A Phase I/II Study of PI3Kγδ Inhibitor Duvelisib in Combination With Nivolumab in Patients With Advanced Unresectable Melanoma Who Have Progressed on Anti-PD1 Therapy
Phase: PHASE1
Conditions: Unresectable Melanoma
Sponsor: John Kirkwood

 
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 Title: A Phase I/II Study of PI3Kγδ inhibitor Duvelisib in Combination with Nivolumab in Patients with 
Advanced Unresectable Melanoma who have Progressed on Anti-PD1 Therapy 
 
Version: 
 
 
 
04/27/2022 
 
Corresponding Organization:   
UPMC Hillman Cancer Center 
Protocol Number:  
 
 
HCC# 20-155 
Sponsor-Investigators:  
Principal Investigator:   
 
John M Kirkwood, MD 
UPMC Hillman Cancer Center 
5117 Centre Ave, Suite 1.32 
Pittsburgh, PA 15213 
(412) 623-7707 
kirkwoodjm@upmc.edu 
 
 
Translational Research Collaborator:  
Tullia Bruno, PhD 
UPMC Hillman Cancer Center 
5117 Centre Avenue, Suite 2.19 
Pittsburgh, PA 15213 
(412) 623-1780 
tbruno@pitt.edu 
 
Biostatistician:   
 
 
Hong Wang, PhD 
UPMC Hillman Cancer Center Biostatistics Facility 
325 Sterling Plaza 
201 North Craig Street 
Pittsburgh, PA 15213 
how8@pitt.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source(s) of Support:   
 
Secura Bio 
 

 
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Table of Contents 
i. Abbreviations ............................................................................................................................................. 5 
ii. Protocol Summary ..................................................................................................................................... 7 
iii. Study Design Schematic ......................................................................................................................... 10 
1.0 Background and Study Rationale .......................................................................................................... 11 
2.0 Study Objectives ................................................................................................................................... 12 
2.2 Primary Objectives ............................................................................................................................ 12 
2.3 Secondary Objectives ........................................................................................................................ 12 
2.4 Exploratory Objectives ...................................................................................................................... 13 
3.0 Investigational Plan ............................................................................................................................... 13 
3.1 General Study Design ........................................................................................................................ 13 
3.1.1 Screening of Subjects ................................................................................................................. 13 
3.1.2 Study Intervention ..................................................................................................................... 13 
3.1.3 Follow-Up Phase ........................................................................................................................ 14 
3.1.4 Allocation to Interventional Group ............................................................................................ 14 
3.2 Study Endpoints ................................................................................................................................ 14 
3.2.1 Primary Endpoints ...................................................................................................................... 14 
3.2.2 Secondary Endpoints ................................................................................................................. 14 
4.0 Study Population and Eligibility ............................................................................................................ 15 
4.1 Inclusion Criteria ............................................................................................................................... 15 
4.2 Exclusion Criteria ............................................................................................................................... 16 
4.3 Subject Recruitment ......................................................................................................................... 19 
4.4 Subject Withdrawal or Termination ................................................................................................. 19 
5.0 Clinical Trial Processes and Procedures ................................................................................................ 21 
5.1 Study Site .......................................................................................................................................... 21 
5.2 Screening and Pretreatment Evaluations ......................................................................................... 21 
5.3 Diagnostic Plan .................................................................................................................................. 22 
5.4 Procedure for Registration of Subjects ............................................................................................. 22 
6.0 Trial Treatments, Evaluations, and Measurements .............................................................................. 22 
6.1 Medical Record Review ..................................................................................................................... 22 
6.2 
Medical History and Physical Examination ................................................................................. 23 
6.3 
Vital Signs .................................................................................................................................... 23 

 
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6.4 
Laboratory Evaluations ............................................................................................................... 23 
6.4.1 
Table: Clinical Laboratory Tests .......................................................................................... 23 
6.5 Pregnancy Testing ............................................................................................................................. 24 
6.6 Efficacy Evaluations ........................................................................................................................... 24 
6.7 Safety Evaluations ............................................................................................................................. 24 
6.8 Prophylactic Medications .................................................................................................................. 26 
7.0 Study Drug Supply and Administration ................................................................................................. 26 
7.1 Drug Inventory Records .................................................................................................................... 26 
7.2 Description ........................................................................................................................................ 26 
7.3 Packaging .......................................................................................................................................... 26 
7.4 Receiving, Storage, Dispensing, and Return ..................................................................................... 27 
7.4.1 Receipt of Drug Supplies ............................................................................................................ 27 
7.4.2 Storage ....................................................................................................................................... 27 
7.4.3 Dispensing of Study Drug ........................................................................................................... 28 
7.4.4 Return or Destruction of Study Drug ......................................................................................... 28 
7.5 Treatment Regimen .......................................................................................................................... 28 
7.6 Dose Adjustments and Adverse Reaction Management .................................................................. 29 
7.7 Method of Subject Assignment to Treatment Groups...................................................................... 36 
7.8 Preparation and Administration of Study Drug ................................................................................ 36 
7.9 Subject Compliance Monitoring ....................................................................................................... 36 
7.10 Prior and Concomitant Therapy ...................................................................................................... 36 
7.11 Blinding of Study Drug .................................................................................................................... 37 
8.0 Safety and Adverse Events Assessing, Recording, and Reporting ........................................................ 37 
8.1 Dose Limiting Toxicities ..................................................................................................................... 38 
8.2 Serious Adverse Events ..................................................................................................................... 39 
8.4 Nonserious Adverse Events .............................................................................................................. 40 
8.5 Laboratory Test Result Abnormalities............................................................................................... 41 
8.6 Pregnancy .......................................................................................................................................... 41 
8.7 Overdose ........................................................................................................................................... 42 
8.8 Potential Drug Induced Liver Injury .................................................................................................. 42 
9.0 Safety Information: Sponsor and Investigator Responsibilities ............................................................ 42 
9.1 Review of Safety Information: Sponsor Responsibilities .................................................................. 42 
9.2 IND Safety Reports ............................................................................................................................ 42 

 
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9.3 Submission of IND safety reports...................................................................................................... 43 
9.4 Follow-up .......................................................................................................................................... 44 
9.5 Disclaimer .......................................................................................................................................... 45 
9.6 Reporting Adverse Events to the responsible IRB ............................................................................ 45 
9.7 Other Safety Considerations ............................................................................................................. 45 
10.0 Data Safety Monitoring Plan ............................................................................................................... 45 
10.1 Study Oversight ............................................................................................................................... 45 
10.2 Data Handling and Record Keeping ................................................................................................ 46 
11.0 Management of Adverse Events with Duvelisib ................................................................................. 47 
11.1 Infections ........................................................................................................................................ 47 
11.2 Diarrhea/Colitis ............................................................................................................................... 47 
11.3 Cutaneous Reactions....................................................................................................................... 47 
11.4 Pneumonitis .................................................................................................................................... 48 
11.5 Neutropenia .................................................................................................................................... 48 
12.0 Assessment of Disease ........................................................................................................................ 48 
12.1 Definitions ....................................................................................................................................... 48 
12.2 Methods for Evaluation of Measurable Disease ............................................................................. 50 
12.3 Response Criteria ............................................................................................................................ 51 
13.0 Tissue and Blood Collection and Biomarker Studies ........................................................................... 54 
13.1 Phase I Correlative Studies ............................................................................................................. 54 
13.2 Phase II Correlative Studies ............................................................................................................ 55 
14.0 Statistical Methods ............................................................................................................................. 57 
15.0 Study Management, Agreement and Ethical Considerations ............................................................. 61 
16.0 References .......................................................................................................................................... 62 
17.0 Appendices .......................................................................................................................................... 65 
17.1 Appendix A: Medications with CYP3A interactions ........................................................................ 65 
17.2 Appendix B: Drug Diary ................................................................................................................... 67 
Summary of Changes…………………………………………………………………………………………………………………………70 
 
 
 

 
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i. Abbreviations 
 
AJCC – American Joint Committee on Cancer 
ANC – Absolute Neutrophil Count 
βhCG – Beta Human Chorionic Gonadotropin 
CNS – Central Nervous System 
COPD – Chronic Obstructive Pulmonary Disease 
CR – Complete Response 
CRF- Case Report File 
CRS – Clinical Research Staff 
CT – Computed Tomography 
CTCAE – Common Terminology Criteria for Adverse Events 
DLT – Dose Limiting Toxicity 
DOR – Duration of Response 
DRESS – Drug Reaction with Eosinophilia and Systemic Symptoms 
DSMB – Data Safety Monitoring Board 
EMR – Electronic Medical Record 
HSV – Herpes Simplex Virus 
IP – Investigational Product 
IRB – Institutional Review Board 
MDSC – Myeloid-Derived Suppressor Cells 
MI – Myocardial Infarction 
MRI – Magnetic Resonance Imaging 
MTD – Maximum Tolerated Dose 
OS – Overall Survival 
PBMC – Peripheral Blood Mononuclear Cells 
PD – Progressive Disease 
PD1 – Programmed Cell Death Receptor  
PDL1 – Programmed Cell Death Ligand 1 

 
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PFS - Progression Free Survival 
PI3K - Phosphoinositide 3-Kinase  
PJP – Pneumocystis jiroveci Pneumonia 
PR – Partial Response 
RECIST - Response Evaluation Criteria in Solid Tumors 
RP2D – Recommended Phase 2 Dose 
SAE – Serious Adverse Event 
SD – Stable Disease 
SJS – Stevens-Johnson Syndrome 
TEN – Toxic Epidermal Necrolysis 
TIA – Transient Ischemic Attack 
TME - Tumor Microenvironment 
T-vec - talimogene laherparepvec  
ULN – Upper Limit of Normal 
UPMC – University of Pittsburgh Medical Center 
VZV – Varicella Zoster Virus 
WCBP – Women of Child Bearing Age 
IRB – Institutional Review Board 
 
 
 
 
 
 
 
 
 
 

 
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ii. Protocol Summary 
Title 
A Phase I/II Study of PI3Kγδ inhibitor Duvelisib in Combination with 
Nivolumab in Patients with Advanced Unresectable Melanoma who have 
Progressed on Anti-PD1 Therapy 
Short Title 
PI3γδ inhibition in PD1 Refractory Melanoma 
Protocol Number 
 20-155 
Phase 
Phase I/II 
Methodology 
Single-arm, open label phase I/II study 
Study Duration 
We expect to enroll patients over 18 months and complete data analysis by 
36 months.  
Study Center(s) 
 UPMC Hillman Cancer Center  
Objectives 
For the Phase I portion, the primary objective is to determine the 
recommended phase II dose of duvelisib when combined with nivolumab 
using dose-limiting toxicity and immunologic parameters, and the secondary 
objectives are to assess early and late toxicities and the anti-tumor effect of 
combination therapy.  The primary objective for the phase II cohort is to 
evaluate the anti-tumor effect of the combination of anti-PD1 therapy and 
duvelisib by comparing disease change using RECIST v1.1 criteria.  Our 
secondary objectives are to assess 1) potential clinical benefit of 
combination therapy, 2) duration of response, 3) progression-free survival, 
4) overall survival, and 5) safety measured by adverse events graded by 
CTCAE v5.0. A number of exploratory objectives will also be pursued 
including laboratory correlatives.  
 
Number of Subjects 
42 

 
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Main Inclusion and 
Exclusion Criteria 
Inclusion criteria: Men and women 18 years of age or older with 
unresectable stage III or stage IV melanoma by AJCC 8th edition who have 
progressed on anti-PD1 therapy after a minimum of 12 weeks of therapy.  
 
Exclusion criteria: Patients with known or suspected symptomatic or 
progressive CNS metastases; patients with treated CNS disease who are 
stable on repeat imaging at 2-4 weeks post SRS and neurologically stable are 
allowed. Patients with active autoimmune disease requiring treatment and 
patients with uveal or mucosal melanoma are not eligible. Patients with 
uncontrolled cardiovascular, pulmonary, and certain infectious disease are 
also excluded. 
Investigational 
Product  
 
Duvelisib is an oral medication that will be administered in doses from 15mg 
once a day to 25mg BID for dose finding studies.  
 
Nivolumab is supplied as a 240mg/24 mL formulation to be administered as 
an IV infusion at 240mg every 2 weeks, and if tolerated, potentially changed 
to 480mg once every 4 weeks.    
Duration of 
administration 
Both duvelisib and nivolumab will be administered in 4-week cycles until 
progression of disease, unacceptable toxicity, or 1 year, whichever is longer.  
Reference therapy 
For patients who have progressed on immunotherapy and targeted agents, 
there is no current standard of care1 and clinical trials are the recommended 
option.  
Correlative studies 
Patients will have peripheral blood draw and tumor biopsy performed at 
baseline and after 12 weeks of treatment in both phases of the trial.  For the 
phase I cohort, changes in immune cell populations, particularly CD8+ T cell 
proliferation, will be used to measure the immunomodulatory effect of 
increasing doses of duvelisib. Additional studies are planned to characterize 
T cell phenotype, function, and metabolism as well to evaluate expression of 
genes involved in autoimmunity and inflammation and to correlate with 
toxicity. Correlative studies will be used along with toxicity data to inform 
the phase II dose. Ideally, the dose chosen will have a potent anti-tumor 
immune profile such as high CD8+ T effector cells, low T regulatory cells, low 
myeloid-derived suppressor cells.  
Statistical 
Methodology 
For the Phase I study, a modified 3+3 dose finding design is used, with 6 
patients at each of 3 dose levels of 15mg daily, 25mg daily and 25mg twice 
daily. For the Phase II expansion, the expected response rate for treatment 
of  patients with anti-PD1 beyond progression is <14% 2. For this study to be 
clinically relevant a response rate of at least 20% is sought from the addition 
of duvelisib. Regimen efficacy will be monitored using a Bayesian method. 
The trial will be stopped for futility if the posterior probability of response 
rate is <5% or is >70%. Response rate, progression free survival and overall 
survival will be analyzed via Kaplan-Meier methods.  For safety analyses, a 
Bayesian monitoring scheme will also be used to monitor the severe adverse 
event rate.  

