Conditions: Non Small Cell Lung Cancer Metastasis Recurrence
Keywords: Non Small Cell Lung Cancer Metastasis Recurrence Immunotherapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is a phase 1b/2 study to determine the safety and effectiveness of the combination of pembrolizumab and idelalisib in NSCLC patients whose disease has stopped responding to immune therapy. This study is being done to see if adding another immune modulator (idelalisib) to standard pembrolizumab will increase response rates, compared to the response seen with pembrolizumab alone.

Detailed description:
This is a phase 1b/2 study to determine the safety and effectiveness of the combination of pembrolizumab and idelalisib in NSCLC patients whose disease has stopped responding to immune therapy. Pembrolizumab is an anti-PD-1 immunotherapy that is given intravenously and is approved for treatment of malignant NSCLC. Idelalisib is the first-in-class oral PI3K-δ inhibitor that is approved for treatment of certain forms of leukemia and lymphoma.

Immune checkpoint inhibitors (such as anti-PD-1) are effective in treating NSCLC as a single agent, but overall response isn't optimal; overall response rates (ORR) are only \~20% on average. The goal of this study is to see whether combining standard therapy with additional immune modulators will increase response rates, compared to the response seen with pembrolizumab monotherapy.

Arms:
arm 1: Sequential cohorts of 3 patients will receive pembrolizumab 200 mg intravenously every 3 weeks, in addition to the oral drug, idelalisib, every day for 21 days. The first group of 3 will receive idelalisib 50 mg twice daily; the next cohort will receive idelalisib 100 mg twice daily; the last cohort will receive idelalisib 150 mg twice daily. arm 2: All patients in the efficacy assessment phase will be treated with pembrolizumab (200 mg intravenously every 3 weeks) in combination with oral idelalisib (dose not exceeding 150 mg twice daily, per the phase 1 assessment) for 18 weeks before maintenance with pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years, until disease progression or unacceptable toxicity.

Interventions: intervention 1: Pembrolizumab intervention 2: Idelalisib
Intervention descriptions: intervention 1: Anti PD-1 immunotherapeutic agent, which blocks a protective mechanism on cancer cells to allow the immune system to destroy cancer cells. Administered intravenously (IV). intervention 2: Phosphatidylinositol 3-kinase (PI3K) inhibitor which promotes anti-tumor immune response. Administered orally (PO).

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
  
 
 
TITLE:  A phase Ib /II trial of pembrolizumab and idelalisib in patients with 
non-small cell lung cancer (NSCLC) who have failed immune 
checkpoint inhibitor. 
 
SPONSOR (PI):  Zhonglin Hao, MD, PhD   
                              Thoracic Oncology Program 
                              Medical College of Georgia, 
                              Georgia Cancer Center at Augusta University 
 
1120 15th Street, CN-2132 
 Augusta, GA  30912 
 
RESEARCH  
CONTACT: 
Georgia Cancer Center Clinical Trials Office 
 
Augusta University 
 
1411 Laney Walker Boulevard, AN-2200 
 
Augusta, GA 30912 
 
Telephone: 706-721-2154 
 
email: Cancer_Center_Trials@augusta.edu 
 
PROTOCOL NUMBER: 
CC-16053 
 
 
IND NUMBER:  130012 
 
ClinicalTrials.gov Identifier:  pending 
 
Investigational Agent(s):     
 
 
 
 
 
 
 
Protocol History 
Original Version: 
10/18/2016 (v12, incorporates previous versions) 
Version 13: 
02/08/2017 
Version 14: 
04/19/2017 
 
Drug Name: 
Pembrolizumab 
Idelalisib 
Other Identifier: 
MK-3475, Keytruda® 
GS-1101,  Zydelig® 
IND Number: 
123,482 
101254 
Manufacturer: 
Merck 
Gilead 


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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN.......................................................................................................... 9 
2.1 
Trial Design ............................................................................................................. 9 
2.2 
Trial Diagram ........................................................................................................ 10 
3.0 
OBJECTIVES & HYPOTHESES ........................................................................... 11 
3.1 
Primary Objective(s) & Hypotheses ................................................................... 11 
3.2 
Secondary Objective ............................................................................................. 11 
4.0 
BACKGROUND & RATIONALE .......................................................................... 11 
4.1 
Background ........................................................................................................... 11 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 11 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 14 
4.2 
Rationale ................................................................................................................ 15 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 15 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 17 
5.0 
METHODOLOGY ................................................................................................... 19 
5.1 
Entry Criteria ........................................................................................................ 19 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 19 
5.1.2 Subject Exclusion Criteria .................................................................................. 20 
5.2 
Trial Treatments, Mandatory Prophylaxis of Pneumocystis pneumonia (PCP)22 
5.2.1 Dose Selection/Modification .............................................................................. 22 
5.2.2 Drug Preparation and Administration ................................................................. 26 
5.2.3 Timing of Dose Administration .......................................................................... 27 
5.2.4 Trial Blinding/Masking ....................................................................................... 27 


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5.2.5 Subject Replacement During the Tolerability Assessment Phase of the Trial ... 28 
5.3 
Randomization or Treatment Allocation ............................................................ 28 
5.4 
Stratification .......................................................................................................... 28 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 28 
5.5.1 Acceptable Concomitant Medications ................................................................ 28 
5.5.2 Prohibited Concomitant Medications and Drug Interactions to Watch .............. 29 
5.6 
Rescue Medications & Supportive Care ............................................................. 31 
5.6.1 Supportive Care Guidelines ................................................................................ 31 
5.7 
Diet/Activity/Other Considerations ..................................................................... 35 
5.7.1 Diet ...................................................................................................................... 35 
5.7.2 Contraception ...................................................................................................... 35 
5.7.3 Use in Pregnancy ................................................................................................ 36 
5.7.4 Use in Nursing Women ....................................................................................... 36 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 36 
5.8.1 Treatment after Initial Radiologic Progression (irRECIST-based Management)38 
5.8.2 Discontinuation of Study Therapy after CR ....................................................... 40 
5.9 
Clinical Criteria for Early Trial Termination ................................................... 41 
6.0 
TRIAL FLOW CHART ........................................................................................... 42 
7.0 
TRIAL PROCEDURES ........................................................................................... 44 
7.1 
Trial Procedures ................................................................................................... 44 
7.1.1 Administrative Procedures .................................................................................. 44 
7.1.2 Clinical Procedures/Assessments ........................................................................ 46 
7.1.3 Laboratory Procedures/Assessments .................................................................. 48 
7.1.4 Other Procedures ................................................................................................. 50 


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7.1.5 Visit Requirements .............................................................................................. 50 
7.2 
Assessing and Recording Adverse Events .......................................................... 53 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Gilead Sciences Inc. ................................................. 54 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor ....................................... 54 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck and 
Gilead Sciences Inc. ............................................................................................ 55 
7.2.4 Evaluating Adverse Events ................................................................................. 57 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 60 
7.2.6 Protocol Deviation .............................................................................................. 60 
7.2.7 Protocol Violation ............................................................................................... 60 
7.2.8 Unanticipated Problem ........................................................................................ 60 
7.3 
AU IRB Adverse Event Reporting ...................................................................... 60 
7.3.1 AU IRB Expedited Reporting of Adverse Events and Deaths ........................... 60 
7.3.2 AU IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review ................................................................................................................ 61 
7.4 
IND PI-Sponsor Reporting Criteria .................................................................... 61 
7.4.1 Expedited reporting to the FDA .......................................................................... 61 
7.4.2 FDA Annual Reports .......................................................................................... 61 
8.0 
STATISTICAL CONSIDERATIONS .................................................................... 62 
8.1 
General consideration ........................................................................................... 62 
8.2 
Study Objectives ................................................................................................... 63 
8.2.1 Primary Objective(s) & Hypotheses ................................................................... 63 
8.2.2 Secondary Objective ........................................................................................... 63 
8.3 
Study Design/Endpoints ....................................................................................... 63 


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8.4 
Sample Size/Accrual Rate .................................................................................... 63 
8.5 
Analysis of Primary Endpoints ............................................................................ 64 
8.6 
Analysis Datasets ................................................................................................... 65 
8.7 
Randomization ...................................................................................................... 65 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 65 
9.1 
Investigational Product ........................................................................................ 65 
9.1.1 Pembrolizumab (MK-3475, Keytruda®) ........................................................ 66 
9.1.2 Idelalisib (GS-1101, Zydelig®) ......................................................................... 66 
9.2 
Packaging and Labeling Information ................................................................. 67 
9.3 
Clinical Supplies Disclosure ................................................................................. 67 
9.4 
Storage and Handling Requirements .................................................................. 67 
9.5 
Returns and Reconciliation .................................................................................. 67 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 67 
10.1 
Confidentiality and Privacy ................................................................................. 67 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 68 
10.3 
Compliance with Law, Audit and Debarment ................................................... 68 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 69 
11.0 
DATA MANAGEMENT .......................................................................................... 69 
11.1 
Forms Design ......................................................................................................... 69 
11.2 
Data Entry ............................................................................................................. 69 
11.2.1 Recording and handling data .............................................................................. 69 
11.2.2 Subject documents (questionnaires, diaries) ....................................................... 69 
11.3 
Study Data Flow .................................................................................................... 69 


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11.4 
Data Export & Reporting..................................................................................... 70 
12.0 
APPENDICES ........................................................................................................... 71 
12.1 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 71 
12.2 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 71 
12.3 
Immune Related Response Criteria .................................................................... 72 
12.4 
References .............................................................................................................. 74 
12.5 
Abbreviations ........................................................................................................ 79 
 
 
Table 1.  Adequate Organ Function Laboratory Values 
19 
Table 2.  Trial Treatment and Prophylaxis of PCP Pneumonia 
22 
Table 3.  Dose Modification Guidelines for Drug-Related Adverse Events 
23 
Table 4. Infusion Reaction Treatment Guidelines 
34 
Table 5.  Imaging and Treatment after First Radiologic Evidence of PD (irRESIST-
based Management) 
40 
Table 6. Study Schedule of events 
42 
Table 7.  Laboratory Tests 
49 
Table 8.  Evaluating Adverse Events 
58 
Table 9. Sample Size Estimation 
64 
Table 10. Product Descriptions 
66 
Table 11.  ECOG Performance 
71 
Table 12. Definitions of irRC: 
72 
Table 13. Definition of Response per irRC 
73 
Table 14.  Abbreviations used in the text 
79 
 
 
 
 
 


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CONTACT INFORMATION 
Protocol Chair /  
Scientific Consultant 
Samir Khleif, MD 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, CN-4151 
Augusta, Georgia  30912 
Phone: 706-721-0570 
Email: SKhleif@augusta.edu 
 
 
Protocol Coordinator/ 
Scientific Consultant 
John Janik, MD, PhD 
Medical Director, GCC Clinical Trial Office 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, CN-4130 
Augusta, Georgia  30912 
Phone: 706-723-0000 
Email: JJanik@augusta.edu 
  
Biostatistician 
Ramses Sadek, PhD 
 
Director, Cancer Research Center Biostatistics Core 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, CN-4123 
Augusta, Georgia  30912 
Phone: 706-721-6930 
Email: RSadek@augusta.edu 
  
Institutional Coordinator/ 
Contact for FDA 
M. Carrie McAteer, BA, CCRC 
Investigator-Sponsored Trial Coordinator 
Address: Georgia Cancer Center, Augusta University 
1120 15th Street, AN-2204 
Augusta, Georgia  30912 
Phone: 706-721-1409 
Email: MMcAteer@augusta.edu 
 Cancer_Center_Trials@augusta.edu 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
pembrolizumab and idelalisib for NSCLC 
Trial Phase 
Ib/II 
Clinical Indication 
NSCLC 
Trial Type 
Therapeutic intervention 
Type of control 
Historical 
Route of administration 
Intravenous/oral 
Trial Blinding 
None 
Treatment Groups  
Pembrolizumab (Keytruda) and idelalisib (Zydelig) 
Number of trial subjects 
40 to 50 ( 6-18 + 32) 
Estimated enrollment period 
1/2017-06/2019M 
Estimated duration of trial 
3 years 
Duration of Participation 
30 months 
 
 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHASE I* 
Recurrent or Metastatic non-small cell lung 
cancer (NSCLC) Patients, Failed/Progressed on 
platinum doublets, Immune checkpoint inhibitors 
OR  
EGFR, ALK, ROS1 mutations failed/progressed 
on small molecule inhibitors and immune 
checkpoint inhibitors  
(up to 18 patients) 
PHASE II 
Recurrent or Metastatic NSCLC Patients,  
Same criteria as Phase I component, 
regardless of PD-L1 status 
(32 patients) 
21-day cycle x 6 Cycles 
(~ 18 total weeks of treatment)  
 
Safety Assessments – CTCAE v.4.03 
 
 
 
Efficacy Assessments – RECIST v.1.1 
ORR, OS, PFS, DOR 
Pembrolizumab 200 mg IV q3w 
+ 
Idelalisib PO x 21 days  
in sequential cohorts of 3 - 6 patients at: 
  
50 mg BID** → 100 mg BID → 150 mg BID 
Pembrolizumab 200 mg IV q3w 
+ 
Idelalisib PO x 21 days  
(dose to be determined from phase I) 
MAINTENANCE THERAPY 
Pembrolizumab 200 mg IV q3w, up to 2 years 


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*In Phase 1, DLT’s will be defined from toxicities observed during the first 9 weeks of combined treatment for each 
dose level.   
**If DLT is found at 50 mg PO BID daily, dose may be reduced to 50 mg PO daily, or reduced further to 50 mg PO 
every other day. 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open labeled, single arm, interventional study combining two drugs: pembrolizumab 
(MK-3475, trade name: Keytruda) and idelalisib (trade name: Zydelig) in non-small cell lung 
cancer (NSCLC). Subjects with metastatic (stage IV, AJCC 7th edition) or recurrent (after 
radiation or chemo/radiation) NSCLC of all histologies (squamous or non-squamous cell) will be 
eligible to enroll. They will have failed or progressed on immune checkpoint inhibitor such as 
nivolumab or pembrolizumab after failing or intolerant to the standard-of-care (SOC) platinum-
based chemotherapy. Patients with EGFR, ALK or ROS mutated tumors must have failed 
treatment with appropriate small molecule inhibitors followed by failure or progression while on 
the immune checkpoint inhibitor to be eligible.  
The study will enroll patients regardless of their PD-L1 status in two phases: a dose 
finding/tolerability assessment phase and an efficacy assessment phase. In the dose finding/ 
tolerability assessment phase, the safe dose of idelalisib in combination with pembrolizumab, 
that down-regulates the activity of T-regulatory function (Treg) by more than 80% of baseline in 
at least 80% of patients (5 out of 6 or more) will be determined. If we cannot find a safe dose that 
suppresses Treg by 80%, the safe dose that offers the highest Treg suppression will be chosen.   
Initially, 3 NSCLC patients will be evaluated at 50 mg twice daily of idelalisib (in combination 
with pembrolizumab, 200 mg every three weeks).  If there is 0/3 or 1/3 dose-limiting toxicity 
(DLT), another 3 will be enrolled. If no more than 1/6 has DLT, Treg will be determined. If at 
this dose level 80% patients have reduction of Treg function of >=80% of baseline level, this 
dose will be the phase 2 recommended dose (P2RD). If dose limiting toxicity occurs in equal to 
2/3 in the initial 3 patients or more than 1/6 patients after another 3 patients, then lower doses of 
idelalisib will be investigated in cohorts with similar number of patients until a dose that causes 
no more than 1/6 DLT is found before functional analysis of Treg.  Other idelalisib doses that 
will be evaluated may include 100 mg twice daily, 150 mg twice daily or 50 mg once daily and 
50 mg every other day.  
In the efficacy assessment phase, patients will be enrolled to detect whether idelalisib added to 
pembrolizumab at the P2RD will result in further objective response.  All subjects in the efficacy 
assessment phase will be treated with pembrolizumab (200 mg IV Q3W) in combination with 
idelalisib (dose not exceeding 150 mg BID per the tolerability assessment phase) for 18 weeks 
before maintenance with pembrolizumab 200 mg IV Q3W for up to 2 years, until disease 
progression or unacceptable toxicity. The primary end point will be objective response rate 
(ORR), based on RECIST 1.1. Patients will be managed using immune response RECIST 
(irRECIST) criteria2.  The secondary endpoint will be duration of response (DOR).   
 


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2.2 Trial Diagram 
 
 
 
 
                                          Metastatic NSCLC  
Failed/Progressed on platinum doublets, Immune checkpoint inhibitors 
OR EGFR, ALK, ROS1 mutations ailed/progressed on small molecule 
inhibitors and immune checkpoint inhibitors 
Phase 2 
Phase 2 
3 pt 
DLT 0/3 
3 more  
 Total 6 
t
=<1/6 
=>2/6 
Treg Func 
DLT =1/3 
3 more 
Total 6 
t
DLT  2-3/3 
Start with a 
Lower Dose 
i.e. 50 mg QD 
Start with a 
Lower Dose 
i.e. 50 mg QD 
=1/6 
=>2/6 
Start with a 
Lower Dose 
i.e. 50 mg QD 
Treg Func 
Find a dose that 
Has <=1/3 DLT 
knock down Treg* 
Find a dose that 
Has <=1/3 DLT 
knock down Treg* 
Pembro 200mg Q3W and Idelalisib 50 mg BID x 9w 
* Successful knock down is defined as a decrease of >80% of baseline Treg activity in =>80% of patients 
tested (n=>6). Or the safe dose that offers the highest Treg suppression activity. Doses to be tested: 50 mg 
QOD, 50mg QD, 50mg BID, 100mg BID, and 150 mg BID   


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3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective(s) & Hypotheses 
(1) Objective: To determine whether addition of idelalisib at the P2RD to pembrolizumab is 
safe in checkpoint inhibitor refractory NSCLC patients.  
 
