Clinical trial NCT04193293
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: Squamous Cell Carcinoma of the Head and Neck Head and Neck Cancer PI3K-δ,γ PI3K Inhibitor
Sponsor: SecuraBio
Start date: 2020-06-01; Completion date: 2020-12-10
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was designed to assess the safety and preliminary efficacy of duvelisib in combination with pembrolizumab in participants with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Detailed description:
This was a non-randomized, open-label Phase 1b/2 study designed to evaluate safety, tolerability, and preliminary efficacy of duvelisib in combination with pembrolizumab in participants with R/M HNSCC who were eligible for pembrolizumab monotherapy based on the current pembrolizumab prescribing information.

Arms: arm 1: Stage 1: Duvelisib twice daily (BID) for 1 week followed by combination therapy with duvelisib BID + pembrolizumab every 3 weeks (q3w) (Cycle 1 was 4 weeks consisting of the 1-week duvelisib monotherapy lead-in period followed by 1 dose of pembrolizumab in combination with 3 additional weeks of continuous dosing of duvelisib; subsequent cycles were 3 weeks).

Stage 2: Duvelisib BID + pembrolizumab q3w in 3-week cycles.
Interventions: intervention 1: Duvelisib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Phosphoinositide 3-kinase (PI3K) Inhibitor intervention 2: Immunotherapy (programmed cell death protein 1 \[PD-1\] inhibitor)

Protocol documents:
Prot_SAP_000.pdf: 
17 September 2019 
CONFIDENTIAL 
Page 1 of 110 
STUDY PROTOCOL 
VS-0145-130 
Protocol Title: 
A Phase 1b/2 Study of Duvelisib in Combination with Pembrolizumab in 
Subjects with Recurrent or Metastatic Head and Neck Squamous Cell 
Cancer 
Protocol Number: 
VS-0145-130 
Version: 
2.0 
Compound:   
Duvelisib 
Study Phase:   
Phase 1b/2 
Short Title:  
A Phase 1b/2 Study of Duvelisib in Combination with Pembrolizumab in 
Head and Neck Cancer 
Sponsor: 
Verastem, Inc. 
117 Kendrick St., Suite 500 
Needham, MA 02494 
Tel: 
 
Regulatory Agency Identifier Number(s) 
IND Number: 
144,887 
Protocol Date:  
17 September 2019 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of 
Verastem, Inc. The protocol is for use by the Principal Investigator and his/her designated 
representatives participating in this investigational trial. This protocol may not be copied or made 
available for review by an unauthorized person or firm without the prior written authorization of 
Verastem, Inc. 
NCT #: NCT04193293




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TABLE OF CONTENTS 
STUDY PROTOCOL ......................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................6 
1. 
PROTOCOL SUMMARY ............................................................................................7 
1.1. 
Synopsis ........................................................................................................................7 
1.2. 
Schema ........................................................................................................................16 
1.3. 
Schedule of Activities (SoA) for Stage 1 ...................................................................19 
1.4. 
Schedule of Activities (SoA) for Stage 2 ...................................................................27 
2. 
INTRODUCTION ......................................................................................................33 
2.1. 
Duvelisib .....................................................................................................................33 
2.2. 
Study Rationale ...........................................................................................................33 
2.3. 
Background .................................................................................................................34 
2.4. 
Benefit/Risk Assessment ............................................................................................37 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
4. 
STUDY DESIGN .......................................................................................................42 
4.1. 
Overall Design ............................................................................................................42 
4.2. 
Scientific Rationale for Study Design ........................................................................44 
4.3. 
End of Study Definition ..............................................................................................44 
5. 
STUDY POPULATION .............................................................................................45 
5.1. 
Inclusion Criteria ........................................................................................................45 
5.2. 
Exclusion Criteria .......................................................................................................46 
5.3. 
Lifestyle Considerations .............................................................................................48 
5.4. 
Definition of Enrolled .................................................................................................49 
5.5. 
Screen Failures ............................................................................................................49 
5.6. 
Replacement of Subjects .............................................................................................49 
6. 
STUDY INTERVENTIONS ......................................................................................50 
6.1. 
Study Interventions Administered ..............................................................................50 
6.2. 
Preparation/Handling/Storage .....................................................................................52 
6.3. 
Measures to Minimize Bias ........................................................................................52 
6.4. 
Study Intervention Compliance ..................................................................................52 


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6.5. 
Concomitant Therapy .................................................................................................53 
6.6. 
Supportive Care, Dose Modifications, and Management of Toxicities ......................55 
6.7. 
DLT Evaluation ..........................................................................................................65 
6.8. 
Intervention after the End of the Study .......................................................................67 
7. 
DISCONTINUATION OF STUDY INTERVENTION(S) AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................68 
7.1. 
Discontinuation of Study Interventions ......................................................................68 
7.2. 
Subject Withdrawal from the Study ...........................................................................68 
7.3. 
Lost to Follow-up .......................................................................................................69 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................70 
8.1. 
Efficacy Assessments .................................................................................................70 
8.2. 
Safety Assessments .....................................................................................................71 
8.3. 
Other Assessments ......................................................................................................72 
8.4. 
Adverse Event Management .......................................................................................73 
8.5. 
Pharmacokinetics ........................................................................................................77 
8.6. 
Pharmacodynamics .....................................................................................................78 
8.7. 
Genetics ......................................................................................................................78 
8.8. 
Biomarkers ..................................................................................................................79 
8.9. 
Medical Resource Utilization and Health Economics ................................................79 
9. 
STATISTICAL METHODOLOGY ...........................................................................80 
9.1. 
Statistical Hypotheses .................................................................................................80 
9.2. 
Sample Size Determination ........................................................................................80 
9.3. 
Populations for Analyses ............................................................................................80 
9.4. 
Statistical Analyses .....................................................................................................81 
9.5. 
Interim Analyses .........................................................................................................83 
9.6. 
Data Monitoring Committee .......................................................................................83 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS: APPENDICES .......................................................................84 
10.1. 
Appendix 1: RECIST Version 1.1 ..............................................................................85 
10.2. 
Appendix 2: CYP3A Inhibitors, Inducers, and Substrates .........................................89 
10.3. 
Appendix 3: Clinical Laboratory Tests .......................................................................91 
10.4. 
Appendix 4: Contraception Guidance ........................................................................93 


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10.5. 
Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance 
Status...........................................................................................................................95 
10.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight Considerations ....................96 
10.7. 
Appendix 7: Abbreviations .......................................................................................100 
10.8. 
Appendix 8: Protocol Amendment History ..............................................................104 
11. 
REFERENCES .........................................................................................................108 
 
LIST OF TABLES 
Table 1: 
Study Activities for Stage 1: Duvelisib Monotherapy Lead-in and in 
Combination with Pembrolizumab .............................................................................19 
Table 2: 
Pharmacokinetic, Pharmacodynamic, and Biomarker Sampling in Stage 1 ..............25 
Table 3: 
Study Activities for Stage 2: Duvelisib in Combination with Pembrolizumab ..........27 
Table 4: 
Pharmacokinetic and Biomarker Sampling in Stage 2 ...............................................31 
Table 5: 
Objectives and Endpoints ...........................................................................................40 
Table 6: 
Duvelisib Dose Levels ................................................................................................43 
Table 7: 
Study Interventions .....................................................................................................50 
Table 8: 
Prohibited Concomitant Therapies .............................................................................54 
Table 9: 
Concomitant Therapies: Use with Caution During Treatment with Duvelisib ..........55 
Table 10: Recommended Dose Modifications for the Management of Overlapping 
Toxicities for Duvelisib in Combination with Pembrolizumab ..................................57 
Table 11: Duvelisib Dose Level Modifications for Toxicities ...................................................60 
Table 12: Recommended Duvelisib Dose Modifications for the Management of 
Duvelisib Toxicities ....................................................................................................60 
Table 13: Recommended Pembrolizumab Dose Modifications for the Management of 
Pembrolizumab Toxicities ..........................................................................................63 
Table 14: NCI CTCAE Grading for Infusion Reactions ............................................................65 
Table 15: CTCAE (Version 5.0 or higher) AE Grading .............................................................75 
Table 16: Populations for Analyses ............................................................................................81 
Table 17: Appendices .................................................................................................................84 
Table 18: Evaluation of Best Overall Response – Subject with Target (± Non-target) 
Disease ........................................................................................................................86 
Table 19: Evaluation of Best Overall Response – Subject with Non-target Disease .................86 
Table 20: Classification of In Vivo Inhibitors of CYP3A ..........................................................89 


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Table 21: Classification of In Vivo Inducers of CYP3A ............................................................90 
Table 22: Cytochrome P450 3A (CYP3A) Substrates ................................................................90 
Table 23: Protocol-required Safety Laboratory Assessments .....................................................91 
Table 24: List of Abbreviations ................................................................................................100 
Table 25: Summary of Changes for Version 2.0 ......................................................................104 
Table 26: Primary Reason for Each Version ............................................................................107 
 
LIST OF FIGURES 
Figure 1: 
Study Stages................................................................................................................16 
Figure 2: 
Treatment/Imaging Scheme in Stage 1 .......................................................................17 
Figure 3: 
Treatment/Imaging Scheme in Stage 2 .......................................................................18 
Figure 4: 
Effect of Duvelisib on Tumor Microenvironment ......................................................34 
Figure 5: 
Combination of Duvelisib and a PD-L1 mAb Resulted in Significantly 
Enhanced Control of Primary Tumor Growth and Survival in a MOC1 
Model ..........................................................................................................................35 
Figure 6: 
Combination of Duvelisib and a PD-1 Inhibitor (anti-PD-1) Is Synergistic in 
Inhibition of Tumor Growth in A20 B-Cell Model ....................................................36 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Study Title: A Phase 1b/2 Study of Duvelisib in Combination with Pembrolizumab in Subjects with 
Recurrent or Metastatic Head and Neck Squamous Cell Cancer 
Protocol Number: VS-0145-130 
Phase: 1b/2 
Investigational Product: duvelisib 
Combination Product: pembrolizumab 
Rationale: 
Head and neck squamous cell carcinoma (HNSCC) represents over 90% of head and neck 
malignancies. Although the majority of patients present with locoregionally advanced disease, the 
clinical course is characterized by a high recurrence rate approaching 50%, as well as the development 
of distal metastases. Despite the recent approval of agents (e.g., pembrolizumab [Keytruda®] and 
nivolumab [Opdivo®]) that inhibit the interaction of programmed cell death protein 1 (PD-1) with its 
ligand (PD-L1), only a small subset of patients appears to derive benefit from these therapies. Although 
the efficacy of anti-PD-1 therapy may vary by PD-L1 expression or human papillomavirus (HPV) 
status, as well as the number of prior therapies, typically the overall response rate (ORR) is 
approximately 15% in the second-line or greater setting and somewhat higher in the first-line setting. 
The majority of responses in either setting are partial responses (PRs). The effectiveness of PD-1 
inhibitors can be limited by infiltration of immunosuppressive myeloid cells (MDSCs) into the tumor 
microenvironment. Thus, there remains a large unmet medical need for better therapy options in 
patients with recurrent or metastatic (R/M) disease. 
Phosphoinositide 3-kinase (PI3K) activity supports the growth and maintenance of cancer cells by 
contributing to the establishment and maintenance of the tumor microenvironment through cell 
proliferation, survival, differentiation, migration, and activation of non-tumor cells. 
Duvelisib is a dual PI3K-δ/-γ inhibitor that reduces the cancer-promoting effects of PI3K on the tumor 
microenvironment and has an established clinical safety and efficacy profile in patients with 
hematologic malignancies (United States [US] approval in relapsed or refractory [R/R] chronic 
lymphocytic leukemia/small lymphocytic leukemia and accelerated approval in R/R follicular 
lymphoma) (COPIKTRA 2018). In in vivo nonclinical studies in solid tumor models (including 
HNSCC), duvelisib induced tumor growth delay. In addition, strong antitumor synergy (i.e., inhibition 
of tumor growth and increased survival) was observed for the combination of duvelisib and a PD-1 
inhibitor vs either monotherapy in a mouse model of B-cell lymphoma (mimicking a solid tumor 
setting). Mechanistically, duvelisib was found to reduce regulatory T-cells (Tregs), M2 tumor-
associated macrophages, and MDSCs in the context of combination with a PD-1 inhibitor. The 
nonclinical data suggest that reduction of Tregs and MDSCs by duvelisib in the tumor 
microenvironment may enhance sensitivity of the tumor to PD-1 inhibitors like pembrolizumab in this 
tumor setting. 
Based on the hypothesis, which is supported by nonclinical data, that duvelisib can enhance the activity 
of PD-1 inhibitors, this study is designed to assess the safety and preliminary efficacy of duvelisib in 
combination with pembrolizumab in subjects with R/M HNSCC who are eligible for pembrolizumab 
monotherapy based on the current pembrolizumab prescribing information. 


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Objectives and Endpoints: 
Objectives 
Endpoints 
Stage 1 - Unique Objectives/Endpoints 
Primary  
Evaluate the safety and tolerability of duvelisib in 
combination with pembrolizumab in subjects with 
R/M HNSCC 
Safety and tolerability of study interventions 
based on dose-limiting toxicities (DLTs), adverse 
events (AEs), serious AEs (SAEs), vital signs, 
physical examinations, and clinical laboratory 
measurements 
Secondary 
Characterize the ORR of duvelisib in combination 
with pembrolizumab in subjects with R/M 
HNSCC 
ORR, which includes PR and complete response 
(CR) according to Response Evaluation Criteria in 
Solid Tumors (RECIST) v 1.1 (Eisenhauer 2009) 
Stage 1 and Stage 2- Combined Objectives/Endpoints 
Primary 
Characterize the ORR of duvelisib in combination 
with pembrolizumab  
ORR, which includes PR and CR, according to 
RECIST v 1.1 (Eisenhauer 2009) 
Secondary 
Characterize other efficacy parameters of 
duvelisib in combination with pembrolizumab  
• 
Duration of response (DOR), defined as time 
from response ≥ PR to documented disease 
progression according to RECIST v 1.1 
(Eisenhauer 2009) 
• 
Progression-free survival (PFS), defined as 
the time from start of treatment to 
documented disease progression according to 
RECIST v 1.1 (Eisenhauer 2009), or death 
due to any cause 
• 
Overall survival (OS), defined as the time 
from start of treatment to the date of death 
Characterize the pharmacokinetics (PK) of 
duvelisib (and metabolite IPI-656) monotherapy 
and of duvelisib in combination with 
pembrolizumab 
PK parameters for duvelisib (and metabolite 
IPI-656) 
Evaluate the safety and tolerability of duvelisib in 
combination with pembrolizumab 
 
Safety and tolerability parameters including AEs, 
SAEs, vital signs, physical examinations, and 
clinical laboratory measurements 


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Exploratory 
Evaluate potential biomarkers for possible 
associations with clinical efficacy and/or safety 
outcomes of duvelisib in combination with 
pembrolizumab 
• 
Blood assessments of immune cell 
populations, chemokines, cytokines and 
circulating tumor DNA 
• 
Fecal assessments of protein, DNA, and/or 
RNA 
• 
Tumor biopsy evaluation of biomarkers such 
as gene and copy number variation, RNA 
expression, protein expression, and/or 
immune cell content (Required biopsies in 
Stage 1 and optional biopsy in Stage 2) 
• 
ORR and its relationship to tumor and/or 
immune cell PD-L1 levels and to tumor HPV 
status 
Overall Design and Intervention Groups: 
This is a multicenter, non-randomized, open-label Phase 1b/2 study of duvelisib in combination with 
pembrolizumab in subjects with R/M HNSCC who are eligible for pembrolizumab monotherapy based 
on the current pembrolizumab prescribing information (Keytruda 2019). 
The study will follow a Simon two-stage design (Simon 1989). 
Subjects will receive duvelisib 25 mg twice daily (BID) orally (PO) in combination with 
pembrolizumab 200 mg every 3 weeks (q3w) intravenously (IV). 
In Stage 1, subjects will have a 1-week lead-in with duvelisib before the initiation of combination 
therapy with duvelisib and pembrolizumab. Approximately 13 subjects are planned to be accrued in 
this stage. The first 6 subjects will be assessed for DLTs. The DLT evaluation period will be Cycle 1 
(4 weeks or 28 days): the 1-week duvelisib monotherapy lead-in period followed by 1 dose of 
pembrolizumab in combination with 3 additional weeks of continuous dosing of duvelisib. Every effort 
will be made to administer the first dose of pembrolizumab on Day 8 of Cycle 1 (C1D8). If the first 
dose of pembrolizumab on C1D8 is delayed, every effort should be made to delay the subsequent 
dosing of the next cycle (within the protocol-allowed window of 3 days) to achieve as close to a 
3-week interval between pembrolizumab doses as possible. The Medical Monitor needs to be consulted 
for such adjustments to ensure uniformity of approach and to account for subject-specific 
circumstances. For example, if the third day of the C2D1 window falls on a weekend, an additional 
adjustment would need to be made on a case-by-case basis. In the event of a delay of the start of 
pembrolizumab therapy, DLTs will be evaluated at the end of the third week of combination therapy. 
The DLT evaluation period will be used to assess DLTs in the first 6 subjects. 
• 
If there is ≤ 1 DLT in the 6 DLT-evaluable subjects, additional subjects will be enrolled to 
bring the total dosed in Stage 1 to approximately 13 subjects. 
• 
If there are ≥ 2 DLTs in the first 6 subjects, enrollment at duvelisib 25 mg BID will stop. 
Enrollment would restart at a reduced duvelisib dose (15 mg BID) to assess DLTs at the lower 
dose. 


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A formal analysis of available safety data will be conducted when the first 10 subjects treated have 
received at least 1 cycle of study treatment. This will enable assessment of toxicities of later onset, 
particularly outside of the DLT-window.  
If an excessive rate of Grade 3 or higher overlapping SAEs (defined as any rate for each SAE that is 
above the highest reported in warnings and precautions of the prescribing information for either 
duvelisib [COPIKTRA 2018] or pembrolizumab [Keytruda 2019], respectively) such as pneumonitis, 
colitis, cutaneous skin reactions, and elevations of AST/ALT, is observed outside of the DLT window, 
a decision for stopping or modifying the study may be made. However, recognizing that the observed 
rate of such events can be highly sensitive due to the small sample size, the totality of safety data will 
be reviewed and carefully considered prior to making a formal decision. 
An interim analysis of ORR will occur after all of the planned 13 subjects in Stage 1 are enrolled, 
dosed, and have been followed through at least the first disease response assessment.  
• 
If there are ≤ 2 responses (CR or PR) in the 13 subjects in Stage 1, further accrual in the study 
may be stopped. However, all available data, including the relative proportion of CRs, will be 
analyzed before a final decision is made. 
• 
If > 2 responses are observed in Stage 1, enrollment will continue in Stage 2. 
In Stage 2, 17 additional subjects will be accrued for a total of 30 subjects in the final analysis. 
Subjects enrolled in Stage 2 will only receive combination therapy with duvelisib and pembrolizumab. 
Enrollment into Stage 2 may proceed prior to completion of the interim analysis as long as at least 2 of 
the 13 subjects enrolled in Stage 1 have a confirmed response. 
Subjects will be monitored continuously for safety while on study treatment. Adverse events will be 
classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Version 5.0 or higher. 
Higher doses of duvelisib may be explored in additional subjects via a protocol amendment, if 
warranted by observed data. 
Subjects will be treated until documented progressive disease (PD), unacceptable toxicity, 
discontinuation criteria are met, withdrawal, or death. The total duration of treatment will not exceed 
24 months. After treatment discontinuation, subjects will be followed for safety for an additional 
30 days. All subjects with treatment-related AEs/SAEs should be observed until resolution or 
stabilization. 
It is anticipated that the study accrual will occur over approximately 18 months. All subjects will be 
followed for survival for 1 year after the last subject is enrolled and dosed. 
Study Population: 
Inclusion Criteria 
Subjects may be eligible for inclusion in the study if they meet the following criteria: 
1. Must be a male or female subject ≥ 18 years of age 
2. Must have histologically or cytologically-confirmed R/M HNSCC of the oral cavity, 
oropharynx, hypopharynx, or larynx that is considered incurable by local therapies. 


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3. Must be eligible for pembrolizumab monotherapy based on the current prescribing information 
for pembrolizumab (Keytruda 2019): (a) for first-line treatment, subjects with metastatic or 
with unresectable, recurrent HNSCC whose tumors express PD-L1 (Combined Positive Score 
[CPS] ≥ 1) as determined by a Food and Drug Administration [FDA]-approved test; 
(b) subjects with R/M HNSCC with disease progression on or after platinum-containing 
chemotherapy, regardless of PD-L1 expression. 
4. Must have had 0 to 2 prior therapies for R/M HNSCC. Therapy for locally or regionally 
advanced HNSCC with or without radiation therapy is not counted as a line of therapy unless 
recurrence and/or metastasis was demonstrated < 6 months from the end of such therapy. 
5. Must have at least 1 measurable lesion (which has not been previously irradiated) according to 
RECIST v 1.1 (Eisenhauer 2009) 
6. For Stage 1 only: Must have at least 1 other lesion that can be biopsied 
7. For Stage 1 only: Must be willing to undergo a pretreatment and on-treatment biopsy of the 
available tumor lesion (described in inclusion criterion #6). Archival tissue (up to 6 months 
before the first dose of duvelisib) may be considered in place of the required pretreatment 
biopsy after consultation with the Sponsor, as long as no intervening systemic regimen had 
been taken during that time frame. 
8. Must provide prior data on PD-L1 expression and HPV status, if available 
9. Must have adequate organ function defined by the following laboratory parameters: 
a. Adequate bone marrow reserve as evidenced by: 
− 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
− 
Platelet count ≥ 100 × 109/L 
− 
Hemoglobin level ≥ 9.0 g/dL 
b. Adequate renal function as evidenced by: 
− 
a serum creatinine level < 1.5 mg/dL, or 
− 
estimated creatinine clearance value ≥ 60 mL/min (as determined by the Cockcroft-
Gault method) for subjects with creatinine levels > 1.5 × institutional upper limit of 
normal (ULN) 
c. Adequate hepatic function as evidenced by: 
− 
Total bilirubin level ≤ 1.5 × ULN (exception: subjects with Gilbert's Syndrome may 
have a bilirubin level > 1.5 × ULN) 
− 
Aspartate aminotransaminase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) and alanine aminotransferase (ALT)/serum pyruvic transaminase (SGPT) 
levels ≤ 2.5 × ULN or ≤ 5 × ULN in subjects with liver metastases 
10. Must have an international normalized ratio (INR) or prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) ≤ 1.5 × ULN, unless subject is receiving anticoagulant 
therapy in which case PT or aPTT must be within therapeutic range of intended use of 
anticoagulants 


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11. Must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
12. For male and female subjects of reproductive potential (i.e., not surgically sterile or female 
subjects who are not postmenopausal), must be willing to use a highly effective method of 
contraception (see Section 10.4) for the duration of the study interventions and for at least 
4 months after the last dose of study interventions 
13. Must have a negative serum human chorionic gonadotropin (hCG) pregnancy test result within 
7 days before the first dose of duvelisib if the subject is a woman of childbearing potential 
(WCBP) 
14. Must provide signed and dated institutional review board (IRB)/independent ethics committee 
(IEC) -approved informed consent form (ICF) before any study-specific screening procedures 
are performed 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Have disease that is suitable for local therapy administered with curative intent 
2. Have been previously treated with 3 or more systemic regimens given for recurrent and/or 
metastatic disease 
3. Have received anticancer treatment, major surgery, or any investigational drug within 30 days 
or 5 half-lives, whichever is shorter, before the first dose of duvelisib 
4. Have received radiation therapy within 14 days before the first dose of duvelisib in this study, 
including, in addition (if necessary), the timeframe for resolution of any actual or anticipated 
toxicities from such radiation. Palliative radiation therapy is allowed if > 7 days before the first 
dose of duvelisib and any toxicity is ≤ Grade 1. 
5. Have received prior radiation therapy to > 25% of bone marrow-bearing areas 
6. Have co-existing head-and-neck carcinoma of the nasopharynx, squamous cell carcinoma of 
unknown primary, salivary gland tumors, or any other non-squamous primary tumors 
involving the head and neck 
7. Have received previous treatment with a PI3K inhibitor 
8. Have received previous treatment with a PD-1 or PD-L1 inhibitor 
9. Have received organ or allogenic bone marrow or peripheral blood stem cell transplant 
10. Have a history or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function 
11. Have a prior history of drug-induced colitis or drug-induced pneumonitis 
12. Have active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (subjects with 
detectable viral load) 
13. Have an infection with hepatitis B or hepatitis C: 
• 
Subjects with a positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody 
(HCVAb) will be excluded 


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• 
Subjects with a positive hepatitis B core antibody (HBcAb) must have negative hepatitis B 
virus (HBV) DNA to be eligible and must be periodically monitored for HBV reactivation 
by institutional guidelines 
• 
Investigators who strongly believe that a positive HBcAb is false-positive due to passive 
immunization from previous immunoglobulin infusion therapy should discuss the potential 
to defer HBV prophylaxis with the Medical Monitor 
14. Have a history of or known human immunodeficiency virus (HIV) infection 
15. Have a history of tuberculosis treatment within the 2 years before the first dose of duvelisib 
16. Have a history of chronic liver disease or veno-occlusive disease/sinusoidal obstruction 
syndrome 
17. Have known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study 
18. Are receiving ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or 
systemic steroids > 20 mg of prednisone (or equivalent) per day 
19. Have an active infection or are receiving ongoing systemic treatment for a clinically significant 
bacterial, fungal, or viral infection at Screening 
NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically 
excluded if all other inclusion/exclusion criteria are met 
20. Have received a live or live attenuated vaccine within 6 weeks of first dose of duvelisib 
21. Have received medications or consumed foods that are strong inhibitors or inducers of 
cytochrome P450 3A (CYP3A) (Section 10.2) within 2 weeks prior to the first dose of 
duvelisib or concurrent with duvelisib treatment 
22. Are unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), or 
herpes zoster (VZV) at screening 
23. Have had prior surgery (e.g., gastric bypass surgery, gastrectomy) or gastrointestinal 
dysfunction that may affect drug absorption 
24. Have any active gastrointestinal dysfunction interfering with the subject’s ability to be 
administered oral medications 
25. Is a female subject who is pregnant or breastfeeding 
26. Have a baseline QT interval corrected using the Fridericia correction method (QTcF) > 500 ms 
(average of triplicate readings). NOTE: This criterion does not apply to subjects with a right or 
left bundle branch block. 
27. Have New York Heart Association Class III or IV congestive heart failure 
28. Have a history of another active malignancy that is progressing or requires active treatment. 
Exceptions include adequately treated non-melanoma skin cancer, curatively treated in-situ 
cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for 
> 3 years. 


