Clinical trial NCT02643303
Conditions: Head and Neck Squamous Cell Carcinoma Breast Cancer Sarcoma Merkel Cell Carcinoma Cutaneous T-Cell Lymphoma Melanoma Renal Cancer Bladder Cancer Prostate Cancer Testicular Cancer Solid Tumor
Keywords: Durvalumab MEDI4736 Tremelimumab Poly-ICLC Hiltonol® Breast Cancer Melanoma In Situ CTLA-4 Antibody PD-L1 Antibody TLR3 Agonist CTCL Imfinzi®
Sponsor: Ludwig Institute for Cancer Research
Start date: 2016-12-28; Completion date: 2022-02-23
Enrollment: 58 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, multicenter, Phase 1/2 study of the CTLA-4 antibody, tremelimumab, and the PD-L1 antibody, durvalumab (MEDI4736), in combination with the tumor microenvironment (TME) modulator poly-ICLC, a TLR3 agonist, in subjects with advanced, measurable, biopsy-accessible cancers.

Detailed description:
This is an open-label, multicenter, Phase 1/2 study of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, tremelimumab, and the programmed cell death ligand-1 (PD-L1) antibody, durvalumab (MEDI4736), in combination with the tumor microenvironment (TME) modulator poly-ICLC, a toll-like receptor 3 (TLR3) agonist, in subjects with advanced, measurable, biopsy-accessible cancers. Subjects will receive intratumoral and intramuscular (IM) administration of poly-ICLC and intravenous (IV) administration of durvalumab, together with either IV or intratumoral administration of tremelimumab. The study will be conducted in 2 phases.

Phase 1: There will be enrollment to 3 subject cohorts in Phase 1, with staggered initiation of enrollment.

* Cohort 1A: IV Durvalumab + Intratumoral/IM Poly-ICLC. After safety is demonstrated in the first 3-6 subjects in Cohort 1A, Cohorts 1B and 1C will open to enrollment.
* Cohort 1B: IV Durvalumab + IV Tremelimumab + Intratumoral/IM Poly-ICLC.
* Cohort 1C: IV Durvalumab + Intratumoral Tremelimumab + Intratumoral/IM Poly-ICLC.

Phase 2: Upon determination of the recommended combination dose in Cohort 1C, up to 66 evaluable subjects will be treated in Phase 2. Up to 6 subjects will be initially enrolled by tumor type (head and neck squamous cell carcinoma, locally recurrent or metastatic breast cancer, sarcoma, Merkel cell carcinoma, cutaneous T-cell lymphoma, melanoma after failure of available therapies, genitourinary cancers and solid tumors with accessible metastases). Subjects enrolled in Cohort 1C will be included in Phase 2 in the applicable tumor type. Data from all subjects in each Phase 2 tumor type will be reviewed for safety/efficacy to select up to 3 tumor types that demonstrate an efficacy signal, defined as at least 1 of 6 subjects within a tumor type who achieve a partial response (PR) or complete response (CR) by immune-related RECIST (irRECIST) or RECIST 1.1, or stable disease (SD) for at least 6 months. Up to 6 additional subjects in each of the selected tumor types may be enrolled in the expansion.

Arms: arm 1: Subjects received durvalumab (1500 mg IV every 4 weeks \[Q4W\] for 12 cycles). Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 2: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (75 mg IV Q4W for the first 4 cycles).

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 3: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 4: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 5: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 6: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 7: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 8: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 9: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3. arm 10: Subjects received durvalumab (1500 mg IV Q4W for 12 cycles) and tremelimumab (10 mg) intratumorally on days 1, 8, and 15 of Cycle 1, days 1 and 15 of Cycle 2 and day 1 of Cycles 3 and 4.

Poly-ICLC (1 mg) was administered intratumorally on days 1, 3, 5, 8, 10 and 15 and intramuscularly on days 17, 22, and 24 of Cycle 1 as well as intramuscularly on days 1, 3, 8, 10, 15, 17, 22 and 24 of Cycle 2 and on days 1 and 4 of Cycle 3.
Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab intervention 3: Poly-ICLC
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
 
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Study Protocol 
LUD2014-011 
US-IND# 130529 
Amendment 6.0 
Final 
02-NOV-2021 
 
Protocol Title 
A Phase 1/2 Study of In Situ Vaccination with Tremelimumab and IV Durvalumab (MEDI4736) 
Plus the Toll-like Receptor Agonist PolyICLC in Subjects with Advanced, Measurable, Biopsy-
accessible Cancers 
 
Objectives and Synopsis 
This is an open-label, multicenter, Phase 1/2 study of the CTLA-4 antibody, tremelimumab, 
and the PD-L1 antibody, durvalumab (MEDI4736), in combination with the tumor 
microenvironment (TME) modulator polyICLC, a TLR3 agonist, in subjects with advanced, 
measurable, biopsy-accessible cancers.  Subjects will receive intratumoral and intramuscular 
(IM) administration of polyICLC and intravenous (IV) administration of durvalumab, together 
with either IV or intratumoral administration of tremelimumab.  The study will be conducted 
in 2 phases. 
Phase 1 Cohorts: There will be enrollment to 3 subject cohorts in Phase 1, with staggered 
initiation of enrollment.  
• Cohort 1A: IV Durvalumab+ intratumoral/IM polyICLC.  After safety is demonstrated in the 
first 3-6 subjects in Cohort 1A, Cohorts 1B and 1C will open to enrollment. 
• Cohort 1B: IV Durvalumab + IV Tremelimumab + intratumoral/IM polyICLC. 
• Cohort 1C: IV Durvalumab + intratumoral Tremelimumab + intratumoral/IM polyICLC. 
Dose de-escalations for determination of the recommended combination doses (RCDs) 
through the assessment of dose-limiting toxicities (DLTs) will be performed based on the dose 
levels in the table below and respective standard 3 + 3 rules. 
Cohort 1A 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
-1 
750 mg 
1 mg 
0 (Starting Level) 
1500 mg 
1 mg 
Cohort 1B 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
Tremelimumab Q4W 
(IV) 
-1 
RCD from Cohort 1A 
1 mg 
22.5 mg 
0 (Starting Level) 
RCD from Cohort 1A 
1 mg 
75 mg  
Cohort 1C 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
Tremelimumab (ITM) 
-1 
RCD from Cohort 1A 
1 mg 
3 mg 
0 (Starting Level) 
RCD from Cohort 1A 
1 mg 
10 mg 
Q4W = every 4 weeks; IV = intravenous; ITM = intratumoral; IM= intramuscular  
Note: See Section 3.1.7.1 for durvalumab doses for instances when a subject’s body weight drops to ≤ 30 kg 
while on the study. 
The primary objective of Phase 1 is to determine the RCDs of the dosing regimen, based on 
assessment of toxicity and tolerability.  The secondary objective is to obtain preliminary 
evidence of clinical efficacy as measured by objective response rate (ORR) by irRECIST and 
RECIST 1.1, progression-free survival (PFS), and overall survival (OS). 


 
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Phase 2 Cohort: Upon determination of the RCD in Cohort 1C, up to 66 evaluable subjects will 
be treated in Cohort 2.  If Cohort 1C is not cleared, the RCD of the previously cleared cohort 
will be used for Phase 2.  The primary objective for Phase 2 is the evaluation of clinical efficacy 
as measured by ORR, PFS, and OS. 
All Cohorts: Secondary objectives are the evaluation of safety and tolerability.  An exploratory 
objective is to evaluate the biological activity, including effects on the TME and immunological 
responses.  Assessment methods include CTCAE V4.03 for safety and irRECIST and RECIST 1.1 
for clinical efficacy. 
Per Amendment 6.0: 
All subjects have completed treatment, and by the date of implementation of this 
amendment, all subjects will have completed On Study Follow-up. This amendment provides 
that the Post Study Follow-up for the collection of survival data will be discontinued as of 
28 February 2022, and the study will be completed. 
 
 
Sponsor: Ludwig Institute for Cancer Research, New York, NY 
Sponsor:  
Ludwig Institute for Cancer Research, Ltd. 
 
 
 
 
 
 
Sponsor Representative Signature and Date 
Study Chairs:  
Nina Bhardwaj, MD, PhD, Tisch Cancer Institute Icahn 
School of Medicine at Mount Sinai 
 
 
 
 
 
Study Chair Signature and Date 
 
Craig L Slingluff Jr, MD, Human Immune Therapy Center 
University of Virginia 
 
 
 
 
 
Study Chair Signature and Date 
 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s).  The information cannot be used or divulged to any third party or published without the written consent of the 
Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from those persons to whom 
study medication may be administered.  Any misappropriation of this information is prohibited by law. 


 
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Table of Contents 
1 
Background ............................................................................................................................. 7 
1.1 
Biopsy-accessible Advanced, Measurable Cancers ......................................................... 7 
1.1.1 
Head and Neck Squamous Cell Carcinoma .............................................................. 7 
1.1.2 
Locally Recurrent Breast Cancer .............................................................................. 7 
1.1.3 
Sarcoma ................................................................................................................... 7 
1.1.4 
Merkel Cell Carcinoma ............................................................................................ 7 
1.1.5 
Cutaneous T-cell Lymphoma ................................................................................... 7 
1.1.6 
Metastatic Melanoma ............................................................................................. 8 
1.1.7 
Genitourinary Cancers with Accessible Metastases (Bladder, Renal, Prostate) ..... 8 
1.2 
Toll-like Receptor: PolyICLC ............................................................................................. 8 
1.3 
CTLA-4 Antibody: Tremelimumab ................................................................................... 9 
1.4 
PD-L1 Antibody: Durvalumab (MEDI4736) .................................................................... 10 
2 
Study Rationale ..................................................................................................................... 13 
3 
Experimental Plan ................................................................................................................. 14 
3.1 
Study Design .................................................................................................................. 14 
3.1.1 
Study Phase ........................................................................................................... 14 
3.1.2 
Enrollment/Randomization ................................................................................... 14 
3.1.3 
Blinding/Unblinding ............................................................................................... 14 
3.1.4 
Subject Population................................................................................................. 14 
3.1.5 
Number of Sites/Subjects ...................................................................................... 15 
3.1.6 
Sample Size and Statistical Considerations ........................................................... 15 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 17 
3.1.7.1 
Phase 1: Dose-finding Cohorts ...................................................................... 19 
3.1.7.2 
Phase 2: Expansion Phase .............................................................................. 20 
3.1.8 
Dosing Adjustments, Delays, and Discontinuations .............................................. 21 
3.1.9 
Dose-limiting Toxicity ............................................................................................ 21 
3.1.10 
Subject Withdrawal from Treatment or from Study ............................................. 22 
3.1.11 
Evaluability and Subject Replacement .................................................................. 23 
3.1.12 
Optional Study Treatment Extension .................................................................... 24 
3.1.13 
Interim Analysis ..................................................................................................... 24 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 24 
3.1.15 
Duration of Treatment and Study ......................................................................... 25 
3.1.15.1 
Duration of Treatment .................................................................................. 25 
3.1.15.2 
Duration of Study .......................................................................................... 25 
3.1.16 
On Study and Post Study Follow-up ...................................................................... 25 
3.2 
Study Flowchart ............................................................................................................. 27 
4 
Study Objectives and Endpoints ........................................................................................... 30 
4.1 
Safety and Tolerability ................................................................................................... 30 
4.1.1 
Endpoints and Assessment Methods .................................................................... 30 
4.1.2 
Subject Evaluation and Statistics ........................................................................... 30 


 
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4.2 
Clinical Efficacy .............................................................................................................. 31 
4.2.1 
Endpoints and Assessment Methods .................................................................... 31 
4.2.1.1 
Objective Response Rate ............................................................................... 31 
4.2.1.2 
Progression-free Survival ............................................................................... 31 
4.2.1.3 
Overall Survival .............................................................................................. 31 
4.2.2 
Subject Evaluation and Statistics ........................................................................... 32 
4.3 
Biological Activity........................................................................................................... 32 
4.3.1 
Endpoints and Assessment Methods .................................................................... 32 
4.3.1.1 
Tumor Microenvironment ............................................................................. 32 
4.3.1.2 
Pharmacodynamics ....................................................................................... 33 
4.3.2 
Subject Evaluation and Statistics ........................................................................... 34 
5 
Subject Eligibility ................................................................................................................... 35 
5.1 
Inclusion Criteria ............................................................................................................ 35 
5.2 
Exclusion Criteria ........................................................................................................... 36 
5.3 
Restrictions on Concomitant Therapies ........................................................................ 40 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 40 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 41 
6 
Study Drug Preparation and Administration ........................................................................ 42 
6.1 
Tremelimumab .............................................................................................................. 42 
6.1.1 
Tremelimumab Study Drug Information ............................................................... 42 
6.1.2 
Tremelimumab Investigational Product Inspection .............................................. 43 
6.1.3 
Tremelimumab for Intratumoral Injection ............................................................ 43 
6.1.3.1 
Preparation and Administration of Tremelimumab for Intratumoral Injection
 