Hypothesis (1): addition of idelalisib at the P2RD to pembrolizumab is safe in NSCLC 
patients 
 
(2) Objective: To determine the P2RD of idelalisib used in combination with 
pembrolizumab in patients with checkpoint inhibitor refractory NSCLC. 
 
Hypothesis (2):  Combination of pembrolizumab (200 mg IV Q3W) with idelalisib can 
down-regulate Treg cell function by 80% in 80% patients at a dose lower than the current 
FDA approved dose of 150 mg BID PO in patients with NSCLC.  
 
(3) Objective:  To determine whether addition of idelalisib to pembrolizumab in   
NSCLC improves ORR over that seen with pembrolizumab or other immune checkpoint 
inhibitors alone in treatment of NSCLC. 
 
Hypothesis (3):  In NSCLC patients previously treated with anti-PD-1/PD-L1 therapies 
the ORR for the combination of idelalisib and pembrolizumab is 10% (it is nearly 0% for 
the refractory patients). 
 
3.2 
Secondary Objective 
Objective:  To evaluate DOR in NSCLC treated with idelalisib at P2RD in combination 
with pembrolizumab 
  
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
PD-1 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 


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T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.3,4  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-regulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28/CTLA-4. PD-1 has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).5,6  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules.  
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-
2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling 
cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  
PD-1 has been shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, Tregs and Natural Killer cells.  Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T-cells as well as on subsets of 
macrophages and dendritic cells.   
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 on T-cells inhibits activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is expressed on antigen-presenting cells found 
in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers 
have been found to express abundant levels of this T-cell inhibitor.  This suggests that the PD-
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
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.  Patients with EGFR or ALK genomic tumor aberrations should have disease 
progression on FDA-approved therapy for these aberrations prior to receiving Keytruda. 


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Keytruda has also been approved for the treatment of patients with unresectable or metastatic 
melanoma and lately head and neck squamous cell cancer.    
In addition to pembrolizumab, nivolumab has also been approved by the US FDA for treatment 
of NSCLC in the second line settings after failing platinum based chemotherapy. Despite all the 
excitement, ORR associated with the immune checkpoint inhibitors in NSCLC was only ~20% 
in all comers and the response is often short-lived. Although PD-L1 positive patients tended to 
respond more, PD-L1 negative patients also responded. It was postulated that other immune 
suppressive mechanisms such as upregulation of Treg and MDSC function in the tumor 
microenvironment play important role in blunting the immune response. Therefore, 
downregulation of such mechanism holds promise of boosting response to immune checkpoint 
inhibitor therapy.   
Phosphatidylinositol 3-kinases  
 
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play central role in regulation of a 
number of important cellular processes such as cell cycle, apoptosis, DNA repair, senescence, 
angiogenesis, and cellular metabolism.7  PI3Ks transmit signals from transmembrane receptors 
such as activated receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs) to 
the cytoplasm by generating phosphorylated phosphatidylinositols as second messengers.  
 
In human, there are three distinct classes of PI3Ks (I – III). They are different in terms of their 
structural characteristics, substrate specificities, and nature of lipid end-products. Class I PI3Ks 
are heterodimers that can be further divided into 2 subfamilies, IA and IB. Class IA PI3Ks are 
the most well studied and frequently implicated in cancer. 8  Structurally, class IA PI3Ks are 
comprised of a catalytic p110 subunit complexed with a regulatory p85 subunit. The catalytic 
p110 isoforms (α, β, and δ) are encoded by the PIK3CA, PIK3CB, and PIK3CD gene 
respectively, whereas the regulatory p85 subunits– p85, p55, and p50 isoforms – are encoded by 
PIK3R1, PIK3R2, and PIK3R3 genes, respectively. 
 
The N-terminus of class IA p110 (α, β, and δ) enzymes carries the p85- binding domain (PI3K-
ABD), which constitutively interacts with the SH2 domain of the regulatory subunit. It also 
contains the Ras-binding domain (PI3K-RBD), which mediates interaction with Ras-GTPases. 
The central region is comprised of the C2 PI3K-type and PIK helical domains, whereas the C-
terminus contains the catalytic domain. The PI3K-RBD domain is the most divergent region of 
the class IA kinase. 
 
P110α and p100β are ubiquitously expressed in all tissues whereas p110δ expression is primarily 
confined to hematopoietic cells.  p110 plays an important role in B-cell homeostasis and 
function. PI3Ks integrate signals from RTKs and GPCRs. p110γ, which is predominantly 
expressed in the pancreas, skeletal muscles, liver and heart, mediates signaling downstream of 
GPCRs.9  
 
In response to signaling from the growth factors, tyrosine phosphate motifs of activated receptors 
recruit PI3Ks to the plasma membrane by direct interaction with the SH2 domains of the 


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regulatory subunit.10  This interaction changes the conformation of the regulatory subunit. As a 
result, the inhibitory activity is abrogated, and the enzymatic activity of the catalytic subunit is 
fully liberated and become activated11. PI3Ks can also be stimulated by activated Ras-GTPases 
that form complex with phosphorylated adapter proteins (e.g. GRB2, SOS).12,13  The activated 
PI3Ks catalyze the generation of second messengers – phosphorylated phosphatidylinositols (PI). 
PIs in turn activate multiple downstream signaling pathways.  
 
Upon generation of second messengers (PIP3, PI 3,4-bisphosphate), the PI3K signaling 
indirectly triggers a cascade of events that culminates in activation of multiple effector kinase 
pathways, including the mTOR, ERK1/2, p38 MAPK, NF-kappa-B, and JNK/SAPK 
pathways7,14,15. Recent studies suggest that activated AKT has a direct effect on the apoptosis 
pathway by targeting and down-regulating the pro-apoptotic activity of Bcl-2 family members 
BAD and BAX resulting in cell survival.  PI3K-AKT signaling also controls cell death and 
survival through NF-kappa-B regulation of pro- and anti-apoptotic genes.16  In addition, AKT 
also signals to other proteins, such as mammalian target of rapamycin–containing protein 
complex (mTORC1) and the forkhead family of transcription factors (FOXOs) and regulates cell 
proliferation. 
 
It has been recognized that deregulation of the PI3K signaling pathway is associated with 
development in one-third of human cancers,17,18 although the mechanism of PI3K activation may 
vary.  For example, it is estimated that ~30% of breast cancers are associated with activating 
missense mutations of PIK3CA, the gene encoding the catalytic p110α subunit of class IA PI3K, 
which provides cells with a growth advantage and promotes tumor progression19. Somatic loss of 
PTEN activity, resulting in upregulated PI3K, by gene mutation, epigenetic silencing or deletion 
is also associated with significantly greater Gleason score, poorer prognosis, and higher rate of 
metastasis in prostate cancer20. Lastly, activating mutations of RTKs such as EGFR and HER2 
has also been implicated in PI3K activation.21,22  Importantly, dysregulated PI3K pathway 
signaling has also been implicated in conferring resistance to therapies in breast cancer, and non-
small cell lung cancer.23,24 The PI3K-BTK signaling also plays an essential role in B-cell 
development, proliferation and survival through recruitment and activation by CD19.25  In 
response to CD28 costimulation, PI3K upregulates BCL-XL expression in T-cells, and confers 
resistance to apoptosis during their activation.26 
  
Idelalisib (Zydelig, marketed by Gilead Sciences Inc), the first-in-class oral PI3K p110-δ 
inhibitor, has recently been approved by the FDA for the treatment of relapsed/ refractory 
chronic lymphocytic leukemia (CLL) in combination with rituximab. It is also approved as 
monotherapy for the treatment of small lymphocytic lymphoma and follicular lymphoma.  As 
discussed below, recent work also suggests that PI3K- inhibition may promote anti-tumor 
immune responses.   
 
4.1.2 Preclinical and Clinical Trial Data 
Therapeutic studies in mouse models show that administration of antibodies blocking PD-1/PD-
L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor 


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rejection, either as a monotherapy or in combination with other treatment modalities. Anti–
mouse PD-1 and anti–mouse PD-L1 have demonstrated antitumor responses as a monotherapy in 
models of squamous cell carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma.  
Blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and 
the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism of action 
involved local infiltration and activation of effector T-cell function in vivo. In addition, the 
combination of gemcitabine and anti–PD-L1 mAb demonstrated synergy in the rejection of 
pancreatic mouse tumors. In-house experiments have confirmed the in vivo efficacy of PD-1 
blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models.  
PI3K- knockout mice have reduced numbers of Treg in the periphery, although Treg numbers 
are increased in the thymus.27  Treg cells from these mice have attenuated suppressor function, 
fail to secrete IL-10 in vitro, and fail to protect mice from experimentally induced colitis in 
adoptive transfer experiments. PI3K- deficiency is associated with an increased sensitivity to 
autoimmune diseases and protects these mice against a broad range of tumors.27,28  PI3K is also 
critical for clonal expansion and differentiation of the T cells. In mice, inhibitors of PI3K- 
deplete Treg, alter myeloid derived suppressor cell (MDSC) function and can protect against 
tumor challenge. Treatment with a PI3K- inhibitor also disrupts the protective 
microenvironment essential for the survival of malignant B cells in B cell malignancies, causing 
rapid shrinkage of lymphadenopathy and transient lymphocytosis. 
 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Immune checkpoint inhibitors (Anti PD-1) are effective in treating NSCLC as single agent, 
but overall response is still not optimal. 
PD-L1 / PD-1 signaling is one immune checkpoint mechanism thought to maintain tolerance to 
self-antigens and prevent autoimmune disease. However, this mechanism appears to have been 
hijacked by numerous types of cancer cells to promote immune escape.3,4  NSCLC is among the 
several solid tumors that utilize this mechanism for immune escape. Early studies found that 
pembrolizumab is effective in treating NSCLC in the Keynote 001 trial,29 with an objective 
response rate of 19.4%, a median duration of response of 12.5 months, and a median overall 
survival of 12 months. Although patients whose tumors expressed higher levels (≥50%) of PD-
L1 had higher response rates (40% ORR) than those will tumors expressing lower levels of PD-
L1 (15% ORR), low levels (<1%) of tumor PD-L1 expression did not completely preclude 
response. For nivolumab, the same was true. Nivolumab is currently approved by the US FDA 
for treatment of advanced NSCLC patients who have failed or progressed on platinum based 
chemotherapy regardless of PD-L1 status. Taking PD-L1 status out of the picture, both 
pembrolizumab and nivolumab induce ~20% ORR. Current hypothesis holds that other 
immunosuppressive mechanisms are involved. Combination therapy with additional immune 
modulators has the potential to increase these response rates seen with pembrolizumab or 
nivolumab monotherapy.   


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Treg inhibition may boost the efficacy of immune checkpoint inhibitors  
Increased numbers of T regulatory cells (Treg) in the peripheral blood and T regulatory cell 
infiltration in the tumor has been observed in murine tumor models and in patients with 
cancer.30,31  Treg depletion dramatically enhances the effect of immunotherapy in murine tumor 
models.32    Treg inhibit the function of tumor specific T cells, particularly in the tumor 
microenvironment, and their elimination allows antigen-specific T cells to proliferate more 
robustly. Treg-mediated immune suppression may in part explain the poor clinical response of 
some cancer patients undergoing immunotherapy.  There is a positive correlation in murine 
models and in patients treated with ipilimumab between the CD8 effector to Treg cell ratio in the 
tumor microenvironment and tumor response.33-36  Agents that increase this ratio are associated 
with improved tumor control. 
Research using lung cancer models and patient studies support the concept that Treg-
targeted intervention has the potential to improve lung cancer control. 
In three models of lung cancer (a Kras mutation, a carcinogen-driven and a transgenic model), 
depletion of Treg with rapamycin, or antibody or genetic ablation, reduced  lung tumorigenesis 
by 90%, 80% and 75% respectively.37  It was observed that Treg exhibited high suppressive 
activity and this activity increased with tumor stage with NSCLC.38  In a retrospective analysis 
of 87 surgically resected NSCLC specimens, it was found that patients with high Treg counts had 
significantly worse prognosis in terms of relapse free survival (RFS) and overall survival (OS).39  
In another animal model, depletion of Treg by repeated injection of CD25 antibody was able to 
reduce the number of malignant lesions induced by peritoneal injection of chemicals coupled 
with a constitutive active NF-kB.40  Compared with healthy individuals, NSCLC patients have 
increased number of Treg in their peripheral blood. The increase in Treg number correlates with 
stage, with higher levels of Treg observed in more advanced stages (IV>III>II).41  Following 
chemotherapy, a greater increase in CD8+ T cell/Treg was predictive of better prognosis in 
advanced thoracic malignancies including NSCLC and mesothelioma.42   Compared with 
squamous cell lung cancer, immune tolerance seems to be more pronounced in 
adenocarcinomas.43  Immunosuppressive Treg increased significantly in adenocarcinoma of the 
lung. Treg depletion using anti-CD25 with cytotoxic chemotherapy significantly extended 
survival in these lung adenocarcinoma patients.44 Inhibition of mTOR signaling enhances 
antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances Treg 
activity. When anti-CD4 antibody was used for Treg control in this mTOR inhibition preclinical 
model, depletion of Treg combined with a pharmacological mTOR inhibitor led to successful 
control of tumor lung metastasis in a syngeneic model.45  Here, depletion of the CD4+ FoxP3+ 
cells (Treg) was responsible for the immunosuppression since adding back the CD4+FoxP3+ 
cells completely negated the effects.  Finally, the drop of Treg during neoadjuvant chemo-
immunotherapy with cisplatin, docetaxel and cetuximab in NSCLC significantly correlated with 
clinical response.46  


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Idelalisib, a newly approved PI3K− inhibitor, may provide clinically applicable approach 
for Treg inhibition 
By using the PC61 monoclonal antibody that targets murine CD25, mice can be depleted of 
Treg, but attempts to deplete Treg in humans have not been highly successful despite multiple 
attempts.  Rosenberg has used three reagents to deplete Treg including denileukin difitox, an IL-
2 diphtheria toxin construct approved for the treatment of cutaneous T cell lymphoma,47 LMB-2, 
a CD25 antibody-pseudomonas immunotoxin,48,49 and the CD25 directed immunotoxin RFT5-
SMPT-dgA.50  Although cells expressing high levels of CD25 are depleted by these strategies, 
Treg, which express lower levels of CD25, are not as well targeted and these approaches have 
not been associated with significant clinical tumor responses. In addition, CD25 is upregulated 
on activated T cells, raising the possibility that depletion of CD25+ cells will deplete effector T 
cells as well as Treg. 
We and others have shown that inhibition of PI3K- in mice alters T regulatory cell numbers and 
function and has the potential to enhance the effects of tumor immunotherapy.  The PI3K- 
knockout mouse has reduced numbers of Treg in the periphery although Treg numbers are 
increased in the thymus.27  PI3K- deficiency is associated with an increased sensitivity to 
autoimmune diseases and protects these mice against a broad range of tumors.27,28   The 
pharmacologic inhibitor of PI3K- idelalisib has been approved by the FDA for the treatment of 
chronic lymphocytic leukemia (when given in combination with rituximab), small lymphocytic 
lymphomas and follicular lymphomas.  In mice, inhibitors of PI3K- deplete Treg, alter myeloid 
derived suppressor cell (MDSC) function, and can protect against tumor challenge.  Combining 
PI3K- inhibition with immune checkpoint blockade has the potential to further increase the 
response rate of these agents by relieving Treg-mediated suppression of tumor antigen-specific T 
cells and thus allowing tumors that are not responsive to immune checkpoint blockade alone to 
respond.   
4.2.2 Rationale for Dose Selection/Regimen/Modification  
Pembrolizumab 
The selection of the 200 mg IV Q3W fixed dosing for pembrolizumab is based on extensive 
analyses performed using population PK modeling showing that the fixed dose of 200 mg every 
3 weeks will provide exposures that (1) are optimally consistent with those obtained with the 2 
mg/kg dose every 3 weeks (the FDA-approved dose for the treatment of metastatic melanoma), 
(2) will maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and (3) will maintain individual patient exposure in 
the exposure range established in melanoma that is well tolerated and safe.  
This fixed dose simplifies the dosing regimen to be more convenient for physicians and to reduce 
potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the logistical 
chain at treatment facilities and reduce wastage. 
Idelalisib in combination with pembrolizumab 