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29. Have known active central nervous system metastases and/or carcinomatous meningitis. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least 4 weeks prior to the first dose of 
duvelisib 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 the first dose 
of duvelisib. The exception does not include carcinomatous meningitis. 
30. Have an active autoimmune disease requiring systemic treatment within the last 3 months prior 
to first dose of study intervention, documented history of clinically severe autoimmune disease, 
or a syndrome that requires systemic or immunosuppressive agents except vitiligo, Type 1 
diabetes mellitus, hypothyroidism stable on hormone-replacement therapy, Sjogren’s 
syndrome, and resolved childhood asthma/atopy. Subjects who require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections may participate in this study. 
31. Have a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia 
requiring medication or mechanical control within the last 6 months prior to first dose of 
duvelisib 
32. Have unstable or severe uncontrolled medical condition or any important medical illness or 
abnormal laboratory finding that would, in the Investigator’s judgment, increase the subject’s 
risk to participating in this study 
Number of Subjects (planned): 
It is anticipated that the study will include approximately 13 subjects in Stage 1 and 17 subjects in 
Stage 2 at multiple sites in the US, for a total of 30 subjects. 
Duration of Treatment and Follow-up: 
Subjects will be treated until documented PD, unacceptable toxicity, discontinuation criteria are met, 
withdrawal, or death. The total duration of treatment will not exceed 24 months. 
All subjects will be followed for survival for 1 year after the last subject is enrolled and dosed. 
Statistical Methods: 
This study will test the null hypothesis that the ORR in subjects is ≤ 16% against the alternative that 
ORR is ≥ 44%.  
The evaluation of the primary endpoint will be conducted at the highest dose that is tolerated during the 
DLT evaluation. Therefore, if the initial dose of 25 mg BID is not tolerated but the reduced dose of 
15 mg BID is tolerated, the primary endpoint will be evaluated in all subjects starting at the tolerated 
dose. 
The ORR (proportion of subjects achieving CR or PR) according to RECIST v 1.1 (Eisenhauer 2009) 
will be estimated on the modified Intent-to-Treat (mITT) population (i.e., all subjects who receive at 
least 1 dose of duvelisib in combination with at least 1 dose of pembrolizumab). A 2-sided exact 95% 
confidence interval (CI) will be calculated. 
The study will follow a Simon two-stage design (Simon 1989). In the first stage, approximately 
13 subjects will be accrued. If there are ≤ 2 responses (CR or PR) in these 13 subjects, further accrual 
in the study may be stopped. However, all available data will be considered before termination. In 
Stage 2, 17 additional subjects will be accrued for a total of 30 subjects in the final analysis. The null 


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hypothesis will be rejected if 10 or more responses (CR or PR) are observed in 30 subjects. This design 
yields an overall type I error rate of 5% and power of 90% when the true response rate is 44%. 
Evaluation of ORR in Stage 1 will occur after the last subject enrolled and dosed in Stage 1, has been 
followed through at least the first disease response assessment. Final analysis of the ORR endpoint 
(combined Stage 1 and Stage 2 ORR) will occur after the last subject enrolled and dosed in Stage 2 has 
been followed for 6 months. 
Safety analyses will be performed on the ITT population, and safety endpoints will be tabulated and 
presented. 
Data Monitoring Committee: None. 
Disclosure Statement: This is an open-label single-arm treatment study. 
 


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1.2. 
Schema 
Figure 1: 
Study Stages 
 
 
 
 
Abbreviations: CR: complete response; DLT: dose-limiting toxicity; PR: partial response; ORR: overall response rate. 


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Figure 2: 
Treatment/Imaging Scheme in Stage 1 
 
 
 
Abbreviations: BID: twice daily; D: day; DLT: dose-limiting toxicity; q3w: every 3 weeks; P: pembrolizumab; PD: progressive disease; PD-L1: programmed cell 
death ligand 1; W: week. 
Notes: 
The total duration of treatment will not exceed 24 months. 
In the case of a CR or PR, a confirmatory scan must be performed per RECIST v 1.1 (Eisenhauer 2009). It is recommended that this scan be performed at 
4 (+1) weeks after the initial response. 
 


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Figure 3: 
Treatment/Imaging Scheme in Stage 2 
 
 
Abbreviations: BID: twice daily; D: day; q3w: every 3 weeks; P: pembrolizumab; PD: progressive disease; PD-L1: programmed cell death ligand 1; W: week. 
Notes: 
The total duration of treatment will not exceed 24 months. 
In the case of a CR or PR, a confirmatory scan must be performed per RECIST v 1.1 (Eisenhauer 2009). It is recommended that this scan be performed at 
4 (+1) weeks after the initial response. 
 


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1.3. 
Schedule of Activities (SoA) for Stage 1 
Table 1: 
Study Activities for Stage 1: Duvelisib Monotherapy Lead-in and in Combination with Pembrolizumab 
 
Duvelisib 
Lead-in 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(4 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety 
F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until 
End of 
Study 
Notes 
W1 
W2 
W3 
W1 
W1 
D1 
D8 ±5 
D15±3 
D1 ±3 
D1 ±3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Potentially eligible subjects must sign an 
ICF before initiating any study specific 
procedures. SOC assessments that fulfill 
study eligibility requirements may be 
performed before the subjects signs the ICF. 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Reconfirm eligibility before first dose. 
Medical and Disease 
History, 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and Disease History includes 
histologic or cytologic diagnosis of 
HNSCC; HPV status; prior PD-L1 
expression; and prior treatment information. 
Archival Tumor 
Tissue  
X 
 
 
 
 
 
 
 
 
Archived tumor tissue is not required for 
enrollment, but should be submitted from 
all enrolled subjects, if available. 
Physical 
Examination 
X 
X 
X 
 
X 
X 
X 
 
 
See Section 8.2.1. Full examination 
(including height) at Screening and 
symptom-directed at subsequent time 
points. Screening results can be used for 
C1D1 if assessments are performed within 
7 days of first dose. 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
See Section 8.2.1. Vital signs measured 
with subject in a semi-supine position after 
5 minutes rest. Includes temperature, 
systolic and diastolic blood pressure, pulse 
rate, and respiratory rate. 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
See Section 8.3.1. Screening ECOG results 
can be used for C1D1 if test is performed 
within 7 days of first dose. 


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Duvelisib 
Lead-in 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(4 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety 
F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until 
End of 
Study 
Notes 
W1 
W2 
W3 
W1 
W1 
D1 
D8 ±5 
D15±3 
D1 ±3 
D1 ±3 
ECG (12-lead) 
X 
 
 
 
 
 
 
 
 
See Section 8.2.2. ECG at Screening will be 
performed in triplicate. QTc measurements 
will use the Fridericia correction method. 
Additional on-treatment ECGs should be 
performed per the Investigator’s discretion 
as clinically indicated. 
Concomitant 
Medications and 
Procedures 
Ongoing 
 
See Section 6.5.1 for required and 
recommended prophylaxis. Concomitant 
medications and procedures occurring 
within 30 days before first dose will be 
recorded at Screening. 
AE/SAE Assessment 
Ongoing 
 
See Section 8.4 for AE management. See 
Section 8.4.3 for reporting requirements. 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
PT, aPTT, and INR. See Table 23. 
Viral Screening 
X 
 
 
 
 
 
 
 
 
Hepatitis serology: HCVAb, HBsAg, 
HBcAb. 
HPV testing (if status not available at 
Screening). 
CMV/EBV serology or viral load. 
HIV test is not required if a prior negative 
test within 9 months is available. See 
Table 23. 
CMV Reactivation 
Monitoring (if 
applicable) 
 
 
X 
 
X 
X 
 
 
 
Subjects with a history of CMV infection 
should be monitored for reactivation by 
PCR at least monthly. 
See Section 6.5.1. 
C-Reactive Protein 
X 
Obtain when Grade ≥ 2 diarrhea, any grade colitis, or any grade immune-
mediated toxicity (e.g., pneumonitis, colitis, hepatitis, endocrinopathies, 
nephritis/renal dysfunction, cutaneous adverse reactions, encephalitis) occurs 
 
See Table 23. 
T3, FT4, and TSH 
X 
 
 
 
X 
X 
 
X 
 
Every other cycle starting at C2D1. 
Serum or Urine hCG 
Pregnancy Test for 
Women of 
X 
Xe 
 
 
X 
X 
 
X 
 
A serum pregnancy test must be performed 
within 7 days of first duvelisib dose. 
At subsequent time points, serum testing is 
preferred but urine testing is allowed if a 


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Duvelisib 
Lead-in 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(4 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety 
F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until 
End of 
Study 
Notes 
W1 
W2 
W3 
W1 
W1 
D1 
D8 ±5 
D15±3 
D1 ±3 
D1 ±3 
Childbearing 
Potential 
blood draw for other assessments is not 
performed. A positive urine test result must 
be confirmed by a serum test. See Table 23.  
Clinical Chemistry 
with Liver Function 
Tests 
X 
X 
X 
X 
X 
X 
X 
X 
 
BUN, potassium, creatinine, sodium, total 
protein, glucose (fasting), calcium, LDH, 
ALT, AST, total and direct bilirubin, and 
ALP. 
Screening test results can be used for C1D1 
if tests are performed within 7 days of first 
dose. See Table 23.  
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology panel plus a 5-part differential. 
Screening test results can be used for C1D1 
if tests are performed within 7 days of first 
dose. See Table 23. 
Urinalysis 
X 
 
X 
 
X 
X 
 
X 
 
See Table 23. 
Imaging and Disease 
Response 
Assessment via 
RECIST v 1.1 
(Eisenhauer 2009) 
X 
 
 
 
 
X 
Xf 
 
 
See Section 8.1. 
After Screening disease assessment, 
response will be assessed at C4D1 
(10 weeks after first dose of duvelisib) and 
then D1 of every third cycle thereafter 
(approximately every 9 weeks). The same 
method of assessment used at Screening 
should be used throughout the study. In the 
case of a CR or PR, a confirmatory scan 
must be performed per RECIST v 1.1. It is 
recommended that this scan be performed at 
4 (+1) weeks after the initial response. 
FDA-approved PD-
L1 Testing (if 
required) 
X 
 
 
 
 
 
 
 
 
Perform if specified in the current 
pembrolizumab prescribing information 
(Keytruda 2019), if results are not already 
available. Information on FDA-approved 
tests is available at: 
http://www.fda.gov/CompanionDiagnostics.  


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Duvelisib 
Lead-in 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(4 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety 
F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until 
End of 
Study 
Notes 
W1 
W2 
W3 
W1 
W1 
D1 
D8 ±5 
D15±3 
D1 ±3 
D1 ±3 
PK, PDn, and 
Biomarker 
Assessments 
(See details in 
Table 2) 
Xg 
X 
X 
X 
Xh 
X 
 
 
Details for these assessments are in Table 2. 
Also obtain stool sample if subject has 
colitis or Grade ≥ 3 diarrhea.  
Tumor Biopsy 
(See details in 
Table 2) 
Xg 
X 
 
 
 
 
 
 
See details for tumor biopsies in Table 2. 
Tumor biopsies at Screening/C1D1and 
C1D8 are mandatory; however, archival 
tissue at Screening/C1D1 may be 
acceptable (See Section 8.8.1). 
Review of Duvelisib 
Self-Administration 
Diaries 
 
X 
X 
X 
X 
X 
 
 
 
Subjects are required to log each self-
administration of duvelisib in a diary during 
first year on treatment only 
Duvelisib 
Administration 
 
Continuous duvelisib BID until PD or discontinuation 
 
 
 
On study visit days, instruct the subject not 
to take the AM duvelisib dose. Duvelisib 
will be administered in the clinic (and 
before the pembrolizumab infusion is 
started, if applicable). See Section 6.1.1 and 
Table 2 for specific timing. 
Please see required and recommended 
prophylaxis in Section 6.5.1.  
Pembrolizumab 
Administration 
 
 
Xi 
 
X 
X 
 
 
 
Pembrolizumab should be administered as 
an IV infusion over 30 minutes See 
Section 6.1.2 and Table 2 for dosing on 
C1D8 and C2D1. 
On days when postdose PK samples are not 
collected, the infusion should be started 
within 10 minutes after the dose of 
duvelisib is administered. 


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Duvelisib 
Lead-in 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(4 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety 
F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until 
End of 
Study 
Notes 
W1 
W2 
W3 
W1 
W1 
D1 
D8 ±5 
D15±3 
D1 ±3 
D1 ±3 
Survival 
 
 
 
 
 
 
 
 
X 
Survival Follow-up will occur every 
3 months (± 2 weeks) from the Safety F/U 
Visit for up to 1 year after the last subject 
starts duvelisib (Section 4.3). Information 
on survival status and anticancer therapy 
will be collected (Section 8.1.3). This 
assessment will be conducted by telephone 
interview and records review (if available). 
Abbreviations: AE/SAE: adverse event/serious adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: 
aspartate aminotransferase; BID: twice daily; BUN: blood urea nitrogen; CMV: cytomegalovirus; CR: complete response; CxDx: Cycle x, Day x; CxWx: Cycle x, Week x; D: 
Day; EBV: Epstein-Barr virus; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EoT: end of treatment; FDA: Food and Drug Administration; FT4: free 
thyroxine; F/U: follow-up; HBcAb: hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HCVAb: hepatitis C antibody; hCG: human chorionic gonadotropin; HIV: 
human immunodeficiency virus; HNSCC: head and neck squamous cell carcinoma; HPV: human papillomavirus; ICF: informed consent form; INR: international normalized ratio; 
LDH: lactate dehydrogenase; PCR: polymerase chain reaction; PD: progressive disease; PD-L1: programmed cell death ligand 1; PDn: pharmacodynamic; PK: pharmacokinetic; 
PR: partial response; PT: prothrombin time; RECIST: Response Evaluation Criteria in Solid Tumors; SOC: standard of care; T3: triiodothyronine; TSH: thyroid-stimulating 
hormone; W: week. 
a Day 1 of each cycle (except Cycle 1) of combination therapy is the day of pembrolizumab administration.  
b The tests detailed in Table 23 will be performed by the local laboratory. See Section 8.2.4 for guidance on repeating/recording laboratory tests with values that 
are considered clinically significant or that require a change in subject management. The PK, PDn, and biomarker assessments detailed in Table 2 will be 
performed by a laboratory selected by the Sponsor, as specified in the Laboratory Manual. 
c For all subjects who permanently discontinue the study interventions (i.e., duvelisib and pembrolizumab), an EoT Visit will be performed within 7 days after 
the decision to discontinue study interventions. EoT assessments need not be repeated if performed within the previous 14 days, or 30 days for imaging. 
d A Safety Follow-up Visit is to be performed 30 + 7 days from last dose. If possible, this visit should occur before the initiation of any subsequent anticancer 
therapy. 
e If the pregnancy test at Screening was performed within 7 days of C1D1, the test does not need to be repeated on C1D1. 
f A scan will be performed at the EoT if one was not previously performed within 30 days of the EoT Visit. 
g Blood for biomarker assessments and tumor biopsy may be obtained either at Screening or at first dose of duvelisib on C1D1 (preferred). 
h Please refer to Table 2 for assessments and timing for C4D1 and beyond. 
i Every effort will be made to administer the first dose of pembrolizumab on Day 8 of Cycle 1 (C1D8). If the first dose of pembrolizumab on C1D8 is delayed, 
every effort should be made to delay the subsequent dosing of the next cycle (within the protocol-allowed window of 3 days) to achieve as close to a 3-week 
interval between pembrolizumab doses as possible. The Medical Monitor needs to be consulted for such adjustments to ensure uniformity of approach and to 
account for subject-specific circumstances. For example, if the third day of the C2D1 window falls on a weekend, an additional adjustment would need to be 


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made on a case-by-case basis. In the event of a delay of the start of pembrolizumab therapy, DLTs will be evaluated at the end of the third week of combination 
therapy. 
 
 


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Table 2: 
Pharmacokinetic, Pharmacodynamic, and Biomarker Sampling in Stage 1 
Cycle 
Day 
Sampling Time Pointsa 
PK 
Samples 
Whole Blood 
for PDn 
Analysis 
Serum and 
Plasma for 
Biomarkers 
Whole 
Blood for 
Immune 
Cell 
Analysis 
Stool Sample 
for 
Biomarker 
Analysisb 
Swab for 
Genomic 
Analysis 
Tumor 
Biopsiesc 
Screening or C1D1 
 
 
 
Xd 
Xd 
Xe 
Xd 
Xd, f 
1 
8 
Pre-duvelisib doseg 
Xg 
X 
X 
X 
 
 
 
1 
8 
1 hour (± 10 min) after 
duvelisib dose 
Xg 
X 
 
 
 
 
 
1 
8 
2 hours (± 10 min) after 
duvelisib dose 
Xg 
 
 
 
 
 
 
1 
8 
Approximately 2 to 4 hours 
after duvelisib dose 
Xg 
 
 
 
 
 
Xf, g 
1 
8 
0 hours (± 5 min) after the 
end of pembrolizumab 
infusion 
X 
 
 
 
 
 
 
1 
15 
Predose 
X 
 
 
 
 
 
 
2 
1 
Predoseh 
X 
X 
X 
X 
 
 
 
2 
1 
0 hours (± 5 min) after the 
end of pembrolizumab 
infusion 
X 
 
 
 
 
 
 
2 
1 
1 hour (± 10 min) after the 
end of pembrolizumab 
infusion 
X 
 
 
 
 
 
 
2 
1 
2 hours (± 10 min) after the 
end of pembrolizumab 
infusion 
X 
 
 
 
 
 
 
3 
1 
Predosei 
X 
 
 
 
 
 
 
4 
1 
Predosei 
X 
 
X 
X 
Xj 
 
 
5 
1 
Predosei 
X 
 
 
 
 
 
 


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Cycle 
Day 
Sampling Time Pointsa 
PK 
Samples 
Whole Blood 
for PDn 
Analysis 
Serum and 
Plasma for 
Biomarkers 
Whole 
Blood for 
Immune 
Cell 
Analysis 
Stool Sample 
for 
Biomarker 
Analysisb 
Swab for 
Genomic 
Analysis 
Tumor 
Biopsiesc 
≥ 7k  
1 
Predosei 
 
 
X 
X 
 
 
 
End of treatment 
 
 
 
X 
X 
 
 
 
Abbreviations: CxDx: Cycle x Day x; min: minutes; PDn: pharmacodynamic; PK: pharmacokinetic; SOC: standard of care. 
 
a Sample collections may be reduced, or limited to certain sites/countries, based on emerging data or feasibility. Reductions/limitations may be implemented 
before amendment of the protocol. Specific collection and processing details (e.g., serum or plasma) will be described in the Laboratory Manual. Any increase 
in the number or type of samples collected will require a protocol amendment. 
b Stool samples may be collected either predose or postdose. Obtain additional stool sample if subject has colitis or Grade ≥ 3 diarrhea. 
c See Section 8.8.1. Request aliquot of colon biopsies if taken due to colitis or Grade ≥ 3 diarrhea or as SOC for any immune-mediated adverse events. 
d The following samples can be obtained either at Screening or before the first dose of duvelisib on C1D1: serum and plasma for biomarkers, whole blood for 
immune cell analysis, swab for genomic analysis, and tumor biopsy. C1D1 is preferred for samples other than the swab. 
e The Screening/C1D1 stool sample may be collected up to 7 days before first dose. 
f See Section 8.8.1. Tumor biopsies at Screening/C1D1 and C1D8 are mandatory. However, archival tissue beyond the 30-day Screening window and up to 
6 months before C1D1 may be considered in place of the required Screening/C1D1 biopsy after consultation with the Sponsor, as long as no intervening 
systemic regimen had been taken during that time frame. Collection procedures and amounts are according to the Laboratory Manual. Please note that the same 
set of tumor biopsies are included in both Table 1 and Table 2. 
g On C1D8, duvelisib will be administered at the start of the visit after the predose PK, PDn, and blood sample collection. Blood samples to evaluate the PK of 
duvelisib and metabolite IPI-656 will be collected at 1 and 2 hours after duvelisib administration. Pembrolizumab will not be administered until the biopsy for 
biomarkers has been collected; the optimal timing for collection of the biopsy is approximately 2 to 4 hours after duvelisib administration, however, a tumor 
biopsy at a later time during this clinic visit on C1D8 is acceptable. The fourth PK sample should be collected at approximately 2 to 4 hours after duvelisib 
dose, as soon as possible after the biopsy, and prior to pembrolizumab administration. 
h Predose sample is to be taken before either study intervention (i.e., duvelisib or pembrolizumab) is administered. On C2D1, duvelisib will be administered 
30 minutes before the start of the pembrolizumab infusion 
i Predose sample is to be taken before either study intervention (i.e., duvelisib or pembrolizumab) is administered. The pembrolizumab infusion should be started 
within 10 minutes after the dose of duvelisib is administered. 
j The C4D1 stool sample may be collected up to 3 days before C4D1. 
k Samples will be collected on C7D1 and D1 of every third cycle thereafter (approximately every 9 weeks) or until the Sponsor terminates the collection. 
 
