable patients, median overall survival was 11.7 
months in the control group and 12.4 months in the Imprime PGG group (hazard ratio of 1.04, 
p=0.90 vs. control). The objective RR (ORR) based on the investigator radiology review of the 
primary efficacy population was 48% in the Imprime PGG group compared to 23% in the 
control group (p= 0.047 vs. control). Three-year survival could not be estimated in the control 
group and was 14% in the Imprime group. Adverse events were consistent with toxicities 
attributable to the carboplatin, paclitaxel, or cetuximab.37 
 
In another multicenter, open-label, international, Phase 2 trial with 92 patients, Imprime PGG 
in carboplatin and paclitaxel and bevacizumab was compared to chemotherapy and 
bevacizumab alone in patients with previously untreated stage IIIb/IV non-squamous NSCLC.  
In 3-week treatment cycles, patients received the standard dose of bevacizumab on Day 1, and 
standard doses of carboplatin and paclitaxel on Day 2 for 4 to 6 cycles, with or without Imprime 
PGG 4 mg/kg (2:1 randomization) on Days 1, 8 and 15.  Based on central independent 
radiology review of the primary efficacy population, Imprime PGG improved overall RR by 
approximately 17% percentage points (60.4% vs 43.5% in control group, p-value 0.2096). The 
duration of response was increased by 4.7 months in the Imprime PGG group (10.3 months vs 
5.6 in control group; p-value 0.940).  There was also a trend towards improved PFS (11.6 
months in Imprime PGG group vs 9.6 months in control group; p-value 0.5639) and OS (16.1 
months in Imprime PGG group vs 11.6 months in control group; hazard ratio 0.66; p-value 
0.1345), yielding a 34% reduction in the risk of death. Rates of overall and serious adverse 
events were similar between groups and were reflective of expected toxicities with the standard 
of care backbone therapy or complications of patients underlying cancer. The incidence of 
grade 3 or higher toxicities was higher in the Imprime PGG group overall with no clear 
preponderance of any specific organ system (93.2% vs 66.7%). Fatal adverse events in the 
Imprime PGG group were associated with progression of patient’s lung cancer. Overall, no 
significant increase in toxicity with the exception of grade 3/4 neutropenia (39% versus 26.7%) 
was observed.38 
 
Imprime PGG Dosing Schedule 
After 12 weeks (4 cycles) of weekly dosing of Imprime PGG during Phase II, the compound 
will be administered on a 3-weekly schedule coinciding with and preceding the administration 
of pembrolizumab on the first day of each cycle. The change to q3wk dosing during the Phase 
II aligns with the q3wk dosing of pembrolizumab and will follow two response assessments 
by RECIST v1.1 (CTs will be done prior to initiation of dosing at Cycle 3 and Cycle 5). 
Previous clinical experience with Imprime PGG in NSCLC indicate that most observed clinical 
responses have occurred within the first 12 weeks of dosing. There are no concerns that this 
change would negatively impact patient safety. This change is intended to explore whether 
parameters of innate immune responses (cytokines, chemokines, myeloid cell mobilization, 
complement activation, etc.) are maintained on a 3-week schedule with maintenance of clinical 
benefits in a more conveniently manageable clinical schedule. 
 
 


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1.2. Study Rationale  
There is recent convincing evidence that anti-PD-1 antibodies, like pembrolizumab, have efficacy in 
treating NSCLC. Imprime PGG improved the overall response rates and improved trends towards 
PFS and overall survival when given in conjunction with standard of care NSCLC therapy. Imprime 
PGG also increased PD-L1 expression in NSCLC cell lines. In addition, preclinical mechanistic 
studies have revealed that Imprime PGG acts as a PAMP to enlist the full functionality of the innate 
immune system, enhancing dendritic cell maturation and antigen presentation and eliciting T cell 
expansion to boost the anti-tumor efficacy of checkpoint inhibitors. The present study is an 
exploratory single-arm study consisting of a dose escalation Phase 1b component and a Phase 2 
component for combination therapy of pembrolizumab and Imprime PGG. The primary endpoint for 
the Phase Ib component is the maximum tolerated dose (MTD) of Imprime PGG in combination with 
pembrolizumab. For the Phase II component of the study, based upon the scientific evidence for 
Imprime PGG’s therapeutic effect, we hypothesize that addition of Imprime PGG to pembrolizumab 
will enhance therapeutic responses to pembrolizumab in second line setting of NSCLC. 
 
2. OBJECTIVES 
 
2.1. Phase Ib Objectives 
 
2.1.1. Primary Objective 
The primary objective of the Phase Ib dose escalation cohort study is to establish the maximum 
tolerated dose (MTD) of Imprime PGG in combination with pembrolizumab for subjects with 
metastatic non-small cell lung cancer (NSCLC) after progression on first-line platinum-based 
chemotherapy. 
 
2.1.2. Secondary Objectives 
 Characterize adverse effects (AE) of Imprime PGG in combination with pembrolizumab 
in subjects with NSCLC who progressed after first-line platinum-based chemotherapy. 
 Estimate clinical benefit rate (CBR: complete response, partial response, or stable disease) 
as measured by RECIST v1.1 of Imprime PGG in combination with pembrolizumab in 
subjects with NSCLC who progressed after first-line platinum-based chemotherapy. 
 Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects 
with NSCLC who progressed after first-line platinum-based chemotherapy when treated 
with Imprime PGG in combination with pembrolizumab.  
 Estimate overall survival (OS) and 1-year OS in subjects with NSCLC who progressed 
after first-line platinum-based chemotherapy when treated with Imprime PGG in 
combination with pembrolizumab.  
 
2.1.3. Correlative Objectives 
 Correlate biomarkers on immune cell subsets (including, but not limited to monocytes, 
macrophages, granulocytes, and lymphocytes, and PD-L1) concentrations and localization 
(peri- vs. intratumoral) in archived diagnostic tumor tissue with PFS and CBR. 
 Correlate change in soluble PD-L1 levels pre-dose Cycles 2 and 3, relative to baseline (i.e., 
pre-dose Day 1 of Cycle 1) level with PFS and CBR. 
 Correlate PD-L1 expression on circulating peripheral mononuclear cells from whole blood 
pre-dose Cycles 2 and 3, relative to baseline (i.e., pre-dose Day 1 of Cycle 1) level.   


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 Correlate baseline (i.e., pre-dose Day 1 of Cycle 1) anti-β-glucan antibody (ABA) (IgM, 
IgG) levels in serum with PFS and CBR. 
 Correlate baseline immune classifiers with PFS and CBR. 
 Correlate FcRIIa polymorphism to PFS and CBR.  
 
 
2.2. Phase II Objectives 
 
2.2.1. Primary Objective 
The primary objective of the Phase II trial is to estimate Progression-Free Survival (PFS) using 
RECIST v1.1 in subjects with metastatic non-small cell lung cancer (NSCLC) treated with 
Imprime PGG in combination with pembrolizumab after progression on first-line systemic 
therapy (either platinum-based chemotherapy with or without immune checkpoint inhibitor or 
immune checkpoint inhibitor as first line therapy).  
 
2.2.2. Secondary Objectives 
 Characterize adverse effects (AE) of Imprime PGG in combination with pembrolizumab 
in subjects with NSCLC who progressed after first-line systemic therapy. 
 Estimate clinical benefit rate (CBR: complete response, partial response, or stable disease) 
of Imprime PGG in combination with pembrolizumab in subjects with NSCLC who 
progressed after first-line systemic therapy. 
 Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects 
with NSCLC when treated with Imprime PGG in combination with pembrolizumab who 
progressed after first-line systemic therapy. 
 Estimate overall survival (OS) and 1-year OS in subjects with NSCLC treated with 
Imprime PGG in combination with pembrolizumab who progressed after first-line systemic 
therapy. 
 
2.2.3. Correlative Objectives 
 Correlate biomarkers on immune cell subsets (including, but not limited to monocytes, 
macrophages, granulocytes, and lymphocytes, and PD-L1) concentrations and localization 
(peri- vs. intratumoral) in archived diagnostic tumor tissue with PFS and CBR. 
 Correlate change in soluble PD-L1 levels pre-dose Cycles 2 and 3, relative to baseline (i.e., 
pre-dose Day 1 of Cycle 1) level with PFS and CBR. 
 Correlate PD-L1 expression on circulating peripheral mononuclear cells from whole blood 
pre-dose Cycles 2 and 3, relative to baseline (i.e., pre-dose Day 1 of Cycle 1) level. 
 Correlate anti-β-glucan antibody (ABA) (IgM, IgG) levels in serum with PFS and CBR. 
 Correlate baseline immune classifiers with PFS and CBR. 
 Correlate FcRIIa polymorphism to PFS and CBR.  
 
 


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3. ELIGIBILITY CRITERIA 
Study entry is open to adults regardless of gender or ethnic background. While there will be every effort 
to seek out and include women and minorities, the subject population is expected to be no different than 
that of other advanced solid tumor cancer studies at each participating institution. 
 
3.1. Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
1. Male or female ≥ 18 years of age at time of consent. 
2. Subjects with histologically or cytologically confirmed non-small cell lung cancer (NCSLC). 
3. Subjects with stage IV non-small cell lung cancer as defined by American Joint Committee on 
Cancer (AJCC) 7th Edition. Patients with locally advanced or recurrent disease who are 
candidates for systemic therapy are also allowed. 
4. Subjects without EGFR activating mutation (Exon 19 del, L858R) or ALK, ROS translocation 
if histology is adenocarcinoma. Subjects with an EGFR activating mutation or ALK 
translocation are eligible only after failing TKI therapy (such as gefitinib, erlotinib, or afatinib). 
Furthermore, if a T790M resistance mutation is found, the patient must have failed a 3rd 
generation TKI such as osimertinib  
5. Phase Ib: Subjects who progressed after first-line platinum-based chemotherapy and who are 
candidates for second-line therapy.  
Phase II: Subjects who have progressed on first-line systemic therapy (either platinum-based 
chemotherapy with or without immune checkpoint inhibitor or immune checkpoint inhibitor as 
first line therapy) who are candidates for second-line systemic therapy. Patients with early 
stage cancer will also be eligible if progression occurs: 
a. within 6 months of adjuvant chemotherapy after curative resection 
b. within 6 months of adjuvant chemotherapy after curative resection while on adjuvant 
immunotherapy, currently only available as part of a clinical trial 
c. within 6 months of curative surgery if chemotherapy is given in the neoadjuvant setting 
d. within 6 months of completion of chemoradiation (or 6 months from completion of 
consolidation chemotherapy if administered after concurrent chemoradiation) 
e. within 6 months of completion of chemoradiation or consolidation chemotherapy (if 
administered) while on consolidation immunotherapy, a setting for which durvalumab is 
FDA approved.  
Phase II: Subjects with an EGFR or ALK mutation who are no longer candidates for TKI 
therapy and have progressed on standard systemic therapy (either platinum-based 
chemotherapy with or without immune checkpoint inhibitor or immune checkpoint inhibitor as 
first line therapy). 
6. Phase II only: Measurable disease according to RECIST v1.1 (Section 8) obtained by imaging 
within 28 days prior to study registration. Phase Ib: subjects may enroll with or without 
measurable disease. 
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 within 
28 days prior to study registration. 
8. Life expectancy of 6 months or greater as determined by the treating physician.  
9. Adequate hepatic function within 28 days prior to study registration defined as meeting all of 
the following criteria: 
 total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects 
with total bilirubin levels > 1.5 x ULN (except subject with Gilbert’s Syndrome, who can 
have total bilirubin < 3.0 mg/dl) 