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Idelalisib has been approved for use in CLL (in combination with rituximab), SLL and follicular 
lymphoma at a recommended dose of 150 mg PO BID. At this dose, the most common side 
effects greater or equal to grade 3 were diarrhea (due to colitis), which was reported in 13% 
patients (16/120), transaminitis (13%, 16/120) and neutropenia (27%, 34/120).51,52   
Similarly, in the KEYNOTE-001 trial treating NSCLC with single agent pembrolizumab, the 
most common grade 3 or higher side effects were dyspnea (3.8%), pneumonitis (1.8%) and 
decreased appetite (1%).  Diarrhea occurred in0.6% and increased alanine transaminase in 0.4% 
of patients. Noted here, many of these significant toxicity are immune mediated and are 
overlapping in nature. These include but are not limited to colitis with diarrhea, hepatotoxicity 
and pneumonitis, hence we favor a cautionary approach in testing the combination (see below). 
In March 2016, six clinical trials exploring idelalisib (Zydelig) in combination with other 
therapies were halted due to reports of an increased rate of adverse events, including death, for 
patients with hematologic malignancies, according to an alert issued by the FDA. The clinical 
trials involved untreated CLL or SLL and indolent NHL patients. Pneumocystis pneumonia 
(PCP) was the cause of mortality in these patients. However detailed analysis did not show 
significant increase of incidence in idelalisib group compared to placebo. In the end, 
PCP/pneumonia was added to the FDA approval for idelalisib Black Boxed Warning for fatal 
and serious side effects which included previously liver toxicity, diarrhea, colitis, pneumonitis, 
and intestinal perforation associated with the first-in-class PI3K-delta inhibitor. Therefore, the 
autoimmune related side effects will be closely monitored. Since mandatory PCP prophylaxis 
would have prevented death from PCP/pneumonia, we will implement strict PCP prophylaxis in 
patients receiving idelalisib throughout the study and continued for 6 months after the study. 
TMP 160 mg, QD, PO, 3 times per week, on alternative day Monday, Wednesday and Friday 
will be implemented. Dapsone 100 mg once daily PO will be the alternative in case of sulfa 
allergy. More importantly, we will start the idelalisib combo at a lower dose (i.e 50 mg BID) and 
going up until a dose that causes no more than 1/6 DLT and meets the functional criteria is 
found. The highest idelalisib dose we will go for the combination will be 150 mg BID PO.  The 
functional criteria require down-regulation of the Treg function by 80% in more than 80% of 
patient tested. In case we still do not have 80% down-regulation of Treg function, we will pick 
the safe idelalisib dose that offers the highest suppression of Treg function. All patients will be 
observed for 18 weeks or >4 months before proceeding to the phase 2 study. 
Rationale for Endpoints 
4.2.2.1 Efficacy Endpoints 
We will use objective response rate (ORR) as the primary end point. Since responses seen in the 
immune therapy trials correlate with clinical benefit, we believe that ORR will translate into 
survival benefit. Therefore, ORR is a surrogate marker for survival (PFS and possibly OS). 
Because loss of response is common in cancer patients, DOR will be assessed as the secondary 
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4.2.2.2 Efficacy in Patients That Have Progressed During PD-1/PD-L1 Blockade 
For patients with NSCLC who have progressed during PD-1/PD-L1 blockade, further treatment 
with pembrolizumab or other immune checkpoint inhibitors would be expected to have limited 
efficacy.  Intratumoral Tregs and/or MDSCs are hypothesized to be a factor that may limit the 
effectiveness of PD-1/PD-L1 blockade.  As such, treating patients with tumors that have 
progressed during PD-1/PD-L1 blockade with idelalisib+pembrolizumab may lead to tumor 
responses.  
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
All subjects to be screened must have documented tissue diagnosis of NSCLC from biopsy, 
either metastatic or recurrent. They must have failed or progressed on platinum-based 
chemotherapy (e.g. cisplatin, carboplatin) as well as immune checkpoint inhibitor (e.g nivolumab 
or pembrolizumab).  Patients with EGFR/ALK mutations/translocations must have failed or 
progressed on small molecule inhibitor therapies (e.g. erlotinib, afatinib, etc.).   
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Expected life expectancy of more than 6 months. 
4. Have at least one measurable lesion based on RECIST 1.1.   
5. Have a performance status of 1 or less on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1.  All screening labs should be 
performed within 10 days of treatment initiation. 
 Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /L 
Platelets 
≥100,000 / L 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 
days of assessment) 
Renal 
 
Serum creatinine OR 
≤1.5 X upper limit of normal (ULN) OR 


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Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 g/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
7. If a female subject of childbearing potential, have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
8. If a female subject of childbearing potential, be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 120 days after the last dose of study medication (Reference Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year.  
9. If a male subject, agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study drugs. 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study drug or has participated in a study of an 
investigational agent and received study drug or used an investigational device within 3 
weeks of the first dose of treatment. 
2. Is within 3 weeks of most recent chemotherapy.  
3. Patients who are currently taking steroid must come off 7 days before come on the trial 
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
5. Has a known history of active TB (Bacillus Tuberculosis) 
6. Has a history of hypersensitivity to pembrolizumab or any of its excipients. 
7. Has a history of hypersensitivity to idelalisib or any of its excipients. 


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8. Has had a prior anti-PD-1 or anti-PD-L1 monoclonal antibody, who discontinued such 
treatment due to adverse events.  Discontinuation of such therapy due to disease 
progression is not grounds for exclusion. Has had prior chemotherapy, targeted small 
molecule therapy, radiation therapy, or other anti-tumor mAb treatment within 3 weeks 
prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
9. Note:  If subject received major surgery, they must have recovered adequately from any 
toxicity and/or complications from the intervention prior to starting therapy (routinely 6-8 
weeks after surgery).  Has a known additional malignancy that is progressing or requires 
active treatment in the past 2 years.  Exceptions include basal cell carcinoma of the skin 
or squamous cell carcinoma of the skin that has undergone potentially curative therapy or 
in situ cervical cancer. 
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging over a period of at least 4 
weeks, with a brain imaging study documenting stability of such brain metastasis(es) 
within 4 weeks of the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are not 
using steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
11. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
12. Has known history of non-infectious pneumonitis that required steroid use or has current 
pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 


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Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. Note:  
Seasonal influenza inactivated vaccines for injection are allowed; however live attenuated 
influenza vaccines (e.g., Flu-Mist®) are not allowed. 
5.2 
Trial Treatments, Mandatory Prophylaxis of Pneumocystis pneumonia (PCP) 
The treatment and prophylaxis to be used in this trial is outlined below in Table 2. 
Table 2.  Trial Treatment and Prophylaxis of PCP Pneumonia 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg*  
Q3W* 
IV infusion 
Day 1 of each 3 week 
cycle* 
Experimental 
Idelalisib 
50 mg† 
BID† 
PO 
Every Day† 
Experimental 
Bactrim DS# 
160mg/800mg 
QD 
PO 
M, W, Friday 3/W 
Prophylaxis 
*Pembrolizumab doses may be withheld due to toxicity as described in Section 5.2.1.2. 
†May be administered at a higher or lower dose and frequency based on results of the tolerability 
assessment/dose finding phase of the study.  
#Dapsone will be used in case of sulfa allergy, 100 mg once daily PO. 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
Pembrolizumab will be administered at a dose of 200 mg IV Q3W.  The rationale for this dosing 
is provided in Section 4.0 – Background and Rationale.  Details on preparation and 
administration of pembrolizumab (MK-3475) are provided in Section 5.2.2., Drug Preparation 
and Administration.  
The planned dose of idelalisib to be utilized in combination with pembrolizumab in this trial is 
≤150 mg PO BID.  If in the tolerability assessment phase of the study this dose is not tolerated in 
the combination with pembrolizumab, a tolerable lower dose will be identified and then used for 
the efficacy assessment phase of the study in combination with pembrolizumab. 
5.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab and idelalisib must be 


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withheld for drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See 
Section 5.6.1 for supportive care guidelines, including use of corticosteroids.  
For idelalisib, the blackbox warning cites fatal and serious hepatotoxicity, severe diarrhea or 
colitis occurring in 14% of the patients taking the drug. Pneumonitis is also life threatening.  
Patients participating in this study will be closely monitored during treatment for signs of 
toxicity. In the tolerability assessment phase of the study, if significant toxicity occurs with a 
given dose regimen of idelalisib, either a lower dose of idelalisib and/or less frequent dosing of 
idelalisib in combination with pembrolizumab may be evaluated in cohorts of additional patients.   
During concurrent administration of idelalisib and pembrolizumab, it will not be possible to 
definitely ascribe any toxicities and severe or life-threatening AEs to one of the two agents.  
Should such toxicities or AEs occur, the guidance for managing pembrolizumab-related AEs 
should be followed, with the additional caveat that idelalisib should be held and then restarted 
concurrently with pembrolizumab. 
Table 3.  Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Neutropenia 
3 
Normalize to above 1,500/mm3 
Grade 4 
Thrombocytopenia 
3 
Once above 100,000/mm3 
Bleeding occurred or grade 4 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1, Idelalisib 
will start at a lower dose level 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia or 
Hypertriglyceride
mia or 
Hypoglycemia 
T1DM or  
3-4 
Hold pembrolizumab and idelalisib for new 
onset Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
Hold idelalisib if grade 3-4 hypoglycemia 
or hypertriglyceridemia 
Resume pembrolizumab and idelalisib when patients are 
clinically and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab and idelalisib 
can be continued while treatment for the 
thyroid disorder is instituted 
Therapy with pembrolizumab and idelalisib can be continued 
while treatment for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Pneumonitis 
1 
Toxicity resolves to Grade 0, idelalisib to 
start at a lower dose level 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
2-4 
Permanently discontinue 
Permanently discontinue 
CMV infection or 
viremia 
Any 
evidence 
Interrupt idelalisib in patients with evidence 
of CMV infection of any grade or viremia 
(positive PCR or antigen test) until the 
infection has resolved. If idelalisib is 
resumed, continue PCR or antigen testing 
on day 1 of each remaining cycle. 
If toxicity does not resolve, permanently discontinue. 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity 
including rash2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical/surgical events or for logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption 
should be documented in the patient's study record. 
5.2.1.3 Selection for Idelalisib Dosing When Administered in Combination with 
Pembrolizumab  
Table 4: Dose Levels of Idelalisib*  
Pembrolizumab 
Idelalisib 
dose level 
Idelalisib Dose 
(mg) 
Idelalisib   
Frequency 
 
200mg Q3W 
-2 
50 
QOD 
-1 
50 
QD 
1* 
50 
BID 
2 
100 
BID 
3 
150 
BID 
*Note: Trial will be started at dose level 1 (in bold) and may go up or down. Pembrolizumab is 
given at a constant dose and frequency intravenously whereas idelalisib will be given orally at 
the dose and frequency specified in the table. 


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The rules for modifying the selected idelalisib dose used in combination with pembrolizumab 
treatment (dose finding and tolerability assessment phase of the study) are as follows (all dose 
adjustments are made only to idelalisib): 
An initial cohort of 3 subjects are enrolled, receiving both pembrolizumab (200 mg Q3W, IV) 
and idelalisib at 50 mg PO BID: 
• If none of the three patients develop a DLT, we will enroll another 3 patients. If no more 
than 1/6 patient develops a DLT, we will test the suppression of Treg function by 80% in 
more than 80% patients. If meeting these criteria, we will declare this dose as the P2RD 
and will proceed to the phase II part using this dose. If more than 1/6 subjects develops a 
DLT, we will follow the dose reduction scheme highlighted below. If the functional 
criteria are not met, then a higher dose will be tested from the beginning. 
• If one of the 3 subjects develops a DLT, an additional 3 will be enrolled. If no more than 
1/6 has a DLT, Treg function test will begin as above. If ≥2/6 subjects with a DLT at this 
dose level, this dose will not be administered to any additional subjects, and the next 
lower dosing regimen for idelalisib 50 mg PO QD) will be studied, in 3 new subjects, 
following this same algorithm. 
• If ≥2/3 subjects develop a DLT, this dose will not be administered to any additional 
subjects, and the next lower dosing regimen for idelalisib (50 mg PO QD) will be studied, 
in 3 new subjects, following this same algorithm. 
It is conceptually acceptable to de-escalate to a lower, not pre-defined and not previously-studied 
dose, if evaluation of toxicity at such a dose is desired in lieu of proceeding directly to the 
subsequent efficacy assessment phase of the study. If this approach is taken, 3 new subjects 
should be enrolled at the new lower dose, and the aforementioned rules should be used to 
determine further enrollment at this dose level.  
DLT’s will be defined from toxicities observed during the first 9 weeks of idelalisib treatment 
for each dose level.  See Section 5.2.4 for rules on replacement of subjects in the tolerability 
assessment phase of the trial. The occurrence of any of the following toxicities during the initial 
9 weeks of idelalisib treatment, if assessed by the Investigator to be possibly, probably or 
definitely related to idelalisib will be considered a DLT: 
1. Grade 4 non-hematologic toxicity (not laboratory) 
2. Grade 4 hematologic toxicity lasting > 7 days, except thrombocytopenia 
a. Grade 4 thrombocytopenia of any duration 
b. Grade 3 thrombocytopenia is a DLT if associated with bleeding: 
3. Grade 3 non-hematologic toxicity (not laboratory) lasting > 3 days despite optimal 
supportive care.  Grade 3 nausea or vomiting will be considered a DLT if lasting more 
than 3 days despite optimal supportive care. 


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4. Any Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
• medical intervention is required, or 
• the abnormality leads to hospitalization, or 
• the abnormality persists for > 1 week 
5. Febrile neutropenia Grade 3 or Grade 4 
6. Any drug-related AE which caused subject to discontinue treatment 
7. Grade 5 toxicity 
 
5.2.2 Drug Preparation and Administration 
5.2.2.1 Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion on an outpatient basis 
every 3 weeks.  Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min).  Preparation and administration of the investigational agent, pembrolizumab, 
will follow the same guidelines as for the FDA-approved agent, pembrolizumab, known 
commercially as Keytruda. 
 
Preparation for Intravenous Infusion 
• Visually inspect the solution for particulate matter and discoloration prior to 
administration. The solution is clear to slightly opalescent, colorless to slightly yellow. 
Discard the vial if visible particles are observed. 
• Dilute pembrolizumab injection (solution) or reconstituted lyophilized powder prior to 
intravenous administration. 
• Withdraw the required volume from the vial(s) of pembrolizumab and transfer into an 
intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the 
diluted solution should be between 1 mg/mL to 10 mg/mL. 
• Discard any unused portion left in the vial. 
 
Storage of Diluted Solutions 
The product does not contain a preservative. Store the diluted solution of pembrolizumab 
either: 


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• At room temperature for no more than 6 hours from the time of dilution. This includes 
room temperature storage of the infusion solution in the IV bag, and the duration of 
infusion. 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of dilution. If refrigerated, allow the diluted solution to come to room temperature 
prior to administration. Do not freeze. 
 
Administration 
• Administer infusion solution intravenously over 30 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line 
or add-on filter. 
• Do not co-administer other drugs through the same infusion line. 
• The patient will be monitored for at least 30 minutes including a determination of blood 
pressure, heart rate, and respiratory rate before and after each infusion.  
• After the patient is monitored for 30 minutes following the first pembrolizumab 
infusion, the patient will be given the first oral dose of idelalisib.  On day 1 of all 
following cycles, idelalisib will be taken by the patient at home, prior to infusion 
appointments.  
 
5.2.3 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/ assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion duration to be as close to 30 minutes as possible.  
However, 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). 
Patients will be given idelalisib for oral self-administration at home. This drug should be taken at 
fixed times of the day, with or without food.   Patients will be required to record oral drug intake 
in a pill diary that is provided by the study site.  Diet restrictions apply. 
5.2.4 Trial Blinding/Masking 
This is an open-label single-arm trial; therefore, the investigator, pharmacist and subject will 
know the treatment administered. 


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5.2.5 Subject Replacement During the Tolerability Assessment Phase of the Trial 
In order to determine safety, all subjects selected must meet the criteria for evaluability for the 
initial 9 weeks of treatment during the tolerability assessment phase of the study. Subjects during 
the tolerability assessment phase of the study are considered non-evaluable and will be replaced 
if: 
• They are enrolled but not treated 
• They discontinue from the trial prior to completing all the safety evaluations for reasons 
other than treatment-related adverse events 
• They receive less than 9 weeks of treatment with idelalisib and did not experience a DLT   
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation. 
If a subject experiences a DLT during the initial 9 weeks of the tolerability assessment phase of 
the trial, treatment may be discontinued at the discretion of the Investigator. However, if the 
subject is deriving clinical benefit from the trial treatment, the subject may be allowed to 
continue. 
5.3 
Randomization or Treatment Allocation 
This is a single arm study comparing with historical controls. No randomization is needed. 
5.4 
Stratification 
 No stratification based on age, sex or other characteristics will be used in this trial. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the 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 may be 
required.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.   
5.5.1 Acceptable Concomitant Medications 
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 medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date should also be included on the CRF. 