43 
6.1.4 
Tremelimumab for Intravenous Infusion .............................................................. 43 
6.1.4.1 
Preparation of Tremelimumab for Intravenous Infusion .............................. 43 
6.1.4.2 
Administration of Tremelimumab for Intravenous Infusion ......................... 44 
6.2 
Durvalumab (MEDI4736) ............................................................................................... 45 
6.2.1 
Durvalumab Study Drug Information .................................................................... 45 
6.2.2 
Durvalumab Investigational Product Inspection ................................................... 46 
6.2.3 
Preparation of Durvalumab for Intravenous Infusion ........................................... 46 
6.2.4 
Durvalumab Administration .................................................................................. 47 
6.3 
PolyICLC ......................................................................................................................... 48 
6.3.1 
PolyICLC Study Drug Information .......................................................................... 48 
6.3.2 
PolyICLC Investigational Product Inspection ......................................................... 48 
6.3.3 
PolyICLC Preparation and Administration ............................................................. 48 
6.4 
Estimated Drug Requirements ...................................................................................... 49 
6.5 
Monitoring of Tremelimumab and Durvalumab IV Dose Administration ..................... 50 
6.6 
Drug Overdose Management ........................................................................................ 50 
7 
Administrative, Legal and Ethical Requirements .................................................................. 51 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 51 
7.1.1 
General AE/SAE Definitions per ICH Guidelines .................................................... 51 
7.1.2 
Additional Expedited Reporting Requirements for this Study .............................. 52 
7.1.2.1 
Pregnancy ...................................................................................................... 52 


 
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7.1.2.2 
Overdose ....................................................................................................... 53 
7.1.2.3 
Hepatic Function Abnormality ....................................................................... 53 
7.1.2.4 
New Cancers .................................................................................................. 53 
7.1.2.5 
Deaths ............................................................................................................ 53 
7.1.3 
Severity of an Adverse Event ................................................................................. 54 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 54 
7.1.5 
General Reporting Requirements .......................................................................... 55 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 55 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 56 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 56 
7.2 
Administrative Sponsor Requirements ......................................................................... 59 
7.2.1 
Study Master Files ................................................................................................. 59 
7.2.2 
Case Report Form Data Collection ........................................................................ 59 
7.2.3 
Language ................................................................................................................ 60 
7.2.4 
Monitoring ............................................................................................................. 60 
7.2.5 
Protocol Amendments ........................................................................................... 60 
7.2.6 
Premature Subject Withdrawal from Treatment or from Study ........................... 60 
7.2.7 
Early Trial Termination .......................................................................................... 61 
7.2.8 
Study Drug Shipments and Accountability ............................................................ 61 
7.3 
Regulatory, Legal, and Ethical Requirements ................................................................ 61 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 61 
7.3.2 
Informed Consent .................................................................................................. 62 
7.3.3 
Institutional Review Board .................................................................................... 62 
7.3.4 
Subject Confidentiality .......................................................................................... 62 
8 
Appendices ........................................................................................................................... 63 
8.1 
Protocol Version History ................................................................................................ 63 
8.2 
Participating Study Sites, Investigators and Staff, Laboratories, and Sponsor 
Information ............................................................................................................................... 80 
8.3 
Dose Adjustments and Delays for Durvalumab and Tremelimumab ............................ 81 
8.3.1 
Durvalumab and Tremelimumab Dose Modifications due to Toxicity .................. 81 
8.3.2 
Durvalumab and Tremelimumab Dose Modification Not Due to Toxicities ......... 83 
8.4 
PolyICLC Toxicity Management, Dose Delays and Adjustments ................................... 85 
8.4.1 
Management of Injection Site Reactions .............................................................. 85 
8.4.2 
Management of Systemic Toxicities ...................................................................... 85 
8.4.3 
PolyICLC Dose Modifications due to Toxicities ...................................................... 85 
8.5 
RECIST 1.1 and irRECIST Guidelines ............................................................................... 86 
8.6 
Exploratory Assessment of Correlative Immunologic Research .................................... 94 
8.6.1 
Effects on the Tumor Microenvironment .............................................................. 94 
8.6.2 
Circulating Soluble Factors .................................................................................... 94 
8.6.3 
Peripheral blood mononuclear cells (PBMC) ......................................................... 94 
8.6.4 
RNA Profiling .......................................................................................................... 94 
8.7 
ECOG Performance Status ............................................................................................. 95 
8.8 
List of Abbreviations ...................................................................................................... 96 
9 
References ............................................................................................................................ 98 


 
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List of Tables 
Table 1. 
Treatment Schema .................................................................................................... 18 
Table 2. 
Phase 1 Dose Levels ................................................................................................... 19 
 
List of Figures  
Figure 1: 
Dose Escalation and De-escalation Schema .............................................................. 20 
 


 
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1 Background 
1.1 Biopsy-accessible Advanced, Measurable Cancers 
The eligible disease types for this study were selected for inclusion based either on their ability 
to be accessed through biopsy (as defined in Section 5.1) and/or on their viral etiologies (i.e., 
non-viral-associated head and neck squamous cell carcinoma [HNSCC] and Merkel cell 
carcinoma [MCC]). 
1.1.1 
Head and Neck Squamous Cell Carcinoma 
The incidence of HNSCC is 45,000 cases per year, with a mortality of > 12,000 subjects per year.  
While viral-associated HNSCC is associated with 80% overall survival (OS) following treatment, 
recurrence rates remain high in non-viral-associated HNSCC, despite treatment with surgical 
resection, chemotherapy, and radiation.  Up to 50% of non-viral-associated cases may present 
with advanced disease, in which the likelihood of complete resection decreases.  Subjects with 
unresectable tumors have been selected for eligibility in this study because of the accessibility of 
the lesions, indications of some responses to immunotherapy, and usual progression and 
regional disfigurement despite treatment with chemotherapy. 
1.1.2 Locally Recurrent Breast Cancer 
Carcinomas of the breast are often cured with surgical management, and metastatic breast 
cancer has a high rate of clinical response with hormonal therapy, cytotoxic chemotherapy, 
and/or trastuzumab.  However, a subset of patients develops recurrent breast cancer locally on 
the chest wall, which is accessible for biopsy, and may include skin, subcutaneous, or nodal 
metastases alone or in addition to systemic disease.  Especially among patients with local 
recurrence within 2 years of breast-conserving surgery, the probability of survival is less than 
10%.(1) 
1.1.3 Sarcoma 
Sarcomas are uncommon malignancies arising from soft tissues and are found most commonly 
in either retroperitoneal or extremity sites.  Sarcomas, particularly in the extremities, are prone 
to local recurrence, and can be challenging to manage, as they do not respond well to most 
systemic therapies.  Sarcomas available for biopsy and injection may be eligible for this study. 
1.1.4 Merkel Cell Carcinoma 
MCC is a malignancy arising from Merkel cells in the skin, which can be aggressive and 
unresponsive to systemic therapy.  MCC is responsive to radiation therapy, but systemic 
metastases are often lethal.  Approximately 80% of MCCs are linked etiologically to the Merkel 
cell polyomavirus (MCV).(2, 3)  MCC arises on the skin and often metastasizes to regional or 
distant skin sites. 
1.1.5 Cutaneous T-cell Lymphoma 
The cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of T-cell 
lymphoproliferative disorders such as mycosis fungoides and Sézary syndromes.  Patients with 
advanced-stage disease with significant nodal, visceral, or blood involvement can be treated 
with biologic-response modifiers, HDAC inhibitors, and/or chemotherapy.  Patients refractory to 


 
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treatment have responded to intratumoral CpG treatment, suggesting that TLR agonists may 
benefit these patients.(4) 
1.1.6 Metastatic Melanoma 
Until recently, darcarbazine (DTIC) and high-dose IL-2 were the only agents approved for use in 
the United States (US) for the treatment of metastatic melanoma.  Durable responses to 
high-dose IL-2 occur in a small subset of responding patients, although administration of 
high-dose IL-2 requires hospitalization and can induce severe toxicities, which limits the 
utilization of this agent.  Over the past few years, targeted therapies interfering with BRAF and 
MEK signaling have been approved by the FDA for patients with BRAF-mutant melanoma, and 
the CTLA-4 antibody ipilimumab (Yervoy®) and PD-1 antibodies pembrolizumab (Keytruda®) and 
nivolumab (Opdivo®) have been approved for the treatment of metastatic melanoma.  Benefits 
of high-dose IL-2, ipilimumab, and PD1 antibodies are mediated directly or indirectly through 
T-cell activation; thus, they are proof-of-principle for the ability of T-cell-directed therapies 
to control melanoma.  However, some patients will fail or be ineligible for all of these 
therapies.  Melanoma often metastasizes to distant skin and regional sites, which are 
accessible for intralesional therapy and biopsies, and there have been reports of responses to 
topical TLR agonists (imiquimod) and intralesional therapies (IL-2, BCG, and talimogene 
laherparepvec). 
1.1.7 Genitourinary Cancers with Accessible Metastases (Bladder, Renal, Prostate) 
Breakthrough status has recently been given for anti-PD-L1 agents in advanced bladder cancers, 
and checkpoint blockade inhibition with other monoclonal antibodies is being actively tested in 
genitourinary (GU) cancers.  Tumor infiltration with T cells and responsiveness to therapies such 
as IL-2 in a limited set of renal cancer patients support the concept that enhancing immunity 
locally may have effects in the TME.  Since these cancers are accessible for intralesional injection 
and biopsy, patients who are refractory to other therapies, including checkpoint blockade 
inhibitors, would be eligible for treatment. 
1.2 Toll-like Receptor: PolyICLC 
The toll-like receptors (TLRs) are a family of pathogen recognition receptors expressed broadly 
on hematopoietic cells (e.g., myeloid dendritic cells [mDC], plasmacytoid [pDC], monocytes, and 
B cells) that recognize pathogen-associated molecular patterns (PAMPs), activate innate 
immune responses, and facilitate the development of adaptive responses.  The engagement of 
specific TLRs leads to the activation of different cell populations and the production of distinct 
patterns of cytokines and other inflammatory mediators, resulting in alternative immune 
response profiles. 
Polyinosinic-polycytidylic acid (polyIC) is a double-stranded RNA (dsRNA) that acts as a TLR3 
agonist.  However, its short half-life limits its usefulness.  To increase half-life and its practical 
use in the clinical setting, polyIC has been stabilized with polylysine and carboxymethylcellulose 
as polyICLC (Hiltonol®, Oncovir Inc.).  Like polyIC, polyICLC is a TLR3 agonist. TLR3 is expressed in 
the early endosome of myeloid DC; thus polyICLC preferentially activates myeloid dendritic cells, 
favoring a Th1 cytotoxic T-cell response.(5, 6)  PolyICLC also activates natural killer (NK) cells and 
induces cytolytic potential.(6)  It has been administered intratumorally in a sarcoma patient with 
dramatic clinical tumor regression.(7)  A clinical trial further testing intratumoral polyICLC is 
underway (NCT02423863). 