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 aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known 
hepatic metastases 
 alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known 
hepatic metastases 
10. Adequate renal function within 28 days prior to study registration defined by either of the 
following criteria:  
 Serum creatinine ≤ 3 mg/dL 
 if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min 
11. Adequate hematologic function within 28 days prior to study registration defined as meeting all 
of the following criteria: 
 hemoglobin ≥ 9 g/dL; subjects requiring transfusion will be eligible to start study  
 and absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
 and platelet count ≥ 100 × 109/L 
12. Adequate coagulation functioning within 28 days prior to study registration defined by either 
of the following criteria:  
 INR < 1.5 × ULN 
 for subjects receiving anticoagulant, the subjects must, in the investigator’s opinion, be 
clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. 
The INR for subjects on warfarin should be in the therapeutic range. Low molecular weight 
heparin (LMWH) is allowed. 
13. Provided written informed consent and HIPAA authorization for release of personal health 
information, approved by an Institutional Review Board (IRB).  
NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 
14. Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A negative 
serum or urine pregnancy test is required within 72 hours of study registration. If the urine test 
cannot be confirmed as negative, a serum pregnancy test will be required. 
15. Women of childbearing potential (WOCP) must be willing to use two effective methods of 
birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an 
intrauterine device (IUD), use of a double barrier method (condoms, sponge, diaphragm, or 
vaginal ring with spermicidal jellies or cream), or total abstinence for the course of the study 
until 120 days after the last dose of study drug.  
NOTE: Women are considered to be of childbearing potential unless they are postmenopausal 
(≥45 years of age and has not had menses for greater than 12 consecutive months), surgically 
sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or not heterosexually 
active for the duration of the study and at least 120 days after the last dose of study drug. 
16. Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of 
contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, 
or who could become pregnant during the study must agree to use condoms from the first dose 
of study drug through at least 120 days after the last dose of study drug. Total abstinence for 
the same study period is an acceptable alternative. 
17. Willingness and ability to comply with scheduled visits (including geographical distance), 
treatment plans, laboratory tests, and other study procedures. 
 
3.2. Exclusion Criteria  
Subjects meeting any of the criteria below may not participate in the study: 
1. Surgery within 4 weeks prior to study registration except for minor procedures.  
NOTE: Hepatic biliary stent placement, PleurX catheter, port placement, ureteral stent or other 
minor surgeries are allowed. NOTE: Subject must have adequately recovered from the toxicity 


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and/or complications of major surgery prior to study registration, as determined by the treating 
physician.   
2. Patients with known untreated or active central nervous system (CNS) metastases. Subjects 
suspected to have brain mets should undergo brain MRI (or CT head if MRI is not feasible) to 
exclude brain metastases. Patients with treated brain metastases will be eligible as long as their 
symptoms are improving or achieved new baseline and not requiring steroids for at least 2 
weeks. Patients with leptomeningeal disease will be excluded regardless of clinical stability. 
3. Previously received a solid organ transplant or allogeneic progenitor/stem cell transplant.   
4. Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of 
live vaccines include, but are not limited to: 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 (e.g. 
Flu-Mist®) are live attenuated vaccines and are not allowed. 
5. History of blood clots, pulmonary embolism, or deep vein thrombosis unless on adequate 
anticoagulant therapy as determined by the treating investigator (subject must be on stable dose 
for 2 weeks) and all symptoms have resolved. 
6. Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies]. 
7. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
8. Current use of immunosuppressive medication at time of study entry. The following are 
exceptions to this exclusion criterion: intranasal, inhaled, topical steroids, or local steroid 
injections (eg, intra-articular injection); steroids as premedication for hypersensitivity reactions 
(eg, CT scan premedication). Cases requiring systemic corticosteroids at physiologic doses 
must be discussed with Big Ten CRC and HiberCell prior to enrollment.  
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent. Exceptions include: patients with controlled diabetes type 1, controlled hypo- or 
hyperthyroidism, resolved childhood asthma/atopy, vitiligo, or psoriasis not requiring 
immunosuppressive treatment. 
10. Received prior chemotherapy, an immune checkpoint inhibitor, or radiation therapy within 2 
weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events from previously administered agents.  
NOTE: Subjects with alopecia, lymphopenia, grade ≤ 2 sensory neuropathy or other grade ≤ 2 
AEs not constituting a safety risk based on investigator judgement are an exception to this 
criterion and can still be considered for the study. 
11. Any clinically significant or active infection requiring anti-infective treatment. Patients with 
infection that is adequately treated will be eligible.  
12. History of interstitial lung disease requiring immunosuppressive/steroids or history of 
immunotherapy related pneumonitis that has required steroids or immunosuppression in the 
past 
13. Known history of active tuberculosis. 
14. Any other severe, uncontrolled medical condition, including uncontrolled diabetes mellitus 
(defined as a Hemoglobin A1C ≥ 9% in subjects with a prior history of diabetes, 28 days prior 
to study registration) or unstable congestive heart failure (Stage III-IV of the New York Heart 
Association Functional Classification) 
15. Previous known allergy or intolerance to pembrolizumab or any of its excipients 
16. Previous exposure or known allergy to Imprime PGG or any of its excipients 
17. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human 
antibodies 


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18. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration, interfere with protocol compliance, or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject inappropriate for 
enrollment in this study. 
19. Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study 
registration. 
20. Any mental or medical condition that prevents the subject from giving informed consent or 
participating in the trial. 
21. No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, in situ breast cancer, Gleason ≤ grade 7 prostate cancers, low 
grade papillary urothelial carcinoma or other cancer for which the subject has been disease-free 
for at least 2 years. And no additional therapy other than hormonal therapy is required or 
anticipated to be required during the trial period. 
22. Treatment with any therapeutic investigational agent within 28 days prior to study registration. 
 
 
4. SUBJECT REGISTRATION  
All subjects must be registered through BTCRC Administrative Headquarters’ electronic data capture 
(EDC) system. A subject is considered registered when an ‘On Study’ date is entered into the EDC 
system. A subject is considered registered when an ‘On Study’ date is entered into the EDC system.  
Subjects must be registered prior to starting protocol therapy.  
 
 
5. OVERALL DESIGN AND TREATMENT PLAN   
 
5.1. Phase Ib Dose Escalation Study 
This Phase Ib dose escalation study will evaluate pembrolizumab in combination with Imprime 
PGG in subjects with metastatic NSCLC after failure of first-line platinum-based chemotherapy. 
Imprime PGG will be given on Day 1, 8 and 15 and pembrolizumab will be given on Day 1 of each 
21-day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject 
refusal, or subject death either from progression of disease, the therapy itself, or from other causes, 
or completion of 16 cycles of treatment. Subjects who voluntarily stop the study, have progressive 
disease, or unacceptable toxicities will be followed for up to 5 years from the start of study 
medication.  
 
Dose 
Cohort 
# of Subjects 
Imprime PGG Pembrolizumab 
(mg) 
1 
3-6 
2 mg/kg 
200 
2 
3-6 
4 mg/kg 
200 
 
5.1.1. Dose Escalation Rules and MTD Definition 
 Three to six subjects will initially be enrolled at dose level 1. If none of the 3 subjects 
experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 
three subjects will be enrolled at dose level 2. If all subjects in dose level 2 complete the 
first cycle of therapy without DLT, 3 more subjects will be enrolled into dose level 2 to 


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ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose 
level 2. 
 
 Alternatively, if 1 of the first 3 subjects within a dose level cohort experiences a DLT, the 
cohort will be expanded to 6 subjects. If this happens within dose level 1 and only 1 of the 
total 6 subjects in dose level 1 experience DLT, the study will proceed to dose level 2. If 2 
or more of 6 subjects in a cohort experience DLTs, or 2 subjects within a cohort of 3 
subjects experience DLT during the first cycle of therapy (>33% of subjects experiencing 
DLT), the MTD is exceeded. If this occurs at dose level 2, 3 additional subjects will be 
enrolled into dose level 1, unless there have been 6 subjects already enrolled into dose level 
1. 
 
 The maximum tolerated dose of Imprime PGG in combination with pembrolizumab is the 
highest tested dose of Imprime PGG combined with pembrolizumab with DLT rate of less 
than 33% in first cycle of therapy (i.e., ≤1 out of 6 subjects with DLT). That dose will be 
recommended for the Phase II study.  
 
 At the discretion of the sponsor-investigator, a lower phase II dose may be recommended 
if other toxicity emerges during the Phase Ib study which does not meet DLT criteria but 
limits the dose that can be administered cumulatively. 
 
5.1.2. Definition of Dose Limiting Toxicity 
Dose limiting toxicity (DLT) is defined as one of the following events occurring during cycle 
1:   
 Grade 3 or greater treatment-related excluding: 
o Grade 3-4 nausea and/or vomiting that resolves in 72 hours. 
o Grade 3-4 laboratory abnormalities that are not clinically significant and which resolve 
in 72 hours. 
o Grade 3 fatigue lasting < 5 days. 
 Delay of cycle 2 treatment start by more than 2 weeks due to unresolved treatment related 
grade 3 or greater non-hematologic toxicity. 
 
DLTs will be counted based on the number of subjects with DLT at a given dose level, not the 
absolute number of DLTs. No single subject can trigger more than one DLT event.  
 
Additional subject cohorts will not be enrolled at the second dosing level until all subjects at 
the initial dosing level complete all planned treatment for cycle 1 (defined as 1 dose of 
pembrolizumab, and 3 doses of Imprime PGG) and are able to start cycle 2 with no more than 
a 2-week delay. 
 
Intra-subject dose escalation is not permitted. 
 
Once the maximum tolerated dose of pembrolizumab in combination with Imprime PGG is 
determined, enrollment will continue until at least 6 subjects total are accrued at the maximum 
tolerated dose. 
 