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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 more than 30 days but within 90 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications and Drug Interactions to Watch 
5.5.2.1 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and idelalisib 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
• 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, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. Dexamethasone affects the 
idelalisib levels and should be avoided while taking idelalisib. 
• Subjects who, in the assessment by the investigator, require the use of any of the 
contraindicated treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
• Drugs metabolized by CYP3A, including some commonly used drugs such as cisapride, 
simvastatin, are contraindicated while taking idelalisib; see section 5.5.2.2 for drug 
interactions with idelalisib).  
• The following drugs will be prohibited while taking idelalisib in this trial: Alfuzocin, 
carbamazepine, cisapride, cobimetinib, conivaptan, cyclosporine, dihydroergotamine, 
eliglustat, ergotamine, fentanyl, flibanserin, ivabradine, ketoconazole, lovastatin, 
lurasidone, midazolam, naloxegol, phenytoin, pimozide, quinidine, rifampin, simvastatin, 
sirolimus, St.John’s Wort tacrolimus, venetoclax, warfarin.  
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.5.2.2 Potential drug interactions with idelalisib 
Idelalisib is metabolized primarily via aldehyde oxidase, and to a lesser extent via CYP3A and 
glucuronidation (UGT1A4). Its primary metabolite is GS-563117. Idelalisib is not an inhibitor of 
the metabolizing enzymes CYP1A2, CYP2B6, CYP2C, CYP2D6, or UGT1A1, or of the 
transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. GS-563117 is a 
mechanism-based inhibitor of CYP3A (KI = 0.18 M, Kinact = 0.033 min-1). GS-563117 is not 
an inhibitor of the metabolizing enzymes CYP1A2, CYP2B6, CYP2C, CYP2D6 or UGT1A1, or 
of the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. 
A clinical drug interaction study found that co-administration of idelalisib with rifampin (a 
strong CYP3A inducer) resulted in a ~75% reduction in idelalisib plasma AUCinf. Co-
administration of idelalisib with strong CYP3A inducers such as rifampin, phenytoin, St. 
John’s Wort, or carbamazepine should be avoided. 
A clinical drug interaction study found that co-administration of idelalisib with ketoconazole (a 
strong CYP3A inhibitor) resulted in a 26% increase in idelalisib Cmax and a 79% increase in 
AUCinf, indicating that ZYDELIG is not a sensitive CYP3A substrate. 
A clinical drug interaction study found that co-administration of idelalisib with midazolam (a 
sensitive CYP3A substrate) resulted in a ~140% increase in Cmax and a ~440% increase in 
AUCinf of midazolam due to the CYP3A inhibition by GS-563117. Accordingly, idelalisib is 
considered to be a strong CYP3A inhibitor. Coadministration of idelalisib with CYP3A 
substrates (e.g., certain antiarrhythmics, calcium channel blockers, benzodiazepines, 
HMGCoA reductase inhibitors, phosphodiesterase-5 (PDE5) inhibitors, and warfarin) may 
increase their systemic exposures, stop the drug or close monitoring is advised. Avoid 
coadministration of idelalisib with narrow therapeutic index CYP3A substrates (e.g. alfentanil, 
cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, ergotamine, 
dihydroergotamine). 
Table 5. Known CYP3A Substrates:  
CYP3A Inhibitors 
CYP3A Inducers 
  Amiodarone 
• Ethosuximide 
  Anastrazole 
• Glucocorticoids 
• Azithromzcin 
• Griseofulvin 
• Cannabinoids 
• Primidone 
• Cimetidine 
• Progesterone 
• Clarithromycin 
• Rifabutin 
• Clotrimazole 
• Rifampin 
• Danazol 
• Nafcillin 
• Delavirdine 
• Nelfinavir 
• Diethyldithiocarbamate 
• Oxcarbazepine 
• Diltiazem 
• Phenobarbital 
• Dirithyromycin 
• Phenylbutazone 
• Disulfiram 
• Rofecoxib (mild) 
• Entacapone (high dose) 
• Sulfadimidine 
• Erythromycin 
• Sulfinpyrazone 


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• Ethinyl estradiol 
• Troglitazone 
• Fluconazole 
 
• Fluoxetine 
 
• Fluvoxamine 
 
• Gestodene 
 
• Grapefruit juice 
 
• Indinavir 
 
• Isoniazid 
 
• Metronidazole 
 
• Mibefradil 
 
• Miconazole 
 
• Nefazodone 
 
• Nelfinavir 
 
• Nevirapine 
 
• Norfloxacin 
 
• Norfluoxetine 
 
• Omeprazole 
 
• Oxiconazole 
 
• Paroxetine (weak) 
 
• Propoxyphene 
 
• Quinine 
 
• Quinupristine and dalfopristin 
 
• Ranitidine 
 
• Ritonavir 
 
• Saquinavir 
 
• Sertindole 
 
• Sertraline 
 
• Troglitazone 
 
• Troleandomycin 
 
• Valproic acid 
 
 
5.6 Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. 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 
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Note: if after the evaluation the event is determined to be not related to pembrolizumab or 
idelalisib, the investigator should follow the adverse event  reporting guidance in section 7.2 of 
this document. Refer to Section 5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Study drug administration will be held during any 
ongoing investigation of the cause of an ECI/AE.   
The following supportive care guidelines should be utilized for management of subjects 
participating in this trial who experience these specific AEs/ECIs: 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  


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▪ Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events and Grade 2-4 hypothyroidism: 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In 
hypothyroidism, 
thyroid 
hormone 
replacement 
therapy, 
with 
levothyroxine or liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• Hepatic: 
Fatal and/or serious hepatotoxicity occurred in 11% of patients treated with idelalisib in 
combination trials. Elevations in ALT or AST greater than 5 times the upper limit of 
normal (ULN) have occurred.  These findings were generally observed within the first 12 
weeks of treatment and were reversible with dose interruption. Monitor ALT and AST in 
all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 
3 months, then every 1 to 3 months thereafter. 
o For Grade 2 events (>3-5 x ULN), monitor liver function tests weekly until 
resolved (<1 x ULN), maintaining idelalisib dose, but holding pembrolizumab 
dose. 
▪ If treating with IV or oral corticosteroids, hold both idelalisib and 
pembrolizumab. 
o For Grade 3-4 events (>5 x ULN), monitor liver function tests at least weekly 
and treat with intravenous corticosteroids for 24 to 48 hours (withhold idelalisib 
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o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.  Study treatment may be restarted if toxicity 
resolves in less than 4 weeks off steroids. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Hypoglycemia: 
o For grade 2 events, corticosteroid should be given 
o For Grade 3-4 events, glucagon should be given.  
o When symptoms improve to grade 1 or less steroid should be taper down and dose 
should be reduced  
• Neutropenia and neutropenic fever: 
Neutropenia (decreased ANC) and neutopenic fever may occur while receiving idelalisib 
o For grade 1 and 2 (ANC>1000/mm3), no intervention needed. 
o For grade 3, hold idelalisib until ANC > 500/mm3 and start at a lower dose. 
o For Grade 4 or neutropenic fever, hold idelalisib and manage per neutropenic 
fever with antibiotics and growth factor at the discretion of the investigator. 
Discontinue idelalisib permanently. 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after pembrolizumab infusion and generally resolve completely within 24 hours 
of completion of infusion.  
• Table 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 6. Infusion Reaction Treatment Guidelines 
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 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Subject may be pre-
medicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab (MK-3475) 
with: 
 


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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
for < =24 hrs 
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 pre-medicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued 
from further trial treatment administration. 
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. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 
 
 
5.7 Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. Grapefruit, grapefruit juice, pomegranate and Seville oranges 
should be excluded from the diet due to their effects on idelalisib. 
5.7.2 Contraception 
Pembrolizumab or idelalisib may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab or idelalisib has transient 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 
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has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  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 study Visit 1 throughout the study period up to 120 days 
after the last dose of study therapy.  
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 requirement (described above) for the duration of the 
study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 
Lactation to the Sponsor.  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. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab or 
idelalisib, the subject will immediately be removed from the study.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor without 
delay and within 24 hours to the Sponsor and within 2 working days 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 the Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab or idelalisib 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. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 


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plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4---Other Procedures. 
In this trial, a subject may discontinue from treatment but continue to participate in the regularly 
scheduled activities, as long as the subject does not withdraw consent.  Once a subject has 
discontinued treatment, even though he/she continues to be monitored in the trial, he/she may be 
allowed to begin treatment again if deemed medically appropriate. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject withdraws consent. 
A subject must be discontinued from treatment (but may continue to be monitored in the trial) for 
any of the following reasons: 
• The subject withdraws consent. 
• Confirmed radiographic disease progression 
Note: Subjects should be managed by irRECIST, with PD confirmed as outlined in 
Section 5.8.1.  
Note: For unconfirmed radiographic disease progression, please see Section 5.8.1 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
5.8.1 and Table 5. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 under Dose 
Modification section in Table 3. 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• The subject has completed 35 administrations of pembrolizumab (approximately 2 years 
of treatment) during the trial 
Note: Subjects who discontinue pembrolizumab after 35 administrations may be eligible 
for up to 17 administrations (approximately one year) of additional study treatment if 


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they progress after discontinuing study treatment provided they meet additional criteria.  
Subjects who discontinue trial treatment before receiving 35 administrations of 
pembrolizumab for reasons other than disease progression or intolerability, or who attain 
a CR and discontinue trial treatment may also be eligible for up to 17 administrations 
(approximately one year of retreatment (Second Course)) after experiencing disease 
progression.  The decision to retreat will be at the discretion of the investigator, provided 
that such a subject meets the criteria for treatment and the trial is ongoing.  
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected for 
90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for 
reasons other than progressive disease (PD) will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be followed 
by telephone for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
5.8.1 Treatment after Initial Radiologic Progression (irRECIST-based Management) 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial apparent increase in tumor burden 
(i.e., pseudoprogression) or even the appearance of new lesions.  Standard RECIST-based 
assessment of disease progression may, thus, not provide an accurate assessment of response to 
immunotherapeutic agents such as pembrolizumab.  For this reason, irRECIST has been 
developed to help guide treatment decisions during tumor immunotherapy. 
For subjects who have initial radiological evidence of radiological PD by RECIST 1.1 as 
determined by the site, the investigator may elect to continue a subject on study treatment until 
repeat imaging is obtained (irRECIST-based subject management) (see Table 7 below).  This 
clinical judgment decision by the investigator should only be made if the subject is clinically 
stable, based on clinical factors including performance status, clinical symptoms, and laboratory 
data.  Such subjects may continue to receive study treatment and a tumor assessment should be 
repeated ≥ 4 weeks later in order to reassess PD by RECIST 1.1 per investigator assessment.   
Clinical stability is defined by the following:  
• Absence of signs and symptoms of clinically significant progression of disease, including 
worsening of laboratory values 
• No decline in ECOG performance status 


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• Absence of rapid progression of disease  
• Absence of tumor progression at critical anatomical sites that requires urgent alternative 
medical intervention (e.g., CNS metastasis with potential for cord compression)  
NOTE:  Subjects exhibiting toxicity from trial therapy as outlined in Section 5.2.1.2 and 
7.2 may NOT continue to receive trial therapy. 
NOTE: Any subject deemed clinically unstable should be discontinued from trial treatment 
at investigator-assessed 1st radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation. 
In determining whether or not the tumor burden has increased or decreased per irRECIST, the 
investigator should consider all target and non-target lesions as well as any incremental new 
lesion(s). 
Upon repeat imaging, PD will be confirmed if ANY of the following occur by irRECIST: 
• Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial diagnosis of PD is worse (qualitative assessment) 
• New lesion resulting in initial diagnosis of PD is worse (qualitative assessment) 
• Additional new lesion(s) since last evaluation 
• Additional new non-target lesion progression since last evaluation 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from trial therapy. 
Upon repeat imaging, PD will have failed to be confirmed if ALL of the following occur by 
irRECIST:  
• Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir 
• Non-target disease resulting in initial diagnosis of PD is stable or improved (qualitative 
assessment) 
• New lesion resulting in initial diagnosis of PD is stable or improved (qualitative 
assessment) 
• No incremental new lesion(s) since last evaluation 
• No incremental new non-target progression since last evaluation 
 


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Table 7.  Imaging and Treatment after First Radiologic Evidence of PD (irRESIST-based 
Management) 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
by RECIST 1.1  
Repeat imaging 
at > 4 weeks at 
site to confirm 
PD 
May continue study treatment 
at the local site investigator’s 
discretion while awaiting 
confirmatory tumor imaging 
by site by irRECIST. 
Repeat imaging at > 4 
weeks to confirm PD 
per physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging 
confirms PD by 
irRECIST at the 
local site 
No additional 
imaging 
required 
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor) 
No additional imaging 
required 
N/A 
Repeat tumor 
imaging shows 
SD, PR or CR 
by irRECIST at 
the local site 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue study treatment at 
the local site investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study treatment if 
condition has improved and/or 
clinically stable at investigator’s 
discretion. Next tumor image 
should occur according to the 
regular imaging schedule 
outlined in the protocol 
 
If repeat local site imaging fails to confirm PD by irRECIST and the subject continues to be 
clinically stable, treatment may continue and follow the regular imaging schedule.  
When feasible, subjects should not be discontinued until progression is confirmed by the local 
site investigator radiology assessment.  This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some subjects can have a transient tumor 
flare in the first few months after the start of immunotherapy, and then experience subsequent 
disease response.  Subjects who are deemed clinically unstable are not required to have repeat 
tumor imaging for confirmation of PD.  Tumor flares include any of the following scenarios: 
• Worsening of existing target lesion(s) 
• Worsening of existing non-target lesion(s) 
• Development of new lesion(s) 
 
5.8.2 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 27 weeks with pembrolizumab and 9 weeks of idelalisib and 
have had at least three treatments with pembrolizumab and 9 weeks of idelalisib beyond the date 
when the initial CR was declared. However, such subjects with a CR may continue treatment (up 


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to a total of 2 years of treatment with pembrolizumab) as long as they are still deriving clinical 
benefit. If such subjects subsequently experience radiographic disease progression, they may be 
eligible for up to one more additional treatment with idelalisib for 18 Weeks and pembrolizumab 
for 2 years via the Second Course Phase, at the discretion of the investigator, if no cancer 
treatment has been administered since the last dose of pembrolizumab, the subject meets the 
safety parameters listed in the Inclusion/Exclusion criteria, and the trial remains open.  Such 
subjects will resume therapy at the same dose and schedule as they received at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.9 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event the drug manufacturer(s) decides to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 


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6.0 TRIAL FLOW CHART 
Table 8. Study Schedule of events 
Trial Period: 
Screening 
Main Study Treatment Perioda 
Maintenance 
Periodb 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
1 
2  
3 
4 
5 
6 
Q3W 
Discon 
Safety 
Follow-up 
Survival 
Follow-Up 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days post 
discon 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Prior and Concomitant Medication Review 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Post-study Survival and cancer therapy status 
 
 
 
 
 
 
 
 
x 
x 
x 
Clinical Procedures/Assessments 
Review Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Full Physical Examination 
x 
 
 
 
 
 
 
 
x 
 
 
Directed Physical Examination 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
Combination Treatment Administration 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
Maintenance Treatment Administration 
 
 
 
 
 
 
 
x 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
x 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
x 
 
 
x 
 
 
 
 
 
 
 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Comprehensive Serum Chemistry Panel 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
x 
x 
x 
x 
x 
x 
? 
x 
x 
x 


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Trial Period: 
Screening 
Main Study Treatment Perioda 
Maintenance 
Periodb 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Study 
Screening 
1 
2  
3 
4 
5 
6 
Q3W 
Discon 
Safety 
Follow-up 
Survival 
Follow-Up 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days post 
discon 
Every 12 
weeks  
CMV serology (IgG and IgM antibody) d 
 
 
x 
x 
x 
x 
x 
 
 
 
 
Efficacy Measurements 
Tumor Imaging c 
x 
 
 
9W 
 
 
18W 
Q9W 
 
x 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue Collection 
x 
 
x 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection (T-reg 
assay)  
x 
 
 
x 
 
 
x 
x 
 
 
 
a: Each treatment cycle is comprised of one infusion of pembrolizumab 200 mg IV on Day 1 in combination with 21 days of idelalisib BID PO in 3 weeks at 
P2RD or test dose BID PO. 
b: Following 6 cycles (18 weeks) of combination treatment, subjects will receive maintenance therapy consisting of one infusion of pembrolizumab 200 mg 
IV every 21 days, for up to 2 years. 
c: The first scheduled tumor imaging after treatment initiation occurs at week 9+/- 3 days and then every 9 weeks for the first year of therapy, then every 12 
weeks for the duration of treatment. 
d: Prophylactic screening for cytomegalovirus CMV infection should begin following the first cycle of idelalisib, and should be performed at the beginning 
(day 1) of each cycle of treatment with idelalisib). 
 
 
 
 
 


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7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. The details will be extracted from prior office visit/hospitalization documents 
including but not limited to office visit notes, hospital discharge summaries, radiology 
reports, pathology reports, mutational analysis etc.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 


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days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.  
7.1.1.6 Assignment of Study Number 
Once the informed consent is signed, the subject to be screened will be assigned a number. 
The number will be designated PILxxazzz: where PIL stands for Pembrolizumab and 
Idelalisib Lung cancer study; xx is the site number and a is the cohort number and zzz is the 
subject screening number. For example, the first subject screened in site 05 in cohort A is 
designated PIL05A001. 
7.1.1.7 Assignment of Randomization Number 
This is a non-randomized trial.  Therefore, a randomization number will not be assigned. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab and idelalisib, all AEs of unknown 
etiology should be evaluated to determine if it is possibly an event of clinical interest (ECI) 
of a potentially immunologic etiology (termed immune-related adverse events, or irAEs).  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.   
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   


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7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, blood pressure, 
pulse, respiratory rate, body weight and O2 saturation.  Height will be measured at screening 
only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging should be performed by computed tomography (CT) (preferred).  Magnetic 
resonance imaging (MRI) should be used only when CT is contraindicated or for imaging of 
the CNS.  The same imaging technique with respect to the modality and use of contrast 
should be used for a given subject throughout the trial to optimize the visualization of 
existing and new tumor burden.  
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  Determination of measurable disease based on RECIST 1.1 will be conducted by 
the local site investigator during screening for initial assessment of subject eligibility. Only 
subjects with confirmation of measurable disease by RECIST 1.1 will be eligible to 
participate in the trial.   
The first imaging assessment during treatment should be performed at 9 weeks (63 days ±7 
days) from Cycle 1, Day 1.  Subsequent imaging should be performed every 9 weeks (63 
days ±7 days) or more frequently if clinically indicated.  After the first 12 months on therapy, 
the imaging interval should be increased to every 12 weeks (84 days ±7 days).  Imaging 
timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Imaging should continue to be performed until disease progression (unless the investigator 
elects to continue treatment and follow irRECIST) (see Section 5.8.1), the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  
Per RECIST 1.1, PRs and CRs should be confirmed by a repeat tumor imaging assessment 
not less than 4 weeks from the date the response was first documented.  The tumor imaging 
for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan (i.e., 9-12 weeks later).  Subjects will 
then return to regular scheduled imaging, starting with the next scheduled imaging time 
point.  Subjects who obtain a confirmatory scan do not need to undergo the next scheduled 


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tumor imaging if it is < 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point. 
Imaging should continue to be performed until PD is documented by local investigator 
assessment (or in cases were the investigator elects to continue treatment and follow 
irRECIST (see Section 5.8.1), confirmed by local investigator assessment of a repeat imaging 
study ≥ 4 weeks later), the start of new anti-cancer treatment, withdrawal of consent, death, 
or the end of the trial, whichever occurs first.   
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
When archival tissue is available, no new tumor biopsy during the screening period, prior to 
receiving the first dose of study drug is necessary. When needed, image-guided biopsy 
should be used for tissue collection.  Tissue collected by fine needle aspiration during 
bronchoscopy or EBUS is not sufficient.  
At each biopsy, a minimum of three 18 gauge cores (or an equivalent volume) of tumor 
tissue should be collected and placed in formalin.  These cores will be embedded in a single, 
paraffin block and sectioned per standard histological procedures.  Tumor tissue sections will 
subsequently be used for H&E staining and IHC.  
One additional tube of blood will be drawn for correlative studies every 9 weeks throughout 
the treatment period.   
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial for 
hematology, chemistry, urinalysis, and others are specified in Table 9.   
 