 
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PolyICLC is provided as a clinical grade reagent for experimental use in single-use vials 
containing 1 mL of approximately 2 mg/mL solution under contract from Oncovir to the Ludwig 
Institute for Cancer Research and the Cancer Vaccine Consortium. 
PolyICLC has been used safely in cancer patients, with intravenous (IV) doses up to 300 µg/kg.(4)  
In this study, 1 mg of polyICLC will be administered per dose, as used in other trials (e.g., 
NCT01008527 and NCT01984892) and as administered intratumorally with clinical benefit (7) 
(e.g., NCT02423863).  
1.3 CTLA-4 Antibody: Tremelimumab 
CTLA-4 (CD152) is constitutively expressed by T lymphocytes within the cytoplasm but is 
expressed at the cell surface upon antigen activation.  Its ligation on CD80 or CD86 down 
regulates the stimulatory signal of the T-cell receptor.  Blockade of CTLA-4 abrogates this 
negative signal, supporting T-cell activation and expansion.  Therapeutic blockade of CTLA-4 in 
murine models and in humans can lead to durable objective regressions of metastatic cancer.  
The mechanism also may be mediated in part by depletion of regulatory T cells.  One CTLA-4 
blocking antibody (ipilimumab) has been approved by the FDA for therapy of advanced 
melanoma.  The CTLA-4 blocking antibody in the present study (tremelimumab) has similar 
clinical activity but has not yet been approved for use in humans. 
Tremelimumab is briefly described in this section below.  Refer to the current Investigator’s 
Brochure for complete and current information. 
Tremelimumab is a human immunoglobulin (Ig)G2 monoclonal antibody (mAb) being 
investigated as a cancer immunotherapeutic agent.  Tremelimumab is specific for human 
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152), a cell surface receptor that is 
expressed primarily on activated T cells and acts to inhibit their activation. 
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a 
cutoff date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of the 
tremelimumab clinical development program. Of these studies, 13 have been completed 
and 9 are ongoing. Tremelimumab has been administered as monotherapy to 973 subjects 
participating in 10 of the 22 clinical studies, 2 of which are ongoing. An additional 497 
subjects have received tremelimumab or placebo in the ongoing double-blinded, Phase 2b 
mesothelioma study, D4880C00003 (DETERMINE; data remain blinded). Tremelimumab in 
combination with other anticancer agents has been administered to 208 subjects with a 
variety of tumor types in 12 of the 22 clinical studies, 7 of which are ongoing. 
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following IV 
infusion. 
Across the clinical development program for tremelimumab, a pattern of efficacy has 
emerged, also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to 
be consistent across tumor types for this mechanism of action. In general, tumor response 
rates to anti-CTLA-4 antibodies are generally low, approximately 10%. However, in subjects 
who respond, the responses are generally durable, lasting several months even in subjects 
with aggressive tumors such as refractory metastatic melanoma. Some subjects may have 
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stabilization or a tumor response. Overall, the impact on conventionally-defined 
progression-free survival (PFS) can be small; however, the durable response or stable 
disease seen in a proportion of subjects can lead to significant prolongation of overall 
survival (OS).  
Ipilimumab was shown to significantly improve OS in both first- and second-line treatment of 
subjects with metastatic melanoma.  The melanoma data with ipilimumab clearly demonstrate 
that a small proportion of subjects with an objective response had significant prolongation of 
OS, supporting the development of this class of agents in other tumors.  Although Phase 2 and 
Phase 3 studies of tremelimumab in metastatic melanoma did not meet the primary endpoints 
of response rate and OS, respectively, the data suggest activity of tremelimumab in 
melanoma.(8, 9)  In a large Phase 3 randomized study comparing tremelimumab with 
dacarbazine (DTIC)/temozolomide in subjects with advanced melanoma, the reported median 
OS in the final analysis was 12.58 months for tremelimumab versus 10.71 months for 
TIC/temozolomide (HR = 1.1416, p = 0.1272).(9) 
The profile of adverse events (AEs) and the spectrum of event severity have remained stable 
across the tremelimumab clinical program and are consistent with the pharmacology of the 
target. To date, no tumor type or stage appears to be associated with unique AEs (except for 
vitiligo that appears to be confined to subjects with melanoma).  As of the data cutoff date of 
12Nov2014 (for all studies except D4190C00006 that has a cutoff date of 04Dec2014), AEs (all 
grades, regardless of causality) reported in > 10% of subjects in the completed and rollover 
tremelimumab monotherapy studies (N = 973, integrated data) were diarrhea (45.3%), fatigue 
(37.5%), nausea (32.5%), rash (28.8%), pruritus (27.3%), decreased appetite (22.8%), vomiting 
(22.5%), pyrexia (15.3%), cough (15.0%), constipation (14.4%), abdominal pain (13.9%), 
headache (13.8%), dyspnea (12.4%), and decreased weight (10.2%). Based on integrated data 
from completed studies of tremelimumab in combination with other agents (N = 116), AEs (all 
grades, regardless of causality) reported in > 15% of subjects were diarrhea (54.3%); nausea 
(40.5%); fatigue (38.8%); rash (35.3%); pruritus, decreased appetite (30.2% each); vomiting 
(27.6%); pyrexia (26.7%); influenza like illness (20.7%); arthralgia (19.8%); constipation (19.0%); 
thrombocytopenia, injection site reaction (18.1% each); and increased aspartate 
aminotransferase (15.5%). Most of these events occurred at a higher rate with tremelimumab 
plus sunitinib than with other combinations. The events of diarrhea, rash, and pruritus are 
considered identified risks of tremelimumab. Acute renal failure was reported in subjects who 
received the combination of tremelimumab and sunitinib; however, acute renal failure has not 
been an expected AE for single-agent tremelimumab. The incidence and/or severity of many of 
the AEs observed following administration of tremelimumab can be reduced by following 
current guidelines for the management of immune-related toxicities. 
Clinical studies of tremelimumab are ongoing in several solid tumor types, including malignant 
mesothelioma, hepatocellular carcinoma (HCC), and non-small-cell lung cancer (NSCLC). 
1.4 PD-L1 Antibody: Durvalumab (MEDI4736) 
Programmed death-1 (PD-1, CD279) is a member of the immunoglobulin superfamily (IGSF) of 
molecules involved in regulation of T cell activation.  PD-1 acquired its name ‘programmed 
death’ when it was identified in 1992 as a gene upregulated in T cell hybridoma undergoing cell 
death.(10)  The structure of PD-1 is composed of 1 IGSF domain, a transmembrane domain, and 
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and an immunoreceptor tyrosine-based switch motif (ITSM).(11-13)  PD-1 has 2 binding 
partners: PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), distant relatives of the B7-1 and B7-2 
molecules.  PD-L1, discovered in 1999, is expressed quite broadly, on both hematopoietic and 
non-hematopoietic lineages.(14-16)  It is found on T cells, B cells, macrophages, NK cells, DCs, 
and mast cells.(17)  It has also been described on peripheral tissues including cardiac 
endothelium, lung, small intestine, keratinocytes, islet cells of the pancreas, and 
syncytiotrophoblasts in the placenta as well as a variety of tumor cell types.(17-28)  PD-L1 is 
constitutively expressed on many hematopoietic cells, but may be upregulated in hematopoietic 
and non-hematopoietic cells.(29)  Regulation of PD-L1 is mediated, in part, by type I and type II 
interferons.  PD-L2 was identified in 2001.(30, 31)  Its expression is far more restricted and is 
confined largely to hematopoietic cells.(32)  However, PD-L2 is expressed on some pulmonary 
epithelial cells and its expression may be increased by pulmonary viral infections or interferon-
gamma.(33) 
Engagement of PD-1 on T cells inhibits activation, with downstream effects on cytokine 
production, proliferation, cell survival, and transcription factors associated with effector T cell 
function.(34-38)  Inhibitory signaling by PD-1 is thought to depend upon the cytosolic ITSM 
domain, which associates with phosphatases SHP-1 and SHP-2.(39, 40)  
Durvalumab is briefly described in this section below.  Refer to the current Investigator’s 
Brochure (IB) for complete and current information. 
Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody (MAb) directed against 
human PD-L1.  Durvalumab has an overall molecular weight of approximately 149 kDa, including 
N-linked oligosaccharides.  The antibody is composed of 2 identical heavy chains of 
approximately 49,670 Da each, and 2 identical light chains of approximately 23,390 Da each. The 
fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant 
domain of the IgG1 heavy chain that reduces binding to the complement component C1q and 
the Fcm receptors, responsible for mediating antibody-dependent cell-mediated cytotoxicity 
(ADCC).(41)  Subsequent to this triple mutation, the anticipated lack of durvalumab-mediated 
ADCC and complement-dependent cytotoxicity were confirmed using cell based functional 
assays. Durvalumab is selective for recombinant PD-L1 and blocks the binding of recombinant 
PD-L1 to the PD-1 and cluster of differentiation (CD) 80 receptors. 
As of the data cutoff dates in the IB (15Apr2015 to 12Jul2015), a total of 1,883 subjects have 
been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored (6 
monotherapy and 14 combination therapy) and 10 collaborative studies. Of the 1,883 subjects, 
1,279 received durvalumab monotherapy, 440 received durvalumab in combination with 
tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), 
and 150 have been treated with blinded investigational product. No studies have been 
completed or terminated prematurely due to toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy / 
neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an 
important potential risk particularly with durvalumab and tremelimumab combination therapy. 


 
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These events are manageable by available/established treatment guidelines as described in the 
study protocols.  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
 


 
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2 Study Rationale 
Recent studies indicate that local (intratumoral) delivery of monoclonal antibodies (including 
anti-CTLA-4 therapy) in mice stimulates equivalent immune responses while limiting the 
autoimmune toxicity often observed with systemic administration of these agents.(42, 43)  An 
ongoing clinical study of intratumoral ipilimumab plus intratumoral SD-101 (a toll-like receptor 9 
agonist) and local radiation is currently investigating the safety and efficacy of this technique in 
subjects with low-grade B-cell lymphomas (ClinicalTrials.gov identifier NCT02254772). 
The current study will implement intratumoral administration of tremelimumab, and 
hypothesizes that (1) the combination of intratumoral and systemic therapy with checkpoint 
blockade agents and polyICLC will be safe, (2) the combination of intratumoral and systemic 
therapy will induce clinical tumor responses in cancers that do not respond well to systemic 
checkpoint blockade alone, (3) the combination regimen will induce systemic antitumor T-cell 
and antibody responses, including responses to autologous tumor antigens, and (4) the 
combination regimen will induce immune signatures in the treated tumors, with upregulation of 
IFNγ, PD-L1 expression, T-cell recruiting chemokines, and T-cell infiltrates. 
According to Medimmune, the combination dose selection of 1 mg/kg Q4W for tremelimumab 
and 20 mg/kg Q4W for durvalumab was based on the identification of an optimal dose of 
durvalumab that would “yield sustained target suppression, optimize synergy of the 
combination, while maintaining the balance of safety in combination with tremelimumab.” This 
is consistent with the dosing regimen to be evaluated in the Medimmune program going 
forward. 
The fixed dosing is based on information from Medimmune, which indicates that the dose and 
schedule of 1500 mg durvalumab Q4W and 75 mg tremelimumab Q4W was selected based on 
PK models as described below.   
Using population PK models, simulations indicated that both body weight-based and fixed 
dosing regimens of durvalumab and tremelimumab yield similar median steady state PK 
concentrations with slightly less between-subject variability with fixed dosing regimens.  A fixed 
dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar PK exposure and variability, Medimmune considers it 
feasible to switch to fixed dosing regimens. Based on an average body weight of 75 kg, a fixed 
dose of 750 mg Q2W durvalumab is equivalent to 10 mg/kg Q2W, 1500 mg Q4W durvalumab is 
equivalent to 20 mg/kg Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W.  
The 1500 mg Q4W dosing of durvalumab is recommended only for subjects with > 30 kg body 
weight in order to limit endotoxin exposure.  See Section 3.1.7.1 for details regarding 
durvalumab dose requirements for instances when a subject’s body weight drops to ≤ 30 kg 
while on the study.  
See Section 3.1.7.1 for additional details regarding the dose de-escalation cohorts for 
durvalumab and tremelimumab. 


 
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3 Experimental Plan 
3.1 Study Design 
This is an open-label, multicenter, Phase 1/2 study to evaluate the CTLA-4 antibody, 
tremelimumab, and the PD-L1 antibody, durvalumab, in combination with the tumor 
microenvironment (TME) modulator polyICLC, a TLR3 agonist, in subjects with advanced, 
measurable, biopsy-accessible cancers (as defined in Section 5.1). 
Subjects will receive intratumoral and intramuscular (IM) administration of polyICLC and 
intravenous (IV) administration of durvalumab, together with either IV or intratumoral 
administration of tremelimumab.  The study will be conducted in 2 phases.  There will be 
enrollment to 3 subject cohorts in Phase 1, as described in Section 3.1.2.   
Dose de-escalations for determination of the recommended combination doses (RCDs) through 
the assessment of dose-limiting toxicities (DLTs) will be performed based on the available dose 
levels and respective standard 3 + 3 rules. 
Once determined, the RCD of the dosing regimen will then be expanded in the Phase 2 portion 
of the study.  If Cohort 1C is not cleared, the RCD of the previously cleared cohort will be used 
for Phase 2.   
3.1.1 Study Phase 
Phase 1/2 
3.1.2 Enrollment/Randomization 
For Phase 1 of the study, there will be enrollment to 3 subject cohorts, with staggered initiation 
of enrollment:  
• 
Cohort 1A: IV Durvalumab + intratumoral/IM polyICLC.   
• 
Cohort 1B: IV Durvalumab + IV Tremelimumab + intratumoral/IM polyICLC. 
• 
Cohort 1C: IV Durvalumab + intratumoral Tremelimumab + intratumoral/IM polyICLC. 
After safety is demonstrated in the first 3-6 subjects in Cohort 1A, Cohorts 1B and 1C will open 
with alternating enrollment.   
For Phase 2 (Cohort 2), enrollment will occur without randomization.  See Section 3.1.7.2 for 
additional details regarding the expansion of Cohort 2. 
Enrollment will be under ongoing review by an internal data safety monitoring panel (see 
Section 3.1.14). 
3.1.3 Blinding/Unblinding 
This is an open-label study. 
3.1.4 Subject Population 
Subjects with advanced, biopsy-accessible (as defined in Section 5.1), measurable cancers are 
eligible for this study, as detailed further in Section 5. 


 
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3.1.5 Number of Sites/Subjects 
This study will be conducted at up to 8 sites in the US, with up to 102 subjects estimated for 
enrollment. 
Phase 1 will enroll up to 36 subjects to determine the RCDs of durvalumab or durvalumab and 
tremelimumab within each cohort (3-6 subjects per dose level for each of the 3 cohorts). The 
RCD for each arm is defined as the highest dose level at which no more than 1 of 6 subjects (i.e., 
< 33%) experience DLTs. 
Phase 2 will evaluate up to 66 subjects treated with the RCDs of the dosing regimen.  
3.1.6 Sample Size and Statistical Considerations 
Phase 1: The primary endpoint for the Phase 1 portion of the study is safety. The objective for 
Phase 1 is to determine the recommended combination dose (RCD). In each of the Phase 1 
cohorts, a 3+3 design is used.  Each cohort will be evaluated on its own.  The only modification 
to the design is that the protocol evaluates up to 2 dose levels and starts at the desired dose 
level (Level 0). As only one drug is being modified in each cohort, the principles of a 3+3 design 
are applicable.  The RCD for each cohort is defined as the highest dose level at which no more 
than 1 of 6 subjects experience DLTs. 
The Cohort 1A doublet (durvalumab + polyICLC) will be enrolled first, starting at Level 0. Dose 
Level -1 will only be evaluated if Level 0 exceeds the RCD. Once safety is demonstrated for the 
subjects in the Cohort 1A doublet, the Cohort 1B triplet (durvalumab + polyICLC + IV 
tremelimumab) and the Cohort 1C triplet (durvalumab + polyICLC + intratumoral tremelimumab) 
will open to enrollment.  
Based on the DLT assessment, the starting dose Level 0 will either be expanded to 6 subjects or 
the dose level will be reduced to Level -1. This is in accordance with a standard 3+3 design, 
whereby a dose level may be reduced as well as escalated based on the DLTs observed. 
The table below gives the probabilities of de-escalation to dose Level -1, based on true DLT 
rate in the 3+3 design. 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
Probability of de-escalation 
0.09 
0.29 
0.51 
0.69 
0.83 
0.92 
0.97 
 
Adverse events will be summarized by maximum toxicity grade for each dose level cohort. Phase 
1 will enroll up to 36 subjects to determine the RCD. Once the RCD of the triplet dosing regimen 
has been determined in Cohort 1C, up to 66 subsequent subjects will be enrolled into the Phase 
2 cohort at the RCD according to Cohort 1C. If Cohort 1C is not cleared, the RCD of the 
previously cleared cohort will be used for Phase 2.  
For the Cohort 1A doublet, if dose Level -1 is too toxic, the RCD cannot be determined and the 
study will stop.  Otherwise, Cohorts 1B and 1C triplets will open in parallel at the doublet RCD of 
Cohort 1A, and the triplet RCD will be determined in both Cohorts 1B and 1C. 