 


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5.2. Phase II Study 
The primary objective of the Phase II trial is to determine the activity of the combination of 
pembrolizumab and Imprime PGG in second line therapy for subjects with NSCLC as assessed by 
progression-free survival (PFS). Pembrolizumab will be given on Day 1 of each 21 day cycle after 
Imprime PGG, and the RP2D dose of Imprime PGG will be given on Days 1, 8 and 15 for Cycles 
1-4, and on Day 1 only for Cycles 5-16 of each 21 day cycle. Treatment will continue up to 16 
cycles, or until disease progression, unacceptable toxicity, subject refusal, or subject death either 
from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop 
the study, have progressive disease, or unacceptable toxicities will be followed for a total of 5 years.  
 
5.3. Correlative Research (all phases) 
Correlative research analyses include examining the relationship between clinical response at the 
end of Cycle 2 (Week 6) with biomarkers on immune cell subsets (including, but not limited to 
monocytes, macrophages, granulocytes, and lymphocytes, and PD-L1) concentrations and 
localization (peri- vs. intratumoral) in archived diagnostic tumor tissue with PFS and CBR. 
Research analyses also include examining the relationship between changes in soluble PD-L1 level 
and PD-L1 expression on circulating mononuclear cells at baseline (i.e., pre-dose Day 1 of Cycle 
1) and during therapy (assessed pre-dose on Day 1 of Cycles 2 and 3) and correlated with PFS and 
to CBR. Additionally, baseline immune classifiers, FcRIIa polymorphism, and anti-β-glucan 
antibody (ABA) (IgM, IgG) levels will be correlated with PFS and CBR.  
 
5.4. Imprime PGG Pre-medication  
Each cycle will be 3 weeks in duration. The most common adverse events leading to treatment 
discontinuation of Imprime PGG in clinical trials as of the Imprime PGG Investigator’s Brochure 
Edition 10 (October 29, 2014) included infusion related reactions/hypersensitivity (rash, nausea, 
dyspnea, tachycardia, urticaria, hypersensitivity). In addition, in a trial comparing Imprime PGG in 
combination with bevacizumab and concomitant paclitaxel and carboplatin (BPC) versus the BPC 
chemotherapy combination without Imprime PGG, events potentially associated with 
hypersensitivity reactions occurred more frequently in the Imprime PGG arm. These included one 
grade 3 event of anaphylactic reaction deemed related to Imprime PGG. Based on this, Imprime PGG 
premedication is recommended, but not mandated. Subjects may receive pre-medication as outlined 
below before dosing of Imprime PGG on each treatment day and as needed post-dosing. 
 
 Cycle 1/Day 1: Pretreat with an H1 antagonist (e.g., 25- 50 mg of diphenhydramine PO or IV) 
along with ranitidine (or equivalent) 50 mg IV or 150 mg PO. 
 Subsequent cycles: Premedication is allowed but preferably would be at reduced doses of those 
used at Cycle 1 Day 1. 
 
 


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5.5. Drug Administration 
5.5.1. Table 1 Phase Ib Imprime PGG + Pembrolizumab Administration:  
 
Drug 
Administration 
Sequence 
Dose1 
Length and route 
of administration 
Frequency of 
administration 
Length 
of cycle 
Imprime PGG 
1st 
2 mg/kg 
2-4 hours2; 
IV 
Day 1, 8, 15 
21 days 
4 mg/kg 
Pembrolizumab 
2nd  
(15-30 minutes post 
Imprime PGG) 
200 mg 
30-min (-5/+10); 
IV 
Day 1 
1Dose of Imprime PGG for phase Ib varies dependent on dose cohort; either 2 or 4mg/kg will be used for phase II.  
2Length of infusion for Imprime PGG will vary dependent on dose and subject’s weight (See section 10 for additional 
information). 
 
Phase Ib: Dosing will occur in 21-day cycles. Imprime PGG in the Phase Ib dose escalation 
study will be dosed at 2 mg/kg IV or 4 mg/kg IV on Day 1, 8, and 15 of the 21 day cycle. On 
day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 
minutes later by the pembrolizumab infusion. Imprime PGG will be administered as a 2-4 hour 
intravenous infusion, based on dose and the subject’s weight. Extended infusion times are 
acceptable and will not incur a deviation; the rate of infusion should not be increased. See 
section 10 and the Imprime PGG Pharmacy Manual.  
 
Pembrolizumab will be administered as a 30-minute intravenous infusion. Given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
 
5.5.2. Table 2 Phase II Imprime PGG + Pembrolizumab Administration: 
 
Drug 
Administration 
Sequence 
Dose1 
Length and route 
of administration 
Frequency of 
administration 
Length 
of cycle 
Imprime PGG 
1st 
At RP2D 
(4mg/kg) 
2-4 hours2; 
IV 
Cycles 1-4: 
Day 1, 8, 15 
21 days 
Cycles 5-16: 
Day 1 
Pembrolizumab 
2nd  
(15-30 minutes post 
Imprime PGG) 
200 mg 
30-min (-5/+10); 
IV 
Day 1 
1Dose of Imprime PGG for phase Ib varies dependent on dose cohort; For phase II, Imprime PGG dose will 
be 4mg/kg as determined by phase Ib part of the study; RP2D = Recommended Phase 2 Dose. 
2Length of infusion for Imprime PGG will vary dependent on dose and subject’s weight (See section 10 for 
additional information). 
 
Phase II: Imprime PGG will be dosed at the dose established as the MTD in Phase Ib (4mg/kg) 
on Day 1, 8, and 15 for Cycles 1-4, and on Day 1 only for Cycles 5-16 of the 21 day cycle. 
Pembrolizumab will be infused at 200 mg on Day 1 of the 21 day cycle. On day 1 of each 
cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by 


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the pembrolizumab infusion. Imprime PGG will be administered as a 2-4 hour intravenous 
infusion, based on dose and the subject’s weight. Extended infusion times are acceptable and 
will not incur a deviation; the rate of infusion should not be increased. See section 10 and the 
Imprime PGG Pharmacy Manual. 
 
Pembrolizumab will be administered as a 30-minute intravenous infusion. Given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
 
Subsequent cycles must meet the criteria found in section 6.1 and may begin 1 day earlier or 
up to 2 days later to accommodate scheduling issues. 
 
For All Phases of Study: 
 Please note that the infusion timeline is approximate and may vary depending on the 
individual subject (weight and reaction to former treatment with study drugs may alter 
length of treatment and monitoring).  
 
 The Imprime PGG dose should be recalculated if the subject’s weight changes by ≥ 10%.  
 
5.5.3. Monitoring:  
 Vital signs including blood pressure, pulse, temperature, respirations, and pulse oximetry, 
will be measured as follows: 
o Imprime PGG infusion: prior to infusion, every 2 hours during infusion (±15 min), and 
within 30 minutes of the completion of the Imprime PGG infusion (and prior to 
pembrolizumab infusion). 
o Pembrolizumab infusion: prior to infusion (NOTE: this can be same as the post 
Imprime PGG infusion timepoint) and within 10 minutes of infusion completion.  
 Subjects will be closely monitored for toxicities. Toxicity will be assessed using CTCAE 
version 4.  
 
5.6. Supportive Care 
Optimal care should be given to all subjects. 
 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be 
given in subsequent cycles to the administration of prophylactic antiemetic therapy according to 
standard institutional practice. If prophylactic antiemetic therapy is needed, 5-HT3 receptor 
antagonists (without corticosteroids) should be tried first. Due to the potential of benzodiazepines to 
cause sedation, the use of benzodiazepines for antiemetic prophylaxis should be reserved for subjects 
who cannot be satisfactorily managed otherwise. Subjects should be strongly encouraged to maintain 
liberal oral fluid intake. 
 
Subjects should receive full supportive care during the study, including transfusion of blood and 
blood products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, when 
appropriate.  
 
Although acetaminophen at doses of ≤2 grams/day is permitted, it should be used with caution in 
subjects with impaired liver function.  
 
 


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5.6.1. Pembrolizumab Supportive Care 
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 in Table 4.  
 
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, the investigator does 
not need to follow the treatment guidance (as outlined in Table 4). 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
5.7. Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for one of these or other medications or vaccinations 
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-investigator 
by contacting the BTCRC Project Manager. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician. 
 
5.7.1. Permitted Concomitant Medications and Procedures  
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the electronic case report form 
(eCRF).  
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered beyond 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 11.  
 
Myeloid growth factors to treat subjects with neutropenia according to the American Society 
of Clinical Oncology (ASCO) Guidelines are permitted. Myeloid growth factors should be 
avoided (if medically appropriate) in Cycle 1 until subjects have developed a DLT or dose-
limiting Grade 4 neutropenia.  
 
Antiemetic agents may be administered at the discretion of the investigator but are not 
commonly required as a prophylactic agent. All other manifestations of the subject’s 
malignancy should be treated at the discretion of the investigator.  


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Medications with potential CNS effects are not prohibited in this study, but it is recommended 
that their use be minimized to avoid confusion in the interpretation of CNS effects should they 
occur during the course of treatment with pembrolizumab and Imprime PGG. 
 
In appropriate settings, such as combinations with agents known to produce frequent 
thrombocytopenia, restricted uses of anticoagulants should be considered.  
 
All other medical conditions should be treated at the discretion of the investigator in 
accordance with local community standards of medical care. 
 
5.7.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy not specified in this protocol 
 Immunotherapy not specified in this protocol 
 Concomitant use of chemotherapy  
 Investigational agents other than Imprime PGG 
 Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with sponsor-investigator via the BTCRC Project Manager.  
 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 (e.g. 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-investigator via the 
BTCRC Project Manager.  
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.8. Diet/Activity/Other Considerations 
 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 
 
Contraception: 
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.  
 


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It is not known if Imprime PGG has adverse effects on a fetus in utero nor if there are adverse effects 
on the composition of sperm.  
 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of 
birth control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 
1) surgically sterilized (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 12 
consecutive months), or 3) not heterosexually active for the duration of the study and at least 120 
days after the last dose of study drug. The two birth control methods can be either two barrier methods 
or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from the first study visit, throughout the study period, and up to 120 days after the last dose 
of study drug.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
 
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 they 
must adhere to the contraception requirements described above for the duration of the study and 120 
days following the last dose of study drug. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
 
Use in Pregnancy: 
If a subject inadvertently becomes pregnant while on study, 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 BTCRC Administrative Headquarters (AHQ) immediately and within 24 hours if the outcome is a 
serious adverse experience (e.g., 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 BTCRC AHQ. BTCRC AHQ will report the event to Merck and HiberCell. 
 
If a male subject impregnates his female partner, he must immediately inform the site study personnel 
and the pregnancy reported to BTCRC AHQ and to Merck and followed as described above and in 
Section 11. BTCRC AHQ will report the event to Merck and HiberCell. 
 
Use in Nursing Women: 
It is unknown whether pembrolizumab or Imprime PGG 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. 
 