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Table 9.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
Pharmacodynamics (PD)# 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 


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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding  
No blinding necessary since this is an open labeled study. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening Period 
Prior to signing the consent, outlines of the current clinical trial and a copy of the informed 
consent may be given to the patient to read at home and record any questions they might 
have.  The screening period starts from the day the informed consent is signed by both the 
patient and the principal investigator or his/her designee, and ends when the trial or treatment 
begins.  Patients are given the opportunity to ask all questions and consent to be screened for 
the current clinical trial. Screening may last up to 4 weeks. They are screened at this period 
per inclusion and exclusion again carefully. Labs, procedures, biopsies when needed are 
ordered promptly so that patients can be started on treatment in a timely fashion. A full 
history and physical is due at this period. Target lesion(s) are determined after the imaging 
(CT with contrast). If archived tissue is available, it can be sent in the place of a fresh biopsy 
for confirmation in Augusta University Medical Center Pathology Department.  


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7.1.5.2 Treatment Period 
Pembrolizumab (200 mg) will be infused intravenously in 30 min at day 1 and repeated every 
3 weeks. Idelalisib will be given at 150 mg PO BID (or possibly at a lesser dose based on 
results from the tolerability assessment phase of the trial) throughout the study starting on the 
day of the first dose of pembrolizumab.   Patients will be given a pill diary to complete at 
home.  
A history is obtained, a focused physical examination is performed, and blood samples for all 
scheduled labs are drawn at each visit, prior to pembrolizumab dose administration (unless 
otherwise indicated in the study flow chart).  
The first scheduled tumor imaging after treatment initiation occurs at week 9+/- 7 days, and 
will follow the schedule specified in section 7.1.2.6. 
Treatment period will continue until either disease progression per irRECIST 1.1 criteria, or 
the treating physician determines that the subject is no longer deriving clinical benefit, or the 
subject withdraws from the trial, or the subject receives 2 years of treatment.        
7.1.5.3 Post-Treatment Visits 
Post-treatment visits include a safety follow up visit, routine follow up visit and survival 
visits listed below. 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
with pembrolizumab and idelalisib (as described in Section 7.1.5.5) may have up to two 
safety follow-up visits, one after the Treatment Period and one after the Second Course 
Phase. 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 12 weeks (84 ± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with pembrolizumab as detailed in Section 


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7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab and idelalisib according 
to the criteria in Section 7.1.5.5 will move from the follow-up phase to the Second Course 
Phase when they experience disease progression.  Details are provided in Section 6.2 – Trial 
Flow Chart for Retreatment.    
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
7.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab and idelalisib with SD or better may be eligible for up to 
one year of additional pembrolizumab therapy if they progress after stopping study treatment.  
This retreatment is termed the Second Course Phase of this study and is only available if the 
study remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab and idelalisib after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
▪ Was treated for at least 12 weeks with pembrolizumab and idelalisib before 
discontinuing therapy. 
▪ Received at least two treatments with pembrolizumab and idelalisib beyond 
the date when the initial CR was declared. 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab and idelalisib treatment after 24 
months of study therapy for reasons other than disease progression or 
intolerability. 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab and idelalisib. 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab and 
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• Has a performance status of 0 or 1 on the ECOG Performance Scale. 
• Demonstrates adequate organ function as detailed in Section 5.1.2. 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication. 
• Subjects of child bearing potential are those who have not been surgically sterilized 
or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab and idelalisib.  Treatment will be administered for up to 
one additional year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event. 
Adverse events may occur within the follow-up period specified by the protocol, or 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
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Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Gilead Sciences Inc. 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  If an adverse event(s) is associated with 
(“results from”) an overdose of pembrolizumab, the adverse event(s) is reported as a serious 
adverse event, even if no other seriousness criteria are met.   
If a dose of pembrolizumab 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.” 
For idelalisib, overdose is not well-defined. However, if it happened that an individual has 
accidentally taken more than 400 mg a day, the patient should be monitored closely for side 
effects. Bone marrow suppression causing neutropenia, diarrhea or liver failure and 
pneumonitis may ensue in case of idelalisib overdose. Appropriate supportive treatment 
should be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
as clinically indicated. The incident should be promptly communicated to the local PI and the 
Sponsor. 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety (Attn: Worldwide Product 
Safety; FAX (215) 993-1220) and Gilead Sciences Inc (1-800-445-3235, option #2). 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor  
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 completing the trial, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
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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 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX (215) 993-1220) and Gilead 
Sciences Inc (1-800-445-3235, option #2). 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck and 
Gilead Sciences Inc. 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck and Gilead Sciences Inc.’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
and Gilead Sciences Inc product, must be reported within 24 hours to the Sponsor and within 
2 working days to Merck Global Safety and Gilead Sciences Inc.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck and Gilead Sciences Inc. product that is brought to the 
attention of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck and Gilead 
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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1 (215) 993-1220 and Gilead Sciences Inc (1-800-445-
3235, option #2). 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by the 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other 
local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission.  Additionally, investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX: (215) 993-1220) at the time of submission to 
FDA. 
The current study uses both pembrolizumab and idelalisib to treat patients. Although the two 
agents seemingly have different mechanism of action, it is not always easy to distinguish. 
Drugs may have overlapping adverse effects. Sites should report all adverse drug effects to 
both Merck and Gilead Science Inc. 
All subjects with serious adverse events must be followed up for outcome.  
7.2.3.2 Events of Clinical Interest 
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 within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX (215) 993-1220) and Gilead Sciences Inc (1-800-
445-3235, option #2). 
Events of clinical interest for this trial include: 
1.  An overdose, as defined in Section 7.2.1 - Definition of an Overdose for This Protocol 
and Reporting of Overdose to the Sponsor, 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 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
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.   
Additional adverse events: 


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ECIs (both non-serious and serious adverse events) identified in this protocol from the date 
of first dose through 90 days following cessation of treatment, or 30 days after the initiation 
of a new anticancer therapy, whichever is earlier, need to be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX (215) 993-1220) and Gilead Sciences Inc (1-800-445-3235, option #2) 
regardless of attribution to study treatment, consistent with standard SAE reporting 
guidelines. 
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. 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness (See 
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Table 10.  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
7.2.6 Protocol Deviation  
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the investigator’s control and that has not been 
approved by the IRB.  
7.2.7 Protocol Violation  
Any change, divergence, or departure from the study procedures in an IRB-approved 
research protocol that has a major impact on the subject’s rights, safety, or well-being and/or 
the completeness, accuracy or reliability of the study data. 
7.2.8 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
7.3 
 AU IRB Adverse Event Reporting 
7.3.1 AU IRB Expedited Reporting of Adverse Events and Deaths 
The Protocol PI will report to the AU IRB: 
• All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research  
• All deaths, except deaths due to PD  
• All Protocol Violations or Deviations 
• All Unanticipated Problems 
Reports must be received by the AU IRB within 24 hours of PI awareness via the IRBNet 
system. 


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7.3.2 AU IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 
The protocol PI will report to the AU IRB:  
• 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 5 events regardless of attribution;  
• 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.4 
IND PI-Sponsor Reporting Criteria  
7.4.1 Expedited reporting to the FDA 
The PI-Sponsor will notify FDA via phone, fax, or email of any unexpected fatal or life-
threatening suspected adverse reactions as soon as possible but no later than 7 calendar days 
of initial receipt of the information.  This will be followed with a written report within 15 
days using the MedWatch Form 3500a.  
The PI-Sponsor will notify FDA in writing of any suspected adverse reaction that is both 
serious and unexpected as soon as possible but no later than 15 calendar days after initial 
receipt of the information using the MedWatch Form 3500a.  If FDA requests any additional 
data or information, the sponsor must submit it to the FDA as soon as possible, but no later 
than 15 calendars days after receiving the request.  
The PI-Sponsor will also report expeditiously as above: 
• any findings from clinical, epidemiological, or pooled analysis of multiple studies or 
any findings from animal or in vitro testing that suggest a significant risk in humans 
exposed to the drug 
• clinically important increase in the rate of a serious suspected adverse reaction over 
that listed in the protocol or investigator brochure.  
7.4.2 FDA Annual Reports  
The study Sponsor will submit a brief report annually of the progress of the trial within 60 
days of the anniversary date that the IND went into effect.  
The Annual Report will include: 


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• 
A summary of the status of the trial, including the title of the study, protocol number, 
purpose (objectives), a description of the patient population, and a statement as to 
whether the study has been completed or is ongoing. 
• 
The accrual ceiling and the number enrolled, tabulated by age group, gender, and 
race. The number whose participation in the study was completed as planned and the 
number who withdrew from the study for any reason. 
• 
Once the study is completed, a brief description of the results should be reported. 
• 
A narrative or tabular summary of the most frequent and most serious adverse 
experiences by body system.  
• 
A summary of all IND Safety Reports  
• 
A list of subjects who died during participation with the cause of death for each 
subject.  
• 
A list of subjects who withdrew prematurely during the course of the study in 
association with any adverse experience, whether or not it was thought to be 
associated to the Sponsor. 
• 
A description of any protocol modifications during the past year if not previously 
reported.  
• 
A description of the general investigation plan for the coming year. 
 
8.0 STATISTICAL CONSIDERATIONS 
This study has two parts: 
• Phase I dose finding/tolerability part to determine the safe dose of idelalisib in 
combination with pembrolizumab that down regulate the activity of Treg by more 
than 80% of baseline in at least 80% of the treated NSCLC patients.  
• Phase 2 assessment of preliminary efficacy of the treatment combination in terms of 
objective response rate (ORR). 
8.1 
General consideration 
Descriptive statistics will be presented for primary and secondary endpoints. Summary 
statistics for continuous variables will include the mean, standard deviation, median, and 
range (minimum/maximum). Categorical variables will be presented as frequency counts and 
percentages; and time-to-event variables will be summarized by Kaplan-Meier medians and 
survival plots. Data listings will be created to support each table and to present all data. The 
data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, for primary efficacy and safety measures per study 
part (Phase I, II), and on a per dose level for phase I part. The primary efficacy analysis will 
be conducted on the efficacy evaluable population and safety analysis will be performed on 
the safety evaluable population. A safe dose below the maximum tolerated dose of idelalisib  
when used in combination with pembrolizumab will be estimated based on the data from 
modified 3+3 dose escalation. RP2D will then be determined based on the dual DLT and 
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patients have down regulated the activity of Treg by at least 80% of baseline.  SAS 9.4 
software, or higher will be used for data analysis.   
 
8.2 
Study Objectives 
8.2.1 Primary Objective(s) & Hypotheses 
1. 
To determine whether addition of idelalisib at the P2RD to pembrolizumab is safe in 
checkpoint inhibitor refractory NSCLC patients. 
 
2. 
To determine the P2RD of idelalisib used in combination with pembrolizumab in 
patients with checkpoint inhibitor refractory NSCLC.  Our hypothesis is the combination 
of pembrolizumab (200 mg IV Q3W) with idelalisib can down-regulate Treg cell function 
by 80% in 80% patients at a dose lower than the current FDA approved dose of 150 mg 
BID PO in patients with NSCLC.  
 
3.   To determine whether addition of idelalisib to pembrolizumab in NSCLC improves 
ORR over that seen with pembrolizumab or other immune checkpoint inhibitors alone in 
treatment of NSCLC.  Our hypothesis is that in NSCLC patients previously treated with 
anti-PD-1/PD-L1 therapies the ORR for the combination of idelalisib and pembrolizumab 
is 10% (it is nearly 0% for the refractory patients). 
 
8.2.2 Secondary Objective 
To evaluate DOR in NSCLC treated with idelalisib at P2RD in combination with 
pembrolizumab 
 
8.3 
Study Design/Endpoints 
Phase I: A modified 3+3 design will be employed and will include dose escalation to 
determine the P2RD of idelalisib in combination with the approved dose of  
pembrolizumab. The starting dose is 50 mg BID and will be de-escalated in case of DLT 
in more than 1/6 patients.  
Phase II: The ORR will be used as the preliminary efficacy endpoint, and DOR will be 
used as a secondary endpoint. 
8.4 
Sample Size/Accrual Rate 
For part 1:  6 to 18 patients will be used for the dose escalation part. The actual number 
of patients will depend on the DLT and functional studies of Treg. We are expecting 3 to 
4 patients per month.  
For Part 2:  We assume the ORR without the treatment combination to be 1% and expect 
an ORR increase with the proposed treatment combination (using P2RD from the phase 


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1). The minimum sample size required for achieving 80% power at one-sided alpha=0.05 
(0.10) depends on the expected improvement of the ORR. The following table provides 
sample size estimation based on one year (3-4 patients per month) accrual and 24 month 
of follow-up using single stage design. We will follow the one stage design in this study 
(32 patients to achieve an 80% power at alpha=0.05). 
Table 11. Sample Size Estimation 
ORR under 
H0 
ORR under 
H1 
alpha 
Sample size (n) 
One-Stage Design 
Sample size (n)    
Two-Stage Design 
0.01 
0.05 
0.05 
99 
50+50=100 
0.01 
0.05 
0.10 
72 
50+37=77 
0.01 
0.10 
0.05 
32 
20 +15=35 
0.01 
0.10 
0.10 
23 
15+10=25 
 
If we consider ORR to increase from 1% to 10% for the proposed combination, the 
sample size would be as follows: 
a. For a one-stage trial, we need a minimum of 23 patients to maintain an 80% power at 
alpha=0.10 OR 32 patients to achieve an 80% power at alpha=0.05. 
 
b. (Included for reference, not implementation in this trial) For two-stage design, would 
need a minimum of 35 patients with 20 patients at stage 1 and 15 patients at the 
second stage for testing the hypothesis (when alpha=0.05 or 25 (15 and 10 patients 
for alpha=0.10.  
 
Statistical References 
Simon, Richard. 'Optimal Two-Stage Designs for Phase II Clinical Trials', Controlled Clinical         
Trials, 1989, Volume 10, pages 1-10. 
A'Hern, R. P. A. 2001. 'Sample size tables for exact single-stage phase II designs.' Statistics in 
Medicine, Volume 20, pages 859-866. 
Fleming, T. R. 1982. 'One-sample multiple testing procedure for Phase II clinical trials.'  
    Biometrics, Volume 38, pages 143-151. 
 
8.5 
Analysis of Primary Endpoints 
For dose de-escalation and determination of P2RD:  


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Modified 3+3 design will be used to determine the P2RD with escalation mechanism. 
The starting dose of idelalisib is 50 mg BID in addition to an approved dose of 
pembrolizumab 200 mg Q3W, which will be a fixed dose for all patients. 
Each dose will be administered to a cohort of 3 patients. If 0 out of 3 patients experienced 
a DLT at the starting level, 3 additional patients will be assigned to the same dose. If we 
still have a ratio of patients with DLT of less than or equal to 1/6, we declare the first 
(highest dose) to be the P2RD. Otherwise the idelalisib dose will be reduced to the lower 
dose (100mg).  See graph in page 4. Section 2.1 
Functional studies of Treg will be performed. The P2RD is at most 1 out of 6 patients 
experiences a DLT.  The P2RD will down regulate Treg function by 80% from baseline 
in more than 80% of the patients. 
For Part 2: 
To assess preliminary evidence of efficacy, the ORR will be calculated and along with 
the associated exact 95% Confidence interval. 
8.6 
Analysis Datasets 
 
Analysis will be conducted on the modified intent-to-treat set (mITT), which Includes all 
enrolled subjects treated with at least 1 dose (or partial dose) of the study medications.  
The mITT set will be used for all safety and preliminary efficacy analysis. 
8.7 
Randomization 
There will be no randomization for this study. 
8.6 Interim Analysis 
No interim analysis is applicable for the proposed study  
This section outlines the statistical analysis strategy and procedures for the study. Post 
hoc exploratory analyses will be clearly identified in the Clinical Study Report (CSR). 
 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
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. 


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Clinical Supplies will be provided by Merck and Gilead Sciences as summarized in Table 10. 
Table 12. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection (Merck) 
Idelalisib 50 mg,100mg or 150 mg tab 
Pill (Gilead Sciences) 
 
9.1.1 Pembrolizumab (MK-3475, Keytruda®) 
Pembrolizumab will be provided by Merck for use in this investigational setting. 
Pembrolizumab is provided as a white to off white lyophilized powder (50 mg/vial) or as a 
liquid solution (100 mg/vial) in Type I glass vials intended for single use only. 
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is reconstituted with sterile 
water for injection prior to use. The drug product is stored as a stable lyophilized powder or 
liquid solution under refrigerated conditions (2 to 8°C). 
 
The lyophilized drug product after reconstitution with sterile water for injection, and the 
liquid drug product are a clear to opalescent solutions, essentially free of visible particles. 
The reconstituted lyophilized product and the liquid product are intended for IV 
administration. The reconstituted drug product solution or the liquid drug product can be 
further diluted with normal saline or 5% dextrose in the concentration range of 1 to 10 
mg/mL in intravenous (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. Diluted 
pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 
hours. This includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. In addition, IV bags can be stored at 2 to 8°C for up to a cumulative 
time of 20 hours. This recommendation is based on up to 24 hours of room temperature and 
up to 24 hours of refrigerated stability data of diluted MK-3475 solutions in the IV bags.  For 
each individual trial, clinical supplies are to be stored in accordance with specific instructions 
on the label. 
 