 
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Safety Evaluations  
Patients will be evaluated at clinic visits at least every 2-4 weeks for safety 
analyses. Blood work will also be tested at these visits to evaluate any 
adverse effects.  For patients with toxicity or other clinical concerns, 
additional visits and imaging may be warranted at the discretion of the 
treating physicians and in consultation with a study investigator.  
Data and Safety 
Monitoring Plan  
The Data Safety Monitoring Board consists of investigators, regulatory staff, 
CRS management, clinical research coordinators, data managers and clinic 
staff, and these will meet regularly at least monthly to discuss trial concerns 
and study data.  The DSMB includes individuals not involved in study design 
or implementation. Information to be reviewed includes serious adverse 
events, safety issues, recruitment, accrual, protocol deviations and 
unanticipated problems. The protocol and investigators will also comply with 
IRB policy for reporting risk to subjects. 
 
 
 
 

 
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iii. Study Design Schematic 
 
 
 
 

 
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1.0 Background and Study Rationale 
Melanoma is an aggressive form of skin cancer with historically poor outcomes, especially prior to the 
advent of modern checkpoint blockade and targeted antitumor agents. Immunotherapy has changed 
the field of melanoma considerably in the last 5 years. In the Checkmate-066 trial, patients with 
metastatic melanoma who received single agent nivolumab had a 1-year overall survival of 72.9%, 
compared to 42.1% with the prior standard of care, dacarbazine 3. While these results are promising, 
only 31% patients with locally advanced or metastatic melanoma have a durable progression free 
survival at 4 years with the remainder progressing or relapsing 4. The potential mechanisms by which 
patients are refractory to or develop resistance to immunotherapy are numerous  and include loss of 
the antigenic target, T-cell exhaustion, and development or enhancement of an immunosuppressive 
tumor microenvironment (TME) 5. Sensitizing these patients to immunotherapy is the focus of current 
drug development and ongoing clinical trials. 
 
The phosphoinositide 3-kinase (PI3K) signaling pathway functions at many stages of cancer biology 
including cell division, differentiation, motility and metabolism 6. Inhibitors downstream of the PI3K 
pathway are active in some solid tumors, including everolimus in neuroendocrine tumors7 and 
everolimus with exemestane in breast cancer8.  While these therapies have clinical benefit, the toxicities 
of  inhibiting such pervasive pathways are often significant9.  A more targeted approach to PI3K 
inhibition may be useful for immune modulation in malignancies treated with immunotherapy.  
 
PI3K has four subunits that are differentially expressed by cell type: α, β, γ and δ. While α and β are 
present in the majority of cell types, the PI3K γ and δ isoforms are expressed primarily in hematopoietic 
cells 10. Duvelisib is a potent inhibitor of both γ and δ isoforms and is FDA approved for relapsed 
refractory CLL/SLL and follicular lymphoma based on the DUO and DYNAMO trials 11,12,13. Tumor biopsies 
and peripheral blood cytokine analyses from lymphoma patients treated with duvelisib demonstrated 
shifts to a pro-inflammatory (anti-tumor) phenotype14.   
 
In pre-clinical tumor models of anti-PD1 resistance, PI3Kγ inhibition in combination with anti-PD1 
therapy was able to restore anti-PD1 activity as demonstrated by a reduction in tumor size 15. In 
xenograft tumor models treated with PI3Kγ inhibition, the TME demonstrated lower proportions of 
suppressive M2 macrophages and T-regulatory cells 15. In a mouse model of head and neck squamous 
cell carcinoma (HNSCC), the combination of PI3Kγ inhibition and anti-PD1 blockade lead to a decrease in 
tumor growth and increased survival compared to mice treated with either agent alone 16. These mice 
were noted to have increased activation and recruitment of CD8+ T cells to tumor sites 16. Duvelisib also 
demonstrated anti-tumor effects in a distinct mouse model of HNSCC, with increased CD8+ T cell 
infiltration and less suppression by tumor-infiltrating myeloid-derived suppressor cells17. Mice treated 
with both duvelisib and anti-PDL1 demonstrated increased survival and decreased rates of tumor 
growth compared to mice treated with anti-PDL1 alone17.   
 
Despite promising preclinical data, there is limited data on the use of PI3K isoform inhibitors in solid 
tumors. Shifts to a pro-inflammatory TME were observed in patients receiving a PI3Kδ inhibitor in 

 
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combination with anti-PD1 in a phase 1b trial of patients with advanced solid tumors18. However, data 
regarding safety and efficacy in patients with melanoma is lacking. Taken together, these studies 
present duvelisib as an immunomodulator of the tumor microenvironment and a potentially effective 
treatment when combined with anti-PD1 therapy.  
 
Our study will explore duvelisib as a means to overcome anti-PD1 resistance in human metastatic 
melanoma patients. We will test the safety and efficacy of the combination of duvelisib and nivolumab 
(anti-PD1) therapy in patients who have shown progression of disease on anti-PD1 therapy alone. We 
hypothesize that duvelisib will act as an immunomodulator, to shift the TME from an 
immunosuppressive to an immunostimulatory setting, helping to overcome acquired resistance in anti-
PD1 treated patients. The phase I portion of our study is uniquely designed to find the ideal dose of 
duvelisib as an immunomodulator, which we suspect to be lower than the previously determined 
maximum tolerated dose (MTD) of duvelisib in lymphoma studies. In the absence of clinical dose-
limiting toxicities (DLTs), immunologic parameters measured in blood and tumor samples will be used to 
determine dosing for the phase II portion of the study. Further, our translational correlative studies on 
peripheral blood and tumor biopsies will help elucidate mechanisms of resistance and the role of 
duvelisib in PD1 refractory settings. This is a promising area with the potential for great clinical benefit in 
multiple solid tumors. 
 
2.0 Study Objectives 
 
2.2 Primary Objectives 
• 
Phase I: 
o To determine the maximum tolerated dose (MTD) and recommended phase II dose 
(RP2D) of duvelisib when combined with anti-PD1 therapy nivolumab by 
immunologic profiling and toxicity data.  
• Phase II: 
o To assess the anti-tumor activity of the combination of duvelisib and nivolumab 
therapy, comparing disease change documented in CT measurements 12 weeks after 
initiation of therapy to baseline scans, and every 12 weeks thereafter.  
2.3 Secondary Objectives  
• Phase I: 
o To assess early (within 4 weeks) and late toxicities (after 4 weeks) of combination 
duvelisib and nivolumab 
o To assess the anti-tumor activity of the combination of duvelisib and nivolumab 
therapy, comparing disease change documented in CT measurements 12 weeks after 
initiation of therapy to baseline scans, and every 12 weeks thereafter.  
 

 
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• Phase II: 
o To assess the potential antitumor response of the combination of duvelisib and anti-
PD1 therapy 
o To assess the duration of response with this combination  
o To assess progression-free survival and overall survival 
o To assess the safety of the combination of duvelisib and anti-PD1 therapy  
o To evaluate differences in response between certain pre-specified subsets of 
melanoma patients, including those who progressed on anti-PD1 therapy within 3 
months (early progressors) and those who progressed after 3 months (late 
progressors), as well as by BRAF mutation status 
2.4 Exploratory Objectives  
• To evaluate how immune cell populations change by duvelisib dose, to help inform 
recommended phase II dosing 
• To evaluate the effects of duvelisib on the tumor microenvironment (TME) 
• To explore mechanism of anti-PD1 resistance and the role of duvelisib in overcoming this 
resistance  
 
3.0 Investigational Plan 
  
3.1 General Study Design 
This trial is a phase I/II, dose-escalation and dose-expansion, open-label,  single-arm trial in which 
duvelisib will be studied in combination with nivolumab.  
 
3.1.1 Screening of Subjects 
Patients will be identified during evaluation by their oncologist. Once identified, patients will meet with 
clinical research staff to determine eligibility, perform screening and discuss consent.  
 
3.1.2 Study Intervention  
Once consented patients should begin protocol treatment within 28 days. Treatment delays should be 
discussed with the Principal Investigator. If protocol is not initiated as specified, the patient’s 
registration for the study may be cancelled.  
 

 
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3.1.3 Follow-Up Phase  
Patients who discontinue study participation will be evaluated as determined by the treating physician 
regardless of the reason(s) for discontinuation (patient withdrawal, disease progression, toxicity). 
Patients will be followed for a minimum of 1 month after discontinuation of the study to complete data 
collection regarding safety. Patients may be contacted for survival follow-up for up to 5 years. Survival 
follow-up will be performed at approximately 3-month intervals. Patients discontinuing the study for 
adverse events will be followed until resolution or stabilization of the adverse event, with a minimum of 
1 month follow-up.  
 
3.1.4 Allocation to Interventional Group  
The study is a single arm trial, and all patients will be allocated to the interventional group. The study 
coordinator at UPMC will be responsible for enrolling patients at each dose level and assigning 
appropriate doses.  
 
3.2 Study Endpoints   
 
3.2.1 Primary Endpoints 
• 
Phase I 
o RP2D of duvelisib when used in combination with nivolumab, as determined by 
immunomodulatory effect in peripheral blood and TME, toxicity, and any early 
efficacy signals.  
o Maximum-tolerated dose of duvelisib in combination with nivolumab. 
  
 
• 
Phase II 
o Overall response rate of the combination of anti-PD1 therapy and duvelisib as 
measured by overall antitumor response (defined as complete response + partial 
response) based on RECIST v1.1 criteria initially assessed at 12 weeks after initiation 
of the combination, compared to baseline imaging obtained immediately prior to 
initiating combination, and subsequently at 12 week intervals until progression.  
 
3.2.2 Secondary Endpoints 
Several secondary endpoints will be analyzed as follows:  
• Acute and late toxicities rates throughout treatment, as graded by CTCAE v5.0 in patients at 
each dosing interval and in the expansion cohort 
• Clinical benefit of combination therapy, defined as complete response, partial response and 
stable disease as assessed by RECIST v1.1, initially assessed at 12 weeks after initiation of 
therapy and subsequently at 12-week intervals until progression  

 
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• Duration of response defined by time at which measurement criteria are first met for 
complete response or partial response until the first time at which progressive disease is 
objectively documented 
• Progression-free survival defined as time at start of treatment and first date of documented 
progression or death due to any cause 
• Overall Survival defined as the time of start of treatment and the date of death due to any 
cause. Patients who are alive will be censored at the time of the last follow-up. Patients will 
be followed for survival for 5 years.  
• Safety of the combination of anti-PD1 and duvelisib measured by adverse events graded by 
CTCAE v5.0. Adverse events will be captured during treatment and 100 days after 
discontinuing treatment. We will continuously for DLTs as defined in section 8.1 that are 
possibly, probably or definitely related to treatment. If the adverse event rate exceeds 
acceptable limits, the study will be modified or discontinued.  
• Subset analysis will be performed to determine how certain disease characteristics affect 
response to the combination, including prior time prior to progression while on anti-PD1 
therapy, presence of CNS disease, radiated CNS disease and tumor BRAF mutation status.  
 
4.0 Study Population and Eligibility  
 
4.1 Inclusion Criteria 
• 
AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID or stage IV melanoma 
who have received at least 3 months of prior treatment with an anti-PD1 or anti-PDL1 antibody 
and who have progressed on this treatment. Patients who have received a combination anti-PD1 
and anti-CTLA4 therapy who exhibit progression at this interval are also permitted.  There are no 
restrictions regarding time since last anti-PD1 treatment, or number of therapies after anti-PD1.  
• 
Age ≥ 18 years; 
• 
ECOG performance status ≤ 2 or Karnofsky ≥ 60% 
• 
Patients must have normal organ and bone marrow function as defined below: 
Lab Test 
Criteria 
Hemoglobin 
≥9.0 g/dL 
Absolute neutrophil count 
≥1500 cells/µL 
Platelets 
≥100,000 cells/µL 
Total bilirubin 
≤ 1.5 x institutional upper limit of normal (ULN). Patients 
with Gilbert’s syndrome must have normal direct bilirubin 
AST/ALT 
≤2.5x ULN in subjects with liver metastasis, must be 
within normal limits for those without liver metastasis 
Creatinine 
< 1.5 mg/dL  
 

 
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• 
For patients with actionable BRAF mutations, treatment with BRAF and MEK inhibitors prior to 
initiation on trial is recommended, unless patients are intolerant of therapy or choose not to 
pursue BRAF targeted therapy.  
• 
Patients must have measurable disease, defined as at least one tumor lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-nodal 
lesions and short axis for nodal lesions) as ≥10mm with CT scan, MRI or by calipers if 
documented on clinical exam. If patients have a single lesion, the lesion must be amenable to 
biopsy without interfering with radiographic assessment as determined by one of the co-PIs.  
• 
Duvelisib and nivolumab therapy may be harmful for a developing fetus. Women of child 
bearing potential (WCBP) must have a negative urine or serum β human chorionic gonadotropin 
(βhCG) pregnancy test within 7 days before starting treatment. WCBP and men must agree to 
use highly effective contraception (pharmacologic birth control, barrier methods or abstinence) 
prior to study entry and for the duration of study participation through 5 months after the last 
dose of study medication. Should a woman become pregnant while she or her partner are 
participating in this study, she should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use highly effective contraception prior to the 
study, for the duration of study participation and 12 weeks following the last dose.  
• 
WCBP defined as a sexually mature woman who as not undergone surgical sterilization or who 
has not been naturally postmenopausal for at least 12 consecutive months for women >55 years 
of age 
• 
Ability to understand and the willingness to sign a written informed consent document.  
 