 


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6. DOSE DELAYS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used to grade 
adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests before and at 
regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring protocol therapy interruption or discontinuation at each study visit for the duration of their 
participation in the study.   
 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated 30 days (± 
7) after the last dose of protocol therapy. 
 
6.1. Start of a New Cycle 
A new treatment cycle will only be initiated when all of the following conditions are met: 
 
ANC ≥ 1,000× 109/L  
 
platelets ≥ 80 × 109/L  
 
non-hematologic treatment related ≥ grade 3 toxicities need to improve to either ≤ Grade 1 or as 
specified in table 4 or to the subject’s baseline values (except alopecia) 
 
If toxicities are outside the acceptable threshold, the subject should be assessed weekly (phone or 
clinic) until toxicities are at an acceptable level. Missed doses will not be made up. If treatment is 
unable to restart within 12 weeks of the planned treatment date, the subject will be permanently 
discontinued from study therapy (both pembrolizumab and Imprime PGG should be stopped).   
 
NOTE:  For cycle 1 only, the inability to start cycle 2 within 2 weeks of the planned date is a DLT; 
however, the subject is allowed an additional week of recovery and is allowed to remain on study if 
treatment restarts within 12 weeks. 
 
6.2. Management of Allergic Reaction/ Hypersensitivity 
 
6.2.1. Imprime PGG 
In case of severe adverse events during infusion of Imprime PGG, the infusion may be interrupted at 
the discretion of the treating physician for 30-60 minutes and restarted when the adverse event has 
resolved. Alternatively, the infusion rate may be decreased by 50% instead of, or after, interruption 
at the discretion of the treating physician.  Management of adverse events should include treatments 
as indicated by symptoms. 
 
An appropriate resuscitation plan should in place and a physician readily available during the period 
of drug administration. 
 
6.2.2. Pembrolizumab 
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.  
 


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Table 3 provides treatment guidelines for subjects who experience an infusion related reaction 
associated with administration of 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 infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion and monitor symptoms. 
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 
(e.g., 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 trial 
treatment administration.
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
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 trial treatment administration.
No subsequent dosing 
Appropriate resuscitation equipment should be available and a physician readily available during the 
period of drug administration. 


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6.3. Other Adverse Event Guidelines 
If treatment is delayed longer than 12 weeks, the subject will be discontinued from study treatment 
(both pembrolizumab and Imprime PGG should be stopped).  
 
6.4. Dose Modifications 
6.4.1. Pembrolizumab Dose Modifications  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These immune-related AEs (irAEs) may occur shortly after the 
first dose or several months after the last dose of pembrolizumab treatment and may affect more than 
on body system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical study 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, 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 in Table 4 below. 


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Table 4: Dose modification 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 
(CTCAEv4.0) 
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 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 Monitor participants for signs and 
symptoms of pneumonitis 
 Evaluate participants 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 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 Monitor participants 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). 
 Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
 Participants 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 1-2 mg/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 participants with 
T1DM  
 Administer anti-hyperglycemic in 
participants with hyperglycemia 
 Monitor participants 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 
discontinue1  
Hyperthyroidism 
Grade 2 
Continue  
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 Monitor for signs and symptoms of 
thyroid disorders.  
Grade 3 or 4  
Withhold or permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid replacement 
hormones (eg, 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 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes 
Grade 3 or 4 
Permanently discontinue 
All other immune-
related AEs 
Intolerable/ persistent 
Grade 2 
Withhold 
 Based on type and severity of AE 
administer corticosteroids  
 Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes 
Grade 3 
Withhold or discontinue 
based on the type of event.  
Events that require 
discontinuation include and 
not limited to:  Guillain-
Barre Syndrome, 
encephalitis
Gr. 4 or recurrent Gr. 3  
Permanently discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE: For participants 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).   
 
Other allowed dose interruption for pembrolizumab 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., elective surgery, 
unrelated medical events, subject vacation). Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the BTCRC Project Manager. The reason for interruption should be documented in the subject's study record. 


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7. STUDY CALENDAR & EVALUATIONS [Cycle = 21 days] 
Study Day 
Screen 
All Phases: 
Cycle 1-44 (±3)
Phase Ib: 
Cycle 5-16 
Phase II: 
Cycle 5-16
Every 2/3 
cycles
Safety  
Follow Up
Long-term  
Follow Up (±14)
-28 
days 
Day 
14 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 1 (± 3) 
C 3, 5, etc. 
Day 1 (±7) 
30 days 
(±7) post 
last dose
Q3 mos for 1 yr;  
Q6 mos for yrs 2-5
REQUIRED ASSESSMENTS 
 
Informed Consent/ HIPAA auth. 
X
 
Medical Hx: prior Tx, pathology, trial awareness question
X
 
Substance use: smoking history (amt, freq, start/stop)
X
 
Physical examination, height (screen only), weight
X
X
X
 
X
X
Vital Signs (BP, pulse, temp, resp. and pulse ox. See 5.5.3)
X
X
X
X
X
X
X 
X
X
ECOG performance status 
X
X
C19
C19
X
 
X
X
Blood Chemistries1 
X
X
C19
C19
X
 
X
Thyroid Function (TSH, T3, T4) 
X
C2-4
X
 
X
PT/INR and aPTT 
X
C1
C19
C19
 
Platelets, ANC & Hgb 
X
X
C19
C19
X
 
X
Urinalysis  
X
X
C19
C19
X
 
X
Pregnancy test for WOCP6 
-72h
 
AE, ECI and irAE assessment 
X
X
C19
C19
X
 
X
X5
Concomitant medications 
X
X
C19
C19
X
 
X
X
Survival 
 
X
DISEASE ASSESSMENT 
 
CT chest, abdomen/pelvis 
X2
 
X2
X10
CT or MRI Brain, if indicated. See Section 3.2.2. 
[X]
 
TREATMENT 
 
Imprime PGG 
X
X
X
X
X
X 
X
Pembrolizumab 
X
X
 
X
CORRELATIVE STUDIES 
 
Unstained slides from archived tumor tissue3 
C1
 
Whole blood for soluble PD-L1and PBMCs 
C1-37
 
Blood for FcRIIa polymorphism  
 
C18 
 
 
 
 
 
 
 
 
 
Phase Ib: Blood for ABAs (Imprime)11 
C1
 
Phase II: Blood for ABAs (Imprime) pre/post infusion11
C1-3
 
C5, 6, 7
Blood for immune classifiers 
C18
 
BANKINGSAMPLES 
 
Whole Blood12 
C1
 
Unstained slides from archived tumor tissue13 
C1
 
Serum and plasma14 
C1
 
X


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Footnotes: 
1: Blood Chemistries to include: sodium, potassium, serum creatinine (or GFR; see 3.1.11), calcium, albumin, ALT, AST, bilirubin, alkaline phosphatase, 
total protein  
2: Appropriate scans to assess disease status will be obtained within 28 days of study registration including CT chest, abdomen/pelvis. CT pelvis is only 
required if there are known pelvic mets. During treatment, scans to assess disease status will be done every 2 cycles, starting within one week before Cycle 
3 Day 1. If the subject has achieved at least stable disease after 7 cycles, disease assessment may be performed every 3 cycles thereafter until disease 
progression.  
3: Submission of unstained slides from archived tumor tissue for (1) evaluation of concentrations and localization (peri- vs. intra-tumoral) of biomarkers on 
immune cell subsets (including monocytes, macrophages, granulocytes, and lymphocytes) and (2) evaluation of expression of PD-L1are to be submitted 
after the subject is registered to the trial. These must be submitted prior to Cycle 2. If archived tumor tissue is not available, the subject does not need to 
undergo a biopsy to obtain tissue. See CLM for collection, labeling and shipping instructions.  
4: For cycle 1 only: labs do not need to be repeated if done within 7 days of day 1. All infusions may be given ±3 days for reasons such as observed 
holidays, inclement weather, scheduling conflicts, etc. This should be clearly documented in subject’s chart and case report forms. 
5: For subjects with unresolved treatment related toxicity, follow as medically appropriate until resolution or stabilization  
6: A negative serum or urine pregnancy test is required within 72 hours of study registration. If the urine test cannot be confirmed as negative, a serum 
pregnancy test will be required.  
7: Whole blood for serum (soluble PD-L1 level, PD-L1 expression on circulating mononuclear cells analyses) will be collected before drug treatment on 
Day 1 of Cycles 1, 2, and 3. See CLM for collection, processing, labeling and shipping instructions.  
8: Whole blood for serum (FcRIIa polymorphism and immune classifiers) will be collected before drug treatment on Day 1 of Cycle 1. See CLM for 
collection, processing, labeling and shipping instructions. 
9: Phase Ib only: To be performed weekly (Days 1, 8, and 15) during Cycle 1 (DLT evaluation period).  
10: Disease assessment will be performed every 6-months for subjects who did not progress during treatment 
11: Phase Ib: Whole blood for serum ABA analyses will be collected before study drugs on Day 1 of Cycle 1. 
Phase II: Whole blood for serum ABA (Imprime) and other immune correlates. Subjects will have ABAs collected pre/ post Imprime PGG infusion at: 
Cycles 1, 2, 3, 5, 6, and 7.  
12: Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling and shipping 
instructions. 
13: Submission of unstained slides for banking from an archived FFPE tumor block is requested. See CLM for collection, labeling, and shipping 
instructions. 
14: Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the Safety Follow Up visit. See CLM for 
collection, labeling, processing, and shipping instructions.


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7.1. Screening Evaluations 
 
7.1.1. Within 28 days prior to study registration 
 Informed consent, HIPAA authorization 
 Medical history including prior therapies, pathology and trial awareness question. 
 Substance use: smoking history. To include: amount, frequency, start and stop dates of 
cigarette, cigar and pipe usage.  
 Physical exam, height (screening only), weight 
 Vital signs (blood pressure, heart rate, temperature) 
 ECOG performance status 
 Blood chemistries (sodium, potassium, serum creatinine [or GFR; see 3.1.11], calcium, 
albumin, ALT, AST, bilirubin, alkaline phosphatase, total protein) 
 Thyroid function (TSH, T3, T4). T3, T4: free or total as per local standards. 
 PT/INR and aPTT 
 Platelets, ANC and hemoglobin 
 Urinalysis 
 Baseline signs and symptoms 
 Concomitant medications 
 CT chest, abdomen, pelvis. CT pelvis is only required if there are known pelvic mets. 
 CT or MRI of brain, if indicated. See Section 3.2.2. 
 