9.1.2 Idelalisib (GS-1101, Zydelig®)  
Idelalisib oral tablets will be supplied by Gilead Sciences for use in this investigational 
setting.  Idelalisib supply details, including how it will be supplied, how it should be stored, 
how it will be ordered, will be appended to the main protocol document when those details 
become available. 
 


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9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
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. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or Gilead Sciences Inc., the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality and Privacy 
Confidentiality: Only the investigator, the members of the research team, the sponsor, 
authorized officials from state and federal governments such as the Food and Drug 
Administration (FDA) or the Office of Human Research Protections (OHRP), and authorized 
representatives of the AU Institutional Review Board and the Augusta University will have 
access to confidential data which would identify participants, unless specifically required to 
be disclosed by state or federal law.  Because of the need to release information to these 
parties, absolute confidentiality cannot be guaranteed. The results of this study may be 
presented at meetings or in publications. However, participants will not be identified in any 


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reports or publications resulting from the study.  All reasonable steps will be taken to ensure 
confidentiality. 
Protection of patient privacy: Following enrollment patients will be assigned a patient 
protocol number.  All data derived from patient visits, laboratory, radiological and other 
examinations will be coded with this number.  Research samples (such as blood samples), 
patient demographic data, and results or images from imaging studies will be encoded with 
this number to insure patient anonymity.  The key relating patient identifiers to patient 
protocol number will be kept in a single secure location under control of the PI. Demographic 
data will be securely stored in a location separate from the encoding key.  
 
10.2 Compliance with Financial Disclosure Requirements 
Investigators participating in the study will comply with federal and Augusta University 
financial disclosure requirements. 
10.3 Compliance with Law, Audit and Debarment 
Investigators will comply with federal and state laws.  This study will be audited by the 
Augusta University/Georgia Cancer Center auditing team. Investigators who have been 
debarred from clinical trial participation by the FDA may not participate in this trial.   
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the ICH guidelines on GCP, any applicable 
laws and requirements, and any conditions required by a regulatory authority and/or IRB/IEC 
that approves this study to be conducted in its territory. Good clinical practice is defined as a 
standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and 
reporting of clinical studies in a way that provides assurance that the data and reported results 
are credible and accurate, and that the rights, safety, and well-being of study subjects are 
protected. 
 
Per GCP, the protocol will be reviewed and approved by the IRB or IEC of each participating 
center prior to study initiation. Serious adverse events regardless of causality will be reported 
to Merck Global Safety or Gilead Sciences Inc., and the investigator will keep the IRB/IEC 
informed as to the progress of the study. 
 
The investigator will explain the nature of the study and will inform the subject/legal 
representative that participation is voluntary and that the subject can withdraw or be 
withdrawn from the study at any time. Written informed consent will be obtained from each 
subject prior to the screening procedures to determine if study eligibility criteria are met. A 
copy of the signed consent form(s) will be given to every subject, and the original(s) will be 
maintained with the subject’s records. 
 


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10.4 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 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.  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 trial site contact information.     
11.0 
DATA MANAGEMENT 
The DM (Data Monitor) Console is OnCore’s data management tool and is the validation and 
management workspace for online forms in OnCore.  
11.1 Forms Design 
Electronic case report forms (eCRFs) are created in the eCRFs Console, and attached to 
specific protocol calendar visits for completion by the coordinator. 
11.2 Data Entry 
11.2.1 Recording and handling data 
In OnCore, when a subject visit as occurred, forms that need to be completed are listed on the 
Forms by Status > To Do Forms tab.  Data is recorded specific to each form/visit.  By 
opening the form, it becomes “Active,” and the coordinator can continue to work on the form 
until the “Complete” button is selected.  In declaring a form as complete, coordinators are in 
effect stating that the form is completely filled-out and is ready for a data monitor (DM) to 
validate the data. 
11.2.2 Subject documents (questionnaires, diaries) 
Subject documents, such as questionnaires and diaries, completed by the subject on paper, is 
then manually transcribed and entered into OnCore by the research staff. 
11.3 Study Data Flow 
Validation 
As online forms are declared as Completed, the data monitor validates the data and either 
raise a query or locks the form. If the data is accurate and the monitor has no questions, the 
form can be Validated by clicking the Validate button (shown for Completed and Amended 
forms) in the DM Console. After all queries have been resolved, the form and be Locked. 
Queries 


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Raising a query sends the form and a question back to the person who entered the data within 
OnCore.   A queried form can be amended and then validated and locked. The process of 
querying and amending a form may have multiple iterations. 
Database lock 
In OnCore, individual validated forms are locked, preventing further edits.  After all forms 
are validated, the database is essentially locked. 
11.4 Data Export & Reporting 
Data export formats 
OnCore’s Biostat Console is used to extract data from OnCore for use in statistical analysis 
tools.  The subject’s full name is never included in the export. The Biostat Console can also 
be used to view the current progress of protocols related to accruals, forms, and adverse 
events.  From the Data Export page, selected data can be exported into Excel spreadsheets or 
files formatted for easier import into SAS. 


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12.0 APPENDICES 
Table 13.  ECOG Performance 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
 
12.1 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.2 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 


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In addition, volumetric analysis will be explored by central review for response assessment. 
12.3 Immune Related Response Criteria 
Responses will be evaluated in the expanded cohorts only.  Because of direct clinical 
observations of immune cell influx into tumor causing enlargement in some patients prior to 
sustained response, recently it has been suggested that clinical trials involving the use of 
immunotherapy use alternative guidelines, called immune related response criteria (irRC) to 
determine radiographic response or progression after therapy.  The criteria for evaluation of 
response are those defined in Wolchok JD, Hoos A, O’Day S, et al#. Guidelines for the 
evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin 
Cancer Res 2009; 15:7412-7420.  These recommendations have been used in recent clinical 
trials.  One study of 227 subjects with metastatic melanoma showed that the approximately 
10% of patients who had PD by modified WHO criteria but either CR, PR or SD by irRC had 
a similar overall survival as those patients who had SD, PR or CR by both criteria. The irRC 
was created using bi-dimensional measurements (as previously widely used in the WHO 
criteria).  We have taken the concepts of the irRC and combined them with the recently 
revised RECIST 1.1* to come up with the modified irRC used in this protocol.  Consistent 
with the irRC, the main changes from RECIST 1.1 are (a) a requirement for confirmation of 
both progression and response by imagining at least 4 weeks after initial imaging and (b) not 
automatically calling the appearance of new lesions PD if the total measurable tumor burden 
has not met criteria for PD.   
For immune-related response criteria (irRC), only index and measurable new lesions are 
taken into account.  At baseline tumor assessment on this trial, target lesions will be 
measured along the longest axis and the measurements will be summed, called sum of largest 
diameter (SLD).  These lesions must be a minimum of 10mm per lesion, maximum of 5 
target lesions, maximum of 2 per organ system.  At each subsequent tumor assessment, the 
uni-dimensional measurement of target lesions and of new measureable lesions are added 
together to provide the total tumor burden:  As per the modified definitions below, all 
responses and progression except stable disease (SD) required confirmation on a consecutive 
scan at least 4 weeks from the initial observation). See Table 12 for definition for irRC. 
Table 14. Definitions of irRC:   
Response 
irRC 
New measurable 
lesions  
Incorporated into tumor burden 
New non-measurable 
lesions  
Do not define progression (but precludes irCR) 
Non-index lesions 
Contributes to defining irCR (complete disappearance required) 


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Overall irCR 
100% disappearance of all lesions, whether measurable or not, and 
no new lesions, in two consecutive observations not less than 4 wks 
from the date first documented.  All measurable lymph nodes also 
must have reduction in short axis to <10mm. 
Overall irPR 
≥ 30% decrease in SLD compared with baseline confirmed by a 
consecutive assessment at least 4 wk after first documentation 
Overall irSD 
Not meeting criteria for irCR or irPR, in absence of irPD:  30% 
decrease in SLD compared with baseline cannot be established nor 
20% increase compared with nadir. 
Overall irPD 
At least 20% increase in SLD compared with nadir (minimum 
recorded tumor burden) and an increase of at least 5mm over the 
nadir, confirmed by a repeat, consecutive observation at least 4 wk 
from the date first documented. 
 
 
 
 
 
 
 
 
 
Overall responses derived from changes in index, non-index and new lesions as demonstrated 
in the following (Table 13): 
Table 15. Definition of Response per irRC 
Measurable response 
Non-measurable response 
Overall response 
using irRC 
Index and new, 
measurable lesions 
Non-index 
lesions 
New, non-
measurable lesions 
 


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(tumor burden)* % 
Decrease 100% 
Absent 
Absent 
irCR& 
Decrease 100% 
Stable 
Any 
irPR& 
Decrease 100% 
Unequivocal 
progression 
Any 
irPR& 
Decrease ≥ 30% 
Absent / Stable 
Any 
irPR& 
Decrease ≥ 30% 
Unequivocal 
progression 
Any 
irPR& 
Decrease < 30% to 
increase < 20% 
Absent / Stable 
Any 
irSD 
Decrease < 30% to 
increase < 20% 
Unequivocal 
progression 
Any 
irSD 
Decrease ≥ 20% 
Any 
Any 
irPD 
• * Decreases assessed relative to baseline 
&  Assuming response (irCR) and progression (irPD) are confirmed by a second, 
consecutive assessment at least 4 weeks apart. 
# Wolchok JD, Hoos A, O’Day S, et al.  Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20. 
 
 
12.4 
References 
1. 
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solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 
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2. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clinical cancer 
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immunoediting: from tumor tolerance to eradication. Immunological reviews. May 
2011;241(1):104-118. 
36. 
Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-
infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against 
melanoma. The Journal of experimental medicine. Aug 26 2013;210(9):1695-1710. 
37. 
Granville CA, Memmott RM, Balogh A, et al. A central role for Foxp3+ regulatory T 
cells in K-Ras-driven lung tumorigenesis. PloS one. 2009;4(3):e5061. 
38. 
Ju S, Qiu H, Zhou X, et al. CD13+CD4+CD25hi regulatory T cells exhibit higher 
suppressive function and increase with tumor stage in non-small cell lung cancer 
patients. Cell cycle. Aug 15 2009;8(16):2578-2585. 
39. 
Tao H, Mimura Y, Aoe K, et al. Prognostic potential of FOXP3 expression in non-
small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung 
cancer. Jan 2012;75(1):95-101. 
40. 
Zaynagetdinov R, Stathopoulos GT, Sherrill TP, et al. Epithelial nuclear factor-
kappaB signaling promotes lung carcinogenesis via recruitment of regulatory T 
lymphocytes. Oncogene. Jun 28 2012;31(26):3164-3176. 
41. 
Erfani N, Mehrabadi SM, Ghayumi MA, et al. Increase of regulatory T cells in 
metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-
small cell lung cancer (NSCLC). Lung cancer. Aug 2012;77(2):306-311. 
42. 
McCoy MJ, Lake RA, van der Most RG, Dick IM, Nowak AK. Post-chemotherapy T-
cell recovery is a marker of improved survival in patients with advanced thoracic 
malignancies. British journal of cancer. Sep 25 2012;107(7):1107-1115. 
43. 
Black CC, Turk MJ, Dragnev K, Rigas JR. Adenocarcinoma contains more immune 
tolerance regulatory t-cell lymphocytes (versus squamous carcinoma) in non-small-
cell lung cancer. Lung. Jun 2013;191(3):265-270. 
44. 
Ganesan AP, Johansson M, Ruffell B, et al. Tumor-infiltrating regulatory T cells 
inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. Journal of 
immunology. Aug 15 2013;191(4):2009-2017. 
45. 
Wang Y, Sparwasser T, Figlin R, Kim HL. Foxp3+ T cells inhibit antitumor immune 
memory modulated by mTOR inhibition. Cancer research. Apr 15 2014;74(8):2217-
2228. 
46. 
Pircher A, Gamerith G, Amann A, et al. Neoadjuvant chemo-immunotherapy 
modifies CD4(+)CD25(+) regulatory T cells (Treg) in non-small cell lung cancer 
(NSCLC) patients. Lung cancer. Jul 2014;85(1):81-87. 
47. 
Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA. Inability of a 
fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, 
ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. Journal 
of immunotherapy (Hagerstown, Md. : 1997). Nov-Dec 2005;28(6):582-592. 
48. 
Attia P, Powell DJ, Jr., Maker AV, Kreitman RJ, Pastan I, Rosenberg SA. Selective 
elimination of human regulatory T lymphocytes in vitro with the recombinant 


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immunotoxin LMB-2. Journal of immunotherapy (Hagerstown, Md. : 1997). Mar-
Apr 2006;29(2):208-214. 
49. 
Powell DJ, Jr., Felipe-Silva A, Merino MJ, et al. Administration of a CD25-directed 
immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective 
partial reduction in regulatory T cells in vivo. Journal of immunology. Oct 1 
2007;179(7):4919-4928. 
50. 
Powell DJ, Jr., Attia P, Ghetie V, Schindler J, Vitetta ES, Rosenberg SA. Partial 
reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant 
immunotoxin administration. Journal of immunotherapy (Hagerstown, Md. : 1997). 
Feb-Mar 2008;31(2):189-198. 
51. 
Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 
3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 
May 29 2014;123(22):3390-3397. 
52. 
Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kdelta inhibitor 
idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 
May 29 2014;123(22):3398-3405. 
53. 
Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-delta 
inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic 
leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. Sep 
23 2010;116(12):2078-2088. 
54. 
Wieland E, Shipkova M. Lymphocyte surface molecules as immune activation 
biomarkers. Clinical biochemistry. Aug 4 2015. 
55. 
Lindsey WB, Lowdell MW, Marti GE, et al. CD69 expression as an index of T-cell 
function: assay standardization, validation and use in monitoring immune recovery. 
Cytotherapy. 2007;9(2):123-132. 
56. 
Posselt AM, Vincenti F, Bedolli M, Lantz M, Roberts JP, Hirose R. CD69 expression 
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recipients. Transplantation. Jul 15 2003;76(1):190-195. 
 
 
 
 
 
 


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12.5 Abbreviations 
Table 16.  Abbreviations used in the text 
Abbreviation 
Definition 
AE  
Adverse Event 
AJCC 
American Joint Committee for Cancer 
ALK 
ALK gene 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Alanine Aspartate Aminotransferase 
BID 
Twice daily 
CBC 
Complete Blood Count 
CLL 
Chronic Lymphocytic Leukemia 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Complete Metabolic Profile 
CMV 
Cytomegalovirus  
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria for Adverse Effects 
CTLA-4 
Cytotoxic T Lymphocyte Associated Protein-4 
DKA 
Diabetic Ketoacidosis 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECI 
Events of Clinical Interests 
ECOG 
East Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
eIRB 
electronic Institutional Review Board 
EPO 
Erythropoietin 
ERC 
Ethical Review Committee 
FDA 
Food and Drug Administration 
FOXO 
Forkhead Box 3 
FT4 
Free Thyroid Hormone T4 
GCC 
Georgia Cancer Center (at Augusta University) 
GCP 
Good Clinical Practice 
GPCR 
G-Protein Coupled Receptor 
GRU 
Georgia Regents University 
HIV 
Human Immune Deficiency Virus 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 


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Abbreviation 
Definition 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
irRECIST 
immune related Response Evaluation Criteria in Solid Tumor 
IV 
Intravenous 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid Derived Suppressor Cells 
MRI 
Magnetic Resonance Imaging 
mTORC1 
(mammalian) Target Of Rapamycin Complex 1 
NCI 
National Cancer Institute 
NSAID 
Non-Steroidal Anti-inflammatory Drug 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office for Human Research Protection 
ORR 
Objective response rate 
OS 
Overall Survival 
OTC 
Over the Counter 
PCP 
Pneumocystis pneumonia  
PD 
Progression Disease 
PD-1 
Programmed Death-1 (receptor) 
PD-L1 
Programmed Death Ligand-1 
PI 
Principal Investigator 
PI3K 
Phosphatidylinositol 3-kinases  
PI3K-RBD 
Phosphatidylinositol 3-kinases Ras Binding Domain 
PI3KCA 
Phosphatidylinositol 3-kinases Catalytic (subunit) Alpha 
PI3KCB 
Phosphatidylinositol 3-kinases Catalytic (subunit) Beta 
PI3KCC 
Phosphatidylinositol 3-kinases Catalytic (subunit) Gamma 
PI3KCD 
Phosphatidylinositol 3-kinases Catalytic (subunit) Delta 
PI3KR1 
Phosphatidylinositol 3-kinases Receptor 1 
PO 
Per Os or orally 
PR 
Partial Response 
QD 
Once daily 
RECIST 
Response Evaluation Criteria In Solid Tumor 
RFS 
Relapse Free Survival 
ROS 
Reactive Oxygen Species 
RTK 
Receptor Tyrosine Kinase 
SD 
Stable Disease 
SLD 
Sum of Largest Diameter 
SOC 
Standard of care 
T1DM 
Type 1 Diabetes Mellitus 
TB 
Bacillus Tuberculosis 
TIL 
Tumor Infiltrating Lymphocytes 


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Abbreviation 
Definition 
Treg 
T regulatory cell 
ULN 
Upper Limit Normal 
WHO 
World Health Organization 
 


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Participant’s Name: ______________________________ 
Participant’s Medical Record Number: _______________ 
 
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Augusta University 
Research Informed Consent Document 
 
TITLE: 
A phase Ib /II trial of pembrolizumab and idelalisib in patients 
with non-small cell lung cancer (NSCLC) who have failed immune 
checkpoint inhibitor. 
 