4.2 Exclusion Criteria 
4.2.1 Target disease 
• Patients with known or suspected CNS metastases  are excluded, unless the following criteria 
are met: 
o Subjects have controlled brain metastasis, defined as metastases without 
radiographic progression for at least 4 weeks following treatment with stereotactic 
radiation and/or surgical treatment  
o Subjects must be off steroids without symptoms of CNS disease for at least 2 weeks 
prior to treatment 
o Subjects with signs or symptoms of brain metastasis are not eligible unless brain 
metastasis is ruled out by computed tomography or magnetic resonance imaging 
• Patients with uveal or mucosal melanoma are excluded 
 
4.2.2 Medical comorbidities 
• Subjects with an active, known or suspected autoimmune disease. Subjects with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such 
as vitiligo, alopecia) not requiring systemic treatment, or conditions not expected to recur in 
the absence of an external trigger are permitted to enroll 

 
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• Subjects with history of chronic liver disease, veno-occlusive disease, active alcohol abuse or 
illicit drug use other than marijuana or its derivatives 
• Uncontrolled or significant cardiovascular disease including but not limited to the following 
o Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 
months prior to consent  
o Uncontrolled angina within the 3 months prior to consent  
o Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation) 
o History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, 
congestive heart failure with New York Heart Association [NYHA] functional 
classification III-IV, pericarditis, significant pericardial effusion, significant coronary 
stent occlusion, poorly controlled deep venous thrombosis, etc)  
o Cardiovascular disease-related requirement for daily supplemental oxygen  
o Subjects with history of myocarditis, regardless of etiology  
o Baseline left ventricular ejection fraction (LVEF) <45%.  ECHO/MUGA not required at 
screening unless history of significant cardiac history.  
o QTc prolongation > 500 msec 
• Uncontrolled or significant pulmonary disease including but not limited to the following 
o Obstructive or restrictive lung disease requiring home oxygen 
o Hospitalization with chronic obstructive pulmonary disease (COPD) exacerbation 
within the last 6 months 
o History or concurrent condition of interstitial lung disease of any severity 
o Prior history of pneumonitis of grade II or higher, regardless of cause 
o Patients with diagnosis of obstructive sleep apnea (OSA) who are compliant with 
prescribed therapy (nocturnal O2, CPAP or BiPAP) are allowed on study 
• Uncontrolled or significant infectious disease including but not limited to the following 
o Ongoing treatment for systemic bacterial, fungal or viral infection at screening 
o Subjects are not excluded for antimicrobial, antifungal or antiviral prophylaxis if 
other inclusion/exclusion criteria are met 
o Active cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection (i.e., subjects with 
known history of detectable viral load) 
o Infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or 
human T-lymphotropic virus type 1 

 
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o Subjects with a positive hepatitis B surface antigen [HBsAg] or hepatitis C antibody 
[HCV Ab] will be excluded, unless documented treatment and resolution of hepatitis 
C treatment  
▪ 
Subjects with a positive hepatitis B core antibody (HBcAb) must have 
negative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) assay to be 
eligible, must receive prophylaxis with entecavir (or equivalent) concomitant 
with duvelisib treatment, and must be periodically monitored for HBV 
reactivation by institutional guidelines. If unable to receive prophylaxis, then 
case will be discussed with investigators to determine eligibility.  
o History of tuberculosis treatment within 2 years prior to enrollment 
• Patients with history of encephalitis, meningitis, or uncontrolled seizures in the year prior to 
informed consent 
• Ongoing chronic treatment with immunosuppressants (e.g. cyclosporine) or systemic steroids 
> 10mg of prednisone or equivalent once daily.  Topical and inhaled steroids are allowed.  
• Subjects with other uncontrolled medical conditions or other illnesses, laboratory findings or 
other factors that would, in the investigator’s judgment, increase the risk to the subject 
associated with his or her participation in the study. 
 
4.2.3 Prior therapies 
• Patients who are receiving other investigational therapies will be excluded 
• Patients who had a history of life-threatening toxicity related to prior immune therapy (e.g. 
anti-CTLA-4, anti-PD1 or any other antibody or drug specifically targeting T-cell co-stimulation 
or immune checkpoint pathways) except those that are well controlled an unlikely to be an 
issue with standard countermeasures (e.g. endocrine disorders managed by hormone 
replacement).   
• Subjects with a history of grade II or greater immune-mediated colitis. Patients whose toxicity 
was clearly attributable to anti-CTLA-4 treatment (tolerated anti-PD1 after receiving anti-
CTLA4) may still be allowed on trial. 
• Subjects with a history of grade II or greater pneumonitis or transaminitis. 
• Prior treatments with PI3K inhibitors 
• Subject has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone therapy with curative intent, or treated in situ cervical cancer for which 
there is appropriate ongoing surveillance 
• Subject had therapy with radiation, surgery or chemotherapy within 4 weeks prior to time of 
consent and/or has not recovered from adverse events to due to prior therapy. Subjects 

 
19 
 
should be adequately recovered from all toxicities, complications, or acute illnesses prior to 
starting investigational therapy. 
• A maximum of three patients who have received talimogene laherparepvec (T-vec) as prior 
therapy will be allowed to enroll in the Phase II portion of the study. However, study-related 
biopsies must be performed at a disease site that was not injected with T-vec or adjacent to a 
T-vec injection site.   
  
4.2.4 Other exclusion criteria 
• Subjects who are unable or unwilling to take prophylaxis for Pneumocystis jirovecii, human 
simplex virus (HSV) or herpes zoster (VZV) at time of screening  
• Subjects with known hypersensitivity to duvelisib and/or its excipients: Microcrystalline 
cellulose and magnesium stearate 
• Prisoners or subjects who are involuntarily incarcerated 
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
illness 
• Subjects who are unable or unwilling to comply with restrictions and prohibited activities and 
treatments 
• Subjects who are unable or unwilling to undergo venipuncture or tolerate venous access 
• Subjects with prior surgery and/or chronic gastrointestinal dysfunction that may affect drug 
absorption, such as gastric bypass, gastrectomy, malabsorption, inflammatory bowel disease, 
chronic diarrhea 
• Concurrent administration of medications or foods that are strong inhibitors of inducers of 
cytochrome p450 3A (CYP3A) within 2 weeks prior to study intervention. Duvelisib can 
increase exposure to CYP3A4 substrates: consider dose reduction of such substrates and 
monitor for signs of toxicities of co-administered sensitive CYP3A substrates See appendix A 
for list of example medications  
 
4.3 Subject Recruitment 
Participants will be enrolled at the UPMC Hillman Cancer Center . The trial will be advertised in weekly 
clinical trials bulletins to community oncologists who are a part of the UPMC Network, which includes 
over 60 locations in Pennsylvania and Ohio. Clinical staff at Hillman Cancer Center will be educated to 
identify potential participants. Each participant will be assigned to a clinical research coordinator (CRC) 
who will aid in ensuring study criteria are met and will serve as a point of contact for the participant.  
 
4.4 Subject Withdrawal or Termination 
4.4.1 Termination of Study Participation 

 
20 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
• Disease Progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from the study 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgement of the investigator 
• Patient non-compliance 
• Pregnancy 
o All WCBP will be instructed to contact the investigator immediately if they suspect 
pregnancy at any time during study participation 
o The investigator must immediately notify the IRB in the event of a confirmed 
pregnancy in a patient participating in the study 
• Termination of the study by sponsor 
•  Loss of access to one or both investigational agents 
• The maximum planned duration treatment of 12 months has been completed.  
 
4.4.1 Duration of Follow Up and Retreatment 
The period of acute toxicity and DLT evaluation is 28 days. Beyond that, AEs that arise while on 
treatment and within 4 weeks (+ 2 weeks) after discontinuation of treatment will be considered late 
toxicities  
Patients will be evaluated by the treating physician after trial discontinuation, regardless of reason for 
discontinuation. Patients will be seen for an additional visit 4 weeks (+ 2 weeks) after study 
discontinuation to evaluate for additional adverse events and will continue to be followed until all 
adverse events have resolved or stabilized. The investigator and treating physician are responsible to 
ensure, within reason, that the patients receive appropriate treatment for their malignancy after trial 
discontinuation. Patients may be contacted for survival follow-up for up to 5 years. Survival follow-up 
will be performed approximately every 3 months. Patients terminated from the trial for adverse events 
will be followed until resolution or stabilization of the adverse event.  Patients will have regular lab work 
and need documentation of CD4 T-cell subset >200 cells/µL prior to stopping PJP prophylaxis. We 
anticipate 3 years of data collection to determine duration of response.  
 
4.4.2 Withdrawal of consent 

 
21 
 
Patients who request to discontinue study treatment will remain on the study and must continue to be 
followed for protocol-specified follow-up procedures and visits. A patient may elect to withdraw consent 
for further contact by study personnel, in which case he or she will be exempt from study procedures. 
Patients should notify investigator of such decisions in writing, whenever possible. The withdrawal of 
consent will be described in detail in the medical records, to clarify withdrawal from treatment and/or 
study procedures and/or post-treatment study follow-up.  
 
4.4.3 Lost to Follow Up 
Lost to follow-up describes inability to reach a subject after a minimum of 3 months of effort to contact 
such patient has been made. This includes documented phone calls, faxes, emails and also at least one 
registered mail letter during the 3-month period. Attempts to contact patients will be documented in 
the EMR. If a patient has died, permissible local information can be used to determine date and cause of 
death. Publicly available information may be used throughout the trial and the survival follow up period 
to determine survival status, in accordance with local law. 
 
5.0 Clinical Trial Processes and Procedures 
 
5.1 Study Site 
The study will be conducted at the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania. 
 
5.2 Screening and Pretreatment Evaluations 
Screening and pretreatment evaluation will take place within 28 days from study initiation. The 
evaluation includes the assessments in the table below 
 
Table 5.2 Screening and Pretreatment Evaluations 
Evaluation 
Description 
Informed consent 
A subject is only considered enrolled when an IRB/IEC approved 
informed consent form is signed and dated.  
Medical Record Review 
The patient will be interviewed and medical history will be 
reviewed in the EMR. Details of risk factors for potential events 
such as pulmonary or infectious complications should be 
evaluated. Toxicities from prior treatments and allergies will also 
be reviewed. 
Inclusion/exclusion criteria 
 
Criteria will be reviewed as well as compared with the medical 
record. 
Pre-treatment tumor biopsy 
Should be performed within 4 weeks of treatment, see laboratory 
manual for further details.  

 
22 
 
Vital signs 
Includes height (at screening only), weight, blood pressure, 
temperature, heart rate, oxygen saturation, respirations, body 
mass index (at screening only). 
Physical Examination 
Physical exam should be performed at screening and within 3 days 
of treatment initiation. 
Performance status 
ECOG performance status will be evaluated and recorded. 
Laboratory tests 
See section 6.4 for tests to be performed at screening and at time 
of drug initiation. Labs are performed locally and may be collected 
within 3 days prior to dosing.  
Pregnancy test 
Urine or serum pregnancy test should be performed in all WCBP 
prior to study initiation. 
Contraceptive use 
Men and women will be evaluated for and counseled about highly 
effective contraceptive use. 
Concomitant medications 
Medication review will take place at screening and at each 
subsequent visit. 
Assessment of signs and 
symptoms 
Evaluation will be performed at screening and at each subsequent 
visit. 
Monitor for adverse events 
AEs are collected from the start of treatment including SAEs. 
Diagnostic imaging 
CT with contrast is the preferred modality and should include 
chest/abdomen/pelvis as well as other body areas based on the 
patients’ disease. CT without contrast or MRI is also permitted.  
Brain imaging 
For patients with a history of brain metastases or concerning 
symptoms, brain imaging should be performed within 4 weeks of 
treatment. Brain MRI is preferred, but CT is also permitted. Brain 
MRI/CT will be required for all patients at screening.   
 
5.3 Diagnostic Plan  
Patients will be evaluated for safety and efficacy at regular intervals. Initial visits will begin 2 weeks after 
starting duvelisib to evaluate labs and for drug tolerance and will continue on 2 week intervals for 4 
cycles. After this time if minimal/no toxicity is noted, visits may be spaced to every 4 weeks. Additional 
visits are permissible at the discretion of the treating physician. For example, additional visits for 
monitoring an AE or for concerns of clinical deterioration may be performed. Additionally, imaging for 
efficacy analyses will be performed at 12-week intervals.  The first imaging evaluation may be performed 
before 12 weeks if there is clinical concern for deterioration or progression.  
 
5.4 Procedure for Registration of Subjects 
Registration will be conducted at UPMC Hillman Cancer Center.  Patients will be enrolled at UPMC 
Hillman Cancer Center.  
6.0 Trial Treatments, Evaluations, and Measurements 
6.1 Medical Record Review 
The medical record will be reviewed at screening for the following variables.  

 
23 
 
• 
Date of birth 
• 
Height 
• 
Weight 
• 
Any history of disease, comorbidities 
• 
Surgical history 
• 
Pathology reports for melanoma diagnosis and any subsequent pathology 
• 
Oncology history and treatment including disease response, and all toxicity 
 
6.2 
Medical History and Physical Examination  
Describe the baseline evaluations including the medical history, physical examination, demographic 
characteristics (age, gender, race) and other information that will be collected. 
• 
Demographics (screening only) – Age, gender (male, female, non-binary), race 
• 
Medical history (screening only) – Comorbidities, surgical history 
• 
Social history(screening only) – Alcohol, tobacco, recreational drugs,  
o For WCBP contraceptive use will be reviewed at each visit 
• 
Physical exam (each visit) – Based on disease and signs and symptoms 
6.3 
Vital Signs 
Vital signs will be measured at each visit. Vitals will be taken on digital machine and repeated manually 
when appropriate 
• 
Weight – Recorded on digital scale in plain clothes, without shoes and jackets 
• 
Height – Recorded on screening visit only, measured by stadiometer  
• 
Blood pressure – Taken seated, using digital blood pressure cuff. Can be repeated with manual 
cuff if clinician feels necessary 
• 
Heart rate – Taken when seated with digital heart rate monitor 
• 
Respirations – Manually observed 
• 
Temperature 
• 
Oxygen saturation – Measured by digital pulse oximeter  
• 
Body mass index – Calculated from height and weight 
 
6.4 
Laboratory Evaluations 
Blood sampling will be performed with the laboratory tests below at each visit, with exceptions noted 
below: 
6.4.1 Table: Clinical Laboratory Tests 
Category 
Tests 
Hematology 
Hemoglobin, hematocrit, platelet count, WBC with differential. 
CD4+ T cell subsets will be checked at screening and at study 
discontinuation and monthly until CD4+ threshold is reached. 

 
24 
 
Serum chemistries 
Sodium, potassium, chloride, Co2, BUN, creatinine, calcium, 
glucose, LDH 
Liver function tests 
SGOT/AST, SGPT/ALT, total Bilirubin, alkaline phosphatase, albumin 
Endocrine tests 
TSH with free T4, T3 as applicable; Cortisol and ACTH if clinician 
concerned for hypophysitis 
Infectious disease 
HIV, Hepatitis C Ab, Hepatitis B Surface Ag, Hepatitis B Surface Ab, 
Hepatitis B Core Ab on screening only 
Pregnancy test 
Serum or urine βhCG testing on screening only 
 
6.5 Pregnancy Testing 
Women of childbearing potential (WCBP) is defined as a sexually mature woman who has not 
undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 
consecutive months. WCBP should have a urine or serum pregnancy test with minimum sensitivity of 
25IU/L of either total hCG or βhCG. WCBP and all men will be counseled on highly effective 
contraceptive methods while on study. Contraceptive use will be reviewed at each study visit. If any 
concern for or chance for pregnancy, study drugs will be held until pregnancy test is performed. Patients 
will also be advised to stop study drug and discuss with treating team if concern for pregnancy.  
 