 
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If no triplet RCD can be determined, Phase 2 of the study will be done at the Cohort 1A doublet 
RCD.  If triplet RCDs are determined for both Cohorts 1B and 1C, the triplet RCD of Cohort 1C will 
be used in Phase 2.  If a triplet RCD can only be determined in Cohort 1B, that triplet RCD will be 
used in Phase 2. 
Phase 2: The phase 2 portion of the study is intended to indicate proof of concept regarding the 
activity of the combination selected in Phase 1, in a study of 8 disease types. The goal is to 
determine if there is any evidence to support future larger clinical trials of specific tumor 
targets. Enrollment of 6 subjects per tumor type will be allowed initially, with enrollment of an 
additional 6 subjects being contingent on at least one response among the initial 6 subjects. 
Response is defined in this protocol as achieving a partial response (PR) or complete response 
(CR) by immune-related RECIST or RECIST 1.1, or stable disease (SD) for at least 6 months. PD-1 
receptors and PD-1 ligand have been previously investigated in Phase 1 and 2 studies. Response 
rates range from 8% to 25% overall, and from 10% to 35% in the squamous subpopulation (44). 
This combination therapy trial seeks to improve on these response rates. The stopping rule for 
lack of sufficient efficacy in the initial 6 subjects for each tumor type, results in a rejection rate 
of <20% if the true response rate for a particular tumor type is 25%. A total of (8)(6)= 48 subjects 
will be initially enrolled for the Phase 2 portion plus a potential additional (3)(6)= 18 subjects for 
three tumor types having at least one response in the initial group (total of 48+18= 66 subjects). 
For tumor types accruing 6+6= 12 subjects, an exact 90% confidence interval for response rate 
will be computed.   
The safety of the regimen taken into Phase 2 will be evaluated by the Medical Monitor on an 
ongoing basis. When 6 subjects have been enrolled and treated in a disease cohort, a review of 
the data from the cohort will be conducted by the internal data safety monitoring panel and a 
decision (based on efficacy as well as safety) will be made whether to expand the disease cohort 
to 12 subjects. At any time during the study, the Medical Monitor and/or the internal data 
safety monitoring panel may stop the cohort or the study if the toxicity seen is not acceptable.  
Respective study stopping rules are described in Section 3.1.14 of the protocol. 
If more than one subject in the initial group of 6 subjects in a disease type have a DLT, then 
accrual to that disease type cohort will be terminated. 
The expansion phase sample size of 66 subjects is deemed to be sufficient for the assessment of 
safety and tolerability as it provides sufficient precision for estimation of adverse events.  The 
confidence intervals (CI) for estimating the incidence of AEs ranging from 10% to 90% (in 
increments of 10%) are listed below.  The margins of error (half width of the CI) are deemed 
acceptable for the estimation of AE incidences in this early phase trial. 


 
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Number of Subjects 
with Event 
Incidence 
95% Confidence Interval 
(Normal approximation) 
Margin of error (half 
width of the CI) 
7/66 
0.1 
(0.028, 0.172) 
0.072 
14/66 
0.2 
(0.103, 0.297) 
0.097 
20/66 
0.3 
(0.189, 0.411) 
0.111 
27/66 
0.4 
(0.282, 0.518) 
0.118 
33/66 
0.5 
(0.379, 0.621) 
0.121 
40/66 
0.6 
(0.482, 0.718) 
0.118 
47/66 
0.7 
(0.589, 0.811) 
0.111 
53/66 
0.8 
(0.703, 0.897) 
0.097 
60/66 
0.9 
(0.828, 0.972) 
0.072 
 
3.1.7 Treatment Arms and Treatment Schema 
Table 1 presents the schedule of treatment administration within each 28-day cycle. 
Section 3.1.7.1 (Phase 1), Table 2 and Section 3.1.7.2 (Phase 2) describe further details regarding 
study drug administration within each phase. See Section 6 for the sequence of drug 
administration on dosing days when multiple drugs are given. 
NOTE: For each subject, there will be one allowed delay of up to one week for a scheduled visit; 
however, the delay can only occur after Cycle 1 is complete.  Starting with Cycle 5, the intervals 
for visit days will change to ±7 days; however, a 3-week interval must be maintained between 
durvalumab doses (See Flowchart in Section 3.2). 
• 
Intratumoral administration  
The intratumoral dose of tremelimumab was based on approximately 10% of the systemic 
dose, utilizing a fixed dose of 10 mg (with a de-escalation dose of 3 mg) for this study, given 
for 4 cycles.  The intratumoral tremelimumab and intratumoral polyICLC will be 
administered according to the schema in Table 1 and Table 2 (see Section 6.1.3.1 for volume 
of tremelimumab dose).   
A 7-day dosing window is permitted for polyICLC dosing provided that all intratumoral 
injections are administered within the first 21 days of Cycle 1, with each injection 
administered at least 24 hours apart. One delay of dosing exceeding specified dosing 
windows may also be permitted for reasons other than toxicity (e.g., scheduling conflict, 
severe weather affecting travel). 
The total volume of study drug to be injected intratumorally should be administered to a 
single tumor if possible, but may be delivered to a maximum of 3 smaller tumors if 
necessary.  Tumor(s) selected for injection must be identified at Baseline (pre-injection), 
including the volume of study drug to be administered, and the selected tumor(s) must be 
treated with this assigned volume for the duration of the study. 
• 
Systemic administration will be delivered in accordance with the dose de-escalation schema 
(see Table 2) to determine the RCDs.  The treatment schema in Table 1 will be followed for 
all cohorts.  Following completion of intratumoral dosing in Cycle 1 and throughout Cycle 2, 
polyICLC will be administered at a dose of 1 mg IM twice weekly.  During Cycle 3, polyICLC 
will be administered on Days 1 and 4 and will be discontinued thereafter.  


 
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Table 1. 
Treatment Schema 
COHORT 
N 
28 DAY 
CYCLE 
CHECKPOINT ANTIBODIESa 
TME MODULATOR 
Cohort 1A 
n = 3 to 6 per 
dose level 
 
Tremelimumab  
Durvalumab  
PolyICLC 
1 
 
IV Day 1 
1 mg ITM (Days 1, 3, 5, 8, 10 and 15)b 
1 mg IM Days 17, 22, and 24 
2 
 
IV Day 1 
1 mg IM Days 1, 3, 8, 10, 15, 17, 22, 24 
3 
 
IV Day 1 
1 mg IM Days 1 and 4 of cycle, then stop 
4-12 
 
IV Day 1 
̶ 
Cohort 1B 
n = 3 to 6 per 
dose level 
1 
IV Day1 
IV Day 1 
1 mg ITM (Days 1, 3, 5, 8, 10 and 15)b 
1 mg IM Days 17, 22, and 24 
2 
IV Day1 
IV Day 1 
1 mg IM Days 1, 3, 8, 10, 15, 17, 22, 24 
3 
IV Day1 
IV Day 1 
1 mg IM Days 1 and 4 of cycle, then stop 
4 
IV Day1 
IV Day 1 
 
5-12 
̶ 
IV Day 1 
̶ 
Cohort 1C 
n = 3 to 6 per 
dose level 
1 
ITM Days 1, 8, and 15 
IV Day 1 
1 mg ITM (Days 1, 3, 5, 8, 10 and 15)b 
1 mg IM Days 17, 22, and 24 
2 
ITM Days 1 and 15 
IV Day 1 
1 mg IM Days 1, 3, 8, 10, 15, 17, 22, 24 
3 
ITM Day 1  
IV Day 1 
1 mg IM Days 1 and 4 of cycle, then stop 
4 
ITM Day 1  
IV Day 1 
 
5-12 
 
IV Day 1 
̶ 
Cohort 2 
n = up to 66 
1 
RCD ITM Days 1, 8 and 15 
IV Day 1 
1 mg ITM (Days 1,3, 5, 8, 10 and 15)b 
1 mg IM Days 17, 22, and 24 
2 
RCD ITM Days 1 and 15 
IV Day 1 
1 mg IM Days 1, 3, 8, 10, 15, 17, 22, 24 
3 
RCD ITM Day 1  
IV Day 1 
1 mg IM Days 1 and 4 of cycle, then stop 
4 
RCD ITM Day 1  
IV Day 1 
 
5-12 
 
IV Day 1 
̶ 
RCD = recommended combination dose; TME = tumor microenvironment; IM = intramuscularly; ITM = intratumorally; IV = intravenously 
a Total doses to be administered are outlined in Table 2. 
b A 7-day dosing window is permitted provided that all injections are administered within the first 21 days of Cycle 1; injections must be administered ≥ 24 hours apart. 
Note: If Cohort 1C is not cleared, the RCD of the previously cleared cohort will be used for Phase 2. 
 
 


 
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3.1.7.1 Phase 1: Dose-finding Cohorts 
During Phase 1, subjects will be evaluated for DLTs as defined in Section 3.1.9.  There will be 
enrollment to 3 subject cohorts, with staggered initiation of enrollment.  The dose levels to be 
evaluated in Phase 1 are presented in Table 2, according to the treatment schema in Table 1.  
Dose de-escalations for the determination of the RCDs will be performed based on the 
respective rules for a standard 3 + 3 study design, as displayed in Figure 1. 
Within each cohort, the first study drug administration for the first subject and the second 
subject will be separated by at least 14 days. 
Table 2. 
Phase 1 Dose Levels 
Cohort 1A 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
-1 
750 mg 
1 mg 
0 (Starting Level) 
1500 mg 
1 mg 
Cohort 1B 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
Tremelimumab Q4W (IV) 
-1 
RCD from Cohort 1A 
1 mg 
22.5 mg 
0 (Starting Level) 
RCD from Cohort 1A 
1 mg 
75 mg  
Cohort 1C 
Dose Level 
Durvalumab Q4W (IV) 
PolyICLC (ITM/IM) 
Tremelimumab (ITM) 
-1 
RCD from Cohort 1A 
1 mg 
3 mg 
0 (Starting Level) 
RCD from Cohort 1A 
1 mg 
10 mg 
Q4W = every 4 weeks; IV = intravenous; ITM = intratumoral; IM = intramuscular 
NOTE: The durvalumab dose of 1500 mg Q4W is for subjects > 30 kg. If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing equivalent to 
20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject would 
receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  When the weight 
improves to >30 kg, the subject may return to fixed dosing of durvalumab 1500 mg. 
 