 
 


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1.4. 
Schedule of Activities (SoA) for Stage 2 
Table 3: 
Study Activities for Stage 2: Duvelisib in Combination with Pembrolizumab 
 
Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(3 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until End 
of Study 
Notes 
W1 
W1 
W1 
D1±3 
D1 ±3 
D1 ±3 
Informed Consent 
X 
 
 
 
 
 
 
Potentially eligible subjects must sign an ICF before 
initiating any study specific procedures. SOC 
assessments that fulfill study eligibility requirements 
may be performed before the subjects signs the ICF. 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
Reconfirm eligibility before first dose. 
Medical and Disease 
History, Demographics 
X 
 
 
 
 
 
 
Medical and Disease History includes histologic or 
cytologic diagnosis of HNSCC; HPV status; prior 
PD-L1 expression; and prior treatment information. 
Archival Tumor Tissue  
X 
 
 
 
 
 
 
Archived tumor tissue should be submitted from all 
enrolled subjects, if available. 
Physical Examination 
X 
X 
X  
X 
X 
 
 
See Section 8.2.1. Full examination (including height) 
at Screening and symptom-directed at subsequent time 
points. Screening results can be used for C1D1 if 
assessments are performed within 7 days of first dose. 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
 
See Section 8.2.1. Vital signs measured with subject in 
a semi-supine position after 5 minutes rest. Includes 
temperature, systolic and diastolic blood pressure, pulse 
rate, and respiratory rate. 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
 
See Section 8.3.1. Screening ECOG results can be used 
for C1D1 if test is performed within 7 days of first 
dose. 
ECG (12-lead) 
X 
 
 
 
 
 
 
See Section 8.2.2. ECG at Screening will be performed 
in triplicate. QTc measurements will use the Fridericia 
correction method. Additional on-treatment ECGs 
should be performed per the Investigator’s discretion as 
clinically indicated. 


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Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(3 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until End 
of Study 
Notes 
W1 
W1 
W1 
D1±3 
D1 ±3 
D1 ±3 
Concomitant 
Medications and 
Procedures 
Ongoing 
 
See Section 6.5.1 for required and recommended 
prophylaxis. Concomitant medications and procedures 
occurring within 30 days before first dose will be 
recorded at Screening. 
AE/SAE Assessment 
Ongoing 
 
See Section 8.4 for AE management. See Section 8.4.3 
for reporting requirements. 
Coagulation tests 
X 
 
 
 
 
 
 
PT, aPTT, and INR. See Table 23. 
Viral Screening 
X 
 
 
 
 
 
 
Hepatitis serology: HCVAb, HBsAg, HBcAb. 
HPV testing (if status not available at Screening). 
CMV/EBV serology or viral load. HIV test is not 
required if a prior negative test within 9 months is 
available. See Table 23. 
CMV Reactivation 
Monitoring (if 
applicable) 
 
X 
X 
X 
 
 
 
Subjects with a history of CMV infection should be 
monitored for reactivation by PCR at least monthly. 
See Section 6.5.1. 
C-Reactive Protein 
X 
Obtain when Grade ≥ 2 diarrhea, any grade colitis, or any 
grade immune-mediated toxicity (e.g., pneumonitis, colitis, 
hepatitis, endocrinopathies, nephritis/renal dysfunction, 
cutaneous adverse reactions, encephalitis) occurs 
 
See Table 23. 
T3, FT4, and TSH 
X 
 
X 
X 
 
X 
 
Every other cycle starting at C2D1. 
Serum or Urine hCG 
Pregnancy Test for 
Women of 
Childbearing Potential 
X 
Xe 
X 
X 
 
X 
 
A serum pregnancy test must be performed within 
7 days of first duvelisib dose. 
At subsequent time points, serum testing is preferred 
but urine testing is allowed if a blood draw for other 
assessments is not performed. A positive urine test 
result must be confirmed by a serum test. See Table 23.  
Clinical Chemistry with 
Liver Function Tests 
X 
X 
X 
X 
X 
X 
 
BUN, potassium, creatinine, sodium, total protein, 
glucose (fasting), calcium, LDH, ALT, AST, total and 
direct bilirubin, and ALP. 
Screening test results can be used for C1D1 if tests are 
performed within 7 days of first dose. See Table 23. 


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Duvelisib in Combination with 
Pembrolizumaba 
End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(3 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until End 
of Study 
Notes 
W1 
W1 
W1 
D1±3 
D1 ±3 
D1 ±3 
Hematology 
X 
X 
X 
X 
X 
X 
 
Hematology panel plus a 5-part differential. 
Screening test results can be used C1D1 if tests are 
performed within 7 days of first dose. See Table 23. 
Urinalysis 
X 
 
X 
X 
 
X 
 
See Table 23. 
Imaging and Disease 
Response Assessment 
via RECIST v 1.1 
(Eisenhauer 2009) 
X 
 
 
X 
Xf 
 
 
See Section 8.1. 
After Screening disease assessment, response will be 
assessed at approximately every 9 weeks after first dose 
of duvelisib plus pembrolizumab (e.g., at C4D1 and 
then D1 of every third cycle thereafter). The same 
method of assessment used at Screening should be used 
throughout the study. In the case of a CR or PR, a 
confirmatory scan must be performed per RECIST 
v 1.1. It is recommended that this scan be performed at 
4 (+1) weeks after the initial response. 
FDA-approved PD-L1 
Testing (if required) 
X 
 
 
 
 
 
 
Perform if specified in the current pembrolizumab 
prescribing information (Keytruda 2019), if results are 
not already available. Information on FDA-approved 
tests is available at: 
http://www.fda.gov/CompanionDiagnostics.  
PK and Biomarker 
Assessments 
(See details in Table 4) 
Xg 
X 
X 
Xh 
X 
 
 
Details for these assessments are in Table 4. 
Also obtain stool sample if subject has colitis or 
Grade ≥ 3 diarrhea. 
Tumor Biopsy 
(optional) 
(See details in Table 4) 
 
 
X 
 
 
 
 
An optional tumor biopsy may be collected after the 
first cycle (on C2D1) for an exploratory analysis of 
biomarkers. If collection of the biopsy is not feasible on 
C2D1, a biopsy collected after the second cycle (on 
C3D1) would also be acceptable. 
Review of Duvelisib 
Self-Administration 
Diaries 
 
X 
X 
X 
 
 
 
Subjects are required to log each self-administration of 
duvelisib in a diary during first year on treatment only 
Duvelisib 
Administration 
 
Continuous duvelisib BID until PD or 
discontinuation 
 
 
 
On study visit days, instruct the subject not to take the 
AM duvelisib dose. Duvelisib will be administered in 
the clinic before the pembrolizumab infusion is started. 
See Table 4 and Section 6.1.1 for specific timing. 


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Duvelisib in Combination with 
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End of Treatment  
and Follow-up 
 
Activityb 
Screening 
(D-30 to 
D -1) 
Cycle 1 
(3 weeks) 
Cycle 2 
and  
Cycle 3 
(3 weeks) 
Cycles 
≥ 4 
(3 weeks) 
EoTc 
Safety F/U 
30 D (+7) 
postdose)d 
Survival 
F/U 
Every 
3 months 
until End 
of Study 
Notes 
W1 
W1 
W1 
D1±3 
D1 ±3 
D1 ±3 
Please see required and recommended prophylaxis in 
Section 6.5.1.  
Pembrolizumab 
Administration 
 
X 
X 
X 
 
 
 
Pembrolizumab should be administered as an IV 
infusion over 30 minutes. See Section 6.1.2 and Table 4 
for dosing on C1D1 and C2D1. 
Survival 
 
 
 
 
 
 
X 
Survival Follow-up will occur every 3 months 
(± 2 weeks) from the Safety F/U Visit for up to 1 year 
after the last subject starts duvelisib (Section 4.3). 
Information on survival status and anticancer therapy 
will be collected (Section 8.1.3). This assessment will 
be conducted by telephone interview and records 
review (if available). 
Abbreviations: AE/SAE: adverse event/serious adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: 
aspartate aminotransferase; BID: twice daily; BUN: blood urea nitrogen; CMV: cytomegalovirus; CR: complete response; CxDx: Cycle x, Day x; CxWx: Cycle x, Week x; D: 
Day; EBV: Epstein-Barr virus; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EoT: end of treatment; FDA: Food and Drug Administration; FT4: free 
thyroxine; F/U: follow-up; HBcAb: hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HCVAb: hepatitis C antibody; hCG: human chorionic gonadotropin; HIV: 
human immunodeficiency virus; HNSCC: head and neck squamous cell carcinoma; HPV: human papillomavirus; ICF: informed consent form; INR: international normalized ratio; 
LDH: lactate dehydrogenase; QTc: corrected QT interval PCR: polymerase chain reaction; PD: progressive disease; PD-L1: programmed cell death ligand 1; PDn: 
pharmacodynamic; PK: pharmacokinetic; PR: partial response; PT: prothrombin time; RECIST: Response Evaluation Criteria in Solid Tumors; SOC: standard of care; T3: 
triiodothyronine; TSH: thyroid-stimulating hormone; W: week. 
a Day 1 of each cycle of combination therapy is the day of pembrolizumab administration. 
b The tests detailed in Table 23 will be performed by the local laboratory. See Section 8.2.4 for guidance on repeating/recording laboratory tests with values that 
are considered clinically significant or that require a change in subject management. The PDn, and biomarker assessments detailed in Table 4 will be performed 
by a laboratory selected by the Sponsor, as specified in the Laboratory Manual. 
c For all subjects who permanently discontinue the study interventions (i.e., duvelisib and pembrolizumab), an EoT Visit will be performed within 7 days after 
the decision to discontinue study interventions. EoT assessments need not be repeated if performed within the previous 14 days, or 30 days for imaging. 
d A Safety Follow-up Visit is to be performed 30 + 7 days from last dose. If possible, this visit should occur before the initiation of any subsequent anticancer 
therapy. 
e If pregnancy test at Screening was performed within 7 days of C1D1, the test does not need to be repeated on C1D1 
f A scan will be performed at the EoT if one was not previously performed within 30 days of the EoT Visit. 
g Biomarker assessments may be obtained either at Screening or at first dose of duvelisib on C1D1 (preferred). 
h Please refer to Table 4 for assessments and timing for C4D1 and beyond.  
 


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Table 4: 
Pharmacokinetic and Biomarker Sampling in Stage 2 
Cycle 
Day 
Sampling Time Pointsa 
PK Samples 
Serum and Plasma 
for Biomarkers 
Whole Blood for 
Immune Cell 
Analysis 
Stool Sample 
for Biomarker 
Analysisb 
Swab for 
Genomic 
Analysis 
Tumor 
Biopsy 
(optional)c 
Screening or C1D1 
 
 
Xd 
Xd 
Xe 
Xd 
 
1 
1 
Pre-duvelisib dosef 
Xf 
 
 
 
 
 
1 
1 
1 hour (± 10 min) after 
duvelisib dose 
Xf 
 
 
 
 
 
1 
1 
2 hours (± 10 min) after 
duvelisib dose 
Xf 
 
 
 
 
 
1 
1 
0 hours (± 5 min) after 
the end of 
pembrolizumab infusion 
X 
 
 
 
 
 
2 
1 
Predoseg 
X 
X 
X 
 
 
Xh 
3 
1 
Predosei 
X 
 
 
 
 
Xh 
4 
1 
Predosei 
 
X 
X 
Xj 
 
 
≥ 7k 
1 
Predosei 
 
X 
X 
 
 
 
End of treatment 
 
 
X 
X 
 
 
 
Abbreviations: CxDx: Cycle x Day x; min: minutes; PK: pharmacokinetic; SOC: standard of care. 
a Sample collections may be reduced, or limited to certain sites/countries, based on emerging data or feasibility. Reductions/limitations may be implemented 
before amendment of the protocol. Specific collection and processing details (e.g., serum or plasma) will be described in the Laboratory Manual. Any increase 
in the number or type of samples collected will require a protocol amendment. 
b Stool samples may be collected either predose or postdose. Obtain additional stool sample if subject has colitis or Grade ≥ 3 diarrhea. 
c See Section 8.8.1. Request aliquot of colon biopsies if taken due to colitis or Grade ≥ 3 diarrhea or as SOC for any immune-mediated adverse events. 
d The following samples can be obtained either at Screening or before the first dose of duvelisib on C1D1: serum and plasma for biomarkers, whole blood for 
immune cell analysis, and swab for genomic analysis. C1D1 is preferred for samples other than the swab. 
e The Screening/C1D1 stool sample may be collected up to 7 days before first dose. 
f On C1D1, duvelisib will be administered at the start of the visit after the predose PK and blood sample collection. Pembrolizumab will be administered 
30 minutes after collection of the 2-hour postdose duvelisib PK sample. 
g Predose sample is to be taken before either study intervention (i.e., duvelisib or pembrolizumab) is administered.  


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h An optional tumor biopsy may be collected after the first cycle (on C2D1) for an exploratory analysis of biomarkers. If collection of the biopsy is not feasible 
on C2D1, a biopsy collected after the second cycle (on C3D1) would also be acceptable. 
i Predose sample is to be taken before either study intervention (i.e., duvelisib or pembrolizumab) is administered. The pembrolizumab infusion should be started 
within 10 minutes after the dose of duvelisib is administered. 
j The C4D1 stool sample may be collected up to 3 days before C4D1. 
k Samples will be collected on C7D1 and D1 of every third cycle thereafter (approximately every 9 weeks) or until the Sponsor terminates the collection. 
 
 
 


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2. 
INTRODUCTION 
2.1. 
Duvelisib 
Duvelisib (VS-0145) is a synthetic, orally-active, small molecule dual inhibitor of 
phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ isoforms that is approved for the treatment of 
adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small 
lymphocytic lymphoma (SLL) after at least 2 prior systemic therapies and has received 
accelerated approval in adult patients with follicular lymphoma (FL) after at least 2 prior 
systemic therapies (COPIKTRA 2018). Duvelisib is being developed by Verastem, Inc. 
(Verastem; study Sponsor) for the treatment of other hematologic malignancies and solid tumors. 
2.2. 
Study Rationale 
Despite the recent approval of agents (e.g., pembrolizumab [Keytruda®] and nivolumab 
[Opdivo®]) that inhibit the interaction of programmed cell death protein 1 (PD-1) with its ligand 
(PD-L1), only a small subset of patients appears to derive benefit from these therapies. Although 
the efficacy of anti-PD-1 therapy may vary by PD-L1 expression or human papillomavirus 
(HPV) status as well as the number of prior therapies, typically the overall response rate (ORR) 
is approximately 15% in the second-line or greater setting and somewhat higher in the first-line 
setting (Ferris 2016, Keytruda 2019). The majority of responses in either setting are partial 
responses (PRs). The effectiveness of PD-1 inhibitors can be limited by infiltration of 
immunosuppressive myeloid cells (MDSCs) into the tumor microenvironment 
(De Henau 2016, Diaz-Montero 2014, Gebhardt 2015). Thus, there remains a large unmet 
medical need for better therapy options in patients with recurrent or metastatic (R/M) disease. 
Duvelisib, a dual PI3K-δ and PI3K-γ inhibitor, was found to reduce regulatory T cells (Tregs), 
M2 tumor-associated macrophages (i.e., macrophages that are alternatively activated by 
exposure to certain cytokines), and MDSCs when combined with a PD-1 inhibitor in a mouse 
model mimicking a solid tumor setting (Pachter 2018). In a study in a head and neck squamous 
cell carcinoma (HNSCC; i.e., murine oral cancer [MOC1]) model, the combination of duvelisib 
and a mouse PD-L1 monoclonal antibody (mAb) resulted in significantly enhanced control of 
primary tumor growth and survival of MOC1 tumor-bearing mice over either monotherapy 
(Davis 2017). These nonclinical data suggest that reduction of Tregs and MDSCs by duvelisib in 
the tumor microenvironment may enhance sensitivity of the tumor to PD-1 inhibitors like 
pembrolizumab in this tumor setting. 
This is the first clinical study of duvelisib in subjects with R/M HNSCC and of duvelisib in 
combination with a PD-1 inhibitor. Based on the hypothesis, which is supported by nonclinical 
data, that duvelisib can enhance the activity of PD-1 inhibitors, this study is designed to assess 
the safety and preliminary efficacy of duvelisib in combination with pembrolizumab in subjects 
with R/M HNSCC who are eligible for pembrolizumab monotherapy based on the current 
pembrolizumab prescribing information (Keytruda 2019). 


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2.3. 
Background 
The PI3K/mammalian target of rapamycin (mTOR) intracellular signaling pathway is known to 
play a critical role in tumorigenesis (Janku 2017). There are 4 PI3K isoforms: alpha (α), beta (β), 
gamma (γ), and delta (δ). PI3K-δ and PI3K-γ activity supports the growth and maintenance of 
cancer cells by contributing to the establishment and maintenance of the tumor 
microenvironment through cell proliferation, survival, differentiation, migration, and activation 
of non-tumor cells. Both isoforms have been shown to suppress antitumor immune responses and 
support solid tumor growth in in vivo studies (Ali 2014, De Henau 2016, Kaneda 2016). 
PI3K-γ inhibition decreases the number of MDSCs and M2 tumor-associated macrophages 
(Kaneda 2016, De Henau 2016), while PI3K-δ inhibition in Tregs may induce tumor regression 
through activation of CD8+ cytotoxic T cells (Ali 2014). Mice lacking functional PI3K-γ showed 
significantly reduced growth of implanted HNSCC, lung carcinoma, and breast carcinoma cells 
(Kaneda 2016). Mice bearing an inactivating mutation in PI3K-δ were resistant to tumor growth 
after inoculation with melanoma, lung carcinoma, or thymoma cell lines, supporting the 
hypothesis that PI3K-δ inhibition decreases immunosuppressive Tregs in the tumor 
microenvironment (Ali 2014, Ahmad 2017). 
2.3.1. 
Duvelisib Mechanism of Action 
Duvelisib is a dual PI3K-δ/-γ inhibitor that reduces the cancer-promoting effects of both 
isoforms through effects on the tumor microenvironment (Figure 4) and has an established 
clinical safety and efficacy profile in patients with hematologic malignancies (United States [US] 
approval in R/R CLL/SLL and accelerated approval in R/R FL) (COPIKTRA 2018). 
Figure 4: 
Effect of Duvelisib on Tumor Microenvironment 
 
Abbreviations: MDSCs: immunosuppressive myeloid cells; PI3K: phosphoinositide 3-kinase; Tregs: regulatory 
T-cells. 


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While the tumor-suppressing effect of duvelisib in hematologic malignancies is well established 
(Dong 2014, Faia 2015), a direct effect of duvelisib and PI3K signaling on tumor cell 
proliferation and survival has not been well characterized in solid tumors. However, because of 
the significant presence of immune cells in the tumor, a cell-based target for duvelisib is thought 
to be the immune-modulating tumor microenvironment consisting of T-, B-, and myeloid lineage 
cells, in particular. 
Data from a study by Davis (Davis 2017) in an HNSCC (i.e., MOC1) model suggest that 
reduction of Tregs and MDSCs in the tumor microenvironment may contribute to the activity of 
duvelisib in combination with PD-1 inhibitors. The combination of duvelisib and PD-L1 mAb 
resulted in significantly enhanced control of primary tumor growth and survival of MOC1 
tumor-bearing mice over either monotherapy (Figure 5) (Davis 2017). In this tumor model, 
which, like human HNSCC, lacks significant responses to PD-1-based inhibition, combination 
therapy induced CD8+ T lymphocyte-dependent primary tumor growth delay and prolonged 
survival. Dual PI3Kδ/γ inhibition with 15 mg/kg duvelisib sensitized T-cell inflamed MOC1 oral 
cavity cancers to PD-L1 inhibition through at least modulation of granulocytic MDSC arginine 
and inducible nitric oxide synthetase expression and T-lymphocyte suppressive capacity. These 
results offer a nonclinical proof of concept for the use of duvelisib to suppress MDSCs to 
enhance responses to immune PD-1 blockade (Davis 2017). 
Figure 5: 
Combination of Duvelisib and a PD-L1 mAb Resulted in Significantly 
Enhanced Control of Primary Tumor Growth and Survival in a MOC1 
Model 
 
Source: Davis 2017. 
Abbreviations: mAb: monoclonal antibody; IPI-145: duvelisib; MOC1: murine oral cancer; PD-L1:. programmed 
cell death ligand 1. 
In a nonclinical study in a mouse model of B-cell lymphoma (mimicking a solid tumor setting), 
duvelisib and PD-1 inhibitor treatments each induced tumor growth delay (Pachter 2018). In 
addition, strong antitumor synergy (i.e., inhibition of tumor growth and increased survival) was 
observed when duvelisib and a PD-1 inhibitor were combined (Figure 6). 


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Figure 6: 
Combination of Duvelisib and a PD-1 Inhibitor (anti-PD-1) Is Synergistic in 
Inhibition of Tumor Growth in A20 B-Cell Model 
 
Source: Pachter 2018. 
Abbreviations: PD-1: programmed cell death protein 1. 
Mechanistically, duvelisib was found to reduce Tregs, M2 tumor-associated macrophages, and 
MDSCs in the context of combination with a PD-1 inhibitor, and duvelisib (dual PI3K-δ/γ 
inhibition) was found to inhibit all 3 immunosuppressive cell populations more effectively than 
idelalisib (PI3K-δ only) or IPI-549 (PI3K-γ only) (Pachter 2018). 
2.3.2. 
Recurrent or Metastatic HNSCC Therapeutic Landscape 
HNSCC represents over 90% of head and neck malignancies. Although the majority of patients 
present with locoregionally advanced disease, the clinical course is characterized by a high 
recurrence rate approaching 50%, as well as the development of distal metastases (Forster 2018, 
Vigneswaran 2014, Rothschild 2018). The current standard of care (SOC) in patients with R/M 
HNSCC in a first-line setting includes platinum-based chemotherapy regimens, which have 
ORRs of 30 to 40% with median overall survival (OS) of 6 to 9 months (NCCN 2019).  
On 10 June 2019, pembrolizumab was approved as a single agent for first-line treatment of 
patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-LI 
(combined positive score [CPS] ≥ 1) as determined by a Food and Drug Administration (FDA)-
approved test and was approved in combination with platinum and 5 fluorouracil (5-FU) for all 
patients with R/M HNSCC (Keytruda 2019). In subjects with CPS ≥ 1, OS was significantly 
longer with pembrolizumab monotherapy vs SOC (12.3 months vs10.3 months, HR 0.78, 
p = 0.0171, respectively). ORR and median DOR were 19% and 20.9 months in the 
pembrolizumab monotherapy group vs 35% and 4.5 months in the SOC group. There was no 
difference in PFS between groups (HR 1.15, 95% CI 0.95 to 1.38).  