6.6 Efficacy Evaluations 
Efficacy evaluations will be based on tumor response on radiographic imaging, preferably CT scans. 
Baseline imaging will be obtained within 28 days prior to starting the trial. The same imagining modality 
will be used for subsequent imaging evaluation. Imaging will be reviewed by investigators for 
measurements. Measurements will be performed according to RECIST v1.1 19 criteria for size response. 
Further details on imaging modalities allowed, performing measurements, definition of lesions and 
evaluation of response are available in section 12.0.  
 
6.7 Safety Evaluations 
Will be conducted according to the table below.  
 
 

 
25 
 
Table 6.7.1: Schedule of Study Procedures  
Study Stage 
Screening 
Intervention 
Safety 
Follow-up 
Visit Number 
 
1 
2 
3 
4-6 
7 
8-9 
10 
11-15 
16+ 
Study Days (+/- 1 week) For 
cycles 1-4, visits every 
14days, then every 28 days 
-28 to 0 
1-14 
15-28 
29-42 
43- 
85-98 
99-126-
168 
169-
196 
197-
364 
365+ 
Cycle Number 
 
C1D1 
and 15 
C2D1 
and 15 
C3D1 
and 15 
C4-6 
Day 1 
and 
C4D15 
C7D1 
C8-9D1 
C10D1 
C11-
15D1 
C16+D1 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs: BP, HR, RR, Temp 
O2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
Assess contraceptive use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications – including PJP 
and VZV prophylaxis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood for 
correlatives (week 0, 4*, 12, 
at progression) *For phase I 
 
X 
X 
 
X Cycle 
4 only 
 
 
 
 
 
Diagnostic imaging (every 12 
weeks +/- 7 days) 
X 
 
 
 
X 
 
X 
 
X 
 
Biopsy for correlatives 
(baseline, 12 weeks +/- 2 
weeks)  
 
X 
 
 
X Cycle 
4 only 
 
 
 
 
 
Dispense Investigational 
Product (IP) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events and 
Unanticipated Problems 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
26 
 
 
6.8 Prophylactic Medications 
In addition to the study drug, patients will be required to start PJP prophylaxis after registration and 
prior to initiation of duvelisib. Prophylaxis will be determined by the treating physician, but examples 
include trimethoprim-sulfamethoxazole, pentamidine, dapsone.  Prophylaxis should start before cycle 1 
of treatment. For patients with history of recurrent or recent HSV or VZV infections, antiviral prophylaxis 
may be considered, at the discretion of the treating physician. 
 
7.0 Study Drug Supply and Administration  
In this study, duvelisib and nivolumab are considered the study drugs. Information regarding handling 
and dispensing when applicable is provided below for clarification. Institutional protocols for nivolumab 
should be followed unless otherwise specified. 
 
7.1 Drug Inventory Records   
Study drug will be shipped to the investigational pharmacies and inventory will be performed by 
pharmacy staff upon receipt of drug. Discrepancies in initial inventory will be immediately documented 
and discussed with the shipping party SecuraBio.  Study drugs will not be returned, and any unused, 
expired or damaged products will be destroyed on site per pharmacy protocol. Inventory will also be 
performed when the last subject has discontinued study drugs  
 
7.2 Description 
 
Duvelisib 
Duvelisib is a white powder encapsulated in a gelatin capsule and is available as 15mg and 25mg 
capsules. It is packaged in an opaque high-density polyethylene bottle with induction sealed child 
resistant caps or thermoform blister strips with push through lidding packaged into wallets.  
Nivolumab 
Nivolumab is commercially available and supplied as single dose vials. Nivolumab solution contains 
mannitol, pentetic acid, polysorbate 80, sodium chloride, sodium citrate and water.  
 
7.3 Packaging 
Duvelisib will be supplied in 32-count blister cards containing either 15mg or 25mg capsules and will be 
labelled as such. The investigational medicinal product will be labeled with a single panel label which 
specifies protocol number, product name, contents of blister card, required storage conditions and 
manufacturer.  
 

 
27 
 
7.4 Receiving, Storage, Dispensing, and Return 
7.4.1 Receipt of Drug Supplies 
Duvelisib will be shipped from SecuraBio to UPMC Hillman Cancer Center Investigational Pharmacy 
under the direction of Brian Miller, PharmD to the address below.  
Brian M. Miller, PharmD 
UPMC Hillman Cancer Center 
Manager, Investigational Drug Service 
Ground Floor, AG40.3 
5115 Centre Avenue 
Pittsburgh, PA 15232 
Phone: 412-623-3381 
Fax: 412-623-0337 
Pager: 412-958-1586 
Email: millerbm2@upmc.edu 
 
 
 
7.4.2 Storage 
Duvelisib  
The drug product blister cards should be stored at room temperature (15 to 30°C). The capsules are 
intended for oral administration. 
Caution is required when handling duvelisib. Personnel dispensing duvelisib should follow standard 
procedures for the handling of investigational drugs, including avoidance of eye or skin contact with the 
drug product. If there is exposure to the drug product, the individual should be treated for physical 
exposure (skin washing) or inhalation (move to fresh air, as necessary), and, if needed, seek medical 
advice. 
When duvelisib capsules are dispensed for self-administration, they should only be handled by the study 
subject. After handling capsules, the subject should wash his or her hands thoroughly. If someone who is 
not enrolled in a duvelisib clinical trial swallows a capsule or inhales drug powder from a broken capsule, 
he or she should contact the relevant Investigator to determine whether safety monitoring is necessary. 
The Investigator should report the incident to Secura Bio,  securabio@parexel.com . Capsules should 
always be stored in the container provided to the study subject. 
 
Nivolumab 
Nivolumab will be stored on site per package insert recommendations and in accordance with Hillman 
Cancer Center. Vials will be stored in refrigeration at 2C - 8C. Vials are protected from light until time of 
use by storing in original packaging.  
 

 
28 
 
7.4.3 Dispensing of Study Drug 
Duvelisib 
Study patients will receive a 4-week supply of duvelisib upon initiation of therapy and at each return 
visit until discontinuation of investigational agents. Pill counts will be performed at each 4-week visit. 
Patients will also be provided a pill drug diary (see Appendix B) to record pills taken, missed pills, 
damaged pills or other issues. This will be reviewed by the CRC at each visit.   
 
Nivolumab 
Nivolumab will be stored in the outpatient pharmacy and prepared by oncology pharmacy at the time of 
infusion. Nivolumab is stored as a clear to opalescent, colorless to pale-yellow solution in a single-dose 
vial at a concentration of 10mg/mL. It is diluted with either 0.9% sodium chloride solution or 5% 
dextrose for a final concentration not to exceed 10mg/mL or less than 1mg/mL in a volume less than or 
equal to 160mL. Dilutions will be made within 8 hours of infusion. Nivolumab will be administered by 
infusion over 30 minutes using a non-pyrogenic, low protein binding-in line filter.  
 
7.4.4 Return or Destruction of Study Drug 
Duvelisib 
At each cycle, patients will return any unused duvelisib. Blister packs with unused duvelisib will have 
their contents destroyed on site per investigational pharmacy procedures 
Nivolumab 
Nivolumab is regularly stocked at the UPMC Hillman Cancer Center and Winship Cancer Institute and 
managed according to current pharmacy protocols.  
 
7.5 Treatment Regimen 
 
Duvelisib 
Duvelisib is available in 15mg and 25mg dose capsules. Based on information provided in the 
Investigators Brochure from SecuraBio, in Phase I trials with duvelisib as monotherapy for lymphoma, 
the maximum tolerated dose of duvelisib was 75mg BID20. After further evaluation 25mg BID was chosen 
to be the preferred therapeutic dose in an effort to minimize toxicity without compromising efficacy. 
Given that duvelisib  acts primarily as an immunomodulator, as opposed to being directly cytotoxic to 
tumor, doses were chosen to maximize T cell proliferation according to pre-clinical data21. These data 
suggest that doses lower than even 25mg BID may result in serum drug concentrations able to optimize 
T cell proliferation.  Thus, doses lower than 25mg BID may be ideal for both maximizing immune changes 
in the TME and reducing patient toxicities. If significant toxicity is noted in the first 3 patients of 
each/any dose level, subsequent patients may be treated with a 2 week lead-in of duvelisib as 
monotherapy prior to the addition of nivolumab.  
Dosing for the dose escalation phase will be as follows: 

 
29 
 
Table 7.5 Duvelisib Dose levels 
Dose Level 
Duvelisib Dose 
Level I 
15mg Daily 
Level II 
25mg Daily 
Level III 
25mg BID 
 
Nivolumab 
Nivolumab will be administered at a flat dose of 240mg every 2 weeks for the first 4 cycles, thereafter it 
then may be switched to 480mg every 4 weeks (+/- 1 week allowed without study deviation) if deemed 
appropriate by the treating physician in consultation with a given patient and his/her caretakers. 
Patients changed to the every 4 weeks schedule for nivolumab will continue to undergo close 
monitoring by the study team for potential toxicities, as deemed necessary and appropriate by the 
treating physician.  
 
7.6 Dose Adjustments and Adverse Reaction Management 
Dose adjustments for toxicity of  duvelisib and nivolumab are detailed below and are excerpted from the 
duvelisib package insert and the nivolumab package insert11,22. Where appropriate, management 
guidelines for immune-related adverse events in patients receiving  immune checkpoint therapy, from 
the American Society of Clinical Oncology (ASCO) Practice Guidelines has been included23. The table 
below is not comprehensive and clinicians should refer to the ASCO Practice Guidelines for more 
detailed management recommendations. When possible, biopsies should be pursued to help determine 
the study drug(s) responsible for a given toxicity. 
Table 7.6 Dose Adjustments for Toxicity 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
Nonhematologic Adverse Reactions 
Infections 
Grade 3 or higher infection 
Duvelisib 
- Withhold duvelisib until resolved 
- Resume at the same or reduced dose 
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
 
Clinical CMV infection or 
viremia (positive PCR or 
antigen test) 
Duvelisib 
- Withhold duvelisib until resolved 
- Resume at the same or reduced dose  
- If duvelisib is resumed, monitor patients 
for CMV reactivation by PCR or antigen test 
at least monthly 
 

 
30 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
 
PJP 
Duvelisib 
- For suspected PJP, withhold duvelisib until 
evaluated 
- For confirmed PJP, discontinue duvelisib 
 
Nivolumab 
- Withhold nivolumab until resolved 
 
Non-infectious 
diarrhea or colitis 
Mild/moderate diarrhea 
(Grade 1-2, up to 4 stools per 
day over baseline) and 
responsive to antidiarrheal 
agents, OR Asymptomatic 
(Grade 1) 
colitis 
Duvelisib 
- No change in dose 
- Initiate supportive therapy with 
antidiarrheal agents as appropriate 
- Monitor at least weekly until resolved 
 
Nivolumab 
- Continue nivolumab or hold until 
symptoms resolve 
 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 stools per 
day over baseline) and 
unresponsive to antidiarrheal 
agents 
Duvelisib 
- Withhold duvelisib until resolved 
- Initiate supportive therapy with systemic 
steroids 
- Monitor at least weekly until resolved 
- Resume at a reduced dose 
- Gastroenterology consultation, 
recommend endoscopy and biopsy 
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
- Support with systemic steroids, 
gastroenterology consultation, recommend 
endoscopy and biopsy 
  
Abdominal pain, stool with 
mucus or blood, change in 
bowel habits, peritoneal 
signs, 
OR Severe diarrhea (Grade 3, 
>6 stools per day over 
baseline) 
Duvelisib 
- 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 

 
31 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
- For recurrent Grade 3 diarrhea or 
recurrent colitis of any grade, discontinue 
duvelisib 
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
- Systemic steroids, gastroenterology 
consultation and biopsy 
- If no improvement in 3-5 days, consider 
addition of infliximab 
 
Life-threatening, grade 4 
Duvelisib 
- Discontinue duvelisib 
 
Nivolumab 
- Permanently discontinue nivolumab 
- Systemic steroids, gastroenterology 
consultation and biopsy 
- If no improvement in 3-5 days, consider 
addition of infliximab 
 
Cutaneous reactions 
Grade 1 
Duvelisib 
- No change in dose 
- Initiate supportive care with emollients, 
antihistamines (for pruritus), or topical 
steroids 
- Monitor closely 
 
Nivolumab 
- Continue nivolumab 
- Support with topical emollients and/or 
mild-moderate potency topical 
corticosteroids 
 
Grade 2 
Duvelisib 
- Consider holding duvelisib, restart at 
same dose  
- Initiate supportive care with emollients, 
antihistamines (for pruritus), or topical 
steroids 
- Monitor closely 
 
Nivolumab 
- Consider holding nivolumab until resolved 
- Resume at same dose once improved to 
grade 1 

 
32 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
- Support with topical emollients and/or 
mild-moderate potency topical 
corticosteroids 
- Consider systemic steroids at 1mg/kg and 
taper over 4 weeks 
- Consider skin biopsy 
 
Grade 3 
Duvelisib 
- Withhold duvelisib until resolved 
- Initiate supportive care with emollients, 
antihistamines (for pruritus), or topical 
steroids 
- Monitor at least weekly until resolved 
- Resume at reduced dose  
- If severe cutaneous reaction does not 
improve, worsens, or recurs, discontinue 
duvelisib 
 
Nivolumab 
- Hold nivolumab until resolved 
- Resume at same dose once improved to 
grade 1 
- Support with topical emollients and high-
potency steroids, dermatology consultation 
- Systemic steroids at 1-2mg/kg and taper 
over 4 weeks 
- Consider dermatology consultation 
- Skin biopsy recommended 
 
Grade 4 
Duvelisib 
- Discontinue duvelisib 
 
Nivolumab 
- Hold nivolumab  
- Dermatology consultation to determine if 
appropriate to resume upon resolution 
- Systemic steroids administered IV 
-Skin biopsy recommended 
 
SJS, TEN, DRESS (any grade) or 
life-threatening skin toxicity 
Duvelisib 
- Discontinue duvelisib 
 