7.1.2. Within 72 hours prior to study registration 
 Pregnancy test for women of childbearing potential (WOCP). A negative serum or urine 
pregnancy test is required within 72 hours of study registration. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
7.2. On Treatment (±3) 
7.2.1. Cycle 1 Day 1: 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 Physical exam, weight 
 Vital signs (blood pressure, heart rate, temperature respirations, and pulse oximetry). See 
Section 5.5.3. 
 ECOG performance status 
 Blood chemistries  
 PT/INR and aPTT 
 Platelets, ANC and hemoglobin 
 Urinalysis 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related adverse 
events (irAE) 
 Concomitant medications 
 Imprime PGG 
 Pembrolizumab 
 Correlative samples: 
o Pre-dose serum sample for analysis of soluble PD-L1 level and PD-L1 expression on 
circulating mononuclear cells. 


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o Phase Ib: Pre Imprime PGG infusion: Serum for anti-β-glucan antibodies (ABAs), 
Imprime 
o Phase II: Pre and post Imprime PGG infusion: Serum for anti-β-glucan antibodies 
(ABAs), Imprime 
o Serum for immune classifiers 
o See Correlative Laboratory Manual (CLM) for specific instructions. 
 Banking samples.  
o Whole blood 
o Unstained slides from archived tissue 
o Serum and plasma 
o See CLM for specific instructions. 
 
7.2.2. Phase Ib: Cycle 1 Days 8, 15 
 Vital signs. See Section 5.5.3. 
 ECOG performance status 
 Blood chemistries  
 PT/INR and aPTT 
 Platelets, ANC and hemoglobin 
 Urinalysis 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related adverse 
events (irAE) 
 Concomitant medications 
 Imprime PGG 
 
7.2.3. Phase II: Cycle 1 Days 8, 15:  
 Vital signs (blood pressure, heart rate, temperature respirations, and pulse oximetry). See 
Section 5.5.3. 
 Imprime PGG  
 
7.2.4. Cycles 2-4 Day 1: 
 Physical exam, weight 
 Vital signs. See Section 5.5.3. 
 ECOG performance status 
 Blood chemistries  
 Thyroid function (TSH, T3, T4). T3, T4: free or total as per local standards. 
 Platelets, ANC and hemoglobin 
 Urinalysis 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related adverse 
events (irAE) 
 Concomitant medications 
 Imprime PGG 
 Pembrolizumab 
 Correlative samples: 
o Prior to Cycle 2: unstained slides from archived tissue for analysis of concentrations 
and localization (peri- vs. intratumoral) of NK cells, neutrophils, CD8+ T cells and 
PD-L1 biomarkers.  


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o Cycle 2 and Cycle 3 pre-dose serum samples for analysis of soluble PD-L1 level and 
PD-L1 expression on circulating mononuclear cells.  
o Phase II only: Pre and post Imprime PGG infusion Cycles 2, 3, 5, 6, 7: Serum for 
anti-β-glucan antibodies (ABAs) 
o See CLM for specific instructions. 
 
7.2.5. Cycles 2-4 Days 8, 15:  
 Vital signs (blood pressure, heart rate, temperature respirations, and pulse oximetry). See 
Section 5.5.3. 
 Imprime PGG.  
o NOTE: For Phase II: Imprime PGG will be given on Day 1 of each cycle after cycle 4.  
 
7.2.6. Cycles 5-16 Day 1: 
 Physical exam, weight 
 Vital signs. See Section 5.5.3. 
 ECOG performance status 
 Blood chemistries  
 Thyroid function (TSH, T3, T4). T3, T4: free or total as per local standards. 
 Platelets, ANC and hemoglobin 
 Urinalysis 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related adverse 
events (irAE) 
 Concomitant medications 
 Imprime PGG 
 Pembrolizumab 
 Phase II Correlative samples: 
o Cycle 5, 6, 7: Pre and post Imprime PGG: serum for anti-β-glucan antibodies (ABAs) 
o See CLM for specific instructions. 
 
7.2.7. Phase Ib: Cycles 5-16 Days 8, 15: 
 Vital signs (blood pressure, heart rate, temperature respirations, and pulse oximetry). See 
Section 5.5.3. 
 Imprime PGG  
 
7.2.8. Day 1 of Every 2/3 Cycles (±7 days): 
 CT chest, abdomen, pelvis every 2 cycles while on study, starting within one week before 
Cycle 3 Day 1. CT pelvis is only required if there are known pelvic mets. If the subject has 
achieved at least stable disease after 7 cycles, disease assessment may be performed every 
3 cycles thereafter until disease progression. 
 
7.3. Off Treatment 
7.3.1. Protocol therapy discontinuation: 
A subject will be discontinued from the protocol therapy under the following circumstances: 
 The subject completes the maximum of 16 cycles of study drug. 
 If there is evidence of disease progression  


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 If the treating physician thinks a change of therapy would be in the best interest of the 
subject 
 If the subject requests to discontinue protocol therapy 
 If the protocol therapy exhibits unacceptable toxicity 
 If a female subject becomes pregnant  
 If there is a ≥ 12-week delay between cycles due to a treatment related adverse event.  
 Subjects can stop study participation at any time. However, if they decide to stop, subjects 
will continue to be followed for survival for 5 years after start of study treatment.  
 
7.3.2. Safety Follow-up Evaluations (±7 days): 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated 
30 days (± 7) after the last dose of study drug or before the initiation of a new anti-cancer 
treatment, whichever comes first. 
 Physical exam, weight 
 Vital signs (blood pressure, heart rate, temperature) 
 ECOG performance status 
 Assess adverse events (AE), events of clinical interest (ECI) and immune-related adverse 
events (irAE) 
 Concomitant medications 
 Banking samples 
o Serum and plasma 
o See CLM for specific instructions. 
 
7.3.3. Long Term Follow-up Evaluations (±14 days): 
 Subjects will continue to be followed for survival every 3 months for the first year from 
the start of study treatment. Thereafter, subjects will be followed for survival every 6 
months for years 2-5 from the start of study treatment. 
 Disease assessment via CT scan will be performed every 6 months for subjects who did 
not progress during treatment. 
 
8. CRITERIA FOR DISEASE EVALUATION 
Response assessments will be made using RECIST v1.1. The same measurable and non-measurable 
lesions will be followed by RECIST v1.1. Disease progression will be determined using RECIST v1.1 
criteria. 
 
8.1. Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 
8.1.1. Measurable disease 
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
8.1.1.1. Measurable lesions:  
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
8.1.1.2. Non-measurable lesions:  


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All other lesions (or sites of disease), including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
8.1.1.3. Malignant lymph nodes.   
To be considered pathologically enlarged and measurable, a lymph node must be >15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
8.1.1.4. Baseline documentation of “Target” and “Non-Target” lesions:  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.   
Target lesions. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up. 
 
 
 


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8.2. Response Criteria for Target Lesions 
 
8.2.1. Evaluation of Target Lesions: 
 
Table 5: Target Lesions Evaluation Response Criteria 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study 
 
8.2.2. Evaluation of Non-Target Lesions: 
 
Table 6: Non-Target Lesion Evaluation Response Criteria 
Response Criteria 
Evaluation of non-target lesions 
* Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
* Incomplete Response/  
  Stable Disease (SD) 
Persistence of one or more non-target 
lesion(s) or/and maintenance of tumor 
marker level above the normal limits 
* Progressive Disease (PD) 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions* 
* Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances. 
 
8.3. Evaluation of Best Overall Response: 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the subject's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
 
 


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Table 7: Best Response Evaluation: 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-PD/ 
not evaluated
No 
PR 
SD 
Non-CR/ Non-PD/ 
not evaluated
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
8.4. Definitions for Response Evaluation –RECIST version 1.1 
 
8.4.1. First Documentation of Response:  
The time between initiation of therapy and first documentation of PR or CR. 
8.4.2. Confirmation of Response:  
To be assigned a status of complete or partial response, changes in tumor measurements must 
be confirmed by repeat assessments performed no less than four weeks after the criteria for 
response are first met. 
8.4.3. Duration of Response:  
Duration of overall response—the period measured from the time that measurement criteria 
are met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
8.4.4. Duration of Overall Complete Response:  
The period measured from the time that measurement criteria are met for complete response 
until the first date that progressive disease is objectively documented. 
8.4.5. Response rate:  
The response rate is the proportion of all subjects with confirmed PR or CR according to 
RECIST v1.  


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8.4.6. Clinical Benefit Rate: 
The proportion of subjects with a confirmed complete response, a partial response or stable 
disease based on RECIST v1.1. 
8.4.7. Progression-Free Survival: 
A measurement from the start of the treatment until the criteria for disease progression is met 
as defined by RECIST v1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. Subjects that receive at least one dose of 
study treatment and complete 1 post-baseline disease assessment or die prior to the first post 
baseline disease assessment will be considered evaluable for PFS. 
8.4.8. Overall Survival 
A measurement from the start of the treatment until death from any cause. Subjects alive at 
last time of contact will be right-censored. 
 
 
9. BIOLOGICAL CORRELATIVES 
 
9.1. Correlate biomarkers on immune cell subset concentrations and localization in archived 
diagnostic tumor tissue with PFS and CBR (HiberCell).  
Biomarkers on immune cell subsets (including monocytes, macrophages, granulocytes, and 
lymphocytes) will be evaluated by multiplex immunofluorescence staining using the tyramide 
signal amplification (TSA) method (PerkinElmer) at HiberCell laboratories. This method allows for 
simultaneous detection of multiple (up to 8 different) markers in the same slide. Marker 
concentrations and localization (peri- vs. intratumoral) will be evaluated for each marker and then 
correlated with clinical response to therapy. Unstained slides will be provided for this analysis. 
 
Refer to the CLM for collection, labeling and shipping instructions. 
 
9.2. Evaluate PD-L1 from diagnostic tissue (Dako) 
Expression of PD-L1 in archived diagnostic tumor tissue will be determined by referring laboratory 
(Dako) used by Merck. Unstained slides are to be submitted; a tumor block is not acceptable.  
A fine needle aspirate, frozen sample, plastic embedded sample, cell block, clot, bone, bone marrow 
or cytologic specimen are not be acceptable for PD-L1 analysis.  Refer to the CLM for collection, 
processing, labeling and shipping instructions. 
 
9.3. Correlate change in soluble PD-L1 level in serum with PFS and CBR (UIC).  
Whole blood for serum submission will be collected at pre-dose Cycle 1 Day 1, Cycle 2 Day 1 and 
Cycle 3 Day 1 for analysis of soluble PD-L1 levels. Change in soluble PD-L1 levels as a result of 
treatment will be examined in relation to PFS and CBR. This analysis will be determined by ELISA 
assay will be conducted at the University of Illinois Cancer Center. Refer to the CLM for collection, 
processing, labeling and shipping instructions. 
 
9.4. Correlate PD-L1 expression on circulating PBMCs from whole blood (HiberCell) 
Peripheral blood mononuclear cells will be collected at baseline (pre-dose Day 1 of Cycle 1) and on 
Cycle 2 Day 1 and Cycle 3 Day 1 for analysis of PD-L1 expression on circulating mononuclear cells. 
This analysis will be done in HiberCell laboratories.  Refer to the CLM for collection, processing, 
labeling and shipping instructions. 