 


 
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Figure 1: 
Dose Escalation and De-escalation Schema 
Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is unsafe
DL is safe
Is DL + 1 available
and not
previously declared unsafe?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared unsafe?
Yes
DL is RCD
No
Is DL - 1 
available?
No
RCD cannot be 
determined
Was DL - 1 
previously declared 
safe?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is RCD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         RCD = Recommended Combination Dose (per DL Table)
 
As per the schema above, the RCD for each cohort is defined as the highest dose level at which 
no more than 1 of 6 subjects (i.e., < 33%) experience DLTs. The RCD cannot be determined if 
none of the predefined dose levels fulfill that criterion.  
3.1.7.2 Phase 2: Expansion Phase 
Once the RCD of the triplet dosing regimen has been determined in Cohort 1C, subsequent 
subjects will be enrolled into Cohort 2 to receive the RCDs of both checkpoint antibodies in 
combination with polyICLC, according to the treatment schema in Table 1.  Up to 66 evaluable 
subjects will be treated in Cohort 2. If Cohort 1C is not cleared, the RCD of the previously cleared 
cohort will be used for Phase 2. 
Cohort 2 will expand the cohort that was treated at the RCD from the dose-finding phase.  Up to 
6 subjects per tumor type will be initially enrolled into Cohort 2.  Data from all subjects who are 
treated with the dosing regimen in either the cleared dose-finding cohort or Cohort 2 will be 
reviewed for safety/efficacy to select up to 3 tumor types that demonstrate an efficacy signal, 
defined as at least 1 of 6 subjects within a tumor type who achieve a partial response (PR) or 
complete response (CR) by immune-related RECIST (irRECIST) or RECIST 1.1, or stable disease 
(SD) for at least 6 months (See Section 3.1.6 regarding DLT assessment during expansion).  Up to 
6 additional subjects with each of the selected tumor types may be enrolled as an expansion of 
Cohort 2.  If more than 3 of the tumor types have a signal, selection of 2-3 with the greatest 
signal may be selected for continuation. 
NOTE: Cutaneous T cell lymphomas (CTCL) may respond very differently than solid tumors; 
therefore, the study will primarily focus on solid tumors, but a “signal-seeking” approach to 


 
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including some subjects with CTCL will be supported.  There will be a limit of < 10-20% CTCL for 
total enrollment.  
See Section 4.3.1.1 for details on tumor biopsies. 
3.1.8 Dosing Adjustments, Delays, and Discontinuations 
Dose adjustment and management guidelines for toxicity related to tremelimumab and 
durvalumab and for polyICLC are outlined in Section 8.3 and Section 8.4, respectively. 
If subject(s) experience excessive toxicity related clearly and exclusively to a single checkpoint 
antibody or polyICLC, that agent will be discontinued, but the subject(s) may continue to receive 
the other study drug(s) within their assigned regimen, provided that no additional safety 
concerns are observed. 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
(i.e., the guideline that provides for the greatest dose reduction, dose delays or holds) should be 
followed. 
3.1.9  Dose-limiting Toxicity 
DLTs will be assessed for the period from Day 1 of the study up to and including the Week 7, 
Cycle 2/Day 15 study visit; this is defined as the “DLT Evaluation Period” for each subject in 
Cohorts 1A through 1C.  The decisions for dose de-escalations and RCD, as described in Section 
3.1.7.1, will be based primarily on the number of subjects with DLTs occurring during the DLT 
Evaluation Period.  DLTs occurring outside the DLT Evaluation Period will also be evaluated and 
may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of tremelimumab, durvalumab, and/or polyICLC and fulfill any of the following 
criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event, or uveitis. 
2. Any Grade 2 pneumonitis, neurological event, or uveitis with the following exception: 
• 
Grade 2 pneumonitis, neurological event, or uveitis that downgrades to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade 3 irAEs (see definition below) that downgrade to Grade ≤ 2 within 3 days, or 
to Grade ≤ 1 or baseline within 14 days after onset, whereby maximal supportive 
care, including systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 


 
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• 
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times 
ULN) within 7 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 or Grade 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which 
appropriate evaluation shows no clinical evidence of pancreatitis. 
IrAEs are defined as adverse events (AEs) of immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology. In the absence of clinical abnormality, repeat laboratory testing 
will be conducted to confirm significant laboratory findings prior to designation as a DLT. 
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or is listed as 
exempt above may also be defined as DLT after consultation with the Sponsor and Investigators, 
based on the emerging safety profiles of tremelimumab, durvalumab, and polyICLC. Likewise, 
subjects who become not evaluable for DLT because they discontinued or interrupted treatment 
due to toxicities other than DLTs may be counted as DLT subjects, if the toxicities cannot be 
managed in accordance with the dosing modifications described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study therapy and will enter the On 
Study and Post Study Follow-up phases of the study (see Section 3.1.16). However, if it is in the 
best interest of the subject, the Investigator and Sponsor may agree to continue treatment, 
possibly at a lower dose level. 
Maximum tolerated doses (MTDs) will not be determined. Instead, RCDs will be determined in 
the context of the predefined dose levels used during the dose de-escalation phase as per 
Section 3.1.7.1.  
3.1.10 Subject Withdrawal from Treatment or from Study 
A subject will be withdrawn from study treatment for any of the following reasons: 
1. Withdrawal of consent for further treatment 
2. Pregnancy or intent to become pregnant. 
3. DLT (see Section 3.1.9, including exception). 
4. Progressive disease by irRECIST requiring alternative systemic treatment (see NOTE 
below). 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal. 
6. Development of intercurrent, non-cancer-related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 


 
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A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator. 
2. Initiation of alternative anticancer therapy (marketed or investigational). 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death. 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If applicable, subjects who are withdrawn from study treatment should undergo 
the planned On Study Follow-up procedures (see Section 3.2) and enter the Post Study follow-
up period (see Section 3.1.16). 
NOTE: Subjects meeting criteria for radiographic progression by irRECIST (Section 8.5) will be 
allowed to continue on therapy until confirmation of progression by irRECIST if the subject 
agrees and signs an appropriate informed consent form regarding continuation of treatment 
and as long as the following criteria are met at the discretion of the Investigator: 
a. Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
Section 7.2.6 provides additional details regarding documentation for early subject withdrawal 
from study treatment and early withdrawal from study. 
See also Sections 8.3 and 8.4 for subject withdrawal from treatment due to necessary dosing 
interruptions or discontinuations. 
3.1.11 Evaluability and Subject Replacement 
Phase 1: Subjects in Cohorts 1A through 1C are fully evaluable for DLT if they fulfill the criteria 
for the Per-Protocol Population for DLT Assessment.  The Per-Protocol (PP) Population for DLT 
Assessment includes: 
(1) All subjects who experience a DLT at any time during the DLT Evaluation Period (as defined 
in Section 3.1.9. 
(2)  All subjects with no DLT who receive at least 75% of the total dose of each study drug and 
undergo respective safety assessments, without major protocol violations, over the entire 
DLT evaluation period. 
Subjects who are not fully evaluable for DLT will be replaced. 


 
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Phase 2: Subjects in Cohort 2 are considered fully evaluable and will be included in the Per-
Protocol (PP) Analysis Population for Clinical Efficacy if they meet the following criteria: 
• 
Receive at least the following minimum quantities of study drugs over the subject’s 
entire treatment period: 
o 2 durvalumab administrations  
o 3 tremelimumab administrations 
o 10 polyICLC administrations (regardless of route) 
• 
Undergo appropriate disease assessments (radiological or clinical) 
• 
Have no major protocol violations that would have an effect on the efficacy evaluation. 
Subjects who are not fully evaluable for PP population for Clinical Efficacy may be replaced. 
3.1.12 Optional Study Treatment Extension 
Treatment extension beyond 12 cycles is not planned.  
3.1.13 Interim Analysis 
Safety analyses will be performed to assess DLTs in Cohorts 1A through 1C (see Section 3.1.9). 
Analyses of the initial 6 subjects treated with each tumor type in Cohort 2 will be assessed to 
determine whether to enroll 6 more subjects (see Section 3.1.6).  
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and co-investigators as needed), the Sponsor’s Medical 
Monitor, and drug safety personnel from Medimmune and Oncovir, providers of the study 
drugs. Additional investigators and staff, or additional Sponsor personnel and consultants, shall 
participate in reviews as indicated. An Independent Data Monitoring Board will not be utilized 
for this open-label study. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to 1 or more of the study drugs. 
2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to 1 or more 
of the study drugs. 
3. Any events that, in the judgment of the medical monitor, are deemed serious enough to 
warrant immediate review by the data safety monitoring panel. This may include any 
symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, colitis, dermatitis, 
or hepatitis or any symptomatic treatment-related Grade ≥ 3 neurological toxicity or uveitis. 
4. Any other safety finding assessed as related to 1 or more study drugs that, in the opinion of 
the internal data safety monitoring panel, contraindicates further dosing of study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest that 
the study treatment has no clinical benefit for the subjects. 


 
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3.1.15 Duration of Treatment and Study 
3.1.15.1 Duration of Treatment 
Subjects may receive study treatment until 1 of the criteria for withdrawal is met (see 
Section 3.1.10) or until the maximum duration for each study drug is met, defined as 12 cycles of 
durvalumab, 4 cycles of tremelimumab, and 3 cycles of polyICLC. 
3.1.15.2 Duration of Study 
Duration of Study per 
Subject: 
Up to 12 months treatment + 3 months On Study Follow-up 
Enrollment Period: 
24 months 
Length of Study: 
39 months (not including Post Study Follow-up as described in 
Section 3.1.16) 
NOTE: Per Amendment 6.0, all post study follow-up for the collection 
of survival data will be discontinued as of 28 February 2022 (see 
rationale in Section 8.1, Amendment 6.0 on Page 80). 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment, or 
prematurely withdraw from the study as per Section 3.1.10, will be followed as per institutional 
guidelines in accordance with the usual standard of care principles.  
For subjects who complete the study or who discontinue treatment prematurely, On Study 
Follow-up will be conducted for 90 days after the last study drug administration according to the 
flowchart in Section 3.2.  Refer to Section 7.1.5 for information on recording AEs during the On 
Study Follow-up.  
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On-Study Follow-up Period (which is 28 days after the last dose of study 
treatment), any assessments required in the 28 day post-last treatment visit that are not 
covered as part of the last on-treatment visit (usually correlative labs) should be done as soon as 
possible.  If these assessments cannot be done on the same day, the subject should be brought 
back in at the earliest opportunity.  Any assessments or correlative samples required by both the 
last on-treatment visit and the 28 day post-last treatment visit should not be repeated. 
In addition to the On Study Follow-up, there will be a Post Study Follow-up, during which clinical 
outcomes data (dates of progression/relapse and survival) will be collected at least every 3 
months for 2 years after completion of treatment, then every 6 months until 5 years from study 
entry, then annually until 10 years from study entry.   
The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 90 days since the last administration of study drug.  
NOTE: Per Amendment 6.0, all post study follow-up for the collection of survival data will be 
discontinued as of 28 February 2022 (see rationale in Section 8.1, Amendment 6.0 on Page 80). 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 


 
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Investigator, will obtain the data through review of outside records or communication with the 
subject or his/her physician. 


 
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3.2 Study Flowchart 
 
Study Week
13
17
Cycle  Day1,2
1±3
3±3
5±3
8±3
10±3 15±3 17±3 22±3 24±3
1±3
3±3
8±3
10±3 15±3 17±3 22±3 24±3
1±3
4±3
1±3
1±7
Study Day
1
3
5
8
10
15
17
22
24
29
31
36
38
43
45
50
52
57
60
85
113
Durvalumab IV (all cohorts)
X
X
X
X
X
Tremelimumab  IV (Cohort 1B only)
X
X
X
X
Tremelimumab, intratumoral (Cohort 1C and 
Cohort 2 if 1C is cleared in Phase 1)
X
X
X
X
X
X
X
Poly ICLC, Intratumoral4
X
X
X
X
X
X
Poly ICLC IM
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Staging (date/stage at 1st diagnosis and 
at study entry)
X
Disease Assessment by irRECIST/RECIST1.1 (and 
imaging)8
X
X
Eligibility Assessment and Informed Consent (IC)9
X
Demographics (DoB, sex, height, race, ethnicity)
X
Physical Examination (incl. weight and ECOG PS)
X
X
X
X
X
X
X
X
X
Medical History
X
Vital Signs (T, HR, BP, RR)10
X
X
X
X
X
X
X
X
X
X
X
X
X
12- Lead ECG
X
Concomitant Medication (name, indication, 
dose, route, start & end dates) /Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting/worsening after IC)6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Hematology (CBC, differential, platelets)3
Day -7 to -1
X
X
X
X
X
X
X
X
Chemistry (Glucose, BUN, creat, Na, K,  Cl, CO2, 
Ca,  Mg, protein, alb, Tbili, AST, ALT,  ALP, LDH)3
Day -7 to -1
X
X
X
X
X
X
X
X
Chemistry cont: Free T3, Free T4, TSH3
Day -7 to -1
X
X
X
X
X
X
X
X
Chemistry cont: Amylase and  lipase3
Day -7 to -1
X
X
X
X
X
X
X
X
Hemoglobin A1c
Day -7 to -1
Serum Pregnancy Test (urine only Day 1)3
Day -7 to -1
X
X
X
X
Coagulation (PT, aPTT, INR)3
Day -7 to -1
X
X
X
X
X
X
X
X
Urinalysis3
Day -7 to -1
X
X
X
X
X
X
X
X
Circulating soluble factors (Antibody, 
Chemokines, Cytokines -serum)
X
X3
X3
X3
X3
X3
X3
PBMCs (Flow cytometry, T-cell Responses and 
Circulating T-cells)
X
X3
X3
X3
X3
X3
X3
RNA profiling (whole blood)
X
X3
X3
X3
X3
X3
Tumor Biopsy5
X
X3
X3
Overall Survival
Progression-free Survival7
Screening / 
Baseline
(Day -21 to -1)
Cycle 1 
(4 weeks)
9
Treatment 
Cycle 2 
(4 weeks)
5
6
7
Cycle 4 
(4 weeks)
Cycle 5 
(4 weeks)
3
1
2
4
Blood for Biological Markers
Other Procedures
Long-Term Follow-up12
Tumor and Disease Assessments
8
Specimens for Routine Laboratory Procedures
Study Drug Administration
LUD 2014-011
Study Flowchart 
Study Procedures and Examinations
Cycle 3 
(4 weeks)