Nivolumab 
- Discontinue nivolumab 
 

 
33 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
Pneumonitis without 
suspected infectious 
cause 
Grade 1 – asymptomatic. If 
repeat imaging with 
progression 
Duvelisib 
- Withhold duvelisib 
- If pneumonitis recovers to Grade 0 or 1, 
duvelisib may be resumed at same dose  
- If no improvement should treat as grade 2 
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
- If no improvement, treat as grade 2 
 
Moderate (Grade 2) 
symptomatic pneumonitis 
Duvelisib 
- Withhold duvelisib 
- Treat with systemic steroid therapy 
- If pneumonitis recovers to Grade 0 or 1, 
duvelisib may be resumed at reduced dose  
- If non-infectious pneumonitis recurs or 
patient does not respond to steroid 
therapy, discontinue duvelisib 
 
Nivolumab 
- Withhold nivolumab until resolved to 
grade 0-1 
- Resume at same dose 
- Prednisone 1-2mg/kg/d, with long taper 
- Consider pulmonology consultation, 
bronchoscopy and biopsy, empiric 
antibiotics 
- Monitor closely, if no improvement in 2-3 
days treat as grade 3 
 
Severe (Grade 3) or Grade 
4life-threatening pneumonitis 
Duvelisib 
- Discontinue duvelisib 
- Treat with systemic steroid therapy 
 
Nivolumab 
- Permanently discontinue nivolumab 
- Treat with high dose IV steroids, consider 
infliximab, empiric antibioitics 
- Pulmonary and infectious disease 
consultations and biopsy if able 
 
ALT/AST elevation 
3 to 5 × upper limit of 
normal (ULN) (Grade 2) 
Duvelisib 
- Maintain duvelisib dose 
- Monitor at least weekly until return to < 3 
x ULN 
 

 
34 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
Nivolumab 
- Withhold nivolumab until resolved to 
grade 1 
- Resume at same dose 
- Consider steroids if abnormality persists 
and clinical symptoms 
 
> 5 to 20 × ULN (Grade 3) 
Duvelisib 
- Withhold duvelisib and monitor at least 
weekly until return < 3 x ULN 
- Resume duvelisib at same dose (first 
occurrence) or at a reduced dose for 
subsequent occurrence 
 
Nivolumab 
- Permanently discontinue nivolumab 
- Start steroids with methylprednisolone at 
1-2mg/kg/d 
- Consider liver biopsy 
 
> 20 × ULN (Grade 4) 
Duvelisib 
- Discontinue duvelisib 
- Systemic steroid treatment 
 
Nivolumab 
- Permanently discontinue nivolumab 
- Start steroids with methylprednisolone at 
1-2mg/kg/d 
- Avoid infliximab 
- Hepatology consultation, consider liver 
biopsy 
 
Hematologic Adverse Reactions 
Neutropenia 
Absolute neutrophil count 
(ANC) 500 to 1000 cells/µL 
Duvelisib 
- Maintain duvelisib dose 
- Monitor ANC at least weekly 
 
Nivolumab 
- Withhold nivolumab until resolved if it is 
felt to contribute to the neutropenia, and 
otherwise continue nivolumab as 
previously 
- Resume at same dose 
 
ANC less than 500 cells/µL  
Duvelisib 
- Withhold duvelisib 

 
35 
 
Toxicity 
Adverse Reaction Grade 
Recommended Management 
- Monitor ANC until > 500 cell/uL 
- Resume duvelisib at same dose (first 
occurrence) or at a reduced dose for 
subsequent occurrence  
 
Nivolumab 
- Withhold nivolumab until resolved if it is 
felt to contribute to the neutropenia, and 
otherwise continue nivolumab as 
previously 
- Resume at same dose 
*If concern for auto-immune neutropenia, 
then hold nivolumab and follow practice 
guidelines 
Thrombocytopenia 
Platelet count 25K to < 50K 
cells/µL (Grade 3) with Grade 
1 bleeding 
Duvelisib 
- No change in dose 
- Monitor platelet counts at least weekly 
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
 
Platelet count 25K to < 50K 
cells/µL with grade 2 bleeding 
OR platelet count <25K 
cells/µL (Grade 4) 
Duvelisib 
- Withhold duvelisib 
- Monitor platelet count until > 25K cells/uL 
and resolution of bleeding if applicable.  
- Resume duvelisib at same dose (first 
occurrence) or resume at a reduced dose 
for subsequent occurrence  
 
Nivolumab 
- Withhold nivolumab until resolved 
- Resume at same dose 
*If concerned for autoimmune 
thrombocytopenia, hold nivolumab and 
follow practice guidelines 
 
 
 
 
Table 7.7 Dose Reductions for Duvelisib 
Initial Dose 
Decreased Dose 
15mg Daily 
None 

 
36 
 
25mg Daily 
15mg Daily 
25mg BID 
25mg Daily 
 
Note: If patient is on dose level 1, 15mg daily and has a dose interruption, duvelisib will be resumed at 
same dose. If patient subsequently requires another dose interruption at this level for the same toxicity, 
duvelisib should be discontinued. No more than 2 dose reductions for the same side effect are allowed 
for any patient, irrespective of starting dose.  
 
7.7 Method of Subject Assignment to Treatment Groups 
 
The study is a single arm, non-randomized trial. Patients will first be allocated to Phase I dose escalation 
cohorts at each dose level listed in Table 7.5. Patients will be enrolled  and allotted to the next available 
opening for each dose cohort as specified. For the Phase II dose expansion cohort, all patients will be 
enrolled at the recommended phase II dose.  
 
7.8 Preparation and Administration of Study Drug 
Duvelisib 
Duvelisib is provided in capsules with no additional preparation. The drug will be stored at the 
investigational pharmacy and dispensed to the patient. The medication can be taken with or without 
food. If a dose is missed by less than 6 hours, the dose should be taken immediately. If it has been more 
than six hours, the dose will be skipped and the next dose will be taken at the scheduled time.  
Nivolumab 
Nivolumab will be prepared per package insert by pharmacy staff. Nivolumab vial is diluted with either 
0.9% sodium chloride solution or 5% dextrose for a final concentration not to exceed 10mg/mL or less 
than 1mg/mL in a volume less than or equal to 160mL. Dilutions will be made within 8 hours of infusion. 
Nivolumab will be administered by infusion over 30 minutes using a non-pyrogenic, low protein binding-
in line filter. 
 
7.9 Subject Compliance Monitoring 
Compliance with duvelisib will be monitored with pill count at each 4-week visit. Patients will also be 
provided a pill drug diary (see Appendix B) to record pills taken, missed pills, damaged pills or other 
issues. This will be reviewed by the CRC at each visit.  If there is significant non-compliance across 
multiple visits that is not due to adverse effects or other reasonable events, patient will be discontinued 
from the study. This will ultimately be at the discretion of the investigator (in discussion with the 
treating physician as appropriate).   
 
7.10 Prior and Concomitant Therapy 
7.10.1 Prohibited and/or Restricted Treatments 

 
37 
 
• Duvelisib is metabolized by CYP3A4 
o Medications and foods that are strong CYP3A inducers will decrease the area under the 
curve (AUC) of duvelisib and should therefore be avoided. 
o Medications that are strong CYP3A inhibitors will increase the AUC of duvelisib and 
should be avoided. If unavoidable, the investigator may permit dose reduction of 
duvelisib to 15mg BID in cases when there is no alternative to a concurrent CYP3A 
inhibitor. 
o Medications that are substrates for CYP3A that are co-administered with duvelisib 
should also be avoided as the exposures to these medications may increase in presence 
of duvelisib. Investigator should consider decreasing doses of these substrates as 
appropriate. 
o Ultimately dose adjustments and medication adjustments are at the discretion of the 
investigator. 
o See Appendix A for a list of medications  
• Immunosuppressive agents unless they are utilized to treat an AE 
• Concurrent administration of any anticancer therapies (investigational or approved) with the 
exception of subjects in the survival period of the study 
• Use of allergen sensitization therapy 
• Use of recreational drugs other than alcohol or tobacco. Marijuana for medical use is permitted. 
• Palliative radiation treatment is not recommended while on combination therapy. If radiation is 
deemed necessary, duvelisib should be held for 1 week prior and 2 weeks after therapy. Any 
radiation-related AEs should resolve to grade 1 or less prior to resuming treatment. 
 
7.10.2 Permitted therapy 
• Inactivated influenza vaccination is permitted. 
• Topical, ocular, intra-articular, intranasal and inhalational corticosteroids are permitted. 
• Oral corticosteroids for premedication prior to scans are permitted. 
• Systemic corticosteroids are permitted for treatment of AEs. 
• Use of growth factors are permitted.  
• Palliative care evaluation for symptom control can be offered to any patient on trial. 
• For patients requiring surgery other than treatment-related biopsies, duvelisib should be held for 
2 weeks before and after if possible. Duvelisib may be restarted sooner than 2 weeks, in 
consultation with the attending surgeon if the subject recovers and surgery-related AEs have 
decreased to grade 1 or baseline.  
 
7.11 Blinding of Study Drug 
This study consists of a single treatment arm, and therefore will not be blinded.   
 
 8.0 Safety and Adverse Events Assessing, Recording, and Reporting 
 

 
38 
 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-
existing medical condition in a clinical investigation subject that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom 
or disease temporally associated with study participation whether or not considered related to the 
investigational product.  
The causal relationship to both/either study drug is determined by a physician and should be used to 
assess all adverse events (AE).   The causal relationship can be one of the following: 
• 
Unrelated: There is no temporal relationship to study drug; there is a reasonable causal 
relationship to another drug product, concurrent disease, or circumstance. 
• 
Unlikely related: There is only a temporal relationship to study drug, but not a reasonable causal 
relationship between the investigational product and the AE. 
• 
Possibly related: There is a reasonable possibility that the drug caused the adverse event. The 
investigator can provide a rationale or evidence to suggest a causal relationship between the 
study drug and the adverse event other than just a temporal relationship. 
• 
Probably related: There is a reasonable causal relationship between the study drug and the AE, 
and/or the event responds to dechallenge. 
• 
Definitely related: There is a reasonable causal relationship between the study drug and the AE. 
The event responds to withdrawal of investigational product (dechallenge), and recurs with 
rechallenge when clinically feasible. 
 
8.1 Dose Limiting Toxicities 
Acute dose limiting toxicities (DLTs) are defined as any of the following AEs and laboratory abnormalities 
considered possibly, probably, or definitely related to study treatment that occur any time from the 
initial dose of duvelisib in combination with nivolumab through day 28 of treatment. Toxicities occurring 
from day 29 through 28 days after completion of treatment will be considered late toxicities. Only acute 
DLTs will be considered for decisions to continue enrollment at the current dose level or proceed to the 
next dose level. Acute and late toxicities will be considered when deciding on the RP2D and will be 
discussed in monthly Data Safety Monitoring Board (DSMB) meetings. See Section 15.0 for further 
details.  
Severity of adverse events will be graded by National Cancer Institute Common Terminology Criteria for 
Adverse Events version 5.0 (CTCAE v5.0). A goal of ≤ 33% DLTs at each dose level will be considered 
acceptable.  
Whenever possible, biopsies are recommended if they can be done safely to help determine between 
immune-related and other etiologies of toxicity, particularly for rash and colitis. Biopsies for elevated 
liver enzymes and/or for pneumonitis should be considered if deemed feasible and safe in the context of 
risk:benefit evaluation.  General criteria for consideration of biopsy: 
• 
Diarrhea/colitis 
o Biopsy proven grade ≥3 immune-related colitis 
o Diarrhea of grade ≥3 that does not respond to treatment with steroids within 5 days 
• 
Pneumonitis 
o Immune-related pneumonitis grade ≥2  

 
39 
 
o Any grade ≥3 pneumonitis 
• 
Hematologic abnormalities 
o Neutropenia grade 4 despite holding duvelisib for 7 days 
o Thrombocytopenia grade ≥3 with bleeding 
o Thrombocytopenia grade 4  
• 
Other immune-related toxicities 
o Any grade ≥3 toxicity that does not respond to treatment within 5d 
• 
For the remainder of non-hematologic toxicities, grade ≥3  
 
8.2 Serious Adverse Events 
8.2.1 SAE Definitions 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above. (Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. 
 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is 
an SAE (e.g. contamination of drug product).  Although pregnancy, overdose, new cancers, and potential 
drug induced liver injury (DILI) are not always serious by regulatory definition, these events must be 
handled as SAEs. Any component of a study endpoint that is considered related to study therapy (e.g., 
death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as an SAE (see below for reporting details).  
The following hospitalizations will not be considered SAEs in this study: 
• 
A visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission, unless otherwise deemed an important medical or life-threatening event 
• 
Elective surgery, planned prior to signing study consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 

 
40 
 
• 
Routine health assessment requiring admission for baseline/trending of health status (e.g. 
routine colonoscopy) 
• 
Medical/surgical admission not intended to remedy ill health and/or planned prior to entry into 
the study. Appropriate documentation is required in these cases 
• 
Admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
 
8.2.2 Serious Adverse Event Collection and Reporting 
All events meeting the definition of a serious adverse event should be reported according to the 
departmental SAE checklist and SAE form. SAEs will be collected from a subject’s first dose of study 
medication until 100 days after the last dose of study medication. The initial SAE form should be sent to 
the following within 24 business hours / 1 business day of the Principal Investigator becoming aware: 
 
1. John M. Kirkwood:  kirkwoodjm@upmc.edu 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
4. SecuraBio, securabio@parexel.com and dlitwak@securabio.com 
 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report within 
the Sections B and C of the departmental SAE form: 
 
• 
CTCAE term(s) and grade(s)  
• 
current status of study drugs 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Follow-up reports:   
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up or by creating supplemental summary 
information and submitting it as follow-up along with a copy of the original departmental SAE form. 
 
8.4 Nonserious Adverse Events 
 
A nonserious adverse event is an AE not classified as serious.  The collection of non-serious AE 
information should begin upon initiation of study drugs. All non-serious adverse events (not only those 
deemed to be treatment-related) should be collected continuously during the treatment period and for 
a minimum of 100 days following the last dose of study treatment. 

 
41 
 
Non-serious AEs should be followed to resolution or stabilization, and/or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment, as appropriate. 
 