PROTOCOL NO.: 
CC-16053 
 
WIRB® Protocol #20170581 
 
1031896 
 
SPONSOR: 
Zhonglin Hao, MD, PhD 
 
Markey Cancer Center 
 
INVESTIGATOR: 
Asha Nayak-Kapoor, MD,  
 
Georgia Cancer Center  
 
1120 15th Street, 
 
 BA-5516A 
 
Augusta, Georgia 30912 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Asha Nayak-Kapoor, MD,  
 
706-721-2505 (24 hours) 
 
 
INVITATION TO TAKE PART IN RESEARCH  
You are being asked to take part in this research study about the safety and effectiveness of 
combining two drugs, pembrolizumab and idelalisib, on patients with non-small cell lung cancer 
(NSCLC).  This study is being offered to you because you have a type of lung cancer that has not 
responded to previous standard treatment.   
 
The purpose of this document is to: 
• Explain your rights and responsibilities 
• Explain the purpose of the study 
• Describe what will happen if you decide to take part in this study 
• Explain the potential risks and benefits of taking part in the study 
 


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Participation in research studies is voluntary.  Please read this consent form carefully and take 
your time making your decision.  As the study staff discusses this consent form with you, please 
ask them to explain any words or information that you do not clearly understand.  You are 
encouraged to talk with your family and friends before you decide to take part in this study.   
 
Please tell the study staff if you are taking part in another study. 
 
Why is this study being done?   
The purpose of this study is to determine the safety and effectiveness of the combination of 
pembrolizumab and idelalisib in NSCLC patients whose disease has stopped responding to 
immune therapy with a drug that blocks the interaction of the T cell molecule PD-1 and its ligand 
PD-L1.  Drugs that block the interaction of these molecules prevent immune cells from being 
“turned off” by cancer cells; this allows the immune system to better fight cancer cells.  
 
Pembrolizumab is an antibody that is made in the laboratory.  An antibody is a natural protein 
made by our immune system that binds other proteins or molecules to fight infection and its ill 
effects.  Pembrolizumab has been approved by the Food and Drug Association (FDA) for 
melanoma skin cancer, head and neck cancer, Hodgkin’s lymphoma and lung cancer.  
Pembrolizumab is an experimental drug therapy for many other types of cancer and has shown 
outstanding effects in certain tumor types like microsatellite repair insufficient tumors 
particularly of the large bowel.  Pembrolizumab binds to PD-1 on T cells and may prevent cancer 
growth by helping certain blood cells of the immune system eliminate the tumor. 
 
Idelalisib belongs to a group of drugs called kinase inhibitors.  These drugs act by blocking 
certain cellular pathways so that cancer cells cannot reproduce and grow.  Idelalisib is FDA 
approved for the treatment of some leukemias and lymphomas (blood cancers).  Like 
pembrolizumab, it is also being investigated as possible therapy for other cancers. 
 
Through this study, the researchers are trying to determine the dose of idelalisib that is safe and 
tolerable when it is combined with pembrolizumab in patients with lung tumors.  This study will 
also evaluate how the combination of pembrolizumab and idelalisib activates your immune 
system in your blood and inside the tumor and how it affects the size and number of tumor(s) in 
your body.  
 
The use of pembrolizumab and idelalisib in combination is investigational in this study. The 
information learned in this study may be helpful in the further development of combining 
immune stimulating agents such as idelalisib and pembrolizumab in patients with specific types 
of tumors that benefit from immunological treatments. 
 
This study will enroll patients into two separate phases: Phase 1 will determine the best tolerated 
dose of idelalisib in combination with pembrolizumab, and Phase 2 will assess the effectiveness 


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of this combination in patients with lung cancer.  Georgia Cancer Center/Augusta University 
Health System will enroll up to 18 participants in the Phase 1 period, and up to 32 participants in 
the Phase 2 period, for a total of 50 patients. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
How long will I be in this study?  
Your active participation in this study is expected to take up to 28 months (about 2 ½ years).  
This will include approximately 18 weeks of combination idelalisib and pembrolizumab 
treatment, followed by 2 years of maintenance therapy with pembrolizumab alone. 
 
You can choose not to be in the study or stop participating at any time without penalty or loss of 
any rights or benefits you are entitled to.  Please talk to the study staff first before you stop 
participating in the study.  
 
What will happen to me in the study?  
(See also the Summary of Assessments later in this document.) 
 
Screening Period 
During the screening period, we will see if you are eligible (qualify) for and can safely 
participate in this study.  The study will be explained to you by the study doctor and study staff, 
and you will be asked to sign this consent form before any tests for the study are done.  This does 
not commit you to being in the study.  It is simply to show that you understand what the study is 
about and that you are willing to participate, if eligible.  You are free to withdraw from the study 
any time.  
 
We will conduct several routine screening procedures that include a physical examination, 
reviewing your current medications, and recording your medical history.  In addition, you will 
have one blood draw of approximately 11.5 tablespoons of which two and a half tablespoons will 
be used to measure your blood chemistry, kidney/liver function and blood counts.  The 
remaining 9 tablespoons of blood will be used to evaluate your immune responses (how your 
body recognizes and defends itself against bacteria, viruses, and substances that appear foreign 
and harmful to the body such as tumors).  
 
You will also have standard urine tests to assess organ function, and an electrocardiogram (ECG) 
to measure and record the electrical activity (heart beat) of your heart.  Your doctor may review a 
tissue sample from the original biopsy that was done to confirm your cancer diagnosis.  
 


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You will have a CT-scan of the chest/abdomen/pelvis and a CT scan of any extremity affected by 
your tumor, or a brain MRI or CT scan of the brain. In some cases, you may have a PET/CT scan 
performed.  You may have an ultrasound performed of the lesions to determine whether they can 
be biopsied under ultrasound guidance.  The scanning imaging tests have to be done within 4 
weeks of your first study treatment.  
 
If you are a female who is able to become pregnant, you will have a pregnancy test taken to 
determine if you are pregnant.  Pregnant women are not allowed to participate in this study 
because the risks of the study for an unborn fetus are unknown.  If you are not pregnant and 
could become pregnant you must use contraceptives during the course of this study, and for 3 
months after going off study (completion or involuntary).  If you are a male you must use 
contraceptives (abstinence, condoms, etc.) while on study and for 3 months after going off study 
(completion or involuntary).  
 
After we complete all of the screening assessments, we will contact you to let you whether you 
are eligible to participate in the study.  If you decide to take part in the study, you will be asked 
to return to the clinic to begin study treatment. 
 
Treatment Period (6 Cycles) 
Phase 1: The first phase of the study will enroll in groups, or cohorts, of three to six patients for 
each dose level: Cohort A for 50 mg twice daily, followed by Cohort B for 100 mg twice daily, 
and then Cohort C for 150 mg twice daily.  Treatments will be given in 21-day cycles.  All 
patients will receive the standard dose of pembrolizumab as a single infusion of 200 milligrams 
by vein on Day 1 of each cycle, followed by oral idelalisib tablets at their designated Cohort 
dose, every day of the cycle.  All patients will be closely monitored for any possible drug 
reactions.   
 
After 3 cycles (9 weeks), Cohort A patients will have blood drawn again to check their body’s 
immune response to the treatment (T-regulatory function).  If these patients haven’t experienced 
any dose limiting toxicities (DLTs) or only one out of the three has a DLT, another three patients 
will be enrolled in Cohort A.  After another 3 cycles, T-regulatory function will be determined.  
If at this dose level, 80% of patients (5 out of 6) have significant reduction of T-reg function 
from their baseline levels, this dose will be the phase 2 recommended dose (P2RD).  Otherwise, 
Cohort B will begin enrollment to test patients’ T-regulatory responses to the idelalisib 100 mg 
twice daily dose. 
 
If DLTs occur in 2 of the initial 3 patients or more than 1/6 patients after another 3 patients, then 
lower doses of idelalisib may be investigated in cohorts with similar number of patients until a 
dose that causes no more than 1/6 DLT is found before functional analysis of Treg.  If dose 
limiting toxicity occurs in more than two of the six tested at the lowest dose level of 50 mg twice 
daily, then lower doses of idelalisib may be investigated in 6 newly enrolled patients.  Other 


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idelalisib doses that may be evaluated may include 50 mg once daily and 50 mg every other day.  
 
Phase 2:  After the phase 2 recommended dose (P2RD) of idelalisib is determined, the efficacy 
assessment phase (phase 2) of the study will begin, enrolling up to 32 patients.  The designated 
dose of idelalisib in combination with the standard dose of 200 mg pembrolizumab on Day 1 of 
each cycle will be given for six 21-day cycles.  Following the treatment period, patients will 
receive maintenance therapy with 200 mg pembrolizumab intravenously every 3 weeks, for up to 
2 years, or until disease progression or unacceptable toxicity 
 
You will have a biopsy taken from the tumor before receiving the 2nd cycle of treatment.  The 
biopsy is done under local anesthesia with the guide of CT scan or ultrasound.  During the 
maintenance period, tumors might need a repeated biopsy if they show progression or 
appearance of new lesions.  Biopsy samples are taken by special needles that can produce a 
minimal scar of a few millimeters. 
 
Maintenance Period 
During the maintenance period you will receive pembrolizumab at a dose of 200 mg every three 
weeks for up to two years.  
 
Summary of Assessments 
 
Normal clinical care procedures 
Research procedures done ONLY 
because of study  
• Pregnancy test (during screening; otherwise only 
as indicated) 
• Blood tests (before each cycle) 
• Thyroid tests (before each cycle, at the same time 
as other standard blood tests) 
• Urine tests (only during screening; otherwise as 
clinically indicated) 
• ECG (only during screening; otherwise as 
clinically indicated) 
• Tumor imaging (CT, PET/CT and/or MRI; During 
screening, and then every 9 weeks) 
• CMV screening blood tests (At 
screening and on day 1 of each 
treatment cycle) 
• T-regulatory cell blood tests (One 
additional tube of blood, drawn at 
the same time as standard blood 
tests; during screening, and then 
every 9 weeks) 
• Biopsy (during screening, if no 
archival tissue is available; and 
before receiving the third cycle of 
treatment) 
 
What additional responsibilities will I have if I take part in this study? 
If you decide to take part in this research study you will be responsible for the following things:  
• Tell the study doctor how you feel and about any side effects.   
• Tell the study doctor about any medication, over-the-counter products, herbal remedies, 
or alternative therapies that you use while you are in this study.  Certain medications 


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cannot be taken while you are in this study.  The study doctor will explain what these 
medications are.  If you need treatment with any medications that are not allowed during 
this study, you must tell the study doctor or the study staff.  You will not be denied 
medications required to treat an illness you may have, but you may be required to stop 
taking the study medication.  This is for your safety, since some medications may not 
work well with idelalisib and you might have physical problems.  You must check with 
the study doctor first if you need to take any new over-the- counter medications or herbal 
supplements, or if you need to change your usual prescription medications during this 
study.   
• You should not have any immunizations (vaccinations) without the study doctor’s 
approval.  
• Tell the study doctor about any medical treatments that you will have to get during the 
study (such as elective surgery).  
• If you decide to take part in the study, it is important that you follow the instructions and 
advice given to you by the study doctor.  
• You should not donate blood for 3 months following the last dose of study treatment. 
• You may be able to return to work or stay home at the time you receive your study drug.  
Normal daily activities need not to be changed unless you experience drug related serious 
adverse events or your study physician recommends you limited activities or special 
considerations. 
 
What are the risks of being in this study? 
Possible risks that could result from being in this study are listed below.  You should discuss 
these with your study doctor and your regular health care provider if you choose to participate in 
this study.  
 
Some possible adverse events include those associated with venipuncture, study drug 
administrations, and tumor biopsies. Imaging studies with CT scan as well as 
electrocardiography (ECG) may also show their own adverse reactions.  Certain of the expected 
events listed below are also due to activation of the patient’s own immune system against the 
tumor, with potentially beneficial inflammation and tumor necrosis. 
 
Possible Risks Associated with Pembrolizumab: 
Most of the possible side effects listed below are mild to moderate.  However, some side effects 
can be very serious and life-threatening and may even result in death.  Some side effects do not 
need treatment while others generally get better with treatment.  Some patients may need to 
delay doses of pembrolizumab to allow the side effects to get better.  The most important 
possible side effects, which are listed below, may occur because of the way pembrolizumab 
works on the immune system and they have been seen in patients treated with pembrolizumab in 
clinical studies.  Side effects like these have also been seen in clinical studies with other drugs 
that are very similar to pembrolizumab. 


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Very 
Common 
side 
effects 
seen 
in 
>20% 
of 
patients 
treated 
with 
pembrolizumab/KEYTRUDA® include the following: 
•Itching of the skin 
•Loose or watery stools 
•Cough 
 
Common side effects seen in >10% to <20% of patients treated with 
pembrolizumab/KEYTRUDA® include the following: 
•Joint pain 
•Fever 
•Back pain 
•Rash 
 
Common 
side 
effects 
seen 
in 
>1% 
to 
<10% 
of 
patients 
treated 
with 
pembrolizumab/KEYTRUDA® include the following: 
•Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble, 
sweat, tired, have loose and watery stools 
•Inflammation of the lungs so you may feel short of breath and cough. Rarely this might lead 
to death. 
•Inflammation of the bowels/gut that may cause pain in your belly with loose or watery 
stools 
•Inflammation of the skin so you may have peeling of the skin, itching, skin redness 
•Pain in your belly 
•Loss of skin color 
•Low level of salt in the blood that may cause you to feel tired, confused, headache, muscle 
cramps or sick to your stomach 
•Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or sick 
to your stomach at the time of receiving your infusion (IV) or just after, or pain at the site of 
infusion 
 
Common serious side effects seen in 1% to 4% of patients treated with 
pembrolizumab/KEYTRUDA® include the following: 
•Inflammation of the lungs so you may feel short of breath and cough. Rarely this might lead 
to death 
•Inflammation of the bowels/gut that can cause pain in your belly with loose or watery stools 
•Fever 
 


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Immune-mediated serious side effects seen in <1.0% of patients treated with 
pembrolizumab/KEYTRUDA® include the following: 
•Inflammation of the skin so you may have widespread peeling of the skin, itching, and skin 
redness. More severe skin reactions may involve the inside of your mouth, the surface of 
your eye and genital areas, and/or may cause the top layer of your skin to peel from all over 
your body which can cause severe infection. Rarely these reactions lead to death. 
•Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever, muscle or 
joint aches, sick to your stomach and vomiting, pain in your belly, yellow eyes and skin, and 
dark urine 
•Inflammation of the pituitary gland (a gland in the head), which may cause headaches, sick 
to your stomach, changes in behavior, double vision, few to no menstrual cycles, weakness, 
vomiting and dizziness or fainting 
•Adrenal glands (glands on top of the kidneys) may not make enough hormone causing 
tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and abdominal aches, 
nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes darkening of the 
skin like a suntan 
•Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble, 
increased sweating, weight loss, hair loss, tired, have loose and watery stools 
•Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have in frequent 
or hard bowel movements 
•Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain 
•Inflammation of the muscles so you may feel weak or pain in the muscles 
•Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe pain in the top part of your belly that may move to the back, sick to your 
stomach, and vomiting that gets worse when you eat 
•Inflammation of the eye so you may have redness of the eye, blurred vision, sensitive to 
light, have eye pain, see floaters or have headaches 
•Too much sugar in your blood (diabetes), so you may feel thirsty, and are likely to need 
regular insulin shots 
•Inflammation of the nerves that may cause pain, weakness or tingling in the hands and feet, 
and may spread to the legs, arms and upper body leading to severe muscle weakness and 
possible temporary paralysis 
•Inflammation of the middle layer of your heart wall (myocarditis) that may cause your heart 
to have difficulty pumping blood throughout your body, which can cause chest pain, 
shortness of breath and swelling of the legs. You may experience a fast or irregular heartbeat 
that may cause dizziness or fainting. Sometimes this condition can lead to death 
 


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Possible Risks Associated with Idelalisib: 
Medical problems, or side effects, that have been reported in clinical studies and are believed to 
be caused by idelalisib are described below.  You should tell your study doctor about any 
medical problems that you notice while you are on the study, even if they are not mentioned 
below.  A side effect is considered “common” if there is between a 1% (one in a hundred) and a 
10% (one in ten) chance, and “very common” if there is a greater than 10% chance that it will 
happen to you during treatment with idelalisib.   
 
Very Common Side Effects (more than 10%): 
• Severe diarrhea or colitis: Some people treated with idelalisib have experienced severe 
diarrhea.  This could happen to you at any time during treatment.  It is important that you 
tell your study doctor if you have any diarrhea, providing an estimated number of loose 
stools per day, even if you do not consider it severe.  This way your study doctor can 
determine if you need treatment.  Your doctor may decide to perform a procedure called a 
colonoscopy.  During this procedure a biopsy is usually taken, which may show a 
condition called colitis.  The complications of severe diarrhea could become life-
threatening if not appropriately treated.  If you develop severe diarrhea or colitis, your 
idelalisib treatment will be stopped.  It is sometimes possible to resume idelalisib after 
improvement. If you do restart idelalisib, your doctor may use a lower dose.  
• Liver injury: Some people taking idelalisib have had blood tests that showed reversible 
liver injury during the first few months of treatment.  If this happens, it is almost always 
without any symptoms.  Your study doctor will closely watch your blood liver test results 
for signs of liver injury, especially when you first start taking the drug.  If necessary, your 
idelalisib treatment may be temporarily stopped.  Most patients are able to resume 
idelalisib after improvement in the blood tests.  If you do restart idelalisib, your doctor 
may use a lower dose. 
• Rash:  Various type rashes may occur in some people who take idelalisib.  Although 
usually mild, rashes may sometimes be severe and rarely life threatening.  If you notice 
any rash or itching, tell your study doctor right away. 
• Neutropenia and Fever:  People who take idelalisib have often experienced a decrease 
in a certain type of white blood cell that helps fight infections, called the neutrophil.  A 
low neutrophil count results in a condition called neutropenia.  If this happens to you, you 
may be at increased risk of infection.  An important early sign of infection can be fever, 
however you may also develop a fever without neutropenia or infection.  If you do 
experience a fever, or otherwise think that you have an infection, it is important to 
contact your study doctor immediately. 
 