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9.5. Correlate ABA levels (IgM, IgG) and FcRIIa polymorphism with PFS and CBR (HiberCell).  
Phase Ib: Whole blood for serum will be collected at baseline (i.e., pre-dose Day 1 of Cycle 1) for 
analysis of anti-beta glucan antibody (ABA) (IgM, IgG) levels. Baseline ABA levels will be 
examined in relation to PFS and CBR.  
 
Phase II: Whole blood for serum will be collected at pre and post Imprime PGG infusion at Cycles 1, 
2, 3, 5, 6, and 7 for analysis of anti-beta glucan antibody (ABA) (IgM, IgG) levels. ABA levels will 
be examined in relation to PFS and CBR.  
 
Both phases: Baseline (i.e., pre-dose Cycle 1 Day 1) FcRIIa polymorphism will be examined in 
relation to PFS and CBR. Samples will be analyzed at HiberCell.  
 
Refer to the CLM for collection, processing, labeling and shipping instructions. 
 
9.6. Correlate baseline proteomic immune classifiers with PFS and CBR. 
Whole blood will be collected at baseline for analysis of immune classifiers. Baseline proteomic 
immune classifiers will be examined in relation to PFS and CBR. Refer to the CLM for collection, 
processing, labeling and shipping instructions. 
 
9.7. Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples that were collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN), as Administrative Headquarters 
for the Big Ten CRC, will manage the banked samples. Samples will be banked indefinitely in the 
Hoosier Cancer Research Network Biorepository and used for future unspecified cancer-related 
research. 
 
9.8. Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples collected for future unspecified Big 
Ten Cancer Research Consortium studies. HCRN will manage the banked samples. Samples will be 
banked indefinitely in the HCRN Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment 
on Cycle 1 Day 1 and at End of Treatment.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment 
on Cycle 1 Day 1 and at End of Treatment. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin fixed 
paraffin embedded tumor sample.  
Please refer to the CLM for all sample collection, processing, labeling, and shipping instructions. 
 
9.9. Confidentiality of Biospecimens 
Samples that are collected will be identified by the subject’s study number assigned at the time of 
trial registration. Any material issued to collaborating researchers will be anonymized and only 
identified by the subject’s study number. 
 
 
 


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10. DRUG INFORMATION 
10.1. Drug name: Imprime PGG: (Beta 1,3/1,6 glucan): 
 
Supplied as:  
Imprime PGG Injection is formulated as a sterile solution at 1.0 mg/mL and is supplied in 20 mL or 
50 mL vials containing 20 mg or 50 mg, respectively, of Imprime PGG (1.0 mg/mL).  
 
Availability:  
Imprime PGG for investigational purposes will be provided by HiberCell at no charge to subjects 
participating in this clinical trial. Imprime PGG must be dispensed only from official study sites and 
to eligible subjects under the supervision of the site investigator. The investigator shall take 
responsibility for and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution, and usage of investigational product in accordance with the 
protocol and any applicable laws and regulations. 
 
Storage, Handling, and Accountability 
Imprime PGG vials will be provided to the investigative site. Vials will be stored at controlled room 
temperature, 20º to 25ºC upon arrival at the site (excursions permitted between 15º and 30ºC). Formal 
studies to assess the stability of drug product at the recommended storage conditions have 
demonstrated that Imprime PGG is stable for at least 48 months. 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, noting any discrepancies or damages. Imprime PGG vials should be inspected visually 
for particulate matter and discoloration prior to administration, whenever solution and container 
permit. The solution should be clear and colorless and may contain a small amount of easily visible, 
white, amorphous particulates. Discard vials containing precipitate and request a replacement 
shipment. 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 2º to 8ºC. 
 
Administration 
Imprime PGG should be 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. Preparation under a hood is not required, but is preferable. An 
infusion pump should be used to ensure accurate and consistent dosing. Imprime PGG is to be 
administered via IV infusion over a 2-4 period depending on the subject’s weight (see table below). 
Subjects will receive Imprime PGG at a dose determined by their weight. The table below describes 
total infusion volumes, administration times, and rate of infusion for study doses of 2 and 4 mg/kg. 
Extended infusion times are acceptable and will not incur a deviation; the rate of infusion should not 
be increased. Premedication as outlined in Section 5.2.  
 
Subject Weight 
(kg) 
Total Infusion Volume 
(mL) 
Infusion Time 
(hours)
Rate of Infusion 
(mL/min) 
2mg/kg Imprime PGG 
<75 
500 
2
4.2 
>75 to <150 
750 
3
4.2 
>150 
1000 
4
4.2 
4 mg/kg Imprime PGG 
<75 
500 
2
4.2 
>75 to <150 
750 
3
4.2 
>150 
1000 
4
4.2 


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The Imprime PGG infusion should be prepared as follows: 
 
Preparation instructions for 2 mg/kg Imprime PGG: 
1. Determine the 2 mg/kg Imprime PGG dose/dose volume needed. 
 Example A (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. 
 Example B (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. 
 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. 
 Example A (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. 
 Example B (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. 
 Example C (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. 
 
3. Withdraw the calculated Imprime PGG dose volume from the Imprime PGG vials (from Step 1). 
 Example A (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. 
 Example B (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. 
 Example C (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 IV tubing, and using an 
infusion pump infuse at the rate determined by the total infusion volume/infusion time described: 
 Example A (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 
 Example B (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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 Example C (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. 
 
Preparation instructions for 4 mg/kg Imprime PGG: 
1. Determine the 4 mg/kg Imprime PGG dose/dose volume needed 
 Example A (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 mLs of Imprime 
PGG. Imprime is supplied in 50 mL vials = 6 50-mL vials needed and prepared as described 
further in Steps 2 – 6 below. 
 Example B (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 
mLs of Imprime PGG. Imprime PGG is supplied in 50 mL vials = 8 50-mL vials needed and 
prepared as described further in Steps 2 – 6 below. 
 Example C (For weight >150 kg): Subject weighs 160 kg, 160 x 4 mg/kg = a total Imprime 
PGG dose of 640 mg. At the Imprime PGG vial concentration of 1mg/mL = 640 mLs of 
Imprime PGG. Imprime PGG is supplied in 50 mL vials = 13 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. 
 Example A (For weight <75 kg): Since subject weighs 70 kg, a 500 mL 0.9% NS bag should 
be used. Withdraw and discard 280 mLs of NS from the 500 mL NS bag. 
 Example B (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 mLs of NS from the 750 mL NS bag. 
 Example C (For weight >150 kg): Since subject weighs 160 kg, a 1000 mL 0.9% NS bag 
should be used. Withdraw and discard 640 mLs of NS from the 1000 mL NS bag. 
 
3. Withdraw the calculated Imprime PGG dose volume from the Imprime PGG vials (from Step 1). 
 Example A (For weight <75 kg): From a total of 6 50-mL vials of Imprime PGG, withdraw 
the required 280 mg (280 mLs) and inject the Imprime PGG into the NS bag and mix gently. 
 Example B (For weight >75 kg, up to ≤150 kg): From a total of 8 50-mL vials of Imprime 
PGG, withdraw the required 400 mg (400 mLs) and inject the Imprime PGG into the NS bag 
and mix gently. 
 Example C (For weight >150 kg): From a total of 13 50-mL vials of Imprime PGG, withdraw 
the required 640 mg (640 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 IV tubing, and using an 
infusion pump infuse at the rate determined by the total infusion volume/infusion time described: 
 Example A (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. 


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 Example b (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. 
 Example C (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.  
 
Risks 
Imprime PGG is an investigational product that may only be used under the terms defined in this 
protocol and associated IB.  
 
To date, 84 of the 103 healthy subjects enrolled into the Imprime PGG studies have been administered 
at least one dose of Imprime PGG. Of these 84 subjects, 27 subjects were administered Imprime PGG 
alone and 57 subjects were administered Imprime PGG and concomitant G-CSF (10 mcg/kg/day for 
four consecutive days). More specifically, 51 of the 84 subjects received single doses of Imprime 
PGG up to 6 mg/kg and 33 of the 84 subjects received multiple doses of Imprime PGG (single doses 
administered on either 2 days, 4 consecutive days, or 7 consecutive days) in doses up to 4 mg/kg. 
With regard to the 19 subjects receiving only placebo, 10 of these subjects were concomitantly also 
administered G-CSF (10 mg/kg/day for four consecutive days). Imprime PGG administration has 
demonstrated no tendency to result in life-threatening AEs, SAEs, or AEs of severe intensity in 
healthy volunteers.  
 
In a metastatic CRC subject population, to date, 50 subjects have been administered Imprime PGG 
in the completed CRC0713 and CRC0821 studies. Subjects in the completed studies have been dosed 
for up to 64 weeks in combination with a standard regimen of cetuximab and irinotecan, or cetuximab 
alone. In the ongoing CRC1031 study, 141 subjects have received the combination of Imprime PGG 
plus standard regimen of cetuximab.  
 
In an NSCLC subject population, to date, 118 subjects have been administered Imprime PGG in the 
ongoing studies LCA0821 and LCA0822. Subjects have been dosed for up to 69 weeks in 
combination with a standard regimen of bevacizumab, carboplatin and paclitaxel, and up to 54 weeks 
in combination with a standard regimen of cetuximab, carboplatin and paclitaxel.   
 
Subjects should be continuously monitored for AEs and/or any safety concerns. 
 
Warnings and Precautions 
The drug is considered to be generally safe and well-tolerated. 
 
 
 


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10.2. Drug Name: Pembrolizumab (MK-3475 [Anti-PD-1 Antibody MK-3475]) 
 
Chemical name and properties 
Humanized X PD-1_mAb (H409A11) IgG4 
 
Availability 
Merck will supply pembrolizumab at no charge to subjects participating in this clinical trial.  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
 
Storage 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
Dosage and Administration 
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab preparation. 
 
Merck will supply pembrolizumab directly to sites at no cost to subjects in this clinical trial.  
 
The product after reconstitution with sterile water for injection and the liquid drug product is a clear 
to opalescent solution, which may contain extraneous and proteinaceous particulates. The 
reconstituted product and liquid product is intended for IV administration. The reconstituted drug 
product solution and liquid drug product can be further diluted with normal saline in IV containers 
made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be immediately 
used to prepare the infusion solution in the IV bag and the infusion solution should be immediately 
administered. If not used immediately, vials and/or IV bags may be stored at 2-8 °C for up to a 
cumulative time of 96 hours. If refrigerated, the vials and/or IV bags should be allowed to equilibrate 
to room temperature prior to subsequent use. Pembrolizumab solutions may be stored at room 
temperature for a cumulative time of up to 6 hours. This includes room temperature storage of 
reconstituted drug product solution and liquid drug product in vials, room temperature storage of 
infusion solution in the IV bag and the duration of infusion. 
 