8.5 Laboratory Test Result Abnormalities 
 
The following laboratory test result abnormalities should be captured on the nonserious AE Case Report 
Form (CRF) page or SAE Report Form (paper or electronic) as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory test result abnormality that required the subject to have study drug discontinued 
or interrupted 
• 
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy. 
It is expected that whenever possible, the clinical rather than laboratory term will be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
 
8.6 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with study agent, the participant 
will immediately be discontinued from the study therapy, and followed for safety and efficacy 
evaluation as possible. The site will contact the participant at least monthly and document the 
participant’s status until the pregnancy has been completed or terminated. The pregnancy will be 
recorded on the case report form (CRF) and reported by the Investigator to the Institutional Review 
Board (IRB). 
Any pregnancy that occurs during a clinical study with an investigational medicinal product must be 
reported within 24 hours of learning of its occurrence. The pregnancy should be followed to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, and/or any pregnancy- or childbirth-related 
and/or newborn complications. The pregnancy should be recorded on a case report form (CRF) and 
reported by the Investigator to Secura Bio. Pregnancy follow-up should be reported using the Pregnancy 
Follow up Form. Any SAE experienced during pregnancy must be reported. 
The Investigator should counsel any pregnant subject and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. Additionally, the pregnant woman should be referred to 
an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. 
Monitoring of the subject should continue at least until delivery or until the pregnancy has terminated. 
If, while on study treatment a male study participant’s sexual partner becomes pregnant by said study 
participant, the pregnancy and pregnancy outcomes must also be reported as described above. Consent 
to report information regarding the pregnancy should be obtained from the pregnant individual. 
 

 
42 
 
8.7 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as an 
SAE.  
 
8.8 Potential Drug Induced Liver Injury 
Whenever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences of potential 
DILIs, meeting the defined criteria below, must be reported as SAEs (see Section 8.1.1 for reporting 
details). 
Potential drug induced liver injury is defined as: 
• 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND 
• 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), AND 
• 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
 9.0 Safety Information: Sponsor and Investigator Responsibilities  
 
9.1 Review of Safety Information: Sponsor Responsibilities 
The sponsor must promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from foreign or domestic sources, including information derived from 
any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from domestic and foreign regulatory 
authorities and reports of domestic and foreign commercial marketing experience. 
Note : The requirements of the manufacturer for the reporting of suspected adverse drug reactions to 
the FDA differ from the requirements of the sponsor Investigators (see below and Investigator 
Responsibilities on the O3IS website) for the reporting of adverse events. Sponsor-investigators of IND 
applications are subject to compliance with both the adverse reaction reporting requirements of the 
Sponsor and the adverse event reporting requirements of the Investigator. 
 
9.2 IND Safety Reports 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
later than 15 calendar days after the sponsor determines that the information qualifies for reporting 
under Sections 9.2.1 to 9.2.4 below. In each IND safety report, the sponsor must identify all IND 

 
43 
 
safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and 
must analyze the significance of the suspected adverse reaction in light of previous, similar reports 
or any other relevant information. 
9.2.1 
Serious and unexpected suspected adverse reaction 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly occur 
in the study population independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical control group. 
• 
 
9.2.2 
Findings from other studies 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple studies, 
or clinical studies (other than those reported under section 1.5.1), whether or not conducted under an 
IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to 
the drug. Ordinarily, such a finding would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or other aspects of the 
overall conduct of the clinical investigation. 
9.2.3 
Findings from animal or in vitro testing 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human 
exposure. Ordinarily, any such findings would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or other aspects of the 
overall conduct of the clinical investigation. 
9.2.4 
Increased rate of occurrence of serious suspected adverse reactions 
The sponsor must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
 
9.3 Submission of IND safety reports 
The sponsor must submit each IND safety report in a narrative format or on Form FDA 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how 
to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and 

 
44 
 
organization of files). The sponsor may submit foreign suspected adverse reactions on a Council for 
International Organizations of Medical Sciences (CIOMS) I Form instead of a Form FDA 3500A. Reports of 
overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format. Each notification to FDA must bear prominent 
identification of its contents, i.e., "IND Safety Report," and must be transmitted to the review division in 
the Center for Drug Evaluation and Research or in the Center for Biologics Evaluation and Research that 
has responsibility for review of the IND. Upon request from FDA, the sponsor must submit to FDA any 
additional data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request. 
9.3.1 
Unexpected fatal or life-threatening suspected adverse reaction reports 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. 
9.3.2 
Reporting format or frequency 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than that 
required under this paragraph. The sponsor may also propose and adopt a different reporting format or 
frequency if the change is agreed to in advance by the director of the FDA review division that has 
responsibility for review of the IND. 
9.3.3 
Investigations of marketed drugs 
A sponsor of a clinical study of a drug marketed and/or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected adverse reactions that are observed 
in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety information 
from the clinical study as prescribed by the post marketing safety reporting requirements. 
9.3.4 
Reporting study endpoints 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 1.7 third bullet of this 
section. However, if a serious and unexpected adverse event occurs for which there is evidence 
suggesting a causal relationship between a study drug and the event (e.g., death from anaphylaxis), such  
event must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (e.g., all-cause mortality). 
9.4 Follow-up 
The sponsor must promptly investigate all safety information it receives. 
Relevant follow-up information to an IND safety report must be submitted as soon as the information is 
available and must be identified as such, eg., "Follow-up IND Safety Report." 
If the results of a sponsor's investigation show that an adverse event not initially determined to be 
reportable under IND safety reporting guidelines is, in fact, so reportable, the sponsor must report such 
suspected adverse reaction in an IND safety report as soon as possible, but in no case later than 15 
calendar days after such determination is made. 

 
45 
 
 
9.5 Disclaimer 
A safety report or other information submitted by a sponsor under this part (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the 
report or information constitutes an admission that the drug caused or contributed to an adverse event. 
A sponsor need not admit, and may deny, that the report or information submitted by the sponsor 
constitutes an admission that the drug caused or contributed to an adverse event. 
 
9.6 Reporting Adverse Events to the responsible IRB 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board (IRB), 
the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse event that is 
determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; and 3) 
unexpected. Adverse event reports will be submitted to the IRB in accordance with the respective IRB 
procedures. 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 10 
calendar days following the sponsor-investigator’s receipt of the respective information. Adverse events 
which are 1) possibly, probably or definitely attributed to the investigational drug(s) or study 
treatment(s); 2) fatal or life-threatening; and 3) unexpected, will be reported to the IRB within 24 hours 
of the Sponsor-Investigator’s receipt of the respective information. 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the relevant 
information is available. If the results of the Sponsor-Investigator’s follow-up investigation show that an 
adverse event that was initially determined to not require reporting to the IRB does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will report the adverse event to the IRB as soon as 
possible, but in no event later than 10 calendar days, after the determination was made. 
 
9.7 Other Safety Considerations 
 
Any significant worsening of condition noted during interim or final physical examinations, 
electrocardiograms, radiologic exams, or any other assessment required or not required by protocol 
should be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
 
10.0 Data Safety Monitoring Plan 
 
10.1 Study Oversight 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet regularly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the following: 
• serious adverse events 

 
46 
 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
Minutes from the disease center DSMB meetings are made available to those who are unable to attend 
in person. 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria Version 5.0. All study treatment associated adverse events that are serious, at 
least possibly related to study drugs, and unexpected will be reported to the IRB. Any modifications 
necessary to ensure subject safety and decisions to continue or close the trial to accrual are also to be 
discussed during DSMB meetings. If any literature becomes available which changes the risk/benefit 
ratio or suggests that conducting the trial is no longer ethical, the IRB will be notified in the form of an 
Unanticipated Problem submission, and the study may be terminated. 
All study data reviewed and discussed during DSMB meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPMC Hillman Cancer Center DSMC which also 
meets monthly following a designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed bi-annually. 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB have the 
authority to suspend accrual or further investigate treatment on any trial based on information 
discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
 
10.2 Data Handling and Record Keeping 
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical study. Source Data 
are the clinical findings and observations, laboratory and test data, and other information contained in 
Source Documents. Source Documents are the original records including, but not limited to, hospital 
medical records, physician or office charts, physician or nursing notes, subject diaries or evaluation 

 
47 
 
checklists, pharmacy dispensing records, recorded data from automated instruments, x-rays, etc. When 
applicable, information recorded on the CRF shall match the Source Data recorded on the Source 
Documents. 
 
 
 
 
 
 11.0 Management of Adverse Events with Duvelisib 
Management of adverse events often depends on clinical context. From prior experience, suggestions 
regarding duvelisib toxicities are below per product insert and investigator’s brochure. Please refer to 
section 7.6 for information on managing AEs with nivolumab and duvelisib. Please also refer to 
published guidelines from ASCO for management of immune-related adverse events23. 
 
11.1 Infections 
Duvelisib carries a black box warning regarding infection risk, most often URI and pneumonia. The 
median time to infection was 3 months, with the majority occurring prior to 6 months. For any grade 3 
or higher infection, duvelisib must be held. For patients with suspected PJP, duvelisib should be held and 
permanently discontinued if PJP is confirmed.  PJP prophylaxis is required for all patients and should 
continue until CD4+ T cell count is > 200 cells/µL or for 14 days after last dose of duvelisib. For patients 
with CMV reactivation or infection, drug should be held until resolved. If resumed, patients should be 
monitored at least monthly for reactivation and prophylaxis should be considered. For other infections, 
recommended dose reductions are listed in Table 7.5. 
  
11.2 Diarrhea/Colitis 
Diarrhea and colitis were also seen frequently. Median time to onset was 4 months, with the majority of 
cases occurring before 8 months, and symptoms could be prolonged (median duration 0.5 months). For 
grade 1-2 diarrhea or asymptomatic colitis, initiate supportive care with antidiarrheal agents, continue 
medication and monitor weekly until resolution. If unresponsive to antidiarrheals then duvelisib should 
be held and enteric steroids such as budesonide should be started. Duvelisib may then be restarted at a 
reduced dose as deemed clinically appropriate by the treating physician.  
For subjects with abdominal pain, stools with mucus or blood, or severe diarrhea, hold duvelisib and 
start systemic or enteric steroids. If possible, a colonoscopy and work-up for immune-mediated colitis 
should be performed. Restart duvelisib at a reduced dose upon resolution of symptoms to less than or 
equal to CTCAE Grade 1. For recurrent events, duvelisib should be permanently discontinued.  
 
11.3 Cutaneous Reactions 
Cutaneous reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic 
epidermal necrolysis (TEN) occurred with duvelisib. Median time to onset was 3 months with a median 
event duration of 1 month. Patients often presented with pruritic, erythematous or maculo-papular 
rash. Subjects should report rashes, sores, ulcers on skin, lips, mouth, blisters, rash, fevers promptly. 
Subjects with Grade 1-2 reactions should continue duvelisib at the current dose, supported with 

 
48 
 
emollients, anti-histamines, topical steroids and close monitoring. If reaction is more severe, duvelisib 
should be held, and steroids (topical and systemic) and antihistamines should be given. Patients should 
be monitored at least weekly. Duvelisib should be discontinued if cutaneous reactions recur. If subjects 
experience, SJS, TEN, or DRESS of any grade, discontinue duvelisib.  
 
11.4 Pneumonitis 
Serious cases of pneumonitis occurred with duvelisib. Median time to onset of any grade was 4 months 
with the majority of cases occurring prior to 9 months and with a mean duration of event of 1 month. 
Subjects should report new cough or shortness of breath. Patients who have pulmonary signs and 
symptoms such as cough, dyspnea, hypoxia, radiologic changes, or decline of >5% in oxygen saturation 
should have duvelisib held and be evaluated. Infectious etiologies should be treated as above. Systemic 
steroids should be considered. For moderate disease, reduced duvelisib doses can be considered. If non-
infectious pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe 
or life-threatening pulmonary disease, duvelisib should be permanently discontinued.  
 
11.5 Neutropenia 
Patients with hematologic conditions treated with duvelisib frequently developed neutropenia. CBC with 
differential should be checked at least every 2 weeks during cycle 1, and more frequently for those with 
ANC < 1000 cells/µL. Withhold duvelisib if ANC < 500 cells/µL, monitor weekly and resume at same dose 
of the first occurrence or at a decreased dose for subsequent occurrence.  Duvelisib can be resumed 
when ANC>100 is reached in the absence of signs of infection. G-CSF may be used per ASCO guidelines.   
 
 12.0 Assessment of Disease  
Patients will be evaluated for response every 12 weeks while on study. If clinicians have clinical 
concerns, evaluation by imaging may be done as there is clinical or subjective evidence of progression 
before 12 weeks, with imaging resumed on a Q 12-week imaging cycle. Assessments for response and 
progression will be carried out according to the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline version 1.1 19 which are reproduced and paraphrased in the sections below. Following RECIST 
criteria, changes in the largest diameter of the tumor lesions and the shortest diameter for malignant 
lymph nodes will be used. 
 
12.1 Definitions 
• 
Evaluable for toxicity – All patients are evaluable for toxicity upon initiating treatment of 
nivolumab and duvelisib. For the phase I portion, patients should have taken 75% of duvelisib 
pills according to pill diary and pill counts. 
• 
Evaluable for objective response – Patients who have measurable disease at baseline and have 
their disease re-evaluated at 12 weeks of therapy will be evaluable for response. Patients who 

 
49 
 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.  
• 
Evaluable non-target disease response – Patients who have baseline lesions that are evaluable 
but do not meet the definitions of measurable disease have received at least one cycle of 
therapy and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
• 
Measurable disease – Tumor lesions that can be accurately measured by the longest diameter in 
the plane of measurement with a minimum size of 10mm by CT scan, 10mm caliper 
measurement on clinical exam, 20mm by chest x-ray. CT scan thickness should be no greater 
than 5mm. Tumor measurements must be recorded in mm or decimal fractions of centimeters.  
• 
Malignant lymph nodes – To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15mm in short axis when measured by CT scan. Only the short axis will be 
measured and followed.  
• 
Non-measurable disease – All other lesions, including small lesions < 10mm and lymph nodes < 
15mm are considered non-measurable disease. Other non-measurable disease examples include 
ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly that don’t correlate to CT or MRI, bone lesions, inflammatory 
breast disease.   
• 
Target lesions – When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (max two per organ) representative of all involved organs should 
be recorded and measured at baseline. If only 2 organs are involved, the maximum number of 
target lesions is four. Target lesions should be selected based on lesions with the longest 
diameter, be representative of involved organs, and should lend themselves to repeated 
measurements. If lesions do not fulfill these requirements, the next largest lesion that can 
reproducibly be measured should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to 
be included in the sum, then only the short axis will be added. The baseline sum will be used as 
a reference to further characterize any objective tumor regression in the measurable dimension 
of the disease.  
• 
Non-target lesions – All other lesions or sites of disease including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as present, absent or 
unequivocal progression.  
Other considerations 
• 
Lesions that meet radiographic criteria for simple cysts should not be considered malignant 
lesions, because they are, by definition, simple cysts. Cystic lesions thought to represent cystic 
metastases can be considered as measurable lesions, if they meet the definition of 

 
50 
 
measurability described above. However, if non-cystic lesions are present in the same patient, 
they are preferred for selection as target lesions. 
• 
Lesions situated in a previously irradiated area, or an area subjected to other loco-regional 
therapy, are usually considered non-measurable unless there has been demonstrated 
progression in the lesion. 
 