 
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Last Study 
Drug 
+ 28±3 days 
Last Study 
Drug 
+ 56±3 days 
Last Study 
Drug  
+ 91±7  days 
Study Week
21
25
29
33
37
41
45
Cycle  Day1,2
1±7
1±7
1±7
1±7
1±7
1±7
1±7
Study Day
141
169
197
225
253
281
309
Study Drug Administration
Durvalumab IV (all cohorts)
X
X
X
X
X
X
X
Tremelimumab  IV (Cohort 1B only)
Tremelimumab, intratumoral (Cohort 1C and 
Cohort 2 if 1C is cleared in Phase 1)
Poly ICLC, Intratumoral4
Poly ICLC IM
Tumor and Disease Assessments
Disease Staging (date/stage at 1st diagnosis and 
at study entry)
Disease Assessment by irRECIST/RECIST1.1 (and 
imaging)8
X
X
X
X
X
Eligibility Assessment and Informed Consent (IC)9
Demographics (DoB, sex, height, race, ethnicity)
Physical Examination (incl. weight and ECOG PS)
X
X
X
X
X
X
X
X
X
X
X
Medical History
Vital Signs (T, HR, BP, RR)10
X
X
X
X
X
X
X
X
X
X
X
12- Lead ECG
Concomitant Medication (name, indication, 
dose, route, start & end dates) /Procedures
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting/worsening after IC)6
X
X
X
X
X
X
X
X
X
X
X
Blood Hematology (CBC, differential, platelets)3
X
X
X
X
X
X
X
X
X
X
X
Chemistry (Glucose, BUN, creat, Na, K,  Cl, CO2, 
Ca,  Mg, protein, alb, Tbili, AST, ALT,  ALP, LDH)3
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont: Free T3, Free T4, TSH3
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont: Amylase and  lipase3
X
X
X
X
X
X
X
X
X
X
X
Hemoglobin A1c
Serum Pregnancy Test (urine only Day 1)3
X
X
X
X
X
X
Coagulation (PT, aPTT, INR)3
X
X
X
X
X
X
X
X
X
X
X
Urinalysis3
X
X
X
X
X
X
X
X
X
X
X
Circulating soluble factors (Antibody, 
Chemokines, Cytokines -serum)
X3
X3
X
X11
PBMCs (Flow cytometry, T-cell Responses and 
Circulating T-cells)
X3
X3
X
X11
RNA profiling (whole blood)
X3
X3
X
X11
Tumor Biopsy5
 optional
optional
Overall Survival
X12
Progression-free Survival7
X12
Cycle 6 
(4 weeks)
On Study Follow-up
Treatment
Cycle 10 
(4 weeks)
Cycle 7 
(4 weeks)
Cycle 12 
(4 weeks)
Cycle 11 
(4 weeks)
Cycle 9 
(4 weeks)
Cycle 8 
(4 weeks)
Blood for Biological Markers
Other Procedures
Long-Term Follow-up12
Specimens for Routine Laboratory Procedures
Post Study 
Follow-up 12
Every 3 mos for 2 yrs 
after completion of 
treatment; then every 
6 mos until 5 yrs from 
study entry; then 
yearly until 10 yrs  
from study entry
LUD 2014-011
Study Flowchart 
(cont.)
Study Procedures and Examinations
Visit for 
Subjects who 
Discontinue 
Treatment 
Prematurely 


 
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Study Flowchart Footnotes 
 
 
4. For intratumoral polyICLC, a 7-day dosing window is permitted provided that all injections are administered within the first 21 days of Cycle 1;
    injections must be administered ≥ 24 hours apart
      Section 6.3.3 for intratumoral and IM polyICLC vitals assessments.
11. There is no need to repeat these assessments if they were done at the Premature Discontinuation Visit or at the last on treatment visit.
12. Per Amendment 6.0, all post study follow-up for the collection of survival data will be discontinued as of 28Feb2022 (see Section 8.1, Amendment 6.0)
10. See Section 6.5 for assessment before/during/after IV infusions; Section 6.1.3.1 for intratumoral tremelimumab vitals assessments; 
1. For each subject, there will be one allowed delay of up to one week for a scheduled visit; however, the delay can only occur after Cycle 1 is complete
6. See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
7.  For subjects who did not experience progression while on study
8.  Subsequent imaging at  4 to 8 weeks after first documentation of irRECIST-defined progression must be performed.
    results are reviewed before dosing.
    Note: the Screening/Baseline biopsy may be done on the Cycle 1/Day 1 Visit as long as it is done prior to start of any treatment.
    criteria or flowchart
5. Also conducted at time of progression and end of treatment; injected and uninjected tumors on Day 15 and Cycle 2 Day 1,  and from the same 
2. Starting with Cycle 5, the intervals for visit days will change to ±7 days; however, a 3-week interval must maintained between durvalumab doses.
    lesion each time if possible. See Sections 4.3.1.1 and 5.1 (#2) for details on biopsies.
3. Collected pre-dose (prior to drug administration). It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) 
9. Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion 


 
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4 Study Objectives and Endpoints 
Primary 
Objective 
[Endpoints] 
Dose-finding Phase (Cohorts 1A – 1C): 
Safety and Tolerability [DLTs, RCDs According to CTCAE V4.03] 
Expansion Phase (Cohort 2): 
Clinical Efficacy by irRECIST and RECIST 1.1 [ORR, PFS, OS] 
Secondary 
Objectives 
[Endpoints] 
 
All Subjects: 
Safety and Tolerability [According to CTCAE V4.03] 
Clinical Efficacy by irRECIST and RECIST 1.1* [ORR, PFS, OS] 
*unless assessed as Primary Objective/Endpoint 
Exploratory 
Objectives 
[Endpoints] 
All Subjects: 
Biologic Activity [Effects on Tumor Microenvironment, Immune Responses] 
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RCD = recommended 
combination dose; RECIST = Response Evaluation Criteria in Solid Tumors  
4.1 Safety and Tolerability 
The safety and tolerability of each regimen will be evaluated to determine the tolerability of 
intratumoral or systemic tremelimumab and/or IV durvalumab in combination with polyICLC. 
Safety will be evaluated by the internal data safety monitoring panel on an ongoing basis, 
based on data review and regular conference calls with the investigators. 
4.1.1 Endpoints and Assessment Methods 
Laboratory tests, vital sign measurements, physical examinations, and subject interviews will be 
performed to detect new abnormalities and deteriorations of any pre-existing conditions.  The 
investigator will evaluate any laboratory abnormalities for clinical significance, and clinically 
significant abnormalities will be recorded as AEs.  All treatment-emergent, clinically significant 
abnormalities and deteriorations from the time of informed consent to the End of Study Visit 
should be recorded in the Case Report Forms as AEs and graded according to the NCI CTCAE, 
Version 4.03. 
4.1.2 Subject Evaluation and Statistics 
See Section 3.1.11 for subject evaluability and replacement for DLT assessments and for 
description of the Per-Protocol (PP) Population for DLT Assessment.   
In addition, all subjects who receive at least 1 dose of tremelimumab, durvalumab, or polyICLC 
will be assessed for safety and tolerability, regardless of whether or not they are fully evaluable 
per protocol as defined in Section 3.1.11; this is the Safety Population. Appropriate summaries 
of AEs, SAEs, DLTs, laboratory data, and vital sign data will be presented. AEs will be listed 
individually per subject according to the NCI CTCAE, Version 4.03, and the number of subjects 
experiencing each AE will be summarized using descriptive statistics. 
Adverse events will be coded using the MedDRA dictionary. Incidences of treatment-emergent 
adverse events (TEAE, those events that started after dosing or worsened in severity after 


 
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dosing) will be presented overall and by maximum severity (according to CTCAE version 4.03) 
and relationship to study medication. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges. Frequencies and percentages will be presented for the 
shifts in these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from baseline to 
each post-treatment assessment time point.  Descriptive statistics will be presented for the 
changes in vital signs from baseline to each post-treatment assessment time point.   
4.2 Clinical Efficacy 
4.2.1 Endpoints and Assessment Methods 
Clinical efficacy will be determined by objective response rate (ORR), progression-free survival 
(PFS), and overall survival (OS). Disease assessments will be done in accordance with the 
flowchart in Section 3.2.  Subsequent imaging at 4 to 8 weeks after first documentation of 
irRECIST-defined progression must be performed. 
4.2.1.1 Objective Response Rate 
The primary method of assessment of response and ORR will be irRECIST (see Section 8.5) and 
the secondary method will be RECIST 1.1, modified for the tumor biopsies such that tumors 
biopsied during the study will not be considered measurable for ORR but will be assessed as 
non-measurable lesions to the extent that marked progression of a non-measurable lesion is 
inconsistent with an objective response; these lesions will be identified prospectively prior to 
the first treatment.  ORR is defined as the percentage of evaluable subjects meeting criteria of 
CR or PR, confirmed at a subsequent time point (≥ 4 weeks). Disease control is defined as SD for 
6 months, PR, or CR.  Every attempt should be made to use whichever imaging technique(s) and 
test(s) are used initially for repeat evaluations throughout the study, whereby the End of Study 
tumor assessments will be at least 4 weeks from the prior assessment. Regression of treated 
and untreated tumors will be recorded separately and tracked as well. 
4.2.1.2 Progression-free Survival 
Progression-free survival will be defined as the number of days from the date of first dose of 
study drug to the date of earliest disease progression based on irRECIST, or to the date of death, 
if disease progression does not occur.  PFS based on RECIST 1.1 will also be recorded but will not 
be the primary endpoint. 
4.2.1.3 Overall Survival 
OS will be measured for each subject from the date of first dose of study drug until the recorded 
date of death or last follow-up.  Subjects who are still alive will be censored on the date of last 
follow-up.  Every effort will be made to follow subjects for OS after they discontinue the study. 
NOTE: Per Amendment 6.0, all post study follow-up for the collection of survival data will be 
discontinued as of 28 February 2022 (see rationale in Section 8.1, Amendment 6.0 on Page 80). 


 
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4.2.2 Subject Evaluation and Statistics 
The analysis of clinical efficacy will be based on both the intent-to-treat (ITT) and the PP 
population for Clinical Efficacy.  Subjects who receive at least 1 dose of any study drug will be 
included in the ITT population.  Subjects who are fully evaluable per protocol, as defined in 
Section 3.1.11, will be included in the PP population for Clinical Efficacy. 
4.3 Biological Activity 
4.3.1 Endpoints and Assessment Methods 
Correlative data will be obtained to assess the effects of the dosing regimen on the TME, 
including PD-L1 expression (baseline by tumor type, changes over time during and after 
intratumoral therapy), T-cell infiltration, chemokine profiles, immune gene signatures, TLR 
signaling, and markers of immunogenic cell death (LC3, intact ER stress response, HMGB1). 
Any observed effects will also be assessed to determine whether these changes (or baseline 
levels) may predict clinical response to combination therapy, including blockade of PD-L1 and 
CTLA-4. 
4.3.1.1 Tumor Microenvironment 
Tumor biopsies will be conducted on all subjects at Baseline (pretreatment), Day 15, and, 
provided there is sufficient tumor to biopsy, at Day 29 (Cycle 2, Day 1), and optionally at the 
time of progression and at the end of treatment.  Subjects must have adequate tissue available 
as outlined in the inclusion criteria (Section 5.1). Biopsies will be obtained via incisional, 
excisional, or core biopsies. Additional biopsies may be obtained as appropriate.  These biopsies 
will be prepared in 3 conditions: formalin-fixed tissue, quick-frozen tissue, and RNAlater®. In 
subjects with large biopsies, viable cell suspensions may be collected and prepared as single-cell 
suspensions and viably cryopreserved.  Endpoints include induction of a favorable immune 
signature and increased T-cell infiltration, as well as pre-treatment and post-treatment immune 
signatures that predict clinical response.  
Ideally, tumor biopsies will include both injected tumor and non-injected tumor, to study 
abscopal effects.  The tumor biopsies ideally will also come from the same lesion each time, if 
possible. 
These specimens will be evaluated for the following endpoints, using the listed assessment 
methods: 


 
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Endpoint 
Approach 
Specific measure 
Analytic method 
PD-L1 expression 
IHC 
PD-L1 
Automated image 
analysis and pathologist 
review 
T cell infiltrates and 
immunotypes 
associated with 
improved survival (45-
49) 
IHC and/or IF  
CD45, CD3, CD8, 
CD4/FoxP3, CD20, 
CD31, Ki67, 
CD45RO 
Automated image 
analysis and pathologist 
review; apply 
Immunoscore 
parameters to assess 
changes in the TME 
Innate immune cell 
infiltrates 
IHC 
macrophage 
markers (CD68, 
CD163), myeloid 
markers (CD11b, 
CD33), DC 
markers (CD11c, 
CD1a, DC-
LAMP/CD208), 
CD1c and NK cell 
markers (CD56) 
 
Chemokine profiles, 
immune signatures 
associated with 
improved survival and 
response to immune 
therapy (50-54) 
Affymetrix gene expression 
arrays, and customized 
nanostring panel with 
100 molecules including 
markers of inflammation, 
common cancer antigens and 
certain biomarkers from 
Melbourne/J Cebon 
Genes associated 
with Th1 
responses; plus 
genes of immune 
regulation (PDL1, 
IDO, etc.) 
Partek Genomic Suite 
and IPA software 
Immunogenic cell 
death machinery 
IHC 
LC3, intact ER 
stress response, 
HMGB1 
Automated image 
analysis 
TLR signaling 
Gene expression arrays as 
specified above 
MyD88, adaptor 
proteins, 
chemokines and 
NFkB activation 
Partek Genomic Suite 
and IPA software 
Functional markers   
IHC, protein array, and/or flow 
cytometry 
Arginase, iNOS, 
CD73, CD39, CD40 
and IDO 
 
Markers of T cell 
activity,  
Flow cytometry 
OX40, GITR, 
CD137, IFN and 
granzyme, 
perforin.   
 