Side Effects 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse events. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in comparison 
to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this mechanism of 
action, immune mediated adverse events are of primary concern. Important identified risks for 
pembrolizumab are of an immune mediate nature, including: pneumonitis, colitis, hepatitis, nephritis, 
endocrinopathies that include adrenal insufficiency (primary and secondary) and hypophysitis 
(including hypopituitarism), thyroid disorder (hypothyroidism, hyperthyroidism and thyroiditis), Type 
I diabetes mellitus, uveitis, myositis, Guillain-Barre Syndrome, pancreatitis, myocarditis, myasthenic 
syndrome/myasthenia gravis (including exacerbation), encephalitis, sarcoidosis, severe skin reactions 


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including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal 
outcome; and “solid organ transplant rejection following pembrolizumab treatment in donor organ 
recipients” (risk applicable to post-marketing setting only, as such patients are currently excluded from 
Merck clinical trials with pembrolizumab).  
 
Immune-mediated adverse reactions (ARs), including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Immune-mediated ARs can occur after discontinuation of treatment. 
Immune-mediated ARs affecting more than one body system can occur simultaneously. In clinical 
studies, most immune-mediated ARs were reversible and managed with interruptions of 
pembrolizumab, administration of corticosteroids, and/or supportive care. 
 
The risk profile for pembrolizumab also includes 2 important potential risks – i.e. increased risk of 
severe complications (such as early severe graft versus host disease and veno-occlusive disease) of 
allogeneic transplant in patients with hematologic malignancies who have previously been treated with 
PD-1 inhibitors; and GVHD after pembrolizumab administration in patients with a history of 
allogeneic HSCT. 
 
One new identified risk of myelitis has been added to the Warnings and Precautions section of the 
Merck company core data sheet for pembrolizumab based on routine pharmacovigilance. In addition, 
new ADRs of Vogt-Koyanagi-Harada syndrome and hemophagocytic lymphohistiocytosis were 
identified based primarily on postmarketing reports. 
 
Further details around frequency, reporting, and management of immune-related adverse events 
(irAEs) can be found in the current version of the Investigator’s Brochure. In addition to the 
previously noted identified risks, infusion-related reactions are a risk but are not considered immune 
mediated; these are also further described in the current IB. 
 
11. ADVERSE EVENTS  
 
11.1. Definitions of Adverse Events:  
11.1.1. Adverse Event (AE):  
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples 
of AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2. Serious Adverse Event (SAE):  


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An SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional therapy, 
resection of primary tumor, or elective surgery, will not be considered serious adverse 
events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 Pembrolizumab overdose. For purposes of this trial, an overdose will be defined as any 
dose exceeding the prescribed dose for pembrolizumab by 20% over the prescribed dose. 
See section 11.3 for further details. 
 
11.1.3. Unexpected Adverse Event:  
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation. 
 
11.1.4. Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
The Adverse Event is clearly not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 


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11.2. Adverse Event (AE) Reporting:  
 Adverse events (AEs) will be recorded from the time of consent until 30 days after treatment 
discontinuation of study drugs or until a new anti-cancer treatment starts, whichever occurs first. 
 AEs will be recorded regardless of whether or not the event(s) are considered related to the study 
drugs.  
 All AEs will be recorded in the subject’s medical record and on the appropriate study specific 
eCRF form within the EDC system. 
 All AEs considered related to study drugs will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever is earlier. 
 
11.3. Definition and Reporting of a Pembrolizumab Overdose:  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by 20% over the prescribed dose. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, subject should be observed closely 
for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated.  
 
 If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 1 working day to 
BTCRC Administrative Headquarters (AHQ). BTCRC AHQ will report the event within 1 working 
day to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-993-1220). 
 
11.4. 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), including the pregnancy of a male subject’s female partner that occurs during the 
trial or within 120 days of completing the trial, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier. All subjects and female partners of male 
subjects who become pregnant 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 events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must 
also be reported. 
 
Such events must be reported within 1 working day to BTCRC AHQ on the Pregnancy Report Form 
(See Documents/Info tab in the EDC). BTCRC AHQ will report the event within 1 working day to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215-993-1220). 
 
 
11.5. Definition and Reporting of Events of Clinical Interest (ECI): 


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Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported to 
BTCRC AHQ within 1 working day of the event. 
Events of clinical interest for this trial include: 
1. An overdose of Merck product, as defined above, that is not associated with clinical symptoms 
or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is greater than or equal to 3 × the upper limit of normal, 
and an elevated total bilirubin lab value that is greater than or equal to 2 × the upper limit of 
normal, and, at the same time, an alkaline phosphatase lab value that is less than 2 × the upper 
limit of normal, 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.  
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and 
subjects should be asked for signs and symptoms suggestive of an immune-related event. Subjects 
who develop an ECI thought to be immune-related should have additional testing to rule out other 
etiologic causes. If lab results or symptoms indicate a possible immune-related ECI, then additional 
testing should be performed to rule out other etiologic causes. If no other cause is found, then it is 
assumed to be immune-related.  
 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates a new anticancer therapy, 
whichever is earlier, whether or not related to the Merck’s product, must be reported within 1 working 
day to BTCRC AHQ. BTCRC AHQ will report the event within 1 working day to Merck Global 
Safety (Attn: Worldwide Product Safety; FAX 215-993-1220). 
 
11.6. Serious Adverse Events (SAEs) 
 
11.6.1. Site Requirements for Reporting SAEs to BTCRC Administrative Headquarters: 
 SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the 
EDC system within 1 business day of discovery of the event.   
 SAEs will be reported whether or not they are related to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer treatment 
starts, whichever occurs first. 
 
Non-serious Events of Clinical Interest will be reported to BTCRC AHQ and will be handled in 
the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator to be related to either 
study drug, which is brought to the attention of the investigator at any time outside of the 90-


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day time period specified in the previous paragraph, also must be reported immediately to 
BTCRC AHQ.  
 
The site will submit the completed SAE Submission Form (see Documents/Info tab in the 
EDC) to BTCRC AHQ within 1 working day of discovery of the event. The form will be sent 
electronically to safety@hoosiercancer.org. The investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved, sites must submit an electronic follow up SAE Submission Form 
within a reasonable timeframe to BTCRC AHQ at safety@hoosiercancer.org. 
 
11.6.2. BTCRC AHQ Requirements for Reporting SAEs to Merck and HiberCell: 
BTCRC AHQ will submit all immediately reportable events (e.g. SAEs, ECIs, overdose, 
pregnancy, etc.) received from sites to Merck and HiberCell within one working day of receipt 
of the SAE Reporting Form and to regulatory authorities (FDA) per federal guidelines.   
 
BTCRC AHQ will submit all SAE reports and any other relevant safety information to: 
 
Merck Global Safety (Attn: Worldwide Product Safety) at: 
Facsimile number:  +1-215-993-1220 
E-mail: AER_mailbox@merck.com 
 
and to APCER (HiberCell Safety Designee): 
SAE hotline 
Fax: 609.531.0154 
E-mail: safety.biothera@apcerpharma.com 
 
BTCRC AHQ will provide follow-up information to Merck and HiberCell as reasonably 
requested. 
 
11.7. BTCRC AHQ Responsibilities for Reporting SAEs to FDA 
BTCRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator.  BTCRC AHQ will cross-
reference this submission to Merck and HiberCell’s parent INDs at the time of submission.  
Additionally, BTCRC AHQ will submit a copy of these documents to Merck and HiberCell at the 
time of submission to FDA. 
 
BTCRC AHQ will be responsible for all communication with the FDA in accordance with 21CFR312 
which includes but is not limited to the 7 and 15 Day Reports, as well as an Annual Progress Report. 
Additionally, BTCRC AHQ will submit a copy of these reports to Merck and HiberCell at the time 
of submission to FDA. 
 
 
 
11.8. Sponsor-Investigator Responsibilities 


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BTCRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day of receipt 
of SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
 
11.9. IND Safety Reports Unrelated to This Trial 
Merck and HiberCell will send IND safety reports from external studies that involve the study drugs 
to BTCRC AHQ (safety@hoosiercancer.org). BTCRC AHQ will forward the safety reports to the 
sponsor-investigator who will review these reports and determine if revisions are needed to the 
protocol or consent. BTCRC AHQ will forward these reports to participating sites every 2 weeks.  
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1. Study Design: 
This is a single arm study. Phase Ib: The primary objective of the Phase Ib dose escalation cohort 
study is to establish the MTD of study drug Imprime PGG when used in combination with 
pembrolizumab for subjects with NSCLC after failure of first line platinum-based chemotherapy. A 
standard “3+3” design will be used to establish the MTD.  
 
Phase II: The primary objective of the Phase II trial is to estimate Progression-Free Survival (PFS) 
using RECIST v1.1 in subjects with metastatic non-small cell lung cancer (NSCLC) treated with 
Imprime PGG in combination with pembrolizumab after progression on first-line systemic therapy 
(either platinum-based chemotherapy with or without immune checkpoint inhibitor or immune 
checkpoint inhibitor as first line therapy). Pembrolizumab will be given on Day 1 and maximum 
tolerated dose of Imprime PGG will be given on Days 1, 8 and 15 for Cycles 1-4, and on Day 1 only 
for Cycles 5-16 of each 21 day cycle. Treatment continues until 16 cycles have been completed, 
disease progression, unacceptable toxicity, subject refusal, or subject death either from progression 
of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have 
progressive disease, or unacceptable toxicities will be followed for a total of 5 years.   
 
Correlative research analyses include examining the relationship between PFS and CBR to immune 
biomarker (NK cells, neutrophils, CD8+ T cells and PD-L1) concentrations as well as localization 
(peri- vs. intratumoral) in the archived diagnostic tumor tissue and tumor vascular density. Research 
analyses also include examining the relationship between changes in soluble PD-L1 level and PD-L1 
expression on circulating mononuclear cells at baseline (i.e., pre-dose Day 1 of Cycle 1) and during 
therapy (assessed pre-dose Cycles 2 and 3) and PFS and to CBR. Additionally, immune classifiers, 
FcRIIa polymorphism, and anti-β-glucan antibody (ABA) (IgM, IgG) levels at will be correlated 
with PFS and CBR. 
 
12.2. Criteria for Stopping Study: 
The Phase Ib portion of the study will be stopped if 2 or more DLTs occur at dose level 1.  
 
The Phase II portion of the study will be stopped if any grade 5 toxicity occurs which is thought to 
be directly attributable to the combination of Imprime PGG and pembrolizumab.  
 