12.2 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in the metric system using ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 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. Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
• 
Clinical lesions - Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
• 
Conventional CT and MRI – CT is the preferred modality for evaluating lesions. By RECIST, the 
measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm (0.5 
cm) or less. If CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
MRI has excellent contrast, spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. Ideally, the 
same type of scanner should be used and the same image acquisition protocol should be 
followed as closely as possible across all scans. Body scans should be performed with breath-
hold scanning techniques, if possible. 
• 
PET-CT - The low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of sufficiently comparable 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  

 
51 
 
• 
FDG-PET - While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
o FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the radiographic protocol and supported by disease-specific medical literature for the 
indication. However, it must be acknowledged that such approaches may lead to false 
positive CR’s due to limitations of FDG-PET resolution/sensitivity. 
• 
Ultrasound – Ultrasound examinations are not reliably reproduced for review and are operator 
dependent.  As such, it cannot be guaranteed that the same techniques and measurements are 
taken on each evaluation, and ultrasound should not be routinely used as a method of lesion 
measurement. If new lesions are identified by ultrasound, they should be verified by another 
modality as described above.  
• 
Cytology and Histology - These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, 
such as germ cell tumors, where known residual benign tumors can remain). The cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 
 
12.3 Response Criteria 
 
12.3.1 Evaluation of target lesions 
• 
Complete response (CR) – Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 

 
52 
 
• 
Partial response (PR) – At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
• 
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. (Note: the appearance of one or more new lesions is also 
considered progression).  
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
• 
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. 
12.3.2 Evaluation of non-target lesions 
• 
Complete response (CR) – Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
• 
Non-CR/Non-PD – Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• 
Progressive disease (PD) – Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single 
lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
12.3.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence. The reference for progressive disease is the smallest 
measurement since treatment initiation. The best response assignment will depend on the 
achievement of both measurement and confirmation criteria, as seen in the tables below, 
excerpted from the RECIST v1.1 manuscript 19.   
 
For patients with measurable disease 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 

 
53 
 
CR 
Non-CR/Non-PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once ≥4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment. 
 
For patients with non-measurable disease (i.e. non-target disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease, since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials, so to assign this category when no 
lesions can be measured is not advised 
12.3.4 Duration of response 
• 
Duration of overall response – The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented. The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 

 
54 
 
• 
Duration of stable disease - Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
12.3.5 Progression-Free survival 
• 
Progression-free survival defined as the time between the date of first treatment and the  
date of first documented progression or death due to any cause, whichever occurs first.  
12.3.6 Overall survival  
• 
Overall survival is defined as the time between the date of first treatment and the date of death 
due to any cause. Patients who are alive will be censored at the time of the last follow-up. 
 
13.0 Tissue and Blood Collection and Biomarker Studies 
Correlative studies will be carried out at UPMC Hillman Cancer Center by Dr. Tullia Bruno and at Emory 
Winship Cancer Institute in the laboratory of Dr. Edmund Waller. The majority of samples will be 
processed at and preserved at UPMC. All samples will be banked at UPMC as the central site of the 
study.  See schema below regarding time of patient samples:  
 
 
13.1 Phase I Correlative Studies 
For the phase I dose escalation study, patients will have blood drawn and tumor biopsies at baseline and 
again after 12 weeks of treatment. These time points were chosen based on prior experience with 
checkpoint inhibitors and duvelisib, as well as for patient convenience (monthly visits) and to correlate 

 
55 
 
with efficacy evaluations (every 12 weeks).  We will also conduct a peripheral blood draw at 4 weeks.  
Previous analysis of peripheral blood samples in melanoma patients being treated with checkpoint 
inhibitors have demonstrated expansion of CD8+ T cells detectable as early as 4 weeks24.  Further, 
changes in peripheral cytokine levels have been seen as early as day 8 in lymphoma patients treated 
with duvelisib14. While evaluation at 4 or 12 weeks may not capture the “peak” of change with this 
therapy, we anticipate alterations attributable to therapy will be observed and can be correlated with 
outcomes in a clinically meaningful way.  
We will use CyTek flow cytometry to evaluate peripheral blood mononuclear cells (PBMCs) and tumor-
infiltrating cells from patients treated with each dose level of duvelisib. Several of the immune cell types 
that correlate with anti-tumor response, including CD8+ T cells, B cells and MDSCs, have been shown to 
be altered with PI3Kγ or PI3Kγδ inhibition 15,14. In particular, CD8+ T cells are often cytotoxic to tumor 
cells, and increased CD8+ TILs correlate with improved survival in patients with melanoma25. 
Proliferation of intratumoral CD8+ T cells after immunotherapy was shown to correlate with anti-tumor 
response24. The ideal RP2D will demonstrate proliferation and activation of CD8+ TILs. We will also 
examine CD8+ and CD4+ T cell subsets, and markers of activation and exhaustion by flow cytometry. 
Additional cell types of importance in the tumor microenvironment will also be queried, including T 
regulatory cells, B cells and monocyte precursors in peripheral blood and tumor biopsies.  
Further, we will use RNA from PBMCs to evaluate the immune profile of patients prior to and on therapy 
with duvelisib with the Nanostring platform.  This includes a panel of 770 genes associated with 
inflammation and autoimmune disease. Nanostring signatures will be correlated with any clinical 
toxicities observed, as a way to evaluate possible biomarkers of toxicity.  
Along with toxicity data from the clinical portion of the phase I trial, this data will also help inform the 
recommended phase 2 dose of duvelisib. Ideally, the chosen dose will minimize patient toxicity while 
maximizing anti-tumor immune profile (high T effector cells, low T regulatory cells, low myeloid-derived 
suppressor cells).  Observations from this portion of the study will be used to focus studies in the Phase 
II portion of exploratory analysis.  
 
13.2 Phase II Correlative Studies 
Patients enrolled in the phase II cohort will have blood draws at baseline and 12 weeks on treatment. 
Tumor biopsies will be performed at baseline and after 12 weeks on treatment. For the phase II 
correlative studies, we will use a multi-level approach to evaluate the interplay of the immune system 
with the tumor microenvironment (pre-treatment, post-treatment with duvelisib, and at progression).  
Studies will be focused on answering several questions pertinent to the mechanism of action of 
duvelisib and resistance to PD1 therapy.  
First, we will characterize T cell responses to duvelisib. In combination with data from flow cytometry in 
Phase I studies, and we will add more detailed studies to characterize T cell activation through 
functional assays. We will also use Cytek to evaluate markers of T cell exhaustion, including LAG3, TIM3, 
TIGIT, CD38, bcl2 and HLA-DR. This data will be corroborated with a Nanostring T cell characterization 
panel which evaluates RNA expression of pathways involved in T cell activation, exhaustion, persistence, 
and metabolism. T cell metabolism will also be evaluated by an assay for mitochondrial mass. 

 
56 
 
Second, we will evaluate changes in the tumor microenvironment while on duvelisib using tumor biopsy 
samples. We will use flow cytometry to evaluate immune populations within tissues and evaluate 
whether these reflect changes in the periphery. Multispectral immunofluorescence will be used to 
evaluate the spatial relationship and interplay between immune populations, particularly between pro-
inflammatory and anti-inflammatory populations. Presence and alterations of B cells in biopsy samples 
are of particular interest, given the known activity of duvelisib on B cells and the prognostic implications 
of B cells and tertiary lymphoid structures.  
Finally, global changes in the tumor microenvironment will be evaluated by single cell RNAseq. For these 
studies, fresh tissue from 9 patient’s tumors with matched peripheral blood samples will be used. In 
addition to providing important data regarding alterations associated with duvelisib, these samples will 
also be informative regarding acquired resistance to anti-PD1 therapy.   
 
The following techniques will be used: 
Single cell RNAseq: We will perform single cell RNAseq on patient PBL and TIL pre and post 
treatment to assess effects on all immune populations for 9 patients who demonstrate a standard 
pattern of anti-PD1 resistance. This will generate a robust data set that could give us information on 
differences that would not be detected by the above methods. Further, because we will utilize the 
10x 5' system, we could ideally get both RNA signatures as well as paired TCR and BCR sequences 
from these patients.  
 
Cytek Aurora (26 parameter flow cytometry): Via the UPMC Hillman Cancer Cytometry Facility, we 
will utilize the Cytek Aurora to analyze changes in immune cells pre and post therapy. We will be 
able to analyze samples with three comprehensive, 26 parameter panels which will assay general 
changes in the immune infiltrate (unbiased, analyzing all populations) as well as specific changes in 
CD8+ T cells, Tregs, macrophages and B cells, given the specific effects of this therapeutic regimen 
described in the literature.  
 
Multispectral IF: We will pair our above flow cytometric analyses with locational studies on the 
immune infiltrate via Vectra Polaris multispectral IF (7 colors in total). Further, we will expand our 
panels to an Akoya CODEX system  able to assay 30+ biological correlates on a single piece of 
paraffin embedded tissue.  
 
In vitro functional assays: The Bruno lab has developed micro-sized functional assays that can assess 
CD8+ T cell, Treg, macrophage and B cell function pre and post treatment, which will be used to 
analyze Study specimens.  
 
Nanostring: RNA Analysis of 770 gene panel for evaluation of multiple aspects of T cell biology, 
including activation, metabolism and exhaustion will be employed. A separate panel will be used to 
evaluate RNA signatures in toxicity which includes genes involved in inflammation and 
autoimmunity.  
 
 
 
 
 
 

 
57 
 
14.0 Statistical Methods 
This clinical trial includes a phase I dose-finding study and a phase II efficacy study. The phase I portion 
requires up to 18 patients. The phase II portion needs an additional 24 patients (6 carried over from 
phase I using the RP2D level) for a study total of up to 42 patients and a phase II total of 30 patients. 
With 2 centers, each accruing 1-2 patients per month, we anticipate completing enrollment in 18 
months.  
 
14.1. Phase I Portion of the Study 
14.1.1. Study Design 
The primary objectives of the phase I portion are to determine the maximum tolerated dose (MTD) of 
duvelisib when combined with anti-PD1 therapy nivolumab, and to decide on its recommended phase II 
dose (RP2D). Dose escalation will follow the decision rule in the following table, using the three dose 
levels defined in Section 7.5 (i.e., 15mg Daily, 25mg Daily, and 25mg BID), starting from the lowest dose. 
The MTD is defined to be the highest dose level at which no more than 1 of 6 treated patients 
experiences a DLT (DLT is defined in Section 8.1). Cohorts of three to six patients each will be treated at 
a dose level. Patients should have taken 75% of pills to be included in analysis of their respective cohort, 
as assessed through pill counts and pill diary. Only toxicities observed during the first treatment cycle 
will affect dose escalation. Late toxicities observed will be discussed at monthly data safety monitoring 
boards to determine if dose adjustments should be made.  
After MTD is determined, we will decide on RP2D based on an overall consideration of DLT data, as well 
as immune cell profiling with laboratory correlatives. For this purpose, our decision rule in the following 
table is a slight modification of the standard “3+3” to make sure 6 patients will be accrued at each safe 
dose in order to have enough patients for laboratory evaluations. RP2D should not be higher than MTD. 
If the MTD is not reached, R2PD will be decided based on safety data from acute and late toxicities as 
well as immune cell profiling data by the investigators (see section 13.1).  
 
DECISION RULES FOR DOSE LEVEL ESCALATION 
 
No. of patients with DLT's at 
this dose level 
No. of patients treated at this 
dose level 
Action 
≤1 
3 
Treat 3 more patients at this 
dose level. 
≤1 
6 
Treat 3 patients at the next 
higher dose level (or if at the 
highest level, stop the trial, 
and declare the dose at this 
level to be the MTD). 

 
58 
 
>1 
3 or 6 
Stop dose escalation. The 
previous dose is defined as 
MTD. 
 
Cohorts need not be completed if clear decisions can be made on the basis of an incomplete cohort.  For 
example, if the first two patients in an intended cohort of three experience DLT’s, escalation can be 
stopped without accruing the third member of the cohort. 
 
14.1.2. Sample Size/Accrual Rate 
The number of patients accrued to the study will depend on the MTD. No more than 18 evaluable 
patients will be treated in the phase I portion. An evaluable patient is defined as one who either a) 
receives at least one dose the study drug and/or suffers DLT, or b) completes a treatment cycle and has 
no DLT observed during this cycle.  
 
14.2. Phase II Portion of the Study 
The study primary endpoint will be analyzed once the last patient on treatment is on study for 18 weeks.  
 
14.2.1. Study Populations: 
Safety population: patients who received any amount of the study regimen. 
Efficacy population: patients who received at least one cycle of the treatment and at least one efficacy 
evaluation. 
 
14.2.2. Study Design and Interim Analysis 
The primary objective of this study is to evaluate the overall response rate to the combination of anti-
PD1 therapy and duvelisib. We would consider the combination futile and not worth further study if the 
response rate is 5% or lower. We will monitor the efficacy of the regimen using a Bayesian method. We 
will consider the trial futile and propose stopping if the posterior probability that response rate is <5% 
given the observed data is >70%.   A non-informative prior of Beta (0.5, 0.5) is used for the true response 
rate and the cohort size is set to be 5. The futility early stopping boundaries are given in the following 
table:  
 

 
59 
 
 
 
Therefore, if none of the first 15 patients responds to the combination, the study will be stopped early 
for futility. Otherwise, the study will continue to recruit all 30 patients. By the end of the study, we will 
consider the study combination effective and worth further study if the posterior probability that the 
response rate is >5% given the observed data is 90% or higher (in our case, if we observe >3 responses in 
30 evaluable patients). The following figure demonstrated the simulation results of the operating 
characteristics of our study design, under the assumption of various true response rates. As shown, 
when the response rate is 5% or lower, the probability of early stop is higher (>0.46) and probability of 
declaring efficacy (i.e. “type I error”) is low (<0.06). When the response rate is 20% or higher, the 
probability of early stopping is less than 3.5% and the probability of declaring efficacy (i.e. “power”) is 
over 86%. 
 