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In a second-line setting, PD-1 inhibitors (pembrolizumab and nivolumab) are a current SOC after 
progression on or during platinum-based therapy (NCCN 2019). Pembrolizumab is approved for 
the treatment of adult subjects with R/M HNSCC whose disease progressed on or after 
platinum-based chemotherapy (Keytruda 2019). The results of the Phase 3 KEYNOTE-040 
confirmatory study in subjects with R/M HNSCC whose disease progressed during or after 
platinum-containing treatment showed a longer OS in subjects who received pembrolizumab 
monotherapy vs SOC (8.4 vs 6.9 months, HR 0.80, p <0.01, respectively). ORR and median 
DOR were 14.6% and 8.4 months in the pembrolizumab monotherapy group vs 10.1% and 
5.0 months in the SOC group, respectively (Cohen 2019). 
Although duvelisib has not yet been evaluated in subjects with solid tumors, several other PI3K 
inhibitors, such as a class 1 pan-isoform PI3K inhibitor (PX-866), a specific oral pan-class 1 
PI3K inhibitor (buparlisib), and a specific α isoform inhibitor of PI3K (alpelisib), are being 
tested in combination with SOC in Phase 1 and Phase 2 studies in subjects with HNSCC 
(De Felice 2017). Preliminary safety and efficacy results for the combination of buparlisib and 
paclitaxel were promising, with increases in PFS, ORR, and OS observed with the 
buparlisib-paclitaxel combination vs placebo + paclitaxel, with a manageable safety profile 
(Soulieres 2017). Pan-isoform PI3K inhibitors are proposed to have antitumor activity by 
targeting the tumor cell PIKα isoform expression. 
Despite the recent approval of agents (e.g., pembrolizumab [Keytruda® and nivolumab 
[Opdivo®]) that inhibit the interaction of PD-1 with its ligand (PD-L1), only a small subset of 
patients appears to derive benefit from these therapies. Although the efficacy of anti-PD-1 
therapy may vary by PD-L1 expression or HPV status, as well as the number of prior therapies, 
typically the ORR is approximately 15% in the second-line or greater setting and somewhat 
higher in the first-line setting (Ferris 2016, Keytruda 2019). The majority of responses in either 
setting are PRs. The effectiveness of PD-1 inhibitors can be limited by infiltration of MDSCs 
into the tumor microenvironment (De Henau 2016, Diaz-Montero 2014, Gebhardt 2015). Thus, 
there remains a large unmet medical need for better therapy options in patients with R/M disease. 
This Phase 1b/2 study will assess the safety and tolerability of duvelisib in combination with 
pembrolizumab in subjects with R/M HNSCC and determine if the addition of duvelisib to 
pembrolizumab will result in increased antitumor responses in subjects with R/M HNSCC. 
2.4. 
Benefit/Risk Assessment 
This is the first clinical study of duvelisib in subjects with R/M HNSCC and of duvelisib in 
combination with a PD-1 inhibitor. 
As there are no clinical data for duvelisib in subjects with R/M HNSCC to date, the benefit/risk 
assessment for duvelisib reflects extensive clinical experience in subjects with hematologic 
malignancies who were treated with duvelisib (COPIKTRA 2018). The approved dose of each 
agent (duvelisib 25 mg BID PO; pembrolizumab 200 mg q3w IV) will be used for assessment of 
initial safety. As the maximal tolerated dose of duvelisib monotherapy is 75 mg twice daily 
(BID) in subjects with hematologic malignancies, which may suggest a relatively wide 
therapeutic window for duvelisib, such an approach is considered reasonable. 


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2.4.1. 
Risk Assessment 
As the effect of duvelisib in subjects with R/M HNSCC is unknown, Stage 1 of the study 
includes a 1-week lead-in with duvelisib monotherapy to monitor for safety and biomarker 
sampling before the initiation of combination therapy with duvelisib and pembrolizumab. 
For subjects with hematologic malignancies, clinical study results to date support a favorable 
benefit-risk assessment of duvelisib. The risks of duvelisib for subjects with hematologic 
malignancies are consistent with the adverse event (AE) profile for the PI3K inhibitor drug class 
and AEs experienced by patients undergoing treatment for advanced cancers. Important 
identified risks of duvelisib include infections, diarrhea/colitis, cutaneous reactions, pneumonitis, 
neutropenia, and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation. 
Potential risks include hepatotoxicity, drug-drug interaction (DDI), and reproductive toxicity. 
These toxicities are managed using a combination of prophylaxis, supportive care, and dose 
modifications. Guidance on management of these AEs, including duvelisib dose interruptions 
and modifications, is provided in Section 6.6 and Section 6.7. Detailed information about the 
known and expected risks and reasonably expected AEs of duvelisib may be found in the 
Investigator’s Brochure (IB). 
The identified risks of pembrolizumab (Keytruda 2019) are infusion reactions and the following 
immune-mediated conditions: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and 
renal dysfunction, and cutaneous adverse reactions (including rash). Refer to the pembrolizumab 
prescribing information for guidance on management of these AEs (Keytruda 2019). 
Based on the monotherapy safety profiles for each drug, potential overlapping toxicities for 
duvelisib in combination with pembrolizumab include non-infectious diarrhea or colitis, 
cutaneous reactions, pneumonitis without suspected infectious cause, and elevations in ALT and 
AST levels (Section 6.6.1). These events will be closely monitored during the study. 
Although duvelisib has not yet been evaluated in subjects with solid tumors, initial safety results 
for an ongoing first-in-human study of the oral selective inhibitor of PI3K-γ (IPI-549) in 
combination with nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or 
HNSCC demonstrated favorable tolerability (Sullivan 2018). 
2.4.2. 
Benefit Assessment 
Subjects may derive benefit due to improvements in symptoms and tumor control. Duvelisib 
treatment produced clinical activity in subjects with hematologic malignancies, including 
CLL/SLL (approval), FL (accelerated approval), and peripheral T-cell lymphoma. More detailed 
information about the clinical efficacy observed in duvelisib studies can be found in the IB and 
the duvelisib prescribing information (COPIKTRA 2018). 
Pembrolizumab has shown benefit in multiple solid tumor indications. Pembrolizumab is 
approved as a single agent for the first-line treatment of patients with metastatic or with 
unresectable, recurrent HNSCC whose tumors express PD-LI (CPS ≥ 1) as determined by an 
FDA-approved test and is approved in combination with platinum and 5-FU for all patients with 
R/M HNSCC (Keytruda 2019). As presented in the pembrolizumab prescribing information 
(Keytruda 2019), results for the pre-specified interim analysis in the KEYNOTE-048 study of 
pembrolizumab as first-line treatment for patients with R/M HNSCC showed that compared with 
standard first-line treatment (i.e., EXTREME, consisting of cetuximab plus carboplatin or 


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cisplatin), pembrolizumab monotherapy had superior OS among patients whose tumors had PD 
L1 CPS of ≥ 20 or ≥ 1, and noninferior OS in the total population with favorable safety. 
Pembrolizumab is approved as a second-line treatment in patients with R/M HNSCC with 
disease progression on or after platinum-containing chemotherapy based on the ORR of 16% 
(complete response [CR] = 5%) and the DOR (2.41 months to 27.71 months; 23 of 28 
responding patients [82%] had response durations of ≥ 6 months) in the KEYNOTE-012 study 
(Keytruda 2019). 
In vivo data from nonclinical studies in solid tumor models, including an HNSCC (i.e., MOC1) 
model, support the hypothesis that the addition of duvelisib may improve the activity of PD-1 
inhibitors in solid tumors (Section 2.3.1). 
Although duvelisib has not yet been evaluated in subjects with solid tumors, initial efficacy 
results from an ongoing study of an oral selective inhibitor of PI3K-γ (IPI-549) in combination 
with nivolumab in patients with melanoma, NSCLC, or HNSCC demonstrated early signs of 
clinical activity and evidence of immune modulation (Sullivan 2018). In this study, 2 patients 
had PR at first assessment (8 weeks) and 40% of patients (n = 12) remained on study ≥ 12 weeks. 
It is anticipated that analysis of safety, tolerability, pharmacokinetics (PK), biomarker and 
preliminary efficacy data will help guide future development of duvelisib in combination with 
pembrolizumab in HNSCC. 
2.4.3. 
Overall Benefit/Risk Conclusion 
As early phase clinical studies are designed to provide information about the safety and efficacy 
of an investigational drug, subjects enrolled in the study cannot expect to receive a direct benefit 
from an experimental treatment. 
Although pembrolizumab is approved for the treatment of patients with HNSCC, the ORR (19% 
for first-line treatment in patients with CPS ≥ 1 and 16% for second-line treatment) was 
relatively low (Keytruda 2019). Based on the strong antitumor synergy (i.e., inhibition of tumor 
growth and prolonged survival) for duvelisib in combination with a PD-1 inhibitor observed in 
the nonclinical in vivo studies and the manageable AE profile for duvelisib in patients with 
hematologic malignancies, subjects with R/M HNSCC could potentially benefit from improved 
response rates. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 5: 
Objectives and Endpoints 
Objectives 
Endpoints 
(See Section 9.4 for definitions) 
Stage 1 - Unique Objectives/Endpoints 
Primary  
Evaluate the safety and tolerability of duvelisib in 
combination with pembrolizumab in subjects with 
recurrent or metastatic (R/M) head and neck 
squamous cell carcinoma (HNSCC) 
Safety and tolerability of study interventions 
based on dose-limiting toxicities (DLTs), adverse 
events (AEs), serious AEs (SAEs), vital signs, 
physical examinations, and clinical laboratory 
measurements 
Secondary 
Characterize the overall response rate (ORR) of 
duvelisib in combination with pembrolizumab in 
subjects with R/M HNSCC 
ORR, which includes partial response (PR) and 
complete response (CR) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) 
v 1.1 (Eisenhauer 2009) 
Stage 1 and Stage 2 – Combined Objectives/Endpoints 
Primary 
Characterize the ORR of duvelisib in combination 
with pembrolizumab  
ORR, which includes PR and CR, according to 
RECIST v 1.1 (Eisenhauer 2009) 
Secondary 
Characterize other efficacy parameters of 
duvelisib in combination with pembrolizumab  
• 
Duration of response (DOR), defined as time 
from response ≥ PR to documented disease 
progression according to RECIST v 1.1 
(Eisenhauer 2009) 
• 
Progression-free survival (PFS), defined as 
the time from start of treatment to 
documented disease progression according to 
RECIST v 1.1 (Eisenhauer 2009), or death 
due to any cause 
• 
Overall survival (OS), defined as the time 
from start of treatment to the date of death 
Characterize the pharmacokinetics (PK) of 
duvelisib (and metabolite IPI-656) monotherapy 
and of duvelisib in combination with 
pembrolizumab 
PK parameters for duvelisib (and metabolite 
IPI-656) 
Evaluate the safety and tolerability of duvelisib in 
combination with pembrolizumab 
Safety and tolerability parameters including AEs, 
SAEs, vital signs, physical examinations, and 
clinical laboratory measurements 


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Objectives 
Endpoints 
(See Section 9.4 for definitions) 
Exploratory 
Evaluate potential biomarkers for possible 
associations with clinical efficacy and/or safety 
outcomes of duvelisib in combination with 
pembrolizumab 
• 
Blood assessments of immune cell 
populations, chemokines, cytokines and 
circulating tumor DNA 
• 
Fecal assessments of protein, DNA, and/or 
RNA 
• 
Tumor biopsy evaluation of biomarkers such 
as gene and copy number variation, RNA 
expression, protein expression, and/or 
immune cell content (Required biopsies in 
Stage 1 and optional biopsy in Stage 2) 
• 
ORR and its relationship to tumor and/or 
immune cell programmed cell death ligand 1 
(PD-L1) levels and to tumor human 
papillomavirus (HPV) status 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multicenter, non-randomized, open-label, Phase 1b/2 study of duvelisib in combination 
with pembrolizumab in subjects with R/M HNSCC who are eligible for pembrolizumab 
monotherapy based on the current pembrolizumab prescribing information (Keytruda 2019). 
This study will be conducted at multiple sites in the US and will include approximately 
13 subjects in Stage 1 and 17 additional subjects in Stage 2, for a total of 30 subjects in the final 
analysis. 
The study will follow a Simon two-stage design (Simon 1989). 
The study stages are depicted in Figure 1 and the treatment/imaging schemes for Stage 1 and 
Stage 2 are depicted in Figure 2 and Figure 3, respectively. 
Subjects will receive duvelisib 25 mg BID orally (PO) in combination with pembrolizumab 
200 mg every 3 weeks (q3w) intravenously (IV). 
In Stage 1, subjects will have a 1-week lead-in with duvelisib before the initiation of 
combination therapy with duvelisib and pembrolizumab. Approximately 13 subjects are planned 
to be accrued in this stage. The first 6 subjects will be assessed for dose-limiting toxicities 
(DLTs). The DLT evaluation period will be Cycle 1 (4 weeks or 28 days): the 1-week duvelisib 
monotherapy lead-in period followed by 1 dose of pembrolizumab in combination with 
3 additional weeks of continuous dosing of duvelisib. Every effort will be made to administer the 
first dose of pembrolizumab on Day 8 of Cycle 1 (C1D8). If the first dose of pembrolizumab on 
C1D8 is delayed, every effort should be made to delay the subsequent dosing of the next cycle 
(within the protocol-allowed window of 3 days) to achieve as close to a 3-week interval between 
pembrolizumab doses as possible. The Medical Monitor needs to be consulted for such 
adjustments to ensure uniformity of approach and to account for subject-specific circumstances. 
For example, if the third day of the C2D1 window falls on a weekend, an additional adjustment 
would need to be made on a case-by-case basis. In the event of a delay of the start of 
pembrolizumab therapy, DLTs will be evaluated at the end of the third week of combination 
therapy. 
The DLT evaluation period will be used to assess DLTs in the first 6 subjects. 
• If there is ≤ 1 DLT in the 6 DLT-evaluable subjects, additional subjects will be enrolled 
to bring the total dosed in Stage 1 to approximately 13 subjects. 
• If there are ≥ 2 DLTs in the first 6 subjects, enrollment at duvelisib 25 mg BID will stop. 
Enrollment would restart at a reduced duvelisib dose (15 mg BID) to assess DLTs at the 
lower dose (dose level -1; see Table 6). 


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Table 6: 
Duvelisib Dose Levels 
Dose Level 
Duvelisib, mg BID PO 
Starting Dose 
25 
-1 
15 
Abbreviations: BID: twice daily; PO: oral. 
A formal analysis of available safety data will be conducted when the first 10 subjects treated 
have received at least 1 cycle of study treatment. This will enable assessment of toxicities of later 
onset, particularly outside of the DLT window.  
If an excessive rate of Grade 3 or higher overlapping SAEs (defined as any rate for each SAE 
that is above the highest reported in warnings and precautions of the prescribing information for 
either duvelisib [COPIKTRA 2018] or pembrolizumab [Keytruda 2019], respectively), such as 
pneumonitis, colitis, cutaneous skin reactions, and elevations of AST/ALT, is observed outside 
of the DLT window, a decision for stopping or modifying the study may be made. However, 
recognizing that the observed rate of such events can be highly sensitive due to the small sample 
size, the totality of safety data will be reviewed and carefully considered prior to making a 
formal decision. 
An interim analysis of ORR will occur after all of the planned 13 subjects in Stage 1 are 
enrolled, dosed, and have been followed through at least the first disease response assessment. 
• If there are ≤ 2 responses (CR or PR) in the 13 subjects in Stage 1, further accrual in the 
study may be stopped. However, all available data, including the relative proportion of 
CRs, will be analyzed before a final decision is made. 
• If > 2 responses are observed in Stage 1, enrollment will continue in Stage 2. 
In Stage 2, 17 additional subjects will be accrued for a total of 30 subjects in the final analysis. 
Subjects enrolled in Stage 2 will only receive combination therapy with duvelisib and 
pembrolizumab. Enrollment into Stage 2 may proceed prior to completion of the interim analysis 
as long as at least 2 of the 13 subjects enrolled in Stage 1 have a confirmed response. 
The ORR and PFS will be assessed according to Response Evaluation Criteria in Solid Tumors 
(RECIST) v 1.1 (Eisenhauer 2009).  
Subjects will be monitored continuously for safety while on study treatment. Adverse events will 
be classified using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 5.0 or higher. 
Higher doses of duvelisib may be explored in additional subjects via a protocol amendment, if 
warranted by observed data. 
Subjects will be treated until documented progressive disease (PD) (Section 8.1.2), unacceptable 
toxicity (Section 6.6), discontinuation criteria are met (Section 7.1), withdrawal (Section 7.2), or 
death. The total duration of treatment will not exceed 24 months. After treatment 
discontinuation, subjects will complete an End of Treatment visit and will be followed for safety 


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for an additional 30 days. All subjects with treatment-related AEs/serious adverse events (SAEs) 
should be observed until resolution or stabilization. 
It is anticipated that the study accrual will occur over approximately 18 months. All subjects will 
be followed for survival for 1 year after the last subject is enrolled and dosed. 
4.2. 
Scientific Rationale for Study Design 
The purpose of the study is to evaluate the safety and tolerability of duvelisib in combination 
with pembrolizumab in subjects with R/M HNSCC and determine if the addition of duvelisib to 
pembrolizumab may improve treatment responses. 
Pembrolizumab was selected for combination with duvelisib in this study for the following 
reasons:  
1. Strong antitumor synergy (i.e., inhibition of tumor growth and increase in survival) was 
observed for the combination of duvelisib and a PD-1 inhibitor vs either monotherapy in 
vivo (Pachter 2018, Davis 2017) 
2. Pembrolizumab (Keytruda®) is approved for R/M HNSCC (Keytruda 2019) 
As this is the first clinical study of duvelisib in subjects with R/M HNSCC, the first 6 subjects in 
Stage 1 will be evaluated for DLTs. Furthermore, a 1-week duvelisib monotherapy lead-in has 
been included so that subjects can be monitored on monotherapy and a steady-state duvelisib PK 
sample and biomarker samples can be obtained before the treatment with pembrolizumab is 
started. The lead-in design with duvelisib is expected to provide scientific and safety information 
for the potential contribution of duvelisib in this combination setting. 
The efficacy endpoints will be assessed using the standard RECIST v 1.1 (Eisenhauer 2009), 
which were also used in the registrational study for pembrolizumab in HNSCC (Keytruda 2019). 
Justification for Dose of Study Interventions 
The combination of the 25 mg BID dosage of duvelisib and the 200 mg q3w dosage of 
pembrolizumab was selected based on the approved dosage for duvelisib in patients with 
hematologic malignancies (COPIKTRA 2018) and the approved dosage for pembrolizumab in 
patients with R/M HNSCC (Keytruda 2019). 
4.3. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed the last scheduled 
procedure shown in the Schedule of Activities (SoA) (Section 1.3 and Section 1.4), including the 
Survival Follow-up of up to 1 year after the last subject is enrolled and dosed. 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
(Section 1.3 and Section 1.4) for the last subject in the study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Subjects may be eligible for inclusion in the study if they meet the following criteria: 
1. Must be a male or female subject ≥ 18 years of age 
2. Must have histologically or cytologically-confirmed R/M HNSCC of the oral cavity, 
oropharynx, hypopharynx, or larynx that is considered incurable by local therapies. 
3. Must be eligible for pembrolizumab monotherapy based on the current prescribing 
information for pembrolizumab (Keytruda 2019): (a) for first-line treatment, subjects 
with metastatic or with unresectable, recurrent HNSCC whose tumors express PD L1 
(CPS ≥ 1) as determined by an FDA-approved test; (b) subjects with R/M HNSCC with 
disease progression on or after platinum-containing chemotherapy, regardless of PD-L1 
expression. 
4. Must have had 0 to 2 prior therapies for R/M HNSCC. Therapy for locally or regionally 
advanced HNSCC with or without radiation therapy is not counted as a line of therapy 
unless recurrence and/or metastasis was demonstrated < 6 months from the end of such 
therapy. 
5. Must have at least 1 measurable lesion (which has not been previously irradiated) 
according to RECIST v 1.1 (Eisenhauer 2009). 
6. For Stage 1 only: Must have at least 1 other lesion that can be biopsied 
7. For Stage 1 only: Must be willing to undergo a pretreatment and on-treatment biopsy of 
the available tumor lesion (described in inclusion criterion #6). Archival tissue (up to 
6 months before the first dose of duvelisib) may be considered in place of the required 
pretreatment biopsy after consultation with the Sponsor, as long as no intervening 
systemic regimen had been taken during that time frame. 
8. Must provide prior data on PD-L1 expression and HPV status, if available 
9. Must have adequate organ function defined by the following laboratory parameters: 
a. Adequate bone marrow reserve as evidenced by: 
− Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
− Platelet count ≥ 100 × 109/L 
− Hemoglobin level ≥ 9.0 g/dL 
b. Adequate renal function as evidenced by: 
− a serum creatinine level < 1.5 mg/dL, or 
− estimated creatinine clearance value of ≥ 60 mL/min (as determined by the 
Cockcroft-Gault method) for subjects with creatinine levels > 1.5 × institutional 
upper limit of normal (ULN) 


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c. Adequate hepatic function as evidenced by: 
− Total bilirubin level ≤ 1.5 × ULN (exception: subjects with Gilbert's Syndrome 
may have a bilirubin level > 1.5 × ULN) 
− AST/serum glutamic-oxaloacetic transaminase (SGOT) and ALT/serum pyruvic 
transaminase (SGPT) levels ≤ 2.5 × ULN or ≤ 5 × ULN in subjects with liver 
metastases 
10. Must have international ratio (INR) or prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) ≤ 1.5 × ULN, unless subject is receiving anticoagulant 
therapy in which case PT or aPTT must be within therapeutic range of intended use of 
anticoagulants 
11. Must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
12. For male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal), must be willing to use a highly effective 
method of contraception (see Section 10.4) for the duration of the study interventions and 
for at least 4 months after the last dose of study interventions 
13. Must have a negative serum human chorionic gonadotropin (hCG) pregnancy test result 
within 7 days before first dose of duvelisib if the subject is a woman of childbearing 
potential (WCBP) (defined in Section 10.4) 
14. Must provide signed and dated institutional review board (IRB)/independent ethics 
committee (IEC)-approved informed consent form (ICF) before any study-specific 
screening procedures are performed 
5.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Have disease that is suitable for local therapy administered with curative intent 
2. Have been previously treated with 3 or more systemic regimens given for recurrent 
and/or metastatic disease 
3. Have received anticancer treatment, major surgery, or any investigational drug within 
30 days or 5 half-lives, whichever is shorter, before the start of study intervention 
4. Have received radiation therapy within 14 days prior to the first dose of duvelisib in this 
study, including, in addition (if necessary), the timeframe for resolution of any actual or 
anticipated toxicities from such radiation. Palliative radiation therapy is allowed if 
> 7 days before first dose of duvelisib and any toxicity is ≤ Grade 1. 
5. Have received prior radiation therapy to > 25% of bone marrow-bearing areas 
6. Have co-existing head-and-neck carcinoma of the nasopharynx, squamous cell carcinoma 
of unknown primary, salivary gland tumors, or any other non-squamous primary tumors 
involving the head and neck 
7. Have received previous treatment with a PI3K inhibitor 
8. Have received previous treatment with a PD-1 or PD-L1 inhibitor 


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9. Have received organ or allogenic bone marrow or peripheral blood stem cell transplant 
10. Have a history or concurrent condition of interstitial lung disease of any severity and/or 
severely impaired lung function 
11. Have a prior history of drug-induced colitis or drug-induced pneumonitis 
12. Have active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (subjects 
with detectable viral load) 
13. Have an infection with hepatitis B or hepatitis C: 
• Subjects with a positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody 
(HCVAb) will be excluded 
• Subjects with a positive hepatitis B core antibody (HBcAb) must have negative 
hepatitis B virus (HBV) DNA to be eligible and must be periodically monitored for 
HBV reactivation by institutional guidelines 
• Investigators who strongly believe that a positive HBcAb is false-positive due to 
passive immunization from previous immunoglobulin infusion therapy should discuss 
the potential to defer HBV prophylaxis with the Medical Monitor 
14. Have a history of or known human immunodeficiency virus (HIV) infection  
15. Have a history of tuberculosis treatment within the 2 years prior to first dose of duvelisib 
16. Have a history of chronic liver disease or veno-occlusive disease/sinusoidal obstruction 
syndrome 
17. Have known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study 
18. Are receiving ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or 
systemic steroids > 20 mg of prednisone (or equivalent) per day 
19. Have an active infection or are receiving ongoing systemic treatment for a clinically 
significant bacterial, fungal, or viral infection at Screening 
NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically 
excluded if all other inclusion/exclusion criteria are met 
20. Have received a live or live attenuated vaccine within 6 weeks of first dose of duvelisib 
21. Have received medications or consumed foods that are strong inhibitors or inducers of 
cytochrome P450 3A (CYP3A) (Section 10.2) within 2 weeks prior to the first dose of 
duvelisib or concurrent with duvelisib treatment 
22. Are unable to receive prophylactic treatment for pneumocystis, herpes simplex virus 
(HSV), or herpes zoster (VZV) at screening 
23. Have had prior surgery (e.g., gastric bypass surgery, gastrectomy) or gastrointestinal 
dysfunction that may affect drug absorption 
24. Have any active gastrointestinal dysfunction interfering with the subject’s ability to be 
administered oral medications 
25. Is a female subject who is pregnant or breastfeeding 


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26. Have a baseline QT interval corrected using the Fridericia correction method (QTcF) 
> 500 ms (average of triplicate readings). NOTE: This criterion does not apply to subjects 
with a right or left bundle branch block. 
27. Have New York Heart Association Class III or IV congestive heart failure 
28. Have a history of another active malignancy that is progressing or requires active 
treatment. Exceptions include adequately treated non-melanoma skin cancer, curatively 
treated in-situ cancer of the cervix, or other solid tumors curatively treated with no 
evidence of disease for > 3 years. 
29. Have known active central nervous system metastases and/or carcinomatous meningitis. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least 4 weeks prior to the first dose of 
duvelisib 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 
the first dose of duvelisib. The exception does not include carcinomatous meningitis. 
30. Have an active autoimmune disease requiring systemic treatment within the last 3 months 
prior to first dose of study intervention, documented history of clinically severe 
autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents 
except vitiligo, Type 1 diabetes mellitus, hypothyroidism stable on hormone-replacement 
therapy, Sjogren’s syndrome, and resolved childhood asthma/atopy. Subjects who require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections may 
participate in this study. 
31. Have a history of stroke, unstable angina, myocardial infarction, or ventricular 
arrhythmia requiring medication or mechanical control within the last 6 months prior to 
first dose of duvelisib 
32. Have an unstable or severe uncontrolled medical condition or any important medical 
illness or abnormal laboratory finding that would, in the Investigator’s judgment, increase 
the subject’s risk to participating in this study 
5.3. 
Lifestyle Considerations 
Male and female subjects of reproductive potential (i.e., not surgically sterile or female subjects 
who are not postmenopausal) must use highly effective contraception for the duration of the 
study interventions and for at least 4 months after the last dose of study interventions. Please see 
Section 10.4 for detailed contraceptive requirements. 
Subjects should be advised to use appropriate protective measures to minimize exposure to direct 
sunlight or UV light sources during the treatment period and for at least 30 days after the last 
dose of duvelisib. Please see the duvelisib IB for additional details on the potential for 
phototoxicity. 
Subjects should refrain from consumption of grapefruit juice and St. John’s Wort, and other 
foods and herbal products that are strong inhibitors or inducers of CYP3A during treatment with 
duvelisib. Please see Section 6.5.2 for additional information on restrictions on the use of CYP 
3A inhibitors, inducers, and substrates, and Section 10.2 for lists of CYP3A inhibitors, inducers, 
and substrates. The duvelisib IB contains additional details on potential interactions with foods. 