12.3. Sample Size: 


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Phase Ib: A standard “3+3” design will be used with maximum number of subjects accrued to be 12. 
 
Phase II: Study endpoint will be progression-free survival (PFS), as assessed by the RECIST v1.1 
criteria. The null hypothesis is that median PFS of combination drug is 3.2 months (equal to single 
agent pembrolizumab among subjects with a proportion score of 1 to 49%); the alternative hypothesis 
is that the PFS is 6.3 months (equal to single agent pembrolizumab among subjects with a proportion 
score of ≥ 50%). 
 
The hypothesized median PFS is 6.3 months. With a total sample size of 24 we will have 90% power 
to detect a difference of 3.1 months (i.e., 6.3 months versus 3.2 months) with a two-sided exponential 
MLE test, controlling for a type I error probability of 5%. The power analysis was conducted using 
power calculation for one arm survival design proposed by Lawless.39 
 
Unevaluable subjects will be replaced. 
 
12.4. Analysis of Primary Objectives/Aims 
 
Phase Ib Analysis of Primary Endpoint:  
The primary endpoint is determination of the MTD of Imprime PGG. The MTD will be defined as 
the highest explored dose of Imprime PGG combined with 200 mg of pembrolizumab at which ≤1 
out of 6 subjects have experienced a DLT within the first cycle of therapy. That dose will be 
recommended for the Phase II study (i.e., will be declared the RP2D). At the discretion of the sponsor-
investigator, a lower phase II dose may be recommended if other toxicity emerges during the Phase 
Ib study which does not meet DLT criteria but limits the dose that can be administered cumulatively. 
 
Phase II Analysis of Primary Endpoint:  
The primary endpoint is determination of the activity of the combination of pembrolizumab and 
Imprime PGG in second line systemic therapy for NSCLC as assessed by progression-free survival 
based on RECIST v1.1. Median PFS times will be computed with associated 95% confidence 
intervals. Kaplan-Meier curves will be plotted.  
 
12.5. Analysis of Secondary Endpoints: 
 
12.5.1. Phase Ib Analysis of Secondary Endpoints 
 
Characterize adverse effects (AEs) of Imprime PGG in combination with pembrolizumab in 
subjects with NSCLC who progressed after first-line platinum-based chemotherapy. 
Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will be 
computed along with 95% confidence intervals and reported in a tabular and descriptive 
manner. 
 
Estimate clinical benefit rate (CBR) (complete response, partial response, or stable disease) of 
Imprime PGG in combination with pembrolizumab in subjects with NSCLC who progressed 
after first-line platinum-based chemotherapy. 
CBR will be assessed every 2/3 cycles +/- 1 week while on study treatment using the Response 
Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1- Section 8).  Response will be 
reported via waterfall plot. Response outcome will be reported in a tabular manner. The 
response rate and 95% confidence interval for the response rate will be computed.  


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Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects 
with NSCLC who progressed after first-line platinum-based chemotherapy when treated with 
Imprime PGG in combination with pembrolizumab. 
Median PFS times will be computed, and PFS rate at 6 months +/- 1 month will be calculated 
with associated 95% confidence intervals. Kaplan-Meier curves will be plotted. Data will be 
analyzed using the PROC LIFETEST in SAS. 
 
Estimate overall survival (OS) and 1-year OS in subjects with NSCLC who progressed after 
first-line platinum-based chemotherapy when treated with Imprime PGG in combination with 
pembrolizumab. 
Median OS times will be computed, and OS rate at 1 year +/- 3 months from start of study 
treatment will be calculated with associated 95% confidence intervals. Kaplan-Meier curves 
will be plotted. Data will be analyzed using the PROC LIFETEST in SAS. 
 
12.5.2. Phase II Analysis of Secondary Endpoints 
 
Characterize adverse effects (AEs) of Imprime PGG in combination with pembrolizumab in 
subjects with NSCLC who progressed after first-line systemic therapy 
Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will be 
computed along with 95% confidence intervals, and reported in a tabular and descriptive 
manner. 
 
Estimate clinical benefit rate (CBR) (complete response, partial response, or stable disease) of 
Imprime PGG in combination with pembrolizumab in subjects with NSCLC who progressed 
on first-line systemic therapy. 
CBR will be assessed every 2/3 cycles +/- 1 week while on study treatment using the Response 
Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1- Section 8). Response will be 
reported via waterfall plot.  
 
Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects 
with NSCLC when treated with Imprime PGG in combination with pembrolizumab who 
progressed after first-line systemic therapy. 
Median PFS times will be computed, and PFS rate at 6 months +/- 1 month will be calculated 
with associated 95% confidence intervals. Kaplan-Meier curves will be plotted. Data will be 
analyzed using the PROC LIFETEST in SAS. 
 
Estimate overall survival (OS) and 1-year OS in subjects with NSCLC treated with Imprime 
PGG in combination with pembrolizumab as first-line systemic therapy who progressed after 
first-line systemic therapy. 
Median OS times will be computed, and OS rate at 1 year +/- 2 months will be calculated with 
associated 95% confidence intervals. Kaplan-Meier curves will be plotted. Data will be 
analyzed using the PROC LIFETEST in SAS. 
 
12.6. Analysis of Phase II Correlative Endpoints: 
 Immune biomarker (NK cells, neutrophils, CD8+ T cells and PD-L1) concentrations and 
localization (peri- vs. intratumoral) in archived diagnostic tumor tissue will be correlated with 
PFS and CBR. Spearman correlation will be computed using PROC CORR in SAS (Cary, NC).  


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 Change in soluble PD-L1 level and PD-L1 expression on circulating mononuclear cells in serum 
pre-dose Cycles 2 and 3 relative to baseline (i.e., pre-dose Day 1 of Cycle 1) will be examined in 
relation to PFS and CBR. Spearman correlation will be computed using PROC CORR in SAS 
(Cary, NC).  
 Correlation of ABA levels (IgM, IgG) to PFS and CBR. Spearman correlation will be computed 
using PROC CORR in SAS (Cary, NC).  
 Correlation of immune classifiers at baseline (i.e., pre-dose Day 1 of Cycle 1) to PFS and CBR. 
Spearman correlation will be computed using PROC CORR in SAS (Cary, NC). 
 
 
13. TRIAL MANAGEMENT 
 
13.1. Data and Safety Monitoring Plan: 
The study will be conducted in accordance with the University of Illinois Cancer Center’s Data and 
Safety Monitoring Plan (DSMP). The University of Illinois Cancer Center Data Safety and 
Monitoring Committee (DSMC) will review and make recommendations on this trial. BTCRC AHQ 
will provide the University of Illinois Cancer Center DSMC with periodic data reports to comply 
with the UICC DSMC review requirements.  
 
In addition, BTCRC AHQ oversight activities include: 
 Review of all adverse events requiring expedited reporting as defined in the protocol. 
 Provide trial accrual progress, safety information, and data summary reports to the sponsor-
investigator. 
 Submit data summary reports to the lead institution DSMC for review as per their DSMP. 
 
13.2. University of Illinois Cancer Center Data Safety Monitoring Committee  
 
BTCRC AHQ will provide the UICC DSMC with the following: 
 Adverse event summary report 
 Audit results, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The University of Illinois Cancer Center DSMC will review study data ever quarter.  Documentation 
of DSMC reviews will be provided to the sponsor-investigator and BTCRC AHQ.  Issues of 
immediate concern by the DSMC will be brought to the attention of the sponsor-investigator and 
other regulatory bodies as appropriate.  The sponsor-investigator will work with BTCRC AHQ to 
address the DSMC’s concerns. 
 
13.3. Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the life 
cycle of the study.  A summary report (QC Report) of these checks together with any queries resulting 
from manual review of the eCRFs will be generated for each site and transmitted to the site and the 
site monitor. Corrections will be made by the study site personnel. 
 


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There will be at least one visit within a year of the first subject accrual per site. Additional for-cause 
visits may occur as necessary. Source documents will be reviewed for verification of agreement with 
data entered into the EDC system.  It is important for the site investigator and their relevant personnel 
to be available for a sufficient amount of time during the monitoring visits or audit, if applicable. The 
site investigator and institution guarantee access to source documents by BTCRC AHQ or its 
designee. 
 
The trial site may also be subject to quality assurance audit by Merck, HiberCell, or their designee as 
well as inspection by appropriate regulatory agencies. 
 
13.4. Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The sponsor-investigator 
has delegated responsibility to BTCRC AHQ for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for 
their disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
 
 
14. DATA HANDLING AND RECORD KEEPING 
 
14.1. Data Management 
BTCRC AHQ will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform compliant with Good Clinical Practices and Federal 
Rules and Regulations. Other study institutions will be given a password to directly enter their own 
data onto the web site via electronic case report forms (eCRFs). BTCRC AHQ personnel will 
coordinate and manage data for quality control assurance and integrity. 
 
All data will be collected and entered into the EDC system by study site personnel from 
participating institutions. 
 
14.2. Case Report Forms and Submission: 
An electronic case report form (eCRF) is required and must be completed for each included subject. 
The completed dataset is housed at BTCRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without permission from the 
sponsor-investigator and BTCRC AHQ. After the initial publication, the complete data set will be 
available to all BTCRC institutions. 
 
14.3. Record Retention: 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations. 
 


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During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRFs will be 
generated for each site and transmitted to the site and the site monitor. Corrections will be made by 
the study site personnel. This will be done on an ongoing basis. 
 
14.4. Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, 
will not be made publicly available.   
 
Information collected will be maintained on secure, password protected electronic systems. Paper 
files that contain personal information will be kept in locked and secure locations only accessible to 
the study team. Samples that are collected will be identified by a subject study number assigned at 
the time of registration to the trial. Any material issued to collaborating researchers will be 
anonymized and only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator and 
his/her research associates, BTCRC AHQ, Merck, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance with local 
data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
15. ETHICS 
 
15.1. Institutional Review Board (IRB) Approval 
The final study protocol, including the final version of the informed consent form, must be approved 
in writing by an IRB. The investigator must submit written approval by the IRB to the BTCRC AHQ 
office before he or she can enroll any subject into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to recruit 
subjects for the study. The protocol must be re-approved by the IRB annually, as local regulations 
require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2. Ethical Conduct of the Study: 
The study will be performed in accordance with ethical principles originating from the Declaration 
of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable regulatory 
requirements. Conduct of the study will be in compliance with ICH Good Clinical Practice, and with 
all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3. Informed Consent Process 


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The site investigator will ensure the subject is given full and adequate oral and written information 
about the nature, purpose, possible risks and benefits of the study.  Subjects must also be notified 
they are free to discontinue from the study at any time.  The subject should be given the opportunity 
to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study.  The site investigator must store the original, signed informed consent form.  
A copy of the signed informed consent form must be given to the subject. 
 
 


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