TCR and/or BCR 
diversity 
High throughput analysis 
TCRV-beta, BCR 
 
IF = immunofluorescence; IHC = immunohistochemistry; IPA = Ingenuity Pathway Analysis; TME = tumor 
microenvironment; TLR = toll-like receptor 
4.3.1.2 Pharmacodynamics 
Blood samples for exploratory pharmacodynamic assessments will be collected at each visit and 
time point as noted in Section 3.2. 


 
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Exploratory pharmacodynamic assessments may include, but are not be limited to: 
• 
PBMCs to assess immune cell phenotypes by flow cytometry, which may include T cell 
phenotype and activation markers, B cells, myeloid derived suppressor cells and/or 
immune diversity.  The PBMCs will also be used for measurement of T cell responses to 
defined antigens. 
• 
Serum levels of circulating soluble factors, including antibodies, cytokines, and 
chemokines. 
• 
Whole blood for mRNA/miRNA profiling. 
4.3.2 Subject Evaluation and Statistics 
Only subjects who receive at least 1 dose of durvalumab, tremelimumab and polyICLC or 
durvalumab and polyICLC, and provide the baseline and at least 1 post-treatment sample (if 
applicable) will be evaluated. Exploratory results will be summarized descriptively. 
 


 
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5 Subject Eligibility 
NOTE:  Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1. 
Subjects must have histologic confirmation of advanced unresectable disease, have failed 
at least one standard of care therapy, and do not have curative options. Tumors should be 
biopsy-accessible (see NOTE 1), measurable cancers of the following histologies: 
• 
Non-viral-associated head and neck squamous cell carcinoma (HNSCC) or HPV-
associated HNSCC after failure of prior therapy 
• 
Locally recurrent or metastatic breast cancer 
• 
Sarcoma 
• 
Merkel Cell Carcinoma (MCC) 
• 
Cutaneous T cell Lymphoma (CTCL) 
• 
Melanoma after failure of available therapies 
• 
GU cancers with accessible metastases (e.g., bladder, renal)  
• 
Any solid tumors with masses that are accessible  
NOTE 1: A biopsy-accessible lesion is defined as a tumor lesion which can be, in the 
opinion of the Investigator or that of consulting physicians, safely accessed for biopsy or 
for injection by means of physical examination or imaging guided means, preferably 
ultrasound (e.g., cutaneous lesions, inguinal nodes, supraclavicular or cervical nodes, 
superficial abdominal lesions, and lesions that are accessible by ultrasound guidance and 
not impacting vital organs/structures). 
NOTE 2: CTCL may respond very differently than solid tumors; therefore, the study will 
primarily focus on solid tumors, but a “signal-seeking” approach to including some 
subjects with CTCL will be supported.  There will be a limit of < 10-20% CTCL for total 
enrollment  
2. 
Subjects need to have at least 2 lesions, as follows: 
(1) 1 lesion considered measurable disease as defined by irRECIST and RECIST 1.1, i.e., 
that can be accurately measured in at least 1 dimension (longest diameter to be 
recorded), where each lesion must be ≥ 10 mm when measured by computed 
tomography (CT), magnetic resonance imaging (MRI), or caliper measurement by 
clinical examination, or ≥ 20 mm when measured by chest x-ray. To be considered 
measurable, lymph nodes must be ≥ 15 mm in short axis when measured by CT or 
MRI. These lesions should not be injected with study drug or biopsied. 
(2) 1 larger lesion (approximately 2 cm or more) amenable to repeated multiple core 
biopsies or at least 3 smaller lesions of at least 6 mm diameter amenable to repeated 
single core biopsy, measured by clinical examination. Multiple small lesions of 
comparable volume may be biopsied on a single date. These lesions must also be 


 
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suitable for repeated injections of study drug, either as single injection in larger 
lesions (preferred) or multiple injections in up to 3 smaller lesions. 
Ideally, subjects should have at least 1 additional lesion amenable to biopsy. This/these 
lesion(s) should not be injected with study drug. 
3. 
Any number of prior systemic therapies. 
4. 
ECOG Performance status 0-1. 
5. 
Laboratory parameters: 
• 
Absolute neutrophil count (ANC) ≥ 1000/mm3; 
• 
Platelets ≥ 100,000/mm3; 
• 
Hemoglobin (Hgb) ≥ 9 g/dL; 
• 
Hgb-A1C ≤ 7.5%; 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × 
upper limit of normal (ULN); 
• 
Bilirubin ≤ 2.5 × ULN (≤ 4 × ULN for subjects with Gilbert’s disease); 
• 
Alkaline phosphatase ≤ 2.5 × ULN; 
• 
Creatinine ≤ 1.5 × ULN; 
• 
International normalized ratio (INR) or prothrombin time (PT) AND activated 
partial thromboplastin time (aPTT)/PTT ≤1.5 X ULN. NOTE: for subjects on 
therapeutic anticoagulation, subject must be stable on current regimen, as 
determined by the Investigator. 
6. 
Age ≥ 18 years. 
7. 
Able and willing to give valid written informed consent. 
5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Prior treatment with combination CTLA-4 and PD-1/PD-L1 blockade, with the exception of 
subjects with melanoma. 
2. 
Participants may not have been treated intratumorally with polyICLC. 
3. 
Unresolved irAEs following prior biological therapy, except that stable and managed irAEs 
may be acceptable (e.g., hypothyroidism or hypopituitarism on appropriate replacement). 
4. 
Subjects with history or evidence upon physical examination of central nervous system 
(CNS) disease, including primary brain tumor, seizures not controlled with standard 
medical therapy, any active brain metastases, or, within 6 months of the first date of 
treatment on this study, history of cerebrovascular accident (CVA, stroke), transient 
ischemic attack (TIA) or subarachnoid hemorrhage. 
5. 
Subjects with clinically significant cardiovascular disease, including: 
a. Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mmHg 
or diastolic BP > 90 mmHg. 
b. Myocardial infarction or unstable angina within 6 months of the first date of 
treatment on this study. 


 
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c. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or 
ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic 
medications, except for atrial fibrillation that is well controlled with 
anti-arrhythmic medication. 
d. Baseline ejection fraction ≤ 50% as assessed by echocardiogram or multi-gated 
acquisition (MUGA) scan. 
e. New York Heart Association (NYHA) Class II or higher congestive heart failure. 
f. Grade 2 or higher peripheral ischemia [brief (< 24 hours) episode of ischemia 
managed non-surgically and without permanent deficit]. 
6. 
History of pneumonitis or interstitial lung disease. 
7. 
Active, suspected or prior documented autoimmune disease (including but not restricted 
to inflammatory bowel disease, celiac disease, Wegner’s granulomatosis and Hashimoto’s 
thyroiditis, etc.). Participants with vitiligo, alopecia, type I diabetes mellitus, residual 
hypothyroidism (e.g., following Hashimoto syndrome) due to autoimmune condition only 
requiring hormone replacement, psoriasis or any chronic skin condition not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. Subjects without active disease in the last 5 years may be 
included but only after consultation with the study physician. Subjects with celiac disease 
controlled by diet alone may also be included. 
8. 
Other malignancy within 2 years prior to entry into the study, except for those treated 
with surgical therapy only (e.g., localized low-grade cervical or prostate cancers). 
9. 
Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who 
require drainage gastrostomy tube and/or parenteral hydration or nutrition. 
10. Known immunodeficiency or HIV, Hepatitis B, or Hepatitis C positivity. Antibody to 
Hepatitis B or C without evidence of active infection may be allowed. 
11. History of severe allergic reactions to any unknown allergens or any components of the 
study drugs. 
12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). 
13. Participation in any other clinical trial involving another investigational agent within 
4 weeks prior to Day 1 of the study. 
14. Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study. 
15. Lack of availability for immunological and clinical follow-up assessment. 
16. Women of child bearing potential who are pregnant as evidenced by positive serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) or nursing. 
17. Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from screening, and must agree to continue using such precautions through 90 
days after the last dose of durvalumab or through 6 months after the last dose of 
durvalumab + tremelimumab (whichever is longer). Nonsterilized male partners of a 
female subject must use male condoms plus spermicide throughout this period. Cessation 
of birth control after this point should be discussed with a responsible physician. Not 
engaging in sexual activity for the total duration of the trial and the drug washout period 


 
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is an acceptable practice; however, periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of birth control. 
Female subjects should refrain from breastfeeding (or pumping breast milk) throughout 
the period described above. 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmeno-
pausal. 
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  
• 
Females <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).   
• 
Females ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy. 
Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use male condoms plus spermicide from screening through 90 days after 
last dose of durvalumab or through 6 months after the last dose of durvalumab + 
tremelimumab (whichever is longer).  Female partners (of childbearing potential) of a 
male subject must use a highly effective method of contraception (see table below) 
throughout this period. Cessation of birth control after this point should be discussed with 
a responsible physician. Not engaging in sexual activity for the total duration of the trial 
and the drug washout period is an acceptable practice; however, periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of 
contraception. 
Male subjects should refrain from sperm donation throughout the period described 
above. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate (i.e. 
less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
Acceptable highly effective methods of contraception are described in the following table: 


 
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Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine system (e.g., Mirena®)b 
• 
“Implants”: Etonogestrel-releasing 
implants: e.g. Implanon® or 
Norplan® 
• 
“Intravaginal devices”: e.g. 
Ethinylestradiol/etonogestrel-
releasing intravaginal devices: e.g., 
NuvaRing® 
• 
“Injection”: Medroxyprogesterone 
injection: e.g. Depo-Provera®  
• 
“Combined Pill”: Normal and low 
dose combined oral contraceptive 
pill 
• 
“Patch”: Norelgestromin 
/ethinylestradiol-releasing 
transdermal system: e.g., Ortho 
Evra® 
• 
“Minipillc”: Progesterone based oral 
contraceptive pill using desogestrel: 
e.g., Cerazette®  
a - Highly effective (i.e., failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill 
18. Any condition that, in the clinical judgment of the treating physician, is likely to interfere 
with the interpretability of the data or to prevent the subject from complying with any 
aspect of the protocol or that may put the subject at unacceptable risk. 
19. History of allogeneic organ transplant 
20. Subjects must not donate blood while on study and for at least 90 days following the last 
durvalumab treatment or for 6 months after the last dose of tremelimumab (whichever is 
longer). 
 
 


 
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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study, except as 
allowed in Section 5.3.2: 
1. 
Systemic treatment with high-dose glucocorticosteroids or other immunosuppressive 
treatments (e.g., methotrexate, chloroquine, azathioprine, adalimumab), with a 
wash-out period of 2 weeks prior to Day 1. 
2. 
Other cancer therapy (e.g., drug, radiation, or immunotherapy). Wash-out period: 4 
weeks or 5 half-lives (whichever is shorter) prior to Day 1. (6 weeks for nitrosoureas 
and 12 weeks for antibodies other than anti-CTLA-4 or anti-PD-1/PD-L1 antibodies). 
3. 
Live/attenuated vaccines 1 month prior to Day 1 and for at least 6 months after the 
last dose of treatment. 
4. 
Sunitinib within 3 months after the last dose of tremelimumab. 
5. 
Drugs with laxative properties and herbal or natural remedies for constipation should 
generally be avoided through 90 days post last dose of tremelimumab because of the 
potential for exacerbation of diarrhea, but, for example, opiate-induced constipation 
may be treated with laxatives at the Investigator’s discretion. 
The wash-out period prior to Day 1 of the study for all non-permitted drugs should be at 
least 1 week, unless stated otherwise above. 


 
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5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies; inhaled 
steroids (e.g., fluticasone propionate/salmeterol, triamcinolone acetonide) are 
permitted at low doses (< 500 µg fluticasone per day, or equivalent). 
2. 
Nasal steroids or topical steroids for localized (< 5% of body surface area) dermatitis.  
3. 
Replacement steroid doses in subjects with stable adrenal or pituitary insufficiency. 
4. 
Non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and specific 
COX-2 inhibitors. 
5. 
Antihistamines and other non-steroidal anti-allergy medication. 
6. 
Hormone or hormone-related anti-cancer therapy, and cancer supportive therapy 
such as bone modifying agents (bisphosphonates/RANK-L inhibitors). 
7. 
At the discretion of the investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high dose corticosteroids to treat 
durvalumab-related immune-mediated adverse reactions. Subjects should receive full 
supportive care, including transfusions of blood and blood products, and treatment 
with antibiotics, anti-emetics, anti-diarrheal, and analgesics, and other care as deemed 
appropriate, and in accordance with their institutional guidelines. Use of 
anticoagulants such as warfarin is permitted; however, caution should be exercised 
and additional international normalized ratio (INR) monitoring is recommended. 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic (preferably) or brand name, indication, dose, 
route, and dates of administration. All non-drug therapies must be recorded in the 
respective sections of the case report form. 