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5.4. 
Definition of Enrolled 
“Enrolled” means a subject's, or their legally acceptable representative’s, agreement to 
participate in a clinical study after completion of the informed consent process. Potential subjects 
who are pre-screened for the purpose of determining eligibility for the study but do not sign an 
ICF are not considered enrolled. 
5.5. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAEs that occur after the ICF is signed. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date. Please note that repeating of clinical 
laboratory assessments during screening does not constitute rescreening. 
5.6. 
Replacement of Subjects 
During the DLT evaluation period in Stage 1, subjects who discontinue duvelisib before the end 
of Cycle 1, for reasons other than a DLT, or who receive < 75% of the scheduled duvelisib doses 
during Cycle 1 may be replaced. 
Any other subjects who withdraw from the study for reasons other than PD or treatment-related 
toxicity before receiving at least 1 cycle of study intervention may be replaced. 


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6. 
STUDY INTERVENTIONS 
Study intervention(s) is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol. 
6.1. 
Study Interventions Administered 
Table 7: 
Study Interventions 
Intervention Name 
Duvelisib 
Pembrolizumab 
Type  
Investigational Drug 
Biologic 
Drug Substance 
Description 
White to off-white crystalline 
solid  
Sterile, preservative-free, 
non-pyrogenic, clear to slightly 
opalescent, colorless 
to slightly yellow solution 
Dose Formulation 
Capsule 
Vial 
Unit Dose Strength(s) 
15 mg, 25 mg 
100 mg/4 mL 
Formulation Excipients 
Excipients (diluent, glidant, 
disintegrant, and lubricant) that 
are listed in the US FDA Inactive 
Ingredients Database for approved 
drug products and/or GRAS 
L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose 
(70 mg), and Water for Injection, 
USP 
Dosage Level(s) and 
Frequencya 
25 mg PO BID 
200 mg IV q3w 
Route of Administration 
Oral 
IV 
Use 
Experimental 
Experimental 
IMP or NIMP 
IMP 
NIMP 
Sourcing 
Provided by the Sponsor 
Site Pharmacy 
Packaging and Labeling 
Prepared to meet all regulatory 
requirements 
As described in Keytruda® US 
prescribing information 
Current/Former Name(s) 
or Alias(es) 
VS-0145, IPI-145, Copiktra® 
Keytruda® 
Abbreviations: BID: twice daily; FDA: Food and Drug Administration; GRAS: Generally Regarded as Safe; 
IMP: Investigational Medicinal Product; IV: intravenous; NIMP: Non-Investigational Medicinal Product; PO: 
oral; q3w: every 3 weeks; US: United States; USP: United States Pharmacopeia. 
a Subjects will be treated until documented PD (Section 8.1.2), unacceptable toxicity (Section 6.7), discontinuation 
criteria are met, withdrawal (Section 7.2), or death. The total duration of treatment will not exceed 24 months. 
 


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6.1.1. 
Duvelisib 
Duvelisib should be swallowed whole with a glass of water (approximately 8 ounces or 240 mL). 
Advise subjects not to open, break, or chew the capsules. 
Duvelisib 25 mg will be administered BID PO. Duvelisib may be administered without regard to 
meals; however, subjects must avoid grapefruit and grapefruit juice while on duvelisib 
(COPIKTRA 2018). 
On days of pembrolizumab dosing, duvelisib will be administered in the clinic before the 
pembrolizumab infusion is started. 
On the days when postdose PK samples are collected, specific timing for the administration of 
duvelisib is required (see Table 2 and Table 4), as follows: 
• Stage 1: On C1D8, duvelisib will be administered at the start of the visit after the predose 
PK, pharmacodynamic, and blood sample collection 
• Stage 1: On C2D1, duvelisib will be administered 30 minutes before the start of the 
pembrolizumab infusion 
• Stage 2: On C1D1, duvelisib will be administered at the start of the visit after the predose 
PK and blood sample collection 
Refer to the Pharmacy Manual for additional instructions regarding duvelisib administration. 
6.1.2. 
Pembrolizumab 
Pembrolizumab will only be administered by qualified site personnel during clinic visits in 
accordance with the prescribing information for pembrolizumab (Keytruda 2019). 
Pembrolizumab 200 mg should be administered q3w as an IV infusion over 30 minutes. 
On the days when postdose PK samples are collected, specific timing for the administration of 
pembrolizumab is required (see Table 2 and Table 4) as follows: 
• Stage 1: On C1D8, pembrolizumab will not be administered until the biopsy for 
biomarkers has been collected; the optimal timing for collection of the biopsy is 
approximately 2 to 4 hours after duvelisib administration, however, a tumor biopsy at a 
later time during this clinic visit on C1D8 is acceptable. The fourth PK sample should be 
collected at approximately 2 to 4 hours after duvelisib dose, as soon as possible after the 
biopsy, and prior to pembrolizumab administration. 
• Stage 1: On C2D1, the pembrolizumab infusion will be started 30 minutes after 
administration of duvelisib 
• Stage 2: On C1D1, pembrolizumab will be administered 30 minutes after collection of 
the 2-hour postdose duvelisib PK sample 
With the exception of the days when postdose PK samples are collected (i.e., C1D8 and C2D1 in 
Stage 1 and C1D1 in Stage 2), the pembrolizumab infusion should be started within 10 minutes 
after the dose of duvelisib is administered. 
Please refer to the prescribing information for current detailed instructions on administration of 
pembrolizumab (Keytruda 2019). 


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6.2. 
Preparation/Handling/Storage 
6.2.1. 
Duvelisib 
Dispensing and storage instructions for duvelisib will be provided in the Pharmacy Manual. On 
receipt at the investigative site, duvelisib should remain in the packaging as provided until use or 
dispensation. The packaged product should be stored at the investigative site at 20 to 25°C (68 to 
77°F), with excursions permitted at 15 to 30°C (59 to 86°F). Temperature excursion procedures 
are provided in the Pharmacy Manual. Expired drug is not to be dispensed (COPIKTRA 2018). 
6.2.2. 
Pembrolizumab 
Please refer to the prescribing information for current instructions on preparation, handling, and 
storage of pembrolizumab (Keytruda 2019). 
Pembrolizumab to be used in combination with duvelisib in this study will be obtained by the 
study sites from commercially available sources. 
6.2.3. 
Accountability 
Only subjects enrolled in the study may receive study interventions (i.e., duvelisib in 
combination with pembrolizumab) and only authorized site staff may supply or administer study 
interventions. 
All study interventions stored at the site must be stored in a secure, environmentally-controlled, 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention(s) accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused duvelisib are provided in the 
Pharmacy Manual. 
6.3. 
Measures to Minimize Bias 
This is an open-label study with a single treatment arm. 
Subjects will be assigned a unique number in ascending numerical order at each study site. 
6.4. 
Study Intervention Compliance 
When subjects are dosed at the site, they will receive study interventions (i.e., duvelisib and 
pembrolizumab) directly from the Investigator or designee, under medical supervision. The date 
and time of each dose administered in the clinic will be recorded in the source documents and 
recorded in the case report form (CRF). The dose of study interventions and study subject 
identification will be confirmed at the time of dosing by a member of the study site staff. 
When subjects administer duvelisib at home, compliance with duvelisib will be assessed by the 
study site at each visit. Compliance of duvelisib dosing will be assessed by reviewing subject 
diaries (first year on treatment only) and counting returned capsules during the site visits and will 


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be documented in the source documents and CRF. Deviation(s) from the prescribed dosage 
regimen should be recorded in the CRF. 
A record of the number of duvelisib capsules dispensed to and taken by each subject must be 
maintained and reconciled with duvelisib and compliance records. Pembrolizumab infusion start 
and stop times and duvelisib start and stop dates, including dates for intervention delays and/or 
dose reductions will also be recorded in the CRF. 
6.5. 
Concomitant Therapy 
Any other medication (e.g., supportive care) that is considered necessary for the subject’s 
welfare and that is not expected to interfere with the evaluation of duvelisib may be given at the 
discretion of the Investigator. 
Any medication that the subject received within 30 days prior to the first dose or receives during 
the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and stop dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Required and Recommended Prophylaxis 
Based on the duvelisib clinical experience to date, the following are required or recommended: 
• Subjects are required to receive pneumocystis prophylaxis concomitant with duvelisib 
treatment per institutional guidelines. After completion/discontinuation of duvelisib 
treatment, continue prophylaxis until the absolute CD4+ T-cell count is greater than 
200 cells/μL. 
• HSV and VZV infections have been observed with duvelisib; therefore, herpes 
(HSV/VZV) prophylaxis concomitant with treatment is recommended, per Investigator 
discretion according to institutional guidelines 
• Subjects with a history of CMV infection/reactivation or viremia should be monitored for 
reactivation by polymerase chain reaction (PCR) or antigen test at least monthly. 
Prophylactic treatment per institutional guidelines is recommended for subjects 
considered by Investigators to be at high risk for CMV reactivation. 
• Antimicrobial prophylaxis and pneumococcal pneumonia vaccine are recommended for 
subjects with history of or considered at high risk for infections and during periods of 
severe neutropenia. Choice of antimicrobial agent (antifungal, antibiotic, antiviral) is per 
Investigator discretion, but the restrictions on the use of CYP3A inducers, inhibitors, and 
substrates should be considered (see Section 6.5.2). 


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6.5.2. 
Concomitant Therapies Restrictions 
Table 8: 
Prohibited Concomitant Therapies 
Prohibited 
Concomitant Therapy 
Guidance 
Use of Vaccines 
For all subjects, the use of live or live attenuated vaccines is prohibited 
during the treatment with either study intervention. 
The use of inactivated (or killed) vaccines (such as pneumococcal 
pneumonia vaccine) is allowed during the study; however, subjects and 
their physicians should be aware that the effectiveness of any vaccine 
administered concomitantly with duvelisib may be diminished. The ability 
to generate an immune response to any vaccine after the administration of 
duvelisib has not been studied and data for pembrolizumab are preliminary 
(Läubli 2018). 
Immunosuppressants 
Subjects are not to receive ongoing treatment with chronic 
immunosuppressants (e.g., cyclosporine) or systemic steroids for > 1 week 
at doses higher than the equivalent of 20 mg prednisone QD. 
Note: Acute treatment for underlying autoimmune disorders (e.g., reactive 
airway disease, rheumatoid arthritis) with corticosteroid doses > 20 mg 
prednisone or equivalent QD for ≤ 1 week is permitted during the study. 
Corticosteroid doses of ≤ 20 mg prednisone or equivalent QD are 
permitted during the study for physiologic replacement or chronic 
treatment for underlying autoimmune disorders (e.g., reactive airway 
disease, rheumatoid arthritis). 
See Table 10 and Table 13 for use of systemic steroids for study 
intervention toxicity when study intervention(s) is withheld or 
discontinued. 
Other Anticancer 
Therapy or 
Investigational Agents 
During the study intervention period, subjects are not to receive any 
additional anticancer therapy or other investigational agents not outlined in 
the protocol. 
Medications or Foods 
that Strongly Inhibit or 
Induce CYP3A4 
Use of a strong CYP3A inhibitor or inducer during treatment with 
duvelisib is prohibited. Co-administration with a strong CYP3A inhibitor 
increases duvelisib exposure, which may increase the risk of duvelisib 
toxicities. Co-administration with a strong CYP3A inducer decreases 
duvelisib exposure, which may reduce duvelisib efficacy. 
Section 10.2 provides a list of medications and foods known to inhibit 
(Table 20) or induce (Table 21) CYP3A. Please note that these tables do 
not provide a comprehensive list of all medications that may modulate 
CYP3A activity. 
No formal PK drug-drug interaction studies have been conducted with 
pembrolizumab (Keytruda 2019). 
Abbreviations: CYP3A: cytochrome P450 3A; QD: once daily; PK: pharmacokinetic. 


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Table 9: 
Concomitant Therapies: Use with Caution During Treatment with Duvelisib 
Concomitant Therapy: 
Use with Caution 
Guidance 
Medications or Foods 
that Weakly or 
Moderately Inhibit or 
Induce CYP3A4 
Please discuss use of weak or moderate CYP3A inhibitors and inducers 
with the Medical Monitor. 
Section 10.2 provides a list of medications and foods known to inhibit 
(Table 20) or induce (Table 21) CYP3A. Please note that these tables do 
not provide a comprehensive list of all medications that may modulate 
CYP3A activity. 
Medications that are 
Substrates of CYP3A 
Co-administration with duvelisib decreases AUC of a sensitive CYP3A4 
substrate which may decrease the efficacy of these drugs. Consider finding 
an alternative drug that is not a substrate of CYP3A4. Table 22 in 
Section 10.2 provides a list of medications known to be substrates of 
CYP3A. Please note that Table 22 is not a comprehensive list of all 
medications that may be substrates of CYP3A. The Sponsor should be 
contacted with any questions regarding concomitant use of medications 
that are CYP3A substrates. 
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A; QD: once daily. 
6.5.3. 
Contraception and Pregnancy 
The effects of duvelisib on conception, pregnancy, and lactation are unknown. 
Refer to the prescribing information for pembrolizumab for the effects of pembrolizumab on 
conception, pregnancy, and lactation (Keytruda 2019). 
At Screening, all male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal) must agree to use a highly effective method of 
contraception for the duration of the study interventions and for at least 4 months after the last 
dose of study interventions. See Section 10.4 for Contraceptive Guidance including examples of 
highly effective contraceptive methods. Pregnancy testing will be performed throughout the 
study as shown in the SoA (Table 1 and Table 3). 
6.6. 
Supportive Care, Dose Modifications, and Management of Toxicities 
Supportive care should be provided as clinically indicated. Granulocyte colony stimulating factor 
may be used according to the American Society of Clinical Oncology (ASCO) guidelines (Smith 
2015). Transfusions may be used at any time as clinically indicated and according to ASCO 
guidelines. Subjects on a stable dose of erythropoietin to treat baseline anemia may continue this 
therapy at this dose. 
General recommendations for the management of overlapping toxicities for duvelisib in 
combination with pembrolizumab (Section 6.6.1), toxicities for duvelisib (non-overlapping 
toxicities or as monotherapy) (Section 6.6.2), and toxicities for pembrolizumab (non-overlapping 
toxicities) (Section 6.6.3) are provided below. 
Please refer to the pembrolizumab prescribing information (Keytruda 2019) for additional 
information regarding management of pembrolizumab toxicities. 


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Additional information regarding management of duvelisib toxicities can be found in the 
Summary of Data and Guidance to the Investigator section of the duvelisib IB. 
In the event that all study interventions are discontinued, subjects should be followed for AEs 
(for 30 days after the last dose of last study intervention) and survival as outlined in the SoA 
(Table 1 and Table 3). 
6.6.1. 
Recommended Dose Modifications for the Management of Overlapping 
Toxicities for Duvelisib in Combination with Pembrolizumab 
Non-infectious diarrhea or colitis, cutaneous reactions, pneumonitis without suspected infectious 
cause), and elevations in ALT and AST levels are potential overlapping toxicities for duvelisib 
with pembrolizumab. Refer to Table 10 for recommended management of these events in 
subjects being treated with duvelisib in combination with pembrolizumab. 
If, during the management of an AE for an individual subject receiving both duvelisib and 
pembrolizumab, the Investigator suspects that pembrolizumab may be the cause of that event, the 
Investigator should discuss the case with the Medical Monitor. If an excessive rate of Grade 3 or 
higher overlapping SAEs is observed, the totality of safety data will be evaluated by the Medical 
Monitor and the Investigators, and a decision to hold enrollment of subjects may be made (see 
Section 4.1). 
For additional information, please refer to the prescribing information for pembrolizumab 
(Keytruda 2019) and the Summary of Data and Guidance to the Investigator section of the 
duvelisib IB. 
 


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Table 10: 
Recommended Dose Modifications for the Management of Overlapping Toxicities for Duvelisib in Combination 
with Pembrolizumab 
 
 
During Treatment with Duvelisib in Combination with Pembrolizumab 
Toxicity 
Adverse Reaction Grade 
Dose Modification 
Recommended Management 
Non-infectious 
Diarrhea or colitis 
 
Grade 1 diarrhea (up to 
3 stools per day over 
baseline) and responsive to 
antidiarrheal agents, 
OR 
Asymptomatic (Grade 1) 
colitis 
• 
No change in 
pembrolizumab dose 
• 
No change in 
duvelisib dose  
• 
Initiate supportive therapy with antidiarrheal agents as appropriate 
• 
Monitor at least weekly until resolved or Grade 0 
Grade 1 diarrhea (up to 
3 stools per day over 
baseline) and unresponsive 
to antidiarrheal agents 
• 
Withhold duvelisib 
dose 
• 
No change in 
pembrolizumab dose 
• 
Treat with enteric acting steroids (e.g., budesonide) 
• 
Monitor at least weekly until resolved 
• 
Resume duvelisib at a reduced dose when event resolves (see Table 11) 
Grade 2 diarrhea or colitis 
• 
Withhold 
pembrolizumab and 
duvelisib 
• 
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone 
or equivalent followed by a taper)  
• 
Resume in subjects with complete or partial resolution (Grades 0 to 1) 
after corticosteroid taper 
Abdominal pain, stool with 
mucus or blood, change in 
bowel habits, peritoneal 
signs 
 
OR 
 
Severe diarrhea or colitis 
(Grade 3, > 6 stools per day 
over baseline) 
• 
Withhold 
pembrolizumab and 
duvelisib 
• 
For Grade 2/Grade 3 colitis, initiate supportive therapy with enteric 
acting steroids (e.g., budesonide) or systemic steroids (initial dose of 1 
to 2 mg/kg/day prednisone or equivalent followed by a taper) 
• 
Monitor at least weekly until resolved 
• 
Resume pembrolizumab treatment when event resolves 
• 
Resume duvelisib at a reduced dose when event resolves (see Table 11) 
• 
For recurrent Grade 3 diarrhea or recurrent colitis of any grade, 
discontinue pembrolizumab and duvelisib  
Life-threatening 
• 
Discontinue 
pembrolizumab and 
duvelisib 
 


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During Treatment with Duvelisib in Combination with Pembrolizumab 
Toxicity 
Adverse Reaction Grade 
Dose Modification 
Recommended Management 
Cutaneous 
reactions 
Grade 1-2 
• 
No change in dose for 
pembrolizumab or 
duvelisib 
• 
Initiate supportive care with emollients, anti-histamines (for pruritus), 
or topical steroids 
• 
Monitor closely 
Grade 3 
• 
Withhold duvelisib 
dose  
• 
Based on the severity 
of the adverse 
reaction, withhold or 
permanently 
discontinue 
pembrolizumab 
• 
Initiate supportive care with emollients, antihistamines (for pruritus), or 
topical steroids 
• 
Monitor at least weekly until resolved  
• 
Resume duvelisib at reduced dose when event resolves (see Table 11) 
• 
If severe cutaneous reaction does not improve, worsens, or recurs, 
discontinue duvelisib  
Life-threatening 
• 
Discontinue 
pembrolizumab and 
duvelisib 
 
SJS, TEN, DRESS (any 
grade) 
• 
Discontinue 
pembrolizumab and 
duvelisib 
Pneumonitis 
without suspected 
infectious cause 
Moderate (Grade 2) 
symptomatic pneumonitis 
• 
Withhold 
pembrolizumab and 
duvelisib 
• 
Treat with corticosteroids (1 to 2 mg/kg/day prednisone or equivalent, 
followed by corticosteroid taper) 
• 
If pneumonitis recovers to Grade 0 or 1 , pembrolizumab may be 
resumed and duvelisib may be resumed at reduced dose (see Table 11) 
• 
If non-infectious pneumonitis recurs or subject does not respond to 
steroid therapy, discontinue duvelisib and pembrolizumab 
Recurrent Grade 2 
pneumonitis, severe 
(Grade 3), or life-threatening 
pneumonitis 
• 
Discontinue 
pembrolizumab and 
duvelisib 
 


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During Treatment with Duvelisib in Combination with Pembrolizumab 
Toxicity 
Adverse Reaction Grade 
Dose Modification 
Recommended Management 
Hepatotoxicity 
 
AST or ALT > 3 and up to 
5 × ULN or total bilirubin 
> 1.5 and up to 3 × the ULN 
• 
Withhold 
pembrolizumab and 
duvelisib 
• 
Treat with corticosteroids (0.5 to 1 mg/kg/day prednisone or equivalent 
followed by corticosteroid taper 
• 
Monitor at least weekly until ALT or AST returns to < 3 × ULN 
• 
Resume treatment when adverse reaction improves to Grade 0 or 1 after 
corticosteroid taper 
In subjects without liver 
metastases, AST or ALT 
> 5 × ULN or total bilirubin 
> 3 × ULN 
• 
Discontinue 
pembrolizumab and 
duvelisib 
 
In subjects with liver 
metastasis and Grade 2 AST 
or ALT at baseline, with an 
increase in AST or ALT of 
50% or more relative to 
baseline that persists for at 
least 1 week 
• 
Discontinue 
pembrolizumab and 
duvelisib 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate transaminase; DRESS: drug reaction with eosinophilia and systemic symptoms; SJS: Stevens 
Johnson syndrome; TEN: toxic epidermal necrolysis; ULN: upper limit of normal. 