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Common Side Effects (from 1% up to 10%) 
• Pneumonitis:  Inflammation of the lungs, known as pneumonitis, has been reported in 
some people receiving treatment with idelalisib, either alone or with other study 
medication.  In some cases, people needed oxygen or help from a machine to breathe and 
a few have died.  Because this is a serious condition, it is very important that you tell 
your study doctor if you experience any new or worsening shortness of breath or 
difficulty breathing, so that your doctor can treat you as soon as possible. 
 
Rare medical problems that have occurred in clinical studies with idelalisib  
Some serious medical problems have occurred in less than 1% (one in a hundred) of people 
taking idelalisib in clinical studies.  It is not known whether idelalisib caused these problems to 
happen, because in most cases other conditions were present that could have been responsible.  
 
Serious or fatal pneumocystis pneumonia (PCP) or cytomegalovirus (CMV) has occurred in less 
than 1% of patients treated with idelalisib.  CMV infection is common in healthy people and it’s 
usually not serious.  Many people have this virus in their bodies and don’t even know it.  But 
when the immune system is weakened, CMV can cause things like serious pneumonia, intestinal 
infection (enteritis), liver infection (hepatitis), and a serious eye infection that can lead to 
blindness if not treated (retinitis). 
 
CMV infection can be very hard to treat in people with low white blood cell (WBC) counts, 
because the drugs used to fight the virus also lower the number of WBCs.  This makes it hard for 
the body to fight the infection.  Often, the best thing to do for patients with weak immune 
systems is try to prevent the infection from flaring up.  This is done by giving patients certain 
anti-viral drugs before any symptoms begin.  Since most people with CMV don’t know they 
have it, blood tests are used to check for it.  Your physician will order lab tests to detect these 
possible rare infections each cycle that you are receiving idelalisib, as well as for 6 months 
following treatment.  
 
There is also risk of a severe, life threatening allergic reaction to a medication or food, called 
anaphylaxis.  The symptoms of anaphylaxis include swelling in the mouth and throat or other 
areas of the body, difficulty breathing, low blood pressure, and hives and other kinds of rashes.  
If this occurs to you outside of a medical facility, an ambulance must be called immediately.  
 
Another condition is called intestinal perforation, which describes a small hole that develops in 
the small or large intestine allowing bacteria to enter the abdominal cavity.  Intestinal perforation 
usually requires emergency surgery.  If you develop severe abdominal pain or hardness of the 
abdomen you must seek medical attention immediately.  
 


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There is also risk of developing an extremely severe blistering rash that is also associated with 
inflammation and blistering of the lining of the mouth, the eyelids and outer surface of the eye.  
If you develop such symptoms, you must seek medical attention immediately. 
 
Possibility of interaction with other medications 
Idelalisib may affect your body’s reaction to other drugs.  In particular, one of the by-products of 
idelalisib may block the ability of an enzyme in the liver, called CYP3A, to inactivate other 
drugs.  The result of taking idelalisib at the same time as drugs that are usually inactivated by 
this enzyme can cause your blood levels of these drugs to be significantly higher than expected 
and, depending on those drugs, could result in undesirable side effects.  
 
Just as idelalisib may affect the blood levels of certain drugs, idelalisib may itself be affected by 
other drugs.  Some drugs increase the activity of the CYP3A enzyme, and these drugs are called 
CYP3A inducers.  Taking a CYP3A inducer with idelalisib could lead to lower blood levels of 
idelalisib, and this can decrease the potential anti-cancer benefit to you.  In addition to certain 
prescription drugs (which will be evaluated by your doctor).  The herbal preparation known as 
St. John’s Wort are CYP3A inducers and should not be taken during your treatment with 
idelalisib.   
 
Because of these potential drug-drug interactions, it is important that you tell the research doctor 
about all prescription and non-prescription drugs, vitamins, herbal preparations, nutritional 
supplements, health foods, street drugs, and birth control methods that you are taking or are 
planning to take.  You should tell any doctor who prescribes medication to you that you are 
taking idelalisib so that they are aware of these possible interactions.  If you are prescribed 
medication by a doctor who is not part of the study staff, you should tell the study staff what 
drug you were prescribed before you take it. 
 
If you are not sure, or if you take something you worry that you should not have taken, it is safest 
to be honest with the study clinic staff.  The study clinic staff needs to know what you are taking 
to protect your health.  They can help decide if any of the drugs you are taking need to be 
stopped or adjusted, or if idelalisib needs to be stopped or adjusted. 
 
Other Medical Problems 
Tell your study doctor about any medical problems you have even if you do not think they are 
caused by the study drug.  Ask your study doctor for more information if you have questions or 
concerns.  There may be more risks that are not known or not expected as this is the first time 
this combination of drugs is being administered.  These risks may be new, more severe, or long 
lasting than seen when these drugs are used alone.  These risks may include death.   
 
The study staff will tell you about new information that may affect your health, welfare, or 
willingness to stay in this study.  


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Biopsy: If you have easily accessible tumors, you will have biopsy samples taken before 
beginning treatment and before receiving the third cycle of the treatment.  There will also be a 
repeated biopsy of the tumor if relapse in encountered during the follow up period.  The biopsies 
are done under the guidance of either ultrasound or CT scan and up to 3 core needle biopsies less 
than 1mm in width will be taken of each lesion.  These procedures are done to evaluate how your 
body recognizes and defends itself against cancer.  A biopsy is a relatively safe surgical 
procedure.  As with any surgical procedure, you may experience side effects that include pain, 
infection, temporary swelling/bleeding, tenderness, scarring at the surgical site and allergic 
reaction to the drugs.  The study doctor will give you specific instructions on how to care for 
your biopsy site and contact information in case of an emergency. 
 
Blood Draw: Symptoms may include bleeding, fainting, injection site infection and/or anemia 
(low red blood cell levels that could result in tiredness, dizziness, sleeplessness, shortness of 
breath, leg cramps).  Fainting can occur during or after a blood draw in some individuals.  Your 
red blood cell level will be monitored periodically during the study.  You may be asked to take 
iron supplements if your level decreases. 
 
Radiation Exposure: If you take part in this research, you will have a number of radiation 
procedures or examinations that are part of the regular medical care for your condition and you 
would have them whether or not you participate in this research.  You will not be exposed to any 
additional radiation because you are participating in this research. 
 
These tests include X-rays, CT scans, and or PET scans, all of which are used routinely to follow 
up on your condition.  The study doctor will decide which test you have, and when you have it, 
based upon your disease, where it is located, and your progress.  You may also have MRI scans, 
but these do not involve radiation exposure. 
 
Some of the scans could involve “contrast”, which is like a dye injected into the bloodstream, 
which makes things appear more clearly on the test.  Since some of the contrast dyes contain 
iodine, it is important that you tell the study doctor if you are allergic to iodine. 
 
The study doctors will always try to keep radiation exposure as low as reasonably achievable by 
choosing tests and procedures that involve the lowest possible exposure while providing the 
necessary information about your condition. 
 
Women of Childbearing Potential  
You cannot participate in this study if you are or plan to become pregnant, or if you are 
breastfeeding.  There may be unknown risks to you, the embryo/fetus or nursing infant if you 
become pregnant during the study. 
 


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You must be using adequate contraception for the duration of the study and for 120 days 
following your participation.  If you become pregnant, suspect pregnancy, if you have a change 
in your menstrual cycle, or in your contraception method you should immediately contact the 
study doctor.  Should you become pregnant during the study, you will be withdrawn from the 
study immediately and should seek care from a doctor who specializes in pregnant women (an 
OB/GYN, or obstetrics and gynecologist physician).  The study doctor or any investigator on this 
study, or Merck and Gilead (the manufacturers of the study drugs), are not responsible for any 
financial aspects of obstetrical, child or related care. 
 
Psycho/Social/Economic Risks: Risks and discomforts not only include physical injury, but also 
possible psychological, social or economic harm, discomfort or inconvenience, or breach of 
confidentiality. 
 
Privacy Risk: There always exists the potential for loss of private information; however, there 
are procedures in place to minimize this risk. 
 
Unknown Risks: It is possible that the study treatment or procedures may involve risks to you 
that are not currently known or foreseeable.  It is important that you should consult with the 
treating physician regarding any questions or concerns you may have about the study treatments. 
 
As well as the important possible risks described above patients with different types of cancer 
who have been treated with pembrolizumab in clinical trials have very commonly (i.e., more 
than 10% of patients) reported: feeling tired, nausea, vomiting, decreased appetite, shortness of 
breath, cough, fever and pain in muscles and joints. 
 
Will I benefit from this study? 
The possible benefits of this study are: Your tumor may decrease in size or there may be 
improvement in your symptoms.  The likelihood of your benefitting from this study is low. 
 
What are my other choices if I do not take part in this study?   
You are not required to take place in this study.  Some other options for you are:  
• You may participate in other clinical trials 
 
You may receive comfort measures to control symptoms of your disease but without any therapy 
for your tumor(s).  Comfort care includes pain medication and other supportive measures.  It 
aims to maintain your comfort and dignity rather than cure disease. This care may be provided at 
home. If you think you might prefer comfort care, please discuss this with your family, friends 
and your doctor. 
 
The study staff will discuss these other options with you. 
 


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Who will see my study information? 
Study team members, the sponsor of the study, and their representatives will be able to see your 
study information.  Your records may also be reviewed in order to meet federal or state 
regulations.  Reviewers may include the Augusta University Institutional Review Board (the 
committee who oversees safety of volunteers in research studies), institutional officials, and 
outside agencies, such as the Food and Drug Administration (FDA) and the Western Institutional 
Review Board (WIRB).  
 
Whenever possible, your identifying information will be protected; for example, your name 
replaced by a study number.  Absolute confidentiality cannot be guaranteed because of the need 
to give information that identifies you to these parties.  The results of this research study may be 
presented at meetings or in publications.  Your identity will not be disclosed in those 
presentations. 
 
How will you keep my study information confidential?   
Study records that identify you will be kept confidential except as required by law.  You will not 
be identified in study records or publications disclosed outside Augusta University.   
 
What are my costs (what will it cost me) for taking part in the study?  
If you agree to participate in this study, you and/or your insurance will not be billed for the tests 
and treatments that are being done only for research.  However, you are still responsible for 
paying for the usual care you would normally receive for the treatment of your illness.  You will 
be responsible for all co-pays, deductibles and denied claims.  
 
You have the right to specifically ask what it will cost you to take part in this study.  You have 
the right to contact your insurance company to discuss the costs of your routine care and whether 
these will be covered if you participate in this study.  You may choose not to be in this study if 
your insurance does not pay for your routine care.  In that case, your doctor will discuss other 
treatment plans with you. 
 
Will I be paid for participation in this study?   
You will not be paid for taking part in this study.   
 
What happens if I am injured or hurt because I took part in this study?  
 
If you think that you have suffered a research related injury seek medical care right away and 
contact the study team as soon as possible at (706) 721-2505.  In the event that this research 
related activity results in an injury, treatment will be made available including first aid, 
emergency treatment, and follow-up care as needed.  Cost for such care will be billed in the 
ordinary manner to you or your insurance company.  No reimbursement, compensation, or free 
medical care is offered by Augusta University (AU), AU Medical Center, AU Medical 


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Associates, AU Dental Associates, AU Nursing Associates, Inc., AU Health Professions 
Associates, Inc. collectively designated AU Affiliates, or any other facility involved with this 
study.  You do not give up your legal rights by participating in this study. 
 
Who can answer my questions about this study?   
You can ask questions about this study at any time.  Please contact the study staff listed on page 
1 of this document if you have questions about: 
• Study procedures or treatments 
• Reporting an illness, injury or other problem 
• Leaving the study before it is finished 
• Expressing a concern about the study 
• Any other questions you may have about the study 
 
If you have questions or concerns about the privacy of your information please contact the 
Enterprise Privacy Officer at 706 721-5631, or through our Toll Free Hotline, 1-800-576-6623. 
Written inquiries or complaints may be emailed to: privacy@augusta.edu or mailed to the: 
Enterprise Privacy Officer, Augusta University, C/O Augusta University IRB Office, Pavilion 
III, CJ-2103, 1120 15th Street, Augusta, Georgia, 30912. 
 
Who can I contact to discuss my rights, problems, concerns, questions, or complaints I 
have as a study participant? 
 
If you have questions about your rights as a research subject or if you have questions, concerns, or 
complaints about the research, you may contact: 
 
 
Western Institutional Review Board® (WIRB®) 
 
1019 39th Avenue SE Suite 120 
 
Puyallup, Washington  98374-2115 
 
Telephone:  1-800-562-4789 or 360-252-2500 
 
E-mail: Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff.  
 
Could there be any harm to me if I decide to stop participating in the study before it’s 
finished?  
If you decide to stop taking part in the study, the study staff will discuss ways to safely remove 
you from the study.  You should follow the instructions the study staff gives you. 


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Can I be removed from the study?  
Yes, you may be removed from the study if:  
• The drug manufacturers or study doctors decide to stop the study. 
• 
Your study doctor stops your taking part in the study for your safety. 
• 
You are not eligible to take part in the study. 
• 
Your condition changes and you need treatment that is not allowed while you are taking 
part in the study. 
• 
You do not follow the instructions from the study staff. 
 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a 
Research Study 
If you sign this document, you give permission to Augusta University and AU Affiliates to use 
or release your health information that identifies you for the study described earlier in this 
document. 
 
The health information Augusta University and AU Affiliates may use or release for this study 
includes information in your medical record, results of physical exams, medical history, lab tests 
or certain health information indicating or relating to your condition.   
 
The health information listed above may be used by and/or released to the following, as 
applicable: 
• Researchers and their staff; 
• The sponsor of the study including its agents such as data storage banks or contract 
research organizations monitoring the study; 
• Other institutions and investigators participating in the study; 
• Data Safety Monitoring Boards; 
• Accrediting agencies; 
• Clinical staff not involved in the study whom may become involved if it is relevant; 
• Health insurers or payers in order to secure payment for covered treatment; 
• Parents/Guardians of children younger than 18 years 
• Federal/state agencies and Augusta University and AU Affiliates committees having 
authority over the study. These may include, but are not limited to: 
o The Institutional Review Board (IRB) overseeing this study; 
o Committees with quality improvement responsibilities; 
o Office of Human Research Protections; 
o Food and Drug Administration; 
o National Institutes of Health; 
o Other governmental offices as required by law. 
 


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Augusta University and AU Affiliates are required by law to protect your health information.  By 
signing this document, you authorize Augusta University and AU Affiliates to use and/or release 
your health information for this research. 
 
Once your information has been released outside Augusta University and AU Affiliates, it may 
no longer be protected by federal laws and regulations and might be disclosed by the persons or 
institutions receiving the information. 
 
Please note that:  
You cannot receive this research-related treatment if you do not sign this Authorization. 
 
Augusta University and AU Affiliates may not withhold treatment whether or not you sign this 
Authorization.  
 
You may change your mind and take back (revoke) this Authorization at any time.  If you revoke 
this Authorization, Augusta University and AU Affiliates may still use or release health 
information and any data and/or specimens already obtained about you as necessary for this 
study.  If you revoke this Authorization, you cannot continue to participate in this study.  To 
revoke this Authorization, you must write to the Principal Investigator listed on page 1 of this 
document. 
 
You may not be allowed to see or copy the study information described on this Authorization as 
long as the study is in progress.  Feel free to ask the study staff if this applies to this study. When 
the study is complete, you have a right to request a copy of your personal health information 
collected for the study.  
 
Your health information will be used or disclosed when required by law.  Your health 
information may be shared with a public health authority that is authorized by law to collect or 
receive such information for the purpose of preventing or controlling disease, injury or disability 
and for conducting public health surveillance, investigations or interventions.  No publication or 
public presentation about the study will reveal your identity without another signed authorization 
from you.   
 
You will be given a copy of this Authorization.  This Authorization does not have an expiration 
date.  If you have questions or concerns about this Authorization or your privacy rights, please 
contact the Augusta University and AU Affiliates Privacy Officer at 706-721-0900. 
 
Regulations require that you be given a copy of the Augusta University and AU Affiliates Notice 
of Privacy Practices describing the practices of Augusta University and AU Affiliates regarding 
your health.  
 


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STATEMENT OF CONSENT 
I have read this form and the information in it was explained to me.  All of my questions were 
answered.  I agree to take part in this research study.  My taking part in the study is voluntary.  I 
will receive a copy of this form for my records.  I am not giving up my legal rights by signing 
this form. 
 
 
_______________________________ 
Participant’s Name (print) 
 
 
________________________________ 
 
____________ /___________   
Participant’s Signature 
Date 
Time (00:00) 
 
 
________________________________ 
Witness’ name (print)  
 
 
_________________________________ 
 
___________ /___________   
My signature indicates that I was present  
Date 
Time (00:00) 
during the informed consent process and  
that informed consent was given freely by  
the subject.  My signature also indicates 
that I was present when the subject signed  
the form. 
 
INVESTIGATOR STATEMENT 
I acknowledge that I have discussed the above study with this participant and answered all of 
his/her questions.  They have voluntarily agreed to participate.  I have documented this action in 
the participant’s medical record source documents or research chart source documents, as 
applicable.  A copy of this signed document will be placed in the participant’s medical record or 
research chart, as applicable.  A copy of this document will be given to the participant or the 
participant’s legally authorized representative.  
 
 
______________________________________ 
Printed name of Investigator obtaining consent 
 
 
______________________________________ 
___________ /___________ 
Signature of Investigator obtaining consent 
Date 
Time (00:00)