 
The simulation is performed using the web tool for Bayesian Efficacy Monitoring Via Posterior Probability 
(http://www.trialdesign.org/one-page-shell.html#BEMPO).  
 
14.2.3. Analysis of Primary and Secondary Endpoints 
14.2.3.1. Analysis of Tumor Response: 
Overall Response Rate (primary endpoint) will be estimated by the proportion of patients with a best 
response of complete response (CR) or partial response (PR) by RECIST 1.1 criteria, with corresponding 
exact 95% confidence limits being reported. The response rate will also be compared between pre-

 
60 
 
specified subsets of melanoma patients with Fisher’s exact tests. These comparisons will be done in an 
exploratory manner. 
The distribution of response duration (defined in Section 12.3.4) will be characterized by median and 
quartiles, with the corresponding Kaplan-Meier estimate being made of PFS among patients responding 
to treatment. To the extent possible from the available data, proportional hazards models will be used to 
assess whether the rate of disease progression varies materially among the three subgroups of disease  
response: CR, PR, and SD. 
 
14.2.3.2. Analysis of Progression Free Survival (PFS) and Overall Survival (OS):  
PFS and OS (defined in Section 12.3.5 and 12.3.6 respectively) will be estimated by the Kaplan-Meier 
method. The corresponding median survival times (with 95% confidence limits) will be determined, as will 
the cumulative percentage of patients remaining progression-free (and the cumulative percentage-alive) 
at selected time points after initial treatment (e.g., 6,12, 18 months). 
 
14.2.3.3. Stopping Rule for Excessive Toxicity 
We will use a Bayesian monitoring scheme to continuously monitor the dose limiting toxicity rate of the 
study combination at 30%. The DLT is defined generally as grade 3 and 4 toxicity, see section 8.1 for 
more detailed definitions.  Again, a non-informative prior of Beta (0.5, 0.5) for the DLT rate will be used. 
We will hold patient recruitment if the posterior probability Pr(SAE rate>30% is >0.7, and the study 
committee and the PI will then decide whether to modify or discontinue the study. The stopping 
boundary for toxicity is given in the following table: 
 
Number of SAEs >= 
in Number of Patients = 
2 
3-5 
3 
6-7 
4 
8-10 
5 
11-13 
6 
14-16 
7 
17-19 
8 
20-22 
9 
23-26 
10 
27-29 
11 
30 
 
 

 
61 
 
We simulate the operating characteristics under various assumed true toxicity ratesratesrates (see the 
following table): 
 
 
14.2.3.4. Analysis of Safety (for both the phase I portion and the phase II portion) 
 
We will consider a toxicity event to be an adverse event (evaluated by CTCAE 5.0) that is possibly, 
probably, or definitely related to treatment. Toxicity will be considered attributable to both study drugs, 
unless investigator determines one of the drugs is a more likely culprit (e.g. CMV due duvelisib).  The 
maximum grade of toxicity for each category of interest will be recorded for each patient and the summary 
results will be tabulated by category and grade. These will also be done for early toxicities (within 4 weeks) 
and late toxicities (after 4 weeks) separately. 
 
14.2.3.5. Analysis of exploratory endpoints 
The effect of duvelisib dose on marker expression will be exploratively analyzed with generalized linear 
models, where baseline marker value, duvelisib dose and measurement time are explanatory variables. 
Also, pre- and post- treatment marker expression values will be compared with paired t-tests or Wilcoxon 
signed rank tests as appropriate.  
 
 
 
 
 
 
 15.0 Study Management, Agreement and Ethical Considerations 
This study will be managed in the UPMC Melanoma Center which has considerable experience in 
managing clinical trials. Screening, registration, safety and efficacy evaluations are described in detail 
above. The study funding will come predominantly from Secura Bio, Inc the manufacturer of duvelisib.  
Study design, operations and procedures were designed independently by the co-investigators and were 
compliantly reviewed by appropriate experts on the Secura Bio clinical/scientific team.  
Without a standard of care option for anti-PD1 refractory disease, clinical trials are a preferred 
treatment according to NCCN guidelines 1.  Our trial is a reasonable option for patients who have 
progressed on anti-PD1 therapy and who have exhausted BRAF targeted therapy, which is ultimately the 
majority of patients with advanced melanoma.  Toxicities with duvelisib were observed in heavily pre-
treated patients with hematologic malignancies 12. Patients with melanoma are less immuno- and 
myeloid suppressed and should tolerate duvelisib with fewer toxicities. Studies with duvelisib in other 
solid tumors are also being planned. 
 

 
62 
 
  
16.0 References  
 
1.  
Network NCC. Cutaneous melanoma. NCCN Guidel. 2019:1-199. 
doi:10.5124/jkma.2018.61.11.662 
2.  
Beaver JA, Hazarika M, Mulkey F, et al. Patients with melanoma treated with an anti-PD-1 
antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis. Lancet 
Oncol. 2018;19(2):229-239. doi:10.1016/S1470-2045(17)30846-X 
3.  
Robert C, Long G V., Brady B, et al. Nivolumab in previously untreated melanoma without BRAF 
mutation. N Engl J Med. 2015;372(4):320-330. doi:10.1056/NEJMoa1412082 
4.  
Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone 
versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a 
multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480-1492. 
doi:10.1016/S1470-2045(18)30700-9 
5.  
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. 
Br J Cancer. 2018;118(1):9-16. doi:10.1038/bjc.2017.434 
6.  
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in 
Human Disease. Cell. 2017;170(4):605-635. doi:10.1016/j.cell.2017.07.029 
7.  
Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl 
J Med. 2011;364(6):514-523. doi:10.1056/NEJMoa1009290 
8.  
Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-
positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. 
doi:10.1056/NEJMoa1109653 
9.  
Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with 
mTOR inhibitors. Transplant Rev. 2014;28(3):126-133. doi:10.1016/j.trre.2014.03.002 
10.  
Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: Insights 
from gene-targeted mice. Trends Biochem Sci. 2005;30(4):194-204. 
doi:10.1016/j.tibs.2005.02.008 
11.  
duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic 
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) | FDA. 
https://www.fda.gov/drugs/resources-information-approved-drugs/duvelisib-copiktra-verastem-
inc-adult-patients-relapsed-or-refractory-chronic-lymphocytic-leukemia. Accessed September 15, 
2019. 
12.  
Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: Duvelisib vs ofatumumab in 
relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-2455. doi:10.1182/blood-2018-05-
850461 
13.  
Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: A Phase II study of duvelisib (IPI-145) in 
patients with refractory indolent non-hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922. 

 
63 
 
doi:10.1200/JCO.18.00915 
14.  
Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,g inhibitor duvelisib in a phase 1 trial 
and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898. doi:10.1182/blood-2017-
08-802470 
15.  
De Henau O, Rausch M, Winkler D, et al. Overcoming resistance to checkpoint blockade therapy 
by targeting PI3Kγ in myeloid cells. Nature. 2016;539(7629):443-447. doi:10.1038/nature20554 
16.  
Kaneda MM, Messer KS, Ralainirina N, et al. PI3Kγ 3 is a molecular switch that controls immune 
suppression. Nature. 2016;539(7629):437-442. doi:10.1038/nature19834 
17.  
Davis RJ, Moore EC, Clavijo PE, et al. Anti-PD-L1 efficacy can be enhanced by inhibition of 
myeloid-derived suppressor cells with a selective inhibitor of PI3Kd/g. Cancer Res. 
2017;77(10):2607-2619. doi:10.1158/0008-5472.CAN-16-2534 
18.  
Kirkwood JM, Iannotti N, Cho D, et al. Abstract CT176: Effect of JAK/STAT or PI3Kδ plus PD-1 
inhibition on the tumor microenvironment: Biomarker results from a phase Ib study in patients 
with advanced solid tumors. In: American Association for Cancer Research (AACR); 2018:CT176-
CT176. doi:10.1158/1538-7445.am2018-ct176 
19.  
Eisenhauer E a, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
doi:10.1016/j.ejca.2008.10.026 
20.  
O’Brien S, Patel M, Kahl BS, et al. Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and 
pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a 
phase 1 study. Am J Hematol. 2018;93(11):1318-1326. doi:10.1002/ajh.25243 
21.  
Christopher Funk, BS, , Shuhua Wang, MD, Alexandra Waller, BS, Lauren Fleischer, BS, Aditi 
Sharma, Harold Spencer, PhD, Vikas Gupta, MD, PhD, Sruthi Ravindranathan, PhD, Mala 
Shanmugam, PhD, Christopher Flowers, MD, MS, Edmund Waller, MD, PhD F. Dual inhibition of 
PI3Kdelta and PI3Kgamma to enhance mitochondrial mass and ex vivo expansion of central and 
stem cell memory T cells from CLL patients. J Immunother Cancer. 2019;7. 
https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0763-1. 
22.  
Opdivo Perscribing INformation. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Published 
2020. 
23.  
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in 
patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology 
clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385 
24.  
Wu TD, Madireddi S, de Almeida PE, et al. Peripheral T cell expansion predicts tumour infiltration 
and clinical response. Nature. 2020;579(September 2018). doi:10.1038/s41586-020-2056-8 
25.  
Fu Q, Chen N, Ge C, et al. Prognostic value of tumor-infiltrating lymphocytes in melanoma: a 
systematic review and meta-analysis. Oncoimmunology. 2019;8(7):1-14. 
doi:10.1080/2162402X.2019.1593806 
26.  
Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and 
adverse effects. Am Fam Physician. 2007;76(3):391-396. 

 
64 
 
27.  
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
2017. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers. 
 
 
 
 
 
 
 
 
 

 
65 
 
17.0 Appendices 
 
17.1 Appendix A: Medications with CYP3A interactions 
 
Table 17.1 Inhibitors and Inducers of CYP3A  
Potent CYP3A Inhibitors 
Antibiotics or antifungals 
Clarithromycin, erythromycin, 
telithromycin 
Anti-emetic 
Aprepitant 
Antifungals 
Itraconazole, ketoconazole, 
voriconazole, posaconazole 
Antiretrovirals 
Ritonavir, idinavir, nelfinavir, 
boceprevir, cobicistat, 
elvitegravir, paritaprevir, 
telaprevir, tipranavir 
Calcium channel inhibitors 
Diltiazem, verapamil 
Foods 
Grapefruit juice 
Antidepressant 
Nefazodone 
Tyrosine Kinase Inhibitor 
Imatinib 
Potent CYP3A Inducers 
Anti-epileptics 
Carbamazepine, phenobarbital, 
phenytoin 
Antibiotics 
Rifampin 
Antiretrovirals 
Efavirenz, etravirine 
Supplements 
St John’s wort 
CYP3A Sensitive Substrates 
Analgesic/Benzodiazapine 
Alfentanil, midazolam, 
naloxegol, triazolam,  
Aldosterone receptor 
antagonist 
eplerenone 
Anti-arrhythmic 
dronedarone 
Anticholinergic 
darifenacin 
Antihistamine 
ebastine 
Anti-retroviral 
Darunavir, indinavir, maraviroc, 
saquinavir, tipranavir,  
Antidepressant/antipsychotic 
Buspirone, lurasidone, 
quetiapine 
Calcinineurin / mTor inhibitors 
Everolimus, sirolimus, 
tacrolimus 
Calcium channel blockers 
Nisoldipine, felodipine 
CONTINUED… 
 

 
66 
 
Platelet aggregation inhibitor 
ticagrelor 
Phosphodiesterase inhibitor 
avanafil, sildenafil, vardenafil 
Statin/lipid lowering agents 
Lomitapide, lovastatin, 
simvastatin 
Steroid 
Budesonide 
Triptan 
Eletriptan 
Tyrosine kinase inhibitor 
dasatinib, ibrutinib 
Vaptans 
Conivaptan, tolvaptan 
 
 
 
References: 26,27 
 
 
 

 
67 
 
17.2 Appendix B: Drug Diary 
 
Participant: ____________________ 
 
Your MD ____________________ Phone ____________________  
Your RN _____________________ Phone ____________________  
 
DOSING LOG 
Duvelisib Dose ____ Cycle: ___ 
 
For each AM dose take: 1 pill 
For each PM dose take: 1 pill 
Date 
Amount Taken 
Comments 
AM dose 
PM dose 
Ex: 
6/1/2019 
8 am - 1 
7:30 pm - 1 
vomited PM pill 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 

 
68 
 
 
Please bring any unused study drug, all empty containers, and your diary to the 
next clinic visit 
 
 
 
 
 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
FOR STUDY TEAM USE ONLY 
Staff Initials: 
Date Dispensed: 
Date Returned: 
# pills/caps/tabs dispensed: 
# pills/caps/tabs returned: 
# pills/caps/tabs that should have been taken: 
Discrepancy Notes: 

 
69 
 
SUMMARY OF CHANGES 
Protocol dated 4-27-22 
Page 1 
Version date changed from 3-11-22 to 4-27-22 
Page 1 - 2 
Removed references to Emory University 
Page 8 
Table ii. Protocol Summary, Methodology, Removed “multi-center” 
Page 8 
Table ii. Protocol Summary, Removed reference to Emory Winship Cancer Institute 
Page 14 
Section 3.1, General Study Design, Removed “multi-center study to be conducted at 
Winship Cancer Institute at Emory University” 
Page 17 
Section 4.2, Exclusion Criteria, 1st bullet, Removed “with” 
Page 20 
Section 4.3, Subject Recruitment, 1st sentence, Removed “Emory Winship Cancer 
Institute” 
Page 23 
Section 5.4, Procedure for Registration of Subjects, Removed “Winship Cancer 
Institute of Emory University; 
Page 22 
Section 5.1, Study Site, Removed “Winship Cancer Institute” 
Page 28 
Section 7.4.1, Receipt of Drug Supplies, Removed “Winship Cancer Institute” 
Page 30 
Table 7.6, Dose Adjustments for Toxicity, Updated recommended management for 
Neutropenia 
Page 37 
Section 7.7, Removed references to Emory