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6.6.2. 
Recommended Duvelisib Dose Modifications for the Management of Duvelisib 
Toxicities 
The dose level of duvelisib may be modified to manage duvelisib toxicities (Table 12) or 
overlapping toxicities in combination with pembrolizumab (Table 10). 
Non-hematologic and hematologic AEs for duvelisib for non-overlapping toxicities in 
combination with pembrolizumab should be managed with supportive care, treatment hold, dose 
reduction, or discontinuation of duvelisib as described in Table 12. Additional information 
regarding management of duvelisib toxicities can be found in the Summary of Data and 
Guidance to the Investigator section of the duvelisib IB. 
Refer to Table 11 for dose level modifications recommended for duvelisib. Subjects who have a 
duvelisib dose reduction due to a toxicity will not be eligible for a dose re-escalation. 
Any subject who develops an unacceptable toxicity at the 15 mg BID dosage of duvelisib should 
discontinue the study interventions. 
Duvelisib may be held up to 42 days due to toxicity. While duvelisib is being held, the subject 
may continue to receive pembrolizumab at the discretion of the Investigator. Doses held for 
> 42 days due to treatment-related toxicity will result in permanent discontinuation of duvelisib. 
If duvelisib is discontinued, the subject will also discontinue pembrolizumab and proceed with 
their End of Treatment (EoT) Visit. 
Table 11: 
Duvelisib Dose Level Modifications for Toxicities 
Dose Level 
Duvelisib 
Starting Dose 
25 mg BID PO 
-1 
15 mg BID POa 
Abbreviations: BID: twice daily; PO: oral. 
a Discontinue duvelisib if subject is unable to tolerate duvelisib 15 mg BID. 
Table 12: 
Recommended Duvelisib Dose Modifications for the Management of 
Duvelisib Toxicities 
Toxicity 
Adverse Reaction Grade 
Dose Modification and Recommended Management 
Non-hematologic Adverse Reactions 
Infections 
Grade 3 or higher infection 
• 
Withhold duvelisib until resolved 
• 
Resume at the same or reduced dose (see Table 11)  
Clinical CMV infection or 
viremia (positive PCR or 
antigen test) 
• 
Withhold duvelisib until resolved 
• 
Resume at the same or reduced dose (see Table 11) 
• 
If duvelisib is resumed, monitor subjects for CMV 
reactivation (by PCR or antigen test) at least 
monthly 
PJP 
• 
For suspected PJP, withhold duvelisib until 
evaluated 


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Toxicity 
Adverse Reaction Grade 
Dose Modification and Recommended Management 
• 
For confirmed PJP, discontinue duvelisib 
Hematologic Adverse Reactions 
Febrile neutropenia 
Grade 3-4 
• 
Interrupt duvelisib until afebrile and resolution of 
Grade 3 or Grade 4 neutropenia to Grade ≤ 2 (ANC 
> 1.0 Gi/L) 
• 
Monitor ANC at least weekly until > 1.0 Gi/L 
• 
Resume at same dose (first occurrence) or at a 
reduced dose for subsequent occurrence 
Neutropenia 
ANC 0.5 to 1.0 Gi/L 
• 
Maintain duvelisib dose 
• 
Monitor ANC at least weekly 
ANC less than 0.5 Gi/L 
• 
Withhold duvelisib. 
• 
Monitor ANC until > 0.5 Gi/L 
• 
Resume duvelisib at same dose (first occurrence) or 
at a reduced dose for subsequent occurrence 
(see Table 11) 
Thrombocytopenia 
Platelet count 25 to 
< 50 Gi/L (Grade 3) with 
Grade 1 bleeding 
• 
No change in dose 
• 
Monitor platelet counts at least weekly 
Platelet count 25 to 
< 50 Gi/L (Grade 3) with 
Grade 2 bleeding  
or  
Platelet count < 25 Gi/L 
(Grade 4) 
• 
Withhold duvelisib 
• 
Monitor platelet counts until ≥ 25 Gi/L and 
resolution of bleeding (if applicable) 
• 
Resume duvelisib at same dose (first occurrence) or 
resume at a reduced dose for subsequent occurrence 
(see Table 11) 


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Toxicity 
Adverse Reaction Grade 
Dose Modification and Recommended Management 
Non-hematologic Adverse Reactions During the Duvelisib Monotherapy Lead-in Onlya 
Non-infectious 
Diarrhea or colitis 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 stools 
per day over baseline) and 
responsive to antidiarrheal 
agents, 
OR 
Asymptomatic (Grade 1) 
colitis 
• 
No change in dose 
• 
Initiate supportive therapy with antidiarrheal agents 
as appropriate 
• 
Monitor at least weekly until resolved 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 stools 
per day over baseline) and 
unresponsive to antidiarrheal 
agents 
• 
Withhold duvelisib until resolved 
• 
Initiate supportive therapy with enteric acting 
steroids (e.g., budesonide) 
• 
Monitor at least weekly until resolved 
• 
Resume at a reduced dose (see Table 11) 
Abdominal pain, stool with 
mucus or blood, change in 
bowel habits, peritoneal 
signs, 
OR 
Severe diarrhea (Grade 3, 
> 6 stools per day over 
baseline) 
• 
Withhold duvelisib until resolved 
• 
Initiate supportive therapy with enteric acting 
steroids (e.g., budesonide) or systemic steroids 
• 
Monitor at least weekly until resolved 
• 
Resume at a reduced dose (see Table 11) 
• 
For recurrent Grade 3 diarrhea or recurrent colitis of 
any grade, discontinue duvelisib 
Life-threatening 
• 
Discontinue duvelisib 
Cutaneous reactions 
Grade 1-2 
• 
No change in dose 
• 
Initiate supportive care with emollients, anti-
histamines (for pruritus), or topical steroids 
• 
Monitor closely 
Grade 3 
• 
Withhold duvelisib until resolved 
• 
Initiate supportive care with emollients, anti-
histamines (for pruritus), or topical steroids 
• 
Monitor at least weekly until resolved 
• 
Resume at a reduced dose (see Table 11) 
• 
If severe cutaneous reaction does not improve, 
worsens, or recurs, discontinue duvelisib 
Life-threatening 
• 
Discontinue duvelisib 
SJS, TEN, DRESS (any 
grade) 
• 
Discontinue duvelisib 
Pneumonitis without 
suspected infectious 
cause 
Moderate (Grade 2) 
symptomatic pneumonitis 
• 
Withhold duvelisib 
• 
Treat with systemic steroid therapy 
• 
If pneumonitis recovers to Grade 0 or 1, duvelisib 
may be resumed at reduced dose (see Table 11)  
• 
If non-infectious pneumonitis recurs or subject does 
not respond to steroid therapy, discontinue duvelisib 
Severe (Grade 3) or life-
threatening pneumonitis 
• 
Discontinue duvelisib 
• 
Treat with systemic steroid therapy 


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Toxicity 
Adverse Reaction Grade 
Dose Modification and Recommended Management 
ALT/AST elevation 
3 to 5 × ULN (Grade 2) 
• 
Maintain duvelisib dose 
• 
Monitor at least weekly until return to < 3 × ULN 
> 5 to 20 × ULN (Grade 3) 
• 
Withhold duvelisib and monitor at least weekly until 
return to < 3 × ULN 
• 
Resume duvelisib at same dose (first occurrence) or 
at a reduced dose for subsequent occurrence (see 
Table 11)  
> 20 × ULN (Grade 4) 
• 
Discontinue duvelisib 
Abbreviations: ALT: alanine aminotransferase; ANC: absolute neutrophil count; AST: aspartate transaminase; 
CMV: cytomegalovirus; DRESS: drug reaction with eosinophilia and systemic symptoms; PCR: polymerase 
chain reaction; PJP: Pneumocystis jiroveci pneumonia; SJS: Stevens Johnson syndrome; TEN: toxic epidermal 
necrolysis; ULN: upper limit of normal. 
a See Table 10 for recommended dose modifications for the management of overlapping toxicities for duvelisib in 
combination with pembrolizumab. 
6.6.3. 
Recommended Pembrolizumab Dose Modifications for the Management of 
Pembrolizumab Toxicities 
Non-hematologic and hematologic AEs for pembrolizumab for non-overlapping toxicities in 
combination with duvelisib should be managed as described in the current pembrolizumab 
prescribing information (Keytruda 2019). The general recommendations cited in the June 2019 
pembrolizumab prescribing information are summarized in Table 13. 
Table 13: 
Recommended Pembrolizumab Dose Modifications for the Management of 
Pembrolizumab Toxicities 
Adverse 
Reaction 
Severitya 
Dose Modification 
Recommended 
Management 
Immune-
mediated 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 2 hypophysitis 
Withhold dose until 
clinically stable 
Treat with 
corticosteroids and 
hormone replacement 
as clinically indicated  
Grade 3 or 4 hypophysitis 
Withhold dose until 
clinically stable or 
permanently 
discontinue 
Immune-
mediated thyroid 
disorders 
Grade 2 thyroid disorders 
No change in dose 
Administer replacement 
hormones for 
hypothyroidism and 
manage 
hyperthyroidism with 
thionamides and beta-
blockers as appropriate 
Grade 3 or 4 thyroid disorders Withhold dose until 
clinically stable or 
permanently 
discontinue 


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Adverse 
Reaction 
Severitya 
Dose Modification 
Recommended 
Management 
Immune-
mediated type 1 
diabetes mellitus 
Grade 3 or 4 hyperglycemia 
Withhold dose until 
clinically stable 
Administer insulin for 
type 1 diabetes and 
administer anti-
hyperglycemics in 
subjects with severe 
hyperglycemia 
Immune-
mediated 
nephritis and 
renal dysfunction 
Grade 2 
Withhold dose 
Treat with 
corticosteroids (1 to 
2 mg/kg/day 
prednisone or 
equivalents followed by 
a taper) 
Grade 3 or 4 
Permanently 
discontinue 
 
Other immune-
mediated adverse 
reactions 
Grade 2 or 3 based on the 
severity and type of reaction 
Withhold dose 
Administer 
corticosteroidsb 
Based on limited data 
from clinical studies in 
subjects whose 
immune-related adverse 
reactions could not be 
controlled with 
corticosteroid use, 
administration of other 
systemic 
immunosuppressants 
can be considered. 
Grade 3 based on the severity 
and type of reaction or 
Grade 4 
Permanently 
discontinue 
 
Recurrent 
immune-
mediated adverse 
reactions 
Recurrent Grades 3 or 4 
Permanently 
discontinue 
 
Inability to taper 
corticosteroid 
dosage 
Requirement for ≥ 10 mg per 
day prednisone or equivalent 
for > 12 weeks after last dose 
of pembrolizumab 
Permanently 
discontinue 
 


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Adverse 
Reaction 
Severitya 
Dose Modification 
Recommended 
Management 
Persistent 
Grade 2 or 3 
adverse reaction 
(excluding 
endocrinopathy) 
Persistent Grade 2 or 3 
adverse reactions lasting 
≥12 weeks after last dose of 
pembrolizumab 
Permanently 
discontinue 
 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; NCI CTCAE: National Cancer 
Institute Common Terminology Criteria for Adverse Events; ULN: upper limit of normal. 
a Severity was graded per NCI CTCAE v4. 
b Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. 
6.6.4. 
Management of Infusion-related Reactions 
Infusion reactions (or suspected hypersensitivity infusion reaction and/or anaphylaxis) are 
defined below (Table 14). 
Table 14: 
NCI CTCAE Grading for Infusion Reactions 
Grade 
Description 
1 
Mild transient reaction; infusion interruption not indicated; intervention not indicated 
2 
Therapy or infusion interruption indicated but responds promptly to symptomatic treatment 
(e.g., NSAIDS, narcotics, IV fluids); prophylactic medications indicated for ≤ 24 hrs. 
3 
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms after initial improvement; hospitalization indicated for 
clinical sequelae 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death 
Abbreviations: IV: intravenous; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse 
Events; NSAID: nonsteroidal anti-inflammatory drug. 
Study site policies shall be used for the management of infusion reactions. 
Treatment should be permanently discontinued for severe and life-threatening infusion reactions. 
The rate of infusion should be slowed or interrupted in subjects with mild or moderate infusion 
reactions (Keytruda 2019). 
6.7. 
DLT Evaluation 
In Stage 1, the DLT evaluation period is Cycle 1 (4 weeks or 28 days): 1 week of duvelisib 
monotherapy lead-in followed by 3 additional weeks of duvelisib in combination with 
pembrolizumab. Every effort will be made to administer the first dose of pembrolizumab on 
Day 8 of Cycle 1 (C1D8). If the first dose of pembrolizumab on C1D8 is delayed, every effort 
should be made to delay the subsequent dosing of the next cycle (within the protocol allowed 


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window of 3 days) to achieve as close to a 3-week interval between pembrolizumab doses as 
possible. The Medical Monitor needs to be consulted for such adjustments to ensure uniformity 
of approach and to account for subject-specific circumstances. For example, if the third day of 
the C2D1 window falls on a weekend, an additional adjustment would need to be made on a 
case-by-case basis. In the event of a delay of the start of pembrolizumab therapy, DLTs will be 
evaluated at the end of the third week of combination therapy. 
The DLT evaluation period will be used to assess DLTs in the first 6 subjects. 
• If there is ≤ 1 DLT in the 6 DLT-evaluable subjects, additional subjects will be enrolled 
to bring the total dosed in Stage 1 to approximately 13 subjects 
• If there are ≥ 2 DLTs in the first 6 subjects, enrollment at duvelisib 25 mg BID will stop. 
Enrollment would restart at a reduced duvelisib dose (15 mg BID) to assess DLTs at the 
lower dose (dose level -1; see Table 6) 
6.7.1. 
Definition of Dose-limiting Toxicity 
Dose-limiting toxicity is defined as an AE that occurs during the initial 4-week period (DLT 
evaluation period, Cycle 1), is at least possibly related to duvelisib, and fulfills at least 1 of the 
following criteria: 
• Grade 3 or higher febrile neutropenia or Grade ≥ 3 neutropenia with infection or Grade 4 
neutropenia lasting more than 7 days 
• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant 
bleeding 
• Grade 3 or Grade 4 treatment-related non-hematologic toxicity, except nausea, vomiting, 
diarrhea and elevations in ALT or AST, which will be considered dose-limiting only if 
the subject develops: 
o Grade 3 nausea, vomiting, or diarrhea lasting more than 48 hours despite use of 
appropriate therapy or Grade 4 vomiting or diarrhea 
o Grade 3 elevations in ALT or AST lasting longer than 1 week, Grade 4 elevation in 
ALT or AST, or any ALT or AST elevations that require permanent discontinuation 
of study treatment 
o Grade 3 elevations in bilirubin elevation > 2 × ULN (> 2 × baseline for subjects with 
Gilbert’s syndrome) lasting longer than 1 week, Grade 4 elevation in bilirubin, or any 
elevations in bilirubin that require permanent discontinuation of study treatment 
o Alkaline phosphatase (ALP) elevations will be evaluated on a case-by-case basis by 
the study team in assessing whether there is a DLT 
• Grade 3 hypersensitivity reaction lasting longer than 24 hours or Grade 4 hypersensitivity 
regardless of duration  
• A DLT for cardiac dysfunction will include any heart failure that is Grade ≥ 2 NCI 
CTCAE (Version 5.0 or higher). The AE must be clinically significant and at least 
possibly related to the study drug in order to be considered a DLT 
• Any other toxicity that does not meet the definition of a DLT but requires permanent 
discontinuation of study treatment or is of concern to the Investigator and Sponsor may 
be considered to be a DLT 


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In rare instances, an event may fall within the definition of a DLT, as defined above, but the 
event may not be considered a DLT (e.g., not clinically meaningful). If this occurs, the 
Investigator and Sponsor will review the event and supporting data, and the reasons for not 
considering the event to be a DLT will be clearly documented with supporting rationale. 
Toxicities will be graded and documented according to the NCI CTCAE (Version 5.0 or higher). 
6.7.2. 
Subjects With a DLT 
In general, a subject who experiences a DLT should discontinue the study interventions. 
However, if there is evidence that a subject who experiences a DLT has also derived clinical 
benefit from the study interventions, the Medical Monitor and Investigator will review the 
specifics of the case, and the subject may be allowed to continue on study at the same dose or at 
a lower dose level of duvelisib if the consensus judgment is that continued treatment is in the 
subject’s best interest. Subjects should have recovered from toxicity to baseline or Grade 1 
(except alopecia) before re-treatment. For a DLT due to low hemoglobin or thrombocytopenia, 
the subject’s hemoglobin concentrations should have returned to baseline grade before re-
treatment; transfusions of packed red blood cells to treat anemia are permitted. 
6.8. 
Intervention after the End of the Study 
Subjects receiving clinical benefit from duvelisib in combination with pembrolizumab therapy 
may continue receiving treatment until either the final analysis of the ORR endpoint has been 
completed or all active subjects have been followed for 1 year after entry of the last subject, 
whichever is later. If the study is ended before all subjects discontinue treatment, any subject 
continuing to receive benefit will be provided the opportunity to continue to receive study 
intervention. However, in any case, the total duration of therapy will not exceed 24 months. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION(S) AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Interventions 
Study interventions will be discontinued for any of the following reasons: 
• Subject withdrawal of informed consent 
• Protocol-specified disease progression 
• Clinical deterioration (at the discretion of the Investigator) 
• Duvelisib interruption for > 42 days due to duvelisib-related toxicity, unless approved by 
study Medical Monitor 
• Unacceptable toxicity (as defined by the Investigator) 
• Pregnancy 
• Termination of the study by the Sponsor 
• Death 
• Maximum treatment duration of 24 months is reached 
• Other reasons, including major protocol violation or noncompliance 
The Investigator must determine the primary reason for discontinuation of study intervention(s) 
and record this information in the CRF. 
Subjects who discontinue the study interventions (i.e., duvelisib and pembrolizumab) will 
complete an EoT Visit and should continue in the study so that follow-up information on 
survival status may be obtained (See Section 8.1.3). See the SoA (Table 1 and Table 3) for data 
to be collected at the time of discontinuation of study interventions and during follow-up and for 
any further evaluations that need to be completed. 
Discontinuation of specific sites or of the study as a whole are described in Section 10.6.8. 
7.2. 
Subject Withdrawal from the Study 
• A subject may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
• If a subject withdraws during the treatment phase, an EoT Visit should be conducted, if 
possible, as described in the SoA (Table 1 and Table 3). 
• Additional visits may be conducted as necessary for any abnormal findings that require 
medical follow-up. 
• The subject will be permanently discontinued from the study interventions and 
withdrawn from the study at that time. 
• If the subject withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 


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• If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible. If contact with the subject is made, the site should counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the 
subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject. These contact attempts (e.g., 3 phone calls 
followed by a certified letter) should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1, Table 2, Table 3, 
and Table 4). Protocol waivers or exemptions are not allowed. 
• Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
intervention(s). 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. Screening activities will be performed within 30 days 
before the first dose (C1D1). Repeat laboratory assessments during the Screening Period 
do not constitute rescreening. The Investigator will maintain a screening log to record 
details of all subjects screened and to confirm eligibility or record reasons for screen 
failure, as applicable. 
• Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• The maximum amount of blood collected from each subject over the duration of the 
study, including any extra assessments that may be required, will be described in the ICF. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Efficacy Assessments 
Assessment of disease response and progression status in all subjects will be evaluated by the 
Investigator according to RECIST v 1.1 (Eisenhauer 2009). Response and progression will be 
evaluated using imaging scans (see Section 8.1.1), as indicated in the SoA (Table 1 and Table 3). 
8.1.1. 
Imaging Scans 
Computed tomography (CT) or magnetic resonance imaging (MRI) scans may be used, but CT is 
preferred. The same method must be used throughout the study. Imaging will occur at fixed 
calendar intervals (i.e., first scan in Stage 1 after 10 weeks [± 3 days], then every 9 weeks 
[± 3 days]; scans every 9 weeks [± 3 days] in Stage 2) regardless of any changes to visit or cycle 
schedules. In the case of a CR or PR, a confirmatory scan must be performed per RECIST v1.1 
(Eisenhauer 2009). It is recommended that this scan be performed at 4 (+1) weeks after the initial 
response. 
8.1.2. 
Investigator Assessment of Response and Progression Status 
Assessment of response and progression status will be evaluated by the Investigator at each 
scheduled disease response assessment as outlined in the SoA (Table 1 and Table 3). Assessment 
of response and progression status in all subjects will be evaluated according to RECIST v 1.1 


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(Eisenhauer 2009) for clinical decision-making and assessment of response. Please see 
Section 10.1 for detailed descriptions of these response criteria. 
8.1.3. 
Survival Follow-up 
Subjects who discontinue both study interventions will participate in the Survival Follow-up 
which will occur every 3 months (± 2 weeks) after the Safety Follow-up Visit for up to 1 year 
after the last subject is enrolled and dosed. This assessment will be conducted by telephone 
interview and records review (if available). Information on survival status and initiation of other 
anticancer therapy (including start date, stop date [if appropriate]; therapy type; and response on 
treatment) will be collected. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 and Table 3). 
Additional visits may be conducted as necessary for any abnormal findings that require medical 
follow-up. 
8.2.1. 
Physical Examinations and Vital Signs 
A full physical examination (PE) will be conducted at Screening. The full PE should include 
measurements of height and weight, vital signs, general appearance, skin, neck, eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, neurological examination, clinical 
assessment of tumor masses (if evaluable by PE), and review of disease-related constitutional 
symptoms. 
Symptom-directed PEs should include body systems as appropriate and will be conducted at 
subsequent time points per the SoA (Table 1 and Table 3). 
Any pre-existing PE abnormality deemed clinically significant by the Investigator during 
Screening will be reported as medical history. Any PE abnormality that emerges or has worsened 
after signing of the ICF and that is assessed as clinically significant by the Investigator will be 
reported as an AE. 
Vital signs will be measured with the subject in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
Vital sign abnormalities will be assessed for clinical significance. 
8.2.2. 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG), including a description of the cardiac rate, rhythm, 
interval durations, and an overall impression, will be conducted at Screening, after an 
approximate 10-minute rest period, per the SoA (Table 1 and Table 3). Corrected QT interval 
(QTc) will be calculated using the Fridericia correction method (QTcF). The ECG will be 
performed in triplicate to rule out clinically significant abnormalities. Additional on-treatment 
ECGs should be performed per the Investigator’s discretion as clinically indicated. 
8.2.3. 
Concomitant Medication and Procedures 
Concomitant medications and procedures will be assessed and recorded in the CRF during 
Screening (including those occurring within 30 days before first dose) and at each visit.  


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8.2.4. 
Clinical Safety Laboratory Assessments 
• See Table 23 for the list of clinical laboratory tests to be performed and the SoA (Table 1 
and Table 3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant* 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
subjects condition.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study interventions 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or the Medical Monitor. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Table 23, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1 and 
Table 3). 
o If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or requiring 
dose modification), then the results must be recorded in the CRF. 
*Note: Clinically significant findings are findings that are directly responsible for 
discontinuation from the study, require treatment or other therapeutic intervention, require 
further monitoring and/or require further diagnostic evaluation (excluding a repetition of the 
same procedure to confirm the abnormality). A result outside of the normal range or different 
from what is expected may be determined to be not clinically significant based on the clinical 
situation and investigator judgment (i.e., laboratory finding just below or above the normal 
limit). 
8.3. 
Other Assessments 
8.3.1. 
ECOG Performance Status 
ECOG performance status will be assessed at the time points as shown in the SoA (Table 1 and 
Table 3). If the ECOG performance status assessed at Screening is performed within 7 days of 
the first dose, the Screening assessment can be used and does not need to be repeated at C1D1. 


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8.4. 
Adverse Event Management 
8.4.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the study (investigational) product. This includes an exacerbation of 
pre-existing conditions or events, concurrent illnesses, drug interaction, or the significant 
worsening of the indication under investigation. Anticipated fluctuations of pre-existing 
conditions, including the disease under study that does not represent a clinically significant 
exacerbation or worsening, need not be considered AEs. 
Symptoms of the disease under study/lack of efficacy/disease progression should not be 
classified as an AE if they are within the normal day-to-day fluctuation or expected progression 
of the disease. 
It is the responsibility of the Investigator to document all AEs that occur during the study. AEs 
should be reported on the appropriate CRF. 
8.4.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose (including those occurring after the ICF 
is signed and before dosing) that: 
• Results in death 
• Is life-threatening (subject is at immediate risk of death from the event as it occurred) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not immediately life-threatening, or do 
not require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
For SAE reporting purposes, hospitalization is defined as inpatient hospital stay. Hospitalizations 
for elective surgery or other medical procedures that are not related to a treatment-emergent AE 
(TEAE) are not considered SAEs. Hospitalization, which in the opinion of the Investigator, is 
unrelated to the study intervention, and due to purely non-medical circumstances (e.g., respite 
care, lack of a caretaker at home, lack of transportation home) is also not considered to be an 
SAE. SAEs resulting from PD during the study (including signs and symptoms of progression) if 
documented by use of appropriate methods, should ONLY be reported as an SAE if the outcome 
of the PD is fatal during the study or within the safety reporting period (see Section 8.4.3). If the 


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malignancy has a fatal outcome during the study or within the safety reporting period, then the 
event should be reported using the term "disease progression" with a CTCAE severity of 
Grade 5. 
Death should not be reported as an SAE. The primary reason for a subject’s death should be 
reported as the SAE, with death reported as the outcome. 
8.4.3. 
Reporting of Adverse Events and Serious Adverse Events 
The AE reporting period begins from the time that the subject signs the ICF through and 
including 30 calendar days after the last study intervention dose. All subjects with 
treatment-related AEs/SAEs should be observed until resolution or stabilization of the event. 
Any SAE occurring after the reporting period must be promptly reported if a causal relationship 
to the study intervention(s) is suspected. If the subject begins a new anticancer therapy, the 
safety reporting period ends at the time the new treatment is started, however, death must always 
be reported if it occurs during the AE reporting period irrespective of intervening treatment. 
Elective or previously scheduled hospitalizations for pre-existing conditions that have not 
worsened after initiation of treatment should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE. 
All AEs should be recorded individually unless, in the opinion of the Investigator or designated 
physician, the AEs constitute components of a recognized condition, disease, or syndrome. In the 
latter case, the condition, disease, or syndrome should be reported rather than each individual 
sign or symptom. If a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE or SAE, as appropriate, on the relevant form(s) (SAE Report Form and/or AE 
CRF). If a diagnosis is subsequently established, it should be reported as follow-up information 
becomes available. If a diagnosis is determined after the reporting of the constellation of 
symptoms, the signs/symptoms should be updated to reflect the diagnosis. 
Each AE will be evaluated for duration, severity, seriousness, and causal relationship to each 
study intervention. The action taken with each study intervention and the outcome must also be 
recorded. 
All SAEs, regardless of relationship to each study intervention, must be reported immediately 
(within 24 hours of awareness of event by Investigator) to the Sponsor and contract research 
organization pharmacovigilance group. Initial SAE notification should be made by e-mailing or 
faxing the SAE report form to the e-mail or fax number provided on the SAE report form. 
An initial SAE Report may be sent without the Investigator’s signature but must be followed by 
a report signed by the Investigator within 48 hours of becoming aware of the event. Follow-up 
SAE reports must be submitted by the Investigator as new information becomes available. 
The Medical Monitors for this study may be contacted for advice or assistance. Contact details 
will be provided separately in a study contact list. 


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8.4.4. 
Severity of Adverse Events 
The severity of the AE will be graded according to the NCI CTCAE, Version 5.0 or higher (see 
web page https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
for details). Only AEs not listed in the CTCAE should be graded as summarized in Table 15. 
Table 15: 
CTCAE (Version 5.0 or higher) AE Grading 
CTCAE 
Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity  
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated, although this 
could improve the overall well-being or symptoms of the 
subject 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated to improve the overall 
well-being or symptoms; delaying the onset of treatment is 
not putting the survival of the subject at direct risk 
Grade 4 
Life-threatening/ 
disabling 
An immediate threat to life or leading to a permanent mental 
or physical condition that prevents work or performing 
normal daily activities; treatment or medical intervention is 
required to maintain survival 
Grade 5 
Death 
AE resulting in death  
Abbreviations: AE: adverse event, CTCAE: Common Terminology Criteria for Adverse Events. 
 
8.4.5. 
Relationship of Adverse Events to Study Intervention 
The Investigator will make a judgment regarding whether or not the AE was related to each 
study intervention, as outlined below: 
• Definitely related: This category applies when, after careful medical consideration, there 
is almost no consideration of other causation. 
• Probably related: There is a clinically plausible time sequence between onset of the AE 
and study intervention administration. The AE is unlikely to be caused by a concurrent or 
underlying illness, other drugs, or procedures. If applicable, the AE follows a clinically 
consistent resolution pattern upon withdrawal of study intervention.  
• Possibly related: There is a clinically plausible time sequence between onset of the AE 
and study intervention administration, but the AE could also have been caused by the 
concurrent or underlying illness, other drugs, or procedures. Information regarding study 
intervention withdrawal may be lacking or unclear. “Possible” should be used when study 
intervention administration is one of several biologically plausible causes of the AE. 


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• Unlikely related: The AE is most likely due to a cause not related to study intervention 
administration. However, association with the study intervention cannot be completely 
ruled out. 
• Unrelated: Another cause of the AE is most plausible, and a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and study intervention administration 
and/or a causal relationship is considered biologically implausible. 
For the purpose of regulatory reporting requirements, causal relationships of definite, probable, 
and possible will be considered treatment-related, while unlikely and unrelated will be 
considered not treatment-related. 
8.4.6. 
Clinical Laboratory Adverse Events 
A clinical laboratory AE is any laboratory value that is deemed clinically significant by the 
Investigator and is accompanied by one of the following: 
• requires a medical intervention 
• requires a modification or interruption of study intervention 
• is accompanied by clinical symptoms 
Laboratory abnormalities that do not require medical intervention should not be recorded as AEs 
and will be captured and reported in the laboratory section of the clinical study report (CSR). If a 
medical intervention occurs, it should be recorded as a treatment with the abnormal laboratory 
finding as the AE (e.g., anemia with treatment required and blood transfusion recorded as a 
procedure, hyperglycemia with treatment required and change in insulin dose recorded on the 
concomitant medications CRF). 
The Investigator should decide, based upon the AE criteria and the clinical condition of the 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. 
If, at the end of the treatment phase with the study intervention, there are pathological laboratory 
values that were not present at Baseline, further clinical or laboratory investigations should be 
performed until the values return to within reference range or until a plausible explanation (i.e., 
concomitant disease) is found for the pathologic laboratory values. 
8.4.7. 
Regulatory Aspects of Adverse Event Reporting 
The Sponsor is responsible for submitting reports of SAEs associated with the use of the study 
interventions to the appropriate Regulatory Authority (e.g., the US FDA), Investigators, and 
IRB/IEC/Central Ethics Committee in accordance with all applicable regulations and guidelines.  
It is the responsibility of the Investigator to notify the IRB of SAEs that occur at his or her site 
per IRB requirements. Investigators will be notified of all suspected, unexpected serious adverse 
reactions (SUSARs; 7-/15-Day Safety Reports) that occur during any clinical studies that are 
using duvelisib. Each site is responsible for notifying their IRB/IEC/Central Ethics Committee of 
these additional SUSARs in accordance with local regulations. 


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8.4.8. 
Overdose 
For this study, overdose is defined as a daily dose of a study intervention higher than the 
prescribed daily dose. 
In the case of overdose, clinic staff should be notified immediately, and supportive care is to be 
given if needed and as indicated. Subjects should be informed to contact their doctor 
immediately if they have taken an overdose and should stop taking study interventions. 
Overdoses will not be considered SAEs unless the outcome of the overdose meets seriousness 
criteria as defined in Section 8.4.2. In the event of an overdose that causes an SAE, the Sponsor 
should be notified within 24 hours. The subject should be carefully monitored for potential 
adverse reactions and symptomatic treatment instituted as per institutional SOC. The Investigator 
will determine if and when dosing should resume. 
8.4.9. 
Pregnancy 
Any pregnancy must be reported to the Sponsor or designee within 24 hours of the Investigator’s 
knowledge of the pregnancy using a Pregnancy Report Form. 
Pregnancy per se is not considered an AE unless there is cause to believe that the study 
interventions may have interfered with the effectiveness of a contraceptive medication or if the 
outcome of the pregnancy meets SAE criteria (miscarriage or congenital anomaly/birth defect, 
etc.), in which case it should be reported in the same manner and timelines as an SAE. In 
addition, any infant death or congenital anomaly occurring after 30 days that the Investigator 
suspects is related to the in-utero exposure to the study interventions should also be reported as 
an SAE. Hospitalization for normal delivery of a healthy newborn is not an SAE.  
Since duvelisib and pembrolizumab have not been evaluated in pregnant or nursing women, the 
treatment of pregnant women or WCBP who are not using highly effective contraception is 
contraindicated (see Table 23 and Section 10.4 for instructions on pregnancy testing and 
contraception). 
Pregnancies occurring in subjects or partners of male subjects during the study intervention 
period and until 30 days after the subject’s last dose of study interventions are considered 
immediately reportable events. If a pregnancy occurs in a subject, study interventions must be 
discontinued immediately. The pregnant woman should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. The Investigator will observe the pregnant woman until completion of the pregnancy 
and must notify the Sponsor of the outcome within 24 hours of the Investigator’s knowledge of 
the pregnancy outcome using a Pregnancy Outcome Form. This notification includes pregnancies 
resulting in live, “normal” births. 
8.5. 
Pharmacokinetics 
PK samples will be collected during the study. 
• Blood samples will be collected to evaluate the PK of duvelisib and metabolite IPI-656 at 
the visits and time points defined in the SoA (Table 2 and Table 4) 


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• On the days when postdose PK samples are collected, specific timing for the 
administration of duvelisib and pembrolizumab is required (see Table 2 and Table 4), as 
follows: 
− Stage 1: On C1D8, duvelisib will be administered at the start of the visit after the 
predose PK, pharmacodynamic, and blood sample collection. Blood samples to 
evaluate the PK of duvelisib and metabolite IPI-656 will be collected at 1 and 
2 hours after duvelisib administration. Pembrolizumab will not be administered 
until the biopsy for biomarkers has been collected; the optimal timing for 
collection of the biopsy is approximately 2 to 4 hours after duvelisib 
administration, however, a tumor biopsy at a later time during this clinic visit on 
C1D8 is acceptable. The fourth PK sample should be collected at approximately 
2 to 4 hours after duvelisib dose, as soon as possible after the biopsy, and prior to 
pembrolizumab administration. 
− Stage 1: On C2D1, duvelisib will be administered 30 minutes before the start of 
the pembrolizumab infusion. 
− Stage 2: On C1D1, duvelisib will be administered at the start of the visit after the 
predose PK and blood sample collection. Pembrolizumab will be administered 
30 minutes after the collection of the 2-hour postdose duvelisib PK sample. 
• Predose samples are preferred, therefore on the days that include PK assessments the 
morning dose of duvelisib should be administered in the clinic to facilitate collection of 
samples before dosing. However, the sample should still be collected even if the morning 
dose of duvelisib has already been taken. The date and time of the sample collection and 
date and time of the previous duvelisib dose must be recorded for all collected samples. 
• Additional PK samples beyond those listed in the SoA (Table 2 and Table 4) may be 
requested (when feasible) for any unusual safety event. (i.e., an AE different in type and 
severity from that which is expected in the setting of duvelisib use). 
• Specific instructions on sample collection and handling will be provided in a separate 
Laboratory Manual. 
• Retained duplicate PK samples may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
• Genetic analyses will not be performed on these PK samples. 
• Subject confidentiality will be maintained. 
8.6. 
Pharmacodynamics 
Pharmacodynamic biomarkers are described in Section 8.8. 
8.7. 
Genetics 
Normal germline genetic studies are not evaluated in this study. Tumor genomic studies may be 
conducted as part of exploratory biomarker research (Section 8.8). A swab of non-tumor tissue 
(genomics control) will be collected to compare polymorphisms in the subject’s non-tumor cells 
vs the tumor cells. 


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8.8. 
Biomarkers 
Blood and tissue specimens are to be collected according to the SoA (Table 2 and Table 4) and 
assessments will be conducted to evaluate potential biomarkers. Each of the specimens listed 
may be analyzed at a central laboratory or at a specialized laboratory vendor as determined by 
the Sponsor, for the various biomarkers outlined below: 
1. Pharmacodynamic markers of target inhibition in HNSCC 
2. Immunophenotypes and functional tests of major immune populations in the blood and/or 
feces 
3. Cytokines and other circulating biomarkers 
4. Prognostic markers assessed by DNA, RNA, and protein analysis from tissue and blood 
specimens 
In addition, C-reactive protein levels in blood (a clinical safety laboratory assessment) will be 
evaluated as a potential biomarker (Table 23). 
Sample collections may be reduced, or limited to certain sites/countries, based on emerging data 
or feasibility. Reductions/limitations may be implemented before amendment of the protocol. 
Specific collection and processing details (e.g., serum or plasma) will be described in the 
Laboratory Manual. Any increase in the number or type of samples collected will require a 
protocol amendment. 
8.8.1. 
Tumor Biopsy and Colon Biopsy 
In Stage 1 of the study, 2 tumor biopsies (Screening/C1D1 and C1D8) are mandatory, as 
specified in the SoA (see Table 2). The 2 biopsies do not need to be done on the same lesion. 
• Screening/C1D1 biopsy: Archival tissue beyond the 30-day Screening window and up to 
6 months before C1D1 may be considered in place of the required Screening/C1D1 
biopsy after consultation with the Sponsor, as long as no intervening systemic regimen 
had been taken during that time frame. 
• C1D8 biopsy: The optimal timing for collection is approximately 2 to 4 hours after 
duvelisib administration but before pembrolizumab administration. However, a tumor 
biopsy at a later time during this clinic visit on C1D8 is acceptable. 
In Stage 2, an optional tumor biopsy may be collected after the first cycle (on C2D1) for an 
exploratory analysis of biomarkers (Table 4). If collection of the biopsy is not feasible on C2D1, 
a biopsy collected after the second cycle (on C3D1) would also be acceptable. 
Collection procedures and amounts are described in the Laboratory Manual. 
If available, aliquots of any colon biopsies taken due to colitis or Grade ≥ 3 diarrhea or as SOC 
for any immune-mediated AEs should also be provided. 
8.9. 
Medical Resource Utilization and Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 


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9. 
STATISTICAL METHODOLOGY 
A detailed description of the statistical methodology for this study can be found in the Statistical 
Analysis Plan (SAP). Deviations from the statistical analyses outlined in this protocol will be 
indicated in the SAP; any further modifications will be noted in the final CSR. 
9.1. 
Statistical Hypotheses 
This study will test the null hypothesis that the ORR is ≤ 16% against the alternative that ORR is 
≥ 44%. The ORR (proportion of subjects achieving CR or PR) according to RECIST v 1.1 
(Eisenhauer 2009) will be estimated on the modified Intent-to-Treat (mITT) population (i.e., all 
subjects who receive at least 1 dose of duvelisib in combination with at least 1 dose of 
pembrolizumab). For this study "response" is defined as a confirmed response, per RECIST v 1.1 
(Eisenhauer 2009), unless otherwise specified. Details for determination of confirmation of 
response will be provided in the SAP. A 2-sided exact 95% CI will be calculated. 
The ORR of 16% being used for the null hypothesis is based on multiple sources. The 
pembrolizumab prescribing information (Keytruda 2019) reports an ORR for pembrolizumab 
monotherapy of 16% in subjects previously treated with a platinum-containing therapy in the 
KEYNOTE-012 study. An ORR of 16% is also reported for subjects naïve to anti-PD-L1 therapy 
in the KEYNOTE-055 study (Bauml 2017). Further, the ORR for pembrolizumab monotherapy 
is reported in the USPI as 19%. Therefore, an uninteresting response rate of 16% will be used for 
all subjects in this study. 
The evaluation of the primary endpoint will be conducted at the highest dose that is tolerated 
during the DLT evaluation. Therefore, if the initial dose of 25 mg BID is not tolerated but the 
reduced dose of 15 mg BID is tolerated, the primary endpoint will be evaluated in all subjects 
starting at the tolerated dose. 
9.2. 
Sample Size Determination 
The study will follow a Simon two-stage design (Simon 1989). In the first stage, approximately 
13 subjects will be accrued. If there are 2 or fewer responses (CR or PR) in these 13 subjects, 
further accrual in the study may be stopped. However, all available data will be considered 
before termination. 
In Stage 2, 17 additional subjects will be accrued for a total of 30 subjects in the final analysis. 
The null hypothesis will be rejected if 10 or more responses (CR or PR) are observed in 
30 subjects. This design yields an overall type I error rate of 5% and power of 90% when the true 
response rate is 44%. 
9.3. 
Populations for Analyses 
The populations for the analyses are described in Table 16. 


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Table 16: 
Populations for Analyses 
Population 
Description 
Enrolleda 
All subjects who sign the ICF 
DLT Evaluable 
The first 6 subjects in Stage 1 who complete Cycle 1 and who 
receive ≥ 75% of the scheduled duvelisib doses during Cycle 1 or 
who have a DLT during Cycle 1 
ITT 
All subjects who receive at least 1 dose of duvelisib. The ITT 
analysis set will serve as the primary analysis set for all safety 
endpoints and baseline parameters. 
mITT 
All subjects who receive at least 1 dose of duvelisib in 
combination with at least 1 dose of pembrolizumab. The mITT 
analysis set will serve as the primary analysis set for all efficacy 
endpoints. 
Abbreviations: DLT: dose-limiting toxicity; ICF: informed consent form; ITT: intent-to-treat; mITT: modified 
intent-to-treat. 
a “Enrolled” means a subject's, or their legally acceptable representative’s, agreement to participate in a clinical 
study after completion of the informed consent process. Potential subjects who are pre-screened for the purpose of 
determining eligibility for the study but do not sign an ICF are not considered enrolled. 
9.4. 
Statistical Analyses 
The SAP will be finalized before database lock and it will include a more technical and detailed 
description of the statistical analyses summarized in this section. This section is a summary of 
the planned statistical analyses of the most important endpoints, including primary and 
secondary endpoints. 
9.4.1. 
General Considerations 
Hypothesis testing will be used for the interim (Stage 1) and final (Stage 1 + Stage 2) analyses of 
the efficacy endpoint of ORR. No formal hypothesis testing will be used for any other endpoints 
or other study data, such as demographics and safety data. 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. For categorical variables, summary tabulations of the number and percentage 
of subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as 2-sided 95% CIs, unless stated otherwise. For continuous variables, the 
number of subjects, mean, median, standard deviation, minimum, and maximum values will be 
presented. Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 
25th, 50th (median), and 75th percentiles with associated 2-sided 95% CIs, as well as number 
and percentage of censored observations. 
The Investigator’s assessments of disease response will be used as the basis for the evaluation of 
the primary and secondary efficacy endpoints. 


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9.4.1.1. 
Procedures for Handling Missing, Unused, and Spurious Data 
All available efficacy and safety data will be included in data listings and tabulations. In general, 
missing data will be treated as missing and no data imputation will be applied, unless otherwise 
specified. Data that are potentially spurious or erroneous will be examined according to standard 
data management operating procedures. Details of procedures for handling missing, unused, or 
spurious data can be found in the SAP. 
9.4.2. 
Primary Endpoint Efficacy Analysis 
ORR will be assessed according to RECIST v 1.1 (Eisenhauer 2009). Final analysis of the 
combined Stage 1 and Stage 2 ORR will occur after the last subject enrolled and dosed in Stage 2 
has been followed for 6 months. 
9.4.3. 
Secondary Efficacy Endpoints Analyses 
• ORR will be assessed according to RECIST v 1.1 (Eisenhauer 2009). Evaluation of ORR 
in Stage 1 will occur after the last subject enrolled and dosed in Stage 1 has been 
followed through at least the first disease response assessment. 
• DOR will be calculated for those subjects with a CR or PR from the time of first response 
to PD using KM methods 
• PFS will be assessed using KM methods from time of first treatment to PD or death 
• OS will be assessed using KM methods from time of first treatment to death 
9.4.4. 
Primary Safety Endpoint Analysis: Stage 1 
• Safety analyses will be performed on the ITT population, and safety endpoints will be 
tabulated and presented. 
• AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.0 or higher for purposes of summarization. All AEs occurring during the 
study will be included in by-subject data listings and tabulated by MedDRA system organ 
class and preferred term. Adverse events will be summarized overall, by relationship to 
each study intervention, and by severity. Events leading to death, SAEs, and events 
resulting in discontinuation of study interventions will be listed and, if warranted by the 
data, tabulated. 
• AEs of special interest (AESI) will be defined for analysis purposes in the SAP and will 
be summarized using the methods as described in the above bullet. 
• Exposure to duvelisib and pembrolizumab, including the proportion of expected doses 
received, will be tabulated. 
• Changes from baseline over time for vital sign measurements (including diastolic and 
systolic blood pressure) will be summarized. 
• Individual subject laboratory parameter values and changes from baseline over time will 
be summarized using descriptive statistics. Severity of select clinical laboratory measures 
will be determined using NCI CTCAE criteria and Grade 3 or 4 laboratory values will be 
presented in a separate table. 


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• The use of concomitant medications, coded using the World Health Organization Drug 
Dictionary, will be tabulated and included in a by-subject listing. 
9.4.5. 
Secondary Safety Endpoint Analysis 
Safety analyses, as described in Section 9.4.4, will be performed on the ITT population for 
Stage 1 and Stage 2 combined, and safety endpoints will be tabulated and presented. 
9.4.6. 
Secondary PK Endpoints Analyses 
• PK analyses will be conducted on the ITT population. 
• Blood samples will be taken for the analyses of duvelisib and metabolite IPI-656 in 
plasma at the time points defined in the SoA (Table 2 and Table 4). PK exposure 
parameters (maximum observed concentration [Cmax] and area under the curve [AUC]) 
will be determined using the bioanalytical data and Population PK (POPPK) modeling. 
The PK data will be summarized using descriptive statistics and will be listed and 
summarized in tabular and/or graphical form. 
• Based on the exposure parameters determined from POPPK model, the relationship 
between duvelisib exposure and response and AEs will be analyzed. 
9.4.7. 
Exploratory Endpoints Analyses 
• Changes from baseline over time for ECOG performance status will be summarized. A 
by-subject listing of ECOG performance status data will be prepared. 
• Pharmacodynamic analyses will be conducted on the ITT population for Stage 1. 
• Pharmacodynamic and prognostic markers will be evaluated relative to baseline levels 
and change from baseline levels. 
• Biomarker effects will be summarized using descriptive statistics; associations of 
biomarkers, including tumor and/or immune cell PD-L1 levels and HPV status, with 
clinical efficacy and/or safety outcomes may be explored. 
9.5. 
Interim Analyses 
An interim analysis of the primary endpoint will be conducted at the end of Stage 1 as part of the 
Simon two-stage design (Simon 1989). 
9.6. 
Data Monitoring Committee 
This study will not use a data monitoring committee. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS: APPENDICES 
 
Table 17: 
Appendices 
Appendix 
Title 
Section 
1 
RECIST Version 1.1 
10.1 
2 
CYP3A Inhibitors, Inducers, and Substrates 
10.2 
3 
Clinical Laboratory Tests 
 10.3  
4 
Contraceptive Guidance  
 10.4  
5 
ECOG Performance Status 
10.5  
6 
Regulatory, Ethical, and Study Oversight Considerations 
 10.6  
7 
Abbreviations 
 10.7  
 
 
 


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10.1. 
Appendix 1: RECIST Version 1.1 
(Modified from Eisenhauer 2009) 
All subjects will have their BEST RESPONSE on study classified as outlined below (Table 18 
and Table 19): 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in the short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum diameters. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions will also be considered PD. 
Response Duration 
Response duration will be measured from the time that the measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or progressive disease 
is objectively documented, taking as reference for PD the smallest measurements recorded on 
study. 
Stable Disease Duration 
Stable disease duration will be measured from the time of start of the intervention until the 
criteria for progression are met, taking as reference the smallest sum of diameters recorded on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 


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Table 18: 
Evaluation of Best Overall Response – Subject with Target (± Non-target) 
Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD/or not all 
evaluated 
No 
PR 
SD 
Non-PD/or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR: complete response; NE: inevaluable; PD: progressive disease; PR: partial response; SD: 
stable disease. 
Table 19: 
Evaluation of Best Overall Response – Subject with Non-target Disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR: complete response; NE: inevaluable; PD: progressive disease. 


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a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease because SD is increasingly used as an 
endpoint for assessment of efficacy in some studies; therefore, to assign this category when no lesions can be 
measured is not advised. 
Note: Subjects with a global deterioration of health status requiring discontinuation of 
intervention without objective evidence of PD at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of study interventions. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and < 10 mm 
diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. 
Chest X-ray 
A chest CT scan is preferred over a chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-rays may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT (preferred) or MRI Scans 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT scan is defined based on the assumption 
that the CT slice thickness is 5 mm or less. When CT scans have a slice thickness > 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. An MRI scan is also 
acceptable in certain situations (e.g., for body scans). 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure with CT, MRI may be used instead of CT in selected 
instances. 


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Cytology, Histology 
These techniques can be used to differentiate between PR and CR in rare cases (e.g., residual 
lesions in tumour types such as germ cell tumours, where known residual benign tumours can 
remain) from PD. 
 
 


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10.2. 
Appendix 2: CYP3A Inhibitors, Inducers, and Substrates 
10.2.1. 
Medications or Foods Known to Inhibit CYP3A 
The following list provides medications or foods known to induce or inhibit CYP3A activity. 
Note that this is not a comprehensive list of all medications or foods which may modulate 
CYP3A activity. Additional information can be found at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm 
Note: Subjects receiving duvelisib are prohibited from concomitant use of medications or 
foods that are known to be strong inhibitors or inducers of CYP3A. 
Table 20: 
Classification of In Vivo Inhibitors of CYP3A 
Strong Inhibitors1 
Moderate inhibitors2 
Weak inhibitors3 
Boceprevir, 
clarithromycin, conivaptan, 
grapefruit juice4, indinavir, 
itraconazole, ketoconazole,  
lopinavir/ritonavir, 
mibefradil5 
nefazodone, nelfinavir, 
posaconazole, ritonavir,  
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir, grapefruit juice4, 
imatinib, verapamil 
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, cimetidine, 
cyclosporine, fluoxetine, 
fluvoxamine, ginkgo6, goldenseal6, 
isoniazid, nilotinib, 
oral contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton 
Abbreviations: AUC: area under the curve; CL: clearance; CYP: Cytochrome P450; US: United States. 
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that 
CYP by ≥ 5-fold or > 80% decrease in CL. 
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by < 5-fold but ≥ 2-fold or 50 to 80% decrease in CL. 
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by < 2-fold but ≥ 5-fold or 20 to 50% decrease in CL. 
4. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
5. Withdrawn from the US market because of safety reasons. 
6. Herbal product.  
 
10.2.2. 
Medications Known to Induce CYP3A 
Please discuss use of weak or moderate CYP3A inhibitors and inducers with the Medical 
Monitor. 


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Table 21: 
Classification of In Vivo Inducers of CYP3A 
Strong Inducers ≥ 80% decrease 
in AUC 
Moderate Inducers 
50-80% decrease in AUC 
Weak Inducers 
20-50% decrease in AUC 
Avasimibe1, arbamazepine, 
phenytoin, rifampin, St. John’s 
Wort2,3 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
Amprenavir, aprepitant, 
armodafinil, Echinacea3 
pioglitazone, prednisone, 
rufinamide 
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A. 
1. Not a marketed drug. 
2. The effect of St. John’s Wort varies widely and is preparation-dependent. 
3. Herbal product. 
10.2.3. 
Medications Known to Be CYP3A Substrates 
Known sensitive CYP3A substrates and CYP3A substrates with a narrow therapeutic range are 
listed in Table 22. Consider finding an alternative drug that is not a substrate of CYP3A4. 
Additional information can be found at: 
https://drug-interactions.medicine.iu.edu/main-table.aspx 
http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687 
Table 22: 
Cytochrome P450 3A (CYP3A) Substrates 
Sensitive CYP3A Substrates 
budesonide 
buspirone 
eplerenone 
eletriptan 
felodipine 
fluticasone 
lovastatin 
midazolam 
saquinavir 
sildenafil 
simvastatin 
triazolam 
vardenafil 
CYP3A Substrates with a Narrow Therapeutic Range 
alfentanil 
astemizole  
cisapride  
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine  
sirolimus 
tacrolimus 
terfenadine 
 
 
 


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10.3. 
Appendix 3: Clinical Laboratory Tests 
• The tests detailed in Table 23 will be performed by the local laboratory. The timing and 
frequency are detailed in the SoA Table 1 and Table 3. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
• The results of each test must be entered in the CRF. 
Table 23: 
Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessmentsa 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean corpuscular 
volume 
Mean corpuscular 
hemoglobin 
%Reticulocytes 
White blood cell 
count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood urea 
nitrogen  
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose 
(fasting)  
Calcium 
Alkaline phosphatase 
(ALP) 
Lactate 
dehydrogenase 
(LDH) 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick. If positive, quantitative analysis is needed if 
not previously noted as part of medical history. 
• 
Microscopic examination (if blood or protein is abnormal) 


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Laboratory 
Assessmentsa 
Parameters 
Pregnancy 
• 
Highly sensitive serum/urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)2 
Other Screening 
Tests 
• 
Viral screening: serology (hepatitis B surface antigen [HBsAg], hepatitis B 
core antibody [HBcAb], hepatitis C virus antibody [HVCAb], Epstein-Barr 
virus [EBV] antibody, human immunodeficiency virus [HIV] antibody); HPV 
testing (if status not available at Screening), cytomegalovirus (CMV) via 
serology, or viral load detection via polymerase chain reaction (PCR). 
Subjects with a negative HBsAg and positive HBcAb require an 
undetectable/negative hepatitis B DNA test (e.g., PCR test) to be dosed. 
o HIV testing is required for subjects without documentation of a prior 
negative test result from within the last 9 months. Results will be analyzed 
locally and will not be captured in the study database. Only subjects with 
negative results will be eligible to begin study intervention. 
• 
Coagulation tests: prothrombin time (PT), activated partial thromboplastin 
time (aPTT), and international normalized ratio (INR) 
• 
C-reactive proteinb 
• 
Triiodothyronine (T3), free thyroxine (FT4), and thyroid-stimulating 
hormone (TSH) 
• 
Food and Drug Administration (FDA)-approved PD-L1 testing is required for 
indications specified in the current pembrolizumab prescribing information 
(Keytruda 2019), unless results are already available. Information on 
FDA-approved tests is available at: 
http://www.fda.gov/CompanionDiagnostics. 
NOTES: 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after 
liver stopping or monitoring event are provided in Table 12 for duvelisib and in Table 13 for 
pembrolizumab. All liver-related SAEs must be reported as described in Section 8.4.3. 
2. A serum pregnancy test must be performed within 7 days of the first dose. At subsequent time 
points, serum testing is preferred but urine testing is allowed if a blood draw for other assessments 
is not performed. A positive urine test result must be confirmed by a serum test. 
a See Section 8.2.4 for guidance on repeating/recording laboratory tests with values that are considered clinically 
significant or that require a change in subject management. 
b Also obtain when Grade ≥ 2 diarrhea, any grade colitis, or any grade immune-mediated toxicity (e.g., pneumonitis, 
colitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, cutaneous adverse reactions, encephalitis) occurs. 
 
 
 


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10.4. 
Appendix 4: Contraception Guidance 
The effects of duvelisib on conception, pregnancy, and lactation are unknown. Every woman of 
childbearing potential (WCBP) and male subjects with a partner who is a WCBP must use 
contraception as described below. A woman is considered to be a WCBP after menarche and 
until becoming postmenopausal (i.e., > 55 years and postmenopausal for at least 1 year), unless 
permanently sterile. 
At Screening, all male and female subjects of reproductive potential (i.e., not surgically sterile or 
female subjects who are not postmenopausal) must agree to use a highly effective method of 
contraception (see Section 10.4.1) for the duration of the study interventions, and for at least 4 
months after the last dose of study interventions. Male subjects must also refrain from donating 
sperm during their participation in the study and for at least 4 months after the last dose of study 
interventions. 
The use of contraceptive methods is not required if the male subject or the male partner (of the 
female subject) has a documented history of a vasectomy or if the female subject or the female 
partner (of the male subject) has a documented history of bilateral oophorectomy, hysterectomy, 
or tubal ligation, or if she is > 55 years of age and postmenopausal for at least 1 year. 
See Section 8.4.9 for requirements for pregnancy reporting. 
10.4.1. 
Highly Effective Methods of Contraception 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Such methods include: 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationa: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulationa: 
− oral 
− injectable 
− implantableb 
• intrauterine device (IUD)b 
• intrauterine hormone-releasing system (IUS)b 
• bilateral tubal occlusionb 
• vasectomized partnerb,c 
• sexual abstinenced 
a Hormonal contraception may be susceptible to interaction with the Investigational 
Medicinal Product (IMP), which may reduce the efficacy of the contraception method. 


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bThis method of contraception should preferably be used, in particular when contraception is 
introduced as a result of participation in the clinical study. 
cVasectomized partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WCBP trial participant and that the vasectomized partner has 
received medical assessment of the surgical success. 
d Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the subject. 
 


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10.5. 
Appendix 5: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
Grade 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Oken 1982. 
 
 
 


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10.6. 
Appendix 6: Regulatory, Ethical, and Study Oversight 
Considerations 
10.6.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.6.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.6.3. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study. 


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• Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements (where applicable), 
and the IRB/IEC or study site. 
• The medical record must include a statement that written informed consent was obtained 
when the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the study as necessary. 
• A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
• A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
Note: The subject must sign the ICF before initiating any study specific procedures. SOC 
assessments that fulfill study eligibility requirements may be performed before the subject 
signs the ICF. 
10.6.4. 
Subject Data Protection 
• Subjects will be assigned a unique identifier during Screening. Any subject records or 
datasets that are transferred to the Sponsor will contain the identifier only; subject names 
or any information that would make the subject identifiable will not be transferred. 
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the subject who will be required to give consent for their data to be used 
as described in the informed consent. 
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.6.5. 
Dissemination of Clinical Study Data 
The Sponsor will comply with current regulatory requirements for disclosure and submission of 
study results. The Sponsor’s policy on publication of study results is described in Section 10.6.9. 
10.6.6. 
Data Quality Assurance 
• All subject data relating to the study will be recorded in the electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 


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• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements (including handling of 
noncompliance issues and monitoring techniques [central, remote, or on-site monitoring]) 
are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after study completion, for a period of 
2 years after a marketing application is approved for duvelisib in the study population, 
until 2 years after shipment and delivery of the drug for investigational use is 
discontinued, or as long as required by local regulations, whichever is longer. No records 
may be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification to 
the Sponsor. 
10.6.7. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported in the CRF or entered in the CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in ICH guidance for industry E6 
Good Clinical Practice: Consolidated Guidance. 
10.6.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor or designee reserves the right to close a study site or terminate the study at any time 
for any reason (e.g., as necessary for subject safety) at the sole discretion of the Sponsor. Study 


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sites will be closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study-site closure visit has been 
performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up. 
10.6.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings with prior 
approval of the Sponsor. The Investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multi-site studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement 
between the Sponsor and the Investigators. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.7. 
Appendix 7: Abbreviations 
Table 24: 
List of Abbreviations 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Clearance 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed concentration 
CMV 
Cytomegalovirus 
CPS 
Combined positive score 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computed tomography 
CxDx 
Cycle x Day x 
CYP3A 
Cytochrome P450 3A 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
EBV 
Epstein-Barr virus 


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Abbreviation 
Definition 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EoT 
End of treatment 
FDA 
Food and Drug Administration 
FL 
Follicular lymphoma 
FT4 
Free thyroxine 
F/U 
Follow-up 
hCG 
Human chorionic gonadotropin 
HBcAb 
Hepatitis B core antibody  
HBsAg 
Hepatitis B surface antigen 
HCVAb 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPV 
Human papillomavirus 
HR 
Hazard ratio 
HSV 
Herpes simplex virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INR 
international normalized ratio 
IPI-145 
Duvelisib 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
KM 
Kaplan-Meier 
L 
Liter 
LDH 
Lactate dehydrogenase 
MDSCs 
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Definition 
mg 
Milligram 
mITT 
Modified intent-to treat 
MOC1 
Murine oral cancer 
MRI 
Magnetic resonance imaging 
mTOR 
Mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
p 
P-value 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PDn 
Pharmacodynamic 
PE 
Physical examination 
PFS 
Progression-free survival 
PI3K 
Phosphoinositide 3-kinase 
PJP 
Pneumocystis jiroveci pneumonia 
PK 
Pharmacokinetic 
PO 
Orally/oral 
POPPK 
Population PK 
PR 
Partial response 
PT 
Prothrombin time 
q3w 
Every 3 weeks 
QD 
Once daily 
QTcF 
QT interval corrected with Fridericia’s method 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 


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Abbreviation 
Definition 
R/M 
Recurrent or metastatic 
R/R 
Relapsed or refractory 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum pyruvic transaminase 
SJS 
Stevens Johnson syndrome 
SLL 
Small lymphocytic lymphoma 
SoA 
Schedule of Activities 
SOC 
Standard of care 
T3 
Triiodothyronine 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic epidermal necrolysis 
Tregs 
Regulatory T-cells 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
vs 
Versus 
VZV 
Varicella zoster virus 
WCBP 
Woman of childbearing potential 
 
 


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10.8. 
Appendix 8: Protocol Amendment History 
10.8.1. 
Protocol Version 2.0 (Amendment 1), 17 September 2019 
10.8.1.1. Amendment Rationale 
The primary purpose for this amendment is to provide updated safety guidance. 
The revised protocol, Version 2.0, dated 17 September 2019 will be submitted by the 
Investigator(s) to all applicable IRBs, IECs, or CECs, and by Verastem, Inc. to all applicable 
Regulatory Authorities. 
A summary of key changes that were made to protocol Version 1.0, including the rationales for 
these changes, is provided in Table 25. 
Table 25: 
Summary of Changes for Version 2.0 
Section(s) 
Description of Change 
Rationale for the Change 
Global 
Updated the version number and date of 
protocol from Version 1.0 dated 18 June 2019 
to Version 2.0 dated 17 September 2019  
Administrative change 
Global 
Minor corrections to grammar/spelling 
Administrative changes 
Title Page 
Updated the IND number to the IND number 
for duvelisib in solid tumors 
The IND number for duvelisib in 
hematologic cancers was used for 
Version 1 because the IND number 
for duvelisib in solid tumors was not 
available until after Version 1 was 
finalized 
Signature Page 
Updated the Sponsor signatory 
Administrative change 
Synopsis 
Figure 1 
Figure 2 
Figure 3 
Table 1 
Table 3 
Section 4.1 
Section 8.1.1 
Section 9.1 
 
• 
Deleted the following from the Synopsis 
and Section 4.1: “During the evaluation of 
available efficacy and safety data at the end 
of Stage 1, enrollment is anticipated to 
remain open for Stage 2 in the absence of 
safety or other concerns that may affect 
further development.” 
• 
Clarified that enrollment in Stage 2 will not 
begin until all of the planned 13 subjects 
are enrolled in Stage 1 and at least 2 of 
13 subjects have a confirmed response. 
• 
In Figures 2 and 3, Tables 1 and 3, and 
Section 8.1.1: Clarified that in the case of a 
CR or PR, a confirmatory scan must be 
performed per RECIST v1.1 and added the 
recommendation that this scan be 
performed at 4 (+1) weeks after the initial 
response. 
• 
In Section 9.1, clarified that "response" is 
defined as a confirmed response, per 
RECIST v 1.1, unless otherwise specified, 
and that details for determination of 
To clarify that enrollment in Stage 2 
will not begin until all of the 
planned 13 subjects are enrolled in 
Stage 1 and at least 2 of 13 subjects 
have a confirmed response and add 
specific criteria related to 
confirmation of response. 


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Section(s) 
Description of Change 
Rationale for the Change 
confirmation of response will be provided 
in the SAP. 
Synopsis 
Figure 2 
Figure 3 
Section 4.1 
Table 7, footnote “a” 
Section 6.8 
Section 7.1 
Limited administration of study treatment to a 
maximum of 24 months 
To align the duration of 
pembrolizumab treatment with the 
prescribing information for 
Keytruda 
Synopsis 
Table 1, footnote “i” 
Section 4.1 
Section 6.7 
• 
Clarified that in cases for which the first 
dose of pembrolizumab on C1D8 is 
delayed, every effort should made to delay 
the subsequent dosing of the next cycle 
(within the protocol-allowed window of 
3 days) to achieve as close to a 3-week 
interval between pembrolizumab doses as 
possible.  
• 
Specified that the Medical Monitor needs to 
be consulted for such adjustments to ensure 
uniformity of approach and to account for 
subject-specific circumstances. For 
example, if the third day of the C2D1 
window falls on a weekend, an additional 
adjustment would need to be made on a 
case-by-case basis. 
• 
To provide details regarding the 
management of subsequent 
dosing of pembrolizumab in 
cases where the first dose is 
delayed 
 
 
 
• 
To ensure uniformity of 
approach and to account for 
subject-specific circumstances 
Synopsis 
Table 2, footnote “g” 
Table 5 
Section 5 
Section 8.5 
Section 9.4.6 
Specified the metabolite of duvelisib as IPI-656 
To clarify PK data analysis 
Synopsis 
Section 4.1 
Section 4.2 
Table 5 
Table 7  
Section 8.1.2.1 
(removed) 
Table 15 (removed) 
Section 10.7 
Section 11 
Removed all references to immune Response 
Evaluation Criteria in Solid Tumors (iRECIST) 
and specified that subjects will not be permitted 
to continue study treatment after 
RECIST-defined progressive disease 
Pseudo-progression does not need to 
be included in the protocol because 
it is rarely seen in subjects with 
HNSCC who receive therapy with 
immune checkpoint inhibitors 
Synopsis 
Section 4.1 
Section 6.6.1 
Added the following to the Synopsis and 
Section 4.1: 
• 
A formal analysis of available safety data 
when the first 10 subjects treated have 
received at least 1 cycle of study treatment. 
To enable assessment of toxicities 
of later onset, particularly outside of 
the DLT window and clarify the 
approach of assessing  the serious 
Grade 3 or higher overlapping 
toxicities (i.e., pneumonitis, colitis, 


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Section(s) 
Description of Change 
Rationale for the Change 
• 
Definition and stopping rule for excessive 
rate of Grade 3 or higher overlapping SAEs 
 
In Section 6.6.1, added that an evaluation of the 
totality of safety data will be performed by the 
Medical Monitor and the Investigators if an 
excessive rate of Grade 3 or higher overlapping 
SAEs is observed and that a decision to hold 
enrollment of subjects may be made. 
cutaneous skin reactions, elevations 
of AST/ALT) 
 
Synopsis 
Section 5.2 
Revised exclusion criterion 14 to remove 
history of human T cell lymphotropic virus 1 
infection as an exclusion criterion 
HTLV-1 screening is not relevant to 
this study 
 
Table 1 
Table 3 
• 
Simplified the duvelisib administration note 
in Table 1 and Table 3 to state “on study 
visit days”  
• 
Added “if applicable” to the duvelisib 
administration note in Table 1 indicating 
that duvelisib will be administered before 
the pembrolizumab infusion is started 
• 
Details are not needed because 
all clinic visits are either C1D1, 
PK assessment days, or 
pembrolizumab dosing days  
• 
There is no pembrolizumab 
infusion for Stage 1 on C1D1 
or C1D15 
Table 1 
Table 3 
Table 23 
Added HPV testing if HPV status is not 
available at Screening 
HPV status is needed for the 
exploratory analysis of the 
relationship of ORR to tumor HPV 
status  
Table 2, footnote “g” 
Section 6.1.2 
Section 8.5 
Revised to state that the PK blood draw after 
biopsy collection should be collected as soon as 
possible after the biopsy and prior to 
pembrolizumab administration 
To clarify the timing for collection 
of the post-biopsy PK blood draw 
Section 2.4.1 
Section 6.6.1 
Section 6.7.1 
Table 10 
In Sections 2.4.1, 6,6,1, and 6.7.1, clarified that 
elevations in ALT and AST levels are potential 
overlapping toxicities. 
Modified Table 10 as follows: 
a. Separated recommendations for Grade 2 
diarrhea or colitis from those for Grade 1; 
specified that duvelisib and pembrolizumab be 
withheld for Grade 2 diarrhea or colitis and 
added recommendations for management. 
b. Modified to contain only 1 set (i.e., the more 
conservative recommendations for immune-
related hepatitis) of recommendations for 
elevations in AST and ALT (e.g., 
hepatoxicity/hepatitis). 
To align with prescribing 
information and use the more 
conservative dose 
modification/management 
recommendations (e.g., those for 
immune-related hepatitis) for AST 
and ALT elevations because it is 
generally not possible to distinguish 
immune-related elevations in AST 
and ALT from non-immune-related 
elevations (without a biopsy) 
Section 5.5 
Deleted text stating that rescreened subjects 
should be assigned the same subject number as 
for the initial screening. 
To align with current practice  
Table 10 
Table 12 
Moved the guidance for duvelisib monotherapy 
adverse reactions from the overlapping 
toxicities table (Table 10) to the monotherapy 
toxicities table (Table 12)  
To streamline the guidance for 
managing  duvelisib toxicities 
during the monotherapy lead-in 
 
Section 6.7.1 
Modified the DLT criteria as follows: 
To tighten the DLT criteria 


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Section(s) 
Description of Change 
Rationale for the Change 
a. Removed “or higher” from the DLT criterion 
related to nausea, vomiting or diarrhea and 
added “or Grade 4 vomiting or diarrhea” 
b. Modified the DLT criterion for elevations in 
ALT or AST to include any elevations in AST 
or ALT requiring permanent discontinuation of 
study treatment  
c. Modified the DLT criterion for elevations in 
bilirubin to include any elevations in bilirubin 
requiring permanent discontinuation of study 
treatment 
d. Modified the DLT criterion for any other 
toxicity to include any toxicity requiring 
permanent discontinuation of study treatment 
Table 13 
Removed the row for “immune-mediated 
hepatitis in subjects with hepatocellular 
carcinoma”  
Subjects with hepatocellular 
carcinoma will not be enrolled in  
this study 
Section 8.4.8 
Clarified that only cases of overdose that cause 
an SAE are required to be reported within 
24 hours 
Reporting of overdose within 
24 hours is only required if it causes 
an SAE 
Section 9.4.6 
Specified that a Population PK model will be 
developed to analyze the relationship between 
duvelisib exposure and response and AEs 
To clarify PK data analysis 
Table 23 
Removed the CD4+ T-cell count as a 
post-treatment test 
Although pneumocystis prophylaxis 
concomitant with duvelisib 
treatment must be done per 
institutional guidelines, collection of 
a post-treatment CD4+ T-cell count 
result is not required in this study 
Table 24 
Updated list of abbreviations 
Administrative change 
Section 10.8.1 
Added Summary of Changes made for 
Version 2.0 
Administrative change 
Section 10.8.2  
Added version history 
Administrative change 
10.8.2. 
Version History 
Table 26: 
Primary Reason for Each Version 
Version 
Primary Reason for Version 
2.0 
To provide updated safety guidance 
1.0 
Original version 


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11. 
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P] Verastem Qncology
05 June, 2020
Clinical Study Protocol: VS-0145-130 Version 2.0 dated 17 September 2019 entitled "A Phase 1b/2 Study
of Duvelisib in Combination with Pembrolizumab in Subjects with Recurrent or Metastatic Head and
Neck Squamous
Cell Cancer"
Memorandum re: Clarification regarding Stage
1 PK draw at Cycle 5 Day 1 (pre-dose)
Section 1.3 Schedule of Activities for Stage 1- Table 2 notes that PK samples should be drawn at Cycle 5
Day 1, pre-dose.
This PK draw is not required and should not be performed. The PK draw will be deleted
from the Protocol's Schedule of Events when/if the protocol is amended
in the future.