 
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6 Study Drug Preparation and Administration 
All study drugs are manufactured in accordance with Good Manufacturing Practices (GMP). 
Order of Drug Administration 
Intravenous infusions will be administered first, followed by intratumoral injections. On days 
when both tremelimumab and durvalumab are to be administered IV, the durvalumab infusion 
will start at least 60 minutes after the end of the tremelimumab infusion. With respect to 
intratumoral injections, tremelimumab will be administered first followed by polyICLC.   
6.1 Tremelimumab 
Tremelimumab is supplied by the Sponsor. Commercially available 0.9% (w/v) saline or 5% (w/v) 
dextrose will be supplied by each site. Please see Section 7.2.8 for additional details. See Section 
6 for order of drug administration. 
6.1.1 Tremelimumab Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: Single-use vial 
Material: Clear glass 
Size: 20 mL 
Formulation 
Liquid solution containing 400 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 
mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5. 
Active Ingredient 
Content 
Mass/Weight: 
400 mg/vial 
Volume: 
20 mL 
Concentration: 
20 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Labeling 
Product name, lot number, and storage conditions 
Tremelimumab is also available in a 25 mg/vial format; the concentration remains 20 mg/mL. 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: Single-use vial 
Material: Clear glass 
Size: 2 mL 
Formulation 
Liquid solution containing 25 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 
mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5. 
Active Ingredient 
Content 
Mass/Weight: 
25 mg/vial 
Volume: 
1.25 mL/vial 
Concentration: 
20 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Labeling 
Product name, lot number, and storage conditions 
 


 
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6.1.2 Tremelimumab Investigational Product Inspection 
Each vial of tremelimumab selected for dose preparation should be inspected. If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.1.3 Tremelimumab for Intratumoral Injection 
6.1.3.1 Preparation and Administration of Tremelimumab 
for Intratumoral Injection 
The volume of tremelimumab to be administered with each intratumoral injection will be 0.5 mL 
for a 10 mg dose and 0.15 mL for a 3 mg dose for all subjects who will receive tremelimumab. 
One syringe should be filled aseptically from 1 vial for each dose.  
The intratumoral injections will be administered by a physician or nurse under physician 
supervision. For particularly large lesions (> 1 cm in longest diameter), the dose can be divided 
and administered into more than 1 quadrant of the lesion. For example, for most lesions, the 
needle can be moved within each quadrant of the lesion, or if the lesion is too large, separate 
injections will be given for the total dose (to cover more of the lesion). During injections, it is 
recommended that the investigator distribute the injectate throughout the lesion targeted. If 
the injected lesion regresses completely before all of the intratumoral injections are 
administered, no further intratumoral injections will be given. Alternatively, if the lesion is too 
small to inject the complete volume of intratumoral study drug, the dose may be divided among 
a maximum of 3 lesions. The same lesions must be injected with the same volume at each time 
point in each subject. 
A physician must be present at the site or immediately available to respond to emergencies 
during administration of all investigational product(s). Fully functional resuscitation facilities 
should be available.  
The subjects will be monitored before and for at least 1 hour after the intratumoral injections, 
including a determination of temperature, blood pressure, heart rate, and respiratory rate. 
The total time between needle puncture of the tremelimumab vial to start of administration 
should not exceed 4 hours at room temperature, or 24 hours at 2°C to 8°C (36°F to 46°F). If 
tremelimumab administration has to be delayed, a new dose must be prepared from new vials. 
Tremelimumab does not contain preservatives, and any unused portion must be discarded. 
6.1.4 Tremelimumab for Intravenous Infusion 
6.1.4.1 Preparation of Tremelimumab for Intravenous Infusion 
For dose preparation steps, the following ancillary items are required:  
• 
IV infusion bags of 0.9% sodium chloride injection or 5% (w/v) dextrose. Infusion bags must 
be latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g., polyethylene), 
manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free.  
• 
IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or polyethylene or 
polyurethane. All DEHP-containing or DEHP-free lines are acceptable. Lines must contain a 


 
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0.22 or 0.2 μm in-line filter. The in-line filter can be made of polyethersulfone (PES) or 
polyvinylidine fluoride DRF (PVDF). 
• 
Syringes made of polypropylene and latex-free.  
• 
Needles made of stainless steel.  
 
Preparation of tremelimumab and preparation of the IV bag are to be performed aseptically by 
the IP manager or designated personnel. No incompatibilities between tremelimumab and 
polyvinylchloride or polyolefin have been observed.  
Tremelimumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. The 
IV bag size should be chosen such that the final concentration of tremelimumab after dilution in 
the bag is between 0.10 mg/mL and 10 mg/mL. The appropriate IV bag size should be chosen for 
the respective dose. For the 75 mg dose only, tremelimumab may be administered using a 250 
mL IV bag.  
Subjects will receive a fixed dose tremelimumab, regardless of weight.   
The volume of tremelimumab required for a 75 mg dose is 3.75 mL. The volume of 
tremelimumab required for a 22.5 mg dose is 1.125 mL. 
The corresponding volume of investigational product should be rounded according to 
institutional practice. 
The investigational product manager or qualified personnel will be responsible for preparing the 
IV doses using the following steps: 
• 
Add the required dose volume of tremelimumab to the IV bag; ensure the allowable 
concentration range stated above is maintained for the IV bag size.  
• 
Gently mix the solution in the bag by inverting up and down. Avoid shaking the IV bag to 
prevent foaming.  
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
6.1.4.2 Administration of Tremelimumab for Intravenous Infusion 
Following preparation of the dose, tremelimumab will be administered according to the 
following guidelines:  
• 
Tremelimumab must be administered at room temperature (25°C) by controlled 
infusion into a peripheral vein or central line.  
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures.  
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available.  
• 
Tremelimumab solution should not be infused with other solutions or medications. 


 
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• 
Tremelimumab must not be administered via IV push or bolus but as a slow IV infusion.  
• 
The infusion lines should be attached only at time of use. Lines used for infusion during 
dose administration must be equipped with 0.22 or 0.2 µm in-line filters.  
• 
The entire contents of the IV bag should be administered by IV infusion over 
approximately 60 (±5) minutes, using a 0.2, or 0.22-μm in-line filter.  
• 
The total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C 
(36°F to 46°F). If there are no requirements to slow, interrupt, or permanently stop the 
infusion, the anticipated infusion time to deliver each dose  is anticipated to be 60 
(± 5) minutes. However, if there are interruptions during infusion, the total allowed time 
should not exceed 8 hours.  In the event that either preparation time or infusion time 
exceeds the time limits, a new IV bag must be prepared from new vials and the 
remaining dose is given. 
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed.   
• 
The date, start time, interruption, and completion time of tremelimumab administration 
must be recorded in the source documents.   
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.5. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
• 
Tremelimumab does not contain preservatives and any unused portion must be 
discarded. 
6.2 Durvalumab (MEDI4736) 
Durvalumab is supplied by the Sponsor. Commercially available 0.9% (w/v) saline or 5% (w/v) 
dextrose will be supplied by each site. Please see Section 7.2.8 for additional details. 
See Section 6 for order of drug administration. 
6.2.1 Durvalumab Study Drug Information 
Liquid formulation for intravenous administration 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented in the  QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container 
Description 
Type: 
Single use vial  
Material: 
clear glass 
Size: 
10 mL 
Formulation 
Liquid solution containing 500 mg durvalumab per vial.  
The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-
HCl, 275 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) 
polysorbate 80, at pH 6.0. 
Active Ingredient 
Content 
Mass/Weight: 
500 mg 
Volume: 
10 mL 
Concentration: 
50 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 


 
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Labeling 
Product name, lot number, and storage conditions 
 
6.2.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected. If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.2.3 Preparation of Durvalumab for Intravenous Infusion 
Preparation of durvalumab and preparation of the IV bag are to be performed aseptically by the 
IP manager or designated personnel. No incompatibilities between durvalumab and 
polyvinylchloride or polyolefin copolymers have been observed. 
Dose Calculation: 
Subjects will receive a fixed dose of durvalumab:  
• 
Starting dose: 1500 mg Q4W  
NOTE: The durvalumab dose of 1500 mg Q4W is for subjects > 30 kg. If a subject’s body 
weight drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 20 mg/kg of durvalumab as long as the body weight remains ≤ 30 kg (e.g., a 30 
kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  
When the weight improves to >30 kg, the subject may return to fixed dosing of durvalumab 
1500 mg. 
• 
Dose de-escalation: 750 mg Q4W. 
The volume of durvalumab (in mL) to be added to the IV bag is calculated as follows: 
Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
÷ 
Durvalumab 
Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter. The 
IV bag size should be chosen such that the final durvalumab concentration after dilution in the 
bag must be 1 mg/mL to 15 mg/mL. The appropriate IV bag size should be chosen for the 
respective dose.  
The calculated volume of durvalumab is added to the IV bag, and the bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag; ensure the allowable concentration 
range stated above is maintained for the IV bag size. 
The following examples are provided for a 250 mL bag. 
Example: 
For a 1500 mg dose, 30 mL of durvalumab is diluted in a 250 mL IV bag. The bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag.  


 
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For a 750 mg dose, 15 mL of durvalumab is diluted in a 250 mL IV bag. The bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Durvalumab does not contain preservatives; any unused portion must be discarded. 
6.2.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during administration of all investigational product(s). Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
• 
Durvalumab must not be administered via IV push or bolus but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 60 (± 5) 
minutes, using a 0.2-μm in-line filter. An infusion time of less than 55 minutes is 
considered a deviation.  
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used. Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time between needle puncture of the durvalumab vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 
8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion, the total allowed time should not exceed 8 hours. In the 
event that either preparation time or infusion time exceeds the time limits, a new IV bag 
must be prepared from new vials and the remaining dose is given. 
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.   
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.5. 
• 
See Section 8.3.1 for guidelines for infusion-related reactions. 
• 
Durvalumab does not contain preservatives, and any unused portion must be discarded. 


 
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6.3 PolyICLC 
See Section 6 for order of drug administration. 
6.3.1 PolyICLC Study Drug Information 
Manufacturer 
Oncovir 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the Certificate of 
Conformance. 
Container 
Description 
Type: 
Single-use unpreserved vial 
Material: 
 
Size: 
1 mL 
Formulation 
PolyICLC is supplied in vials containing 1 mL of opalescent white 
suspension (approximately 2 mg/mL). Each mL of polyICLC for injection 
contains approximately 2 mg/mL poly-IC, 1.5 mg/mL poly-L-lysine, and 5 
mg/mL sodium carboxymethylcellulose in 0.9% sodium chloride solution 
and adjusted to pH 7.6-7.8 with sodium hydroxide. 
Active Ingredient 
Content 
Mass/Weight: 
approximately 2 mg 
Volume: 
1 mL 
Concentration: 
approximately 
2 mg/mL 
Storage Conditions 
+2°C to +8°C (approximately 40°F) Do not freeze 
Labeling 
Product name, concentration, lot number, date of manufacture, 
manufacturer, and investigational use statement 
6.3.2 PolyICLC Investigational Product Inspection 
Each vial of polyICLC selected for dose preparation should be inspected. If there are any defects 
noted with the investigational product, the Investigator and Sponsor should be notified 
immediately. 
6.3.3 PolyICLC Preparation and Administration 
PolyICLC is supplied by the Ludwig Institute for Cancer Research in vials containing 1 mL of 
opalescent white suspension (approximately 2 mg/mL). PolyICLC is withdrawn from the vial 
under sterile conditions and is to be administered intatumorally or IM as supplied. It can also be 
diluted with normal saline. For both routes of administration (intratumoral and IM), the dose of 
polyICLC will be 1 mg. 
PolyICLC does not contain preservatives, and any unused portion must be discarded. 
NOTE:  
Lot PJ215-1-10-01 of PolyICLC has a labeled concentration of 2 mg/mL. As the PolyICLC dose 
is 1 mg, this corresponds to 0.5 mL. Lot PJ215-1-10-01 expired on 28 FEB 2018 and was 
replaced by Lot PJ215B03.  
Lot PJ215B03 has a concentration of 1.8 mg/mL. For a 1 mg dose using this lot, the volume 
to be administered is 0.556 mL (this number may be rounded according to institutional 
practice).  
The volume administered for subsequent lots should be adjusted accordingly so that the 
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Intratumoral injection 
Intratumoral injections as scheduled will be administered by a physician or nurse under 
physician supervision at a dose of 1 mg. For particularly large lesions (> 1 cm in longest 
diameter), the polyICLC dose can be divided and administered into more than 1 quadrant of the 
lesion. For example, for most lesions, the needle can be moved within each quadrant of the 
lesion, or if the lesion is too large, separate injections will be given for a total dose of 1 mg (to 
cover more of the lesion). During injections, it is recommended that the investigator distribute 
the injectate throughout the lesion targeted.  If the lesion is too small to inject the complete 
volume of intratumoral study drug, the dose may be divided among a maximum of 3 lesions.  If 
the injected lesion regresses completely before all of the intratumoral injections are 
administered, no further intratumoral injections will be given unless the lesion grows again 
during the intratumoral injection period. 
One syringe should be filled aseptically from 1 vial according to the directions above. 
Pain medication to be administered includes, if needed, acetaminophen, diphenhydramine, 
benzodiazepines, and/or opiates. Other analgesics may be given at the discretion of the 
investigator.  
Some degree of inflammatory response in the injected lesion is expected as part of the therapy. 
Prior to each intratumoral injection, the maximal diameter of peritumoral inflammation will be 
recorded in millimeters and photographically, if appropriate in the judgment of the investigator, 
as a baseline for subsequent post-injection measurements. 
The subjects will be monitored before and for at least 1 hour after each of the intratumoral 
injections, including a determination of temperature, blood pressure, heart rate, and respiratory 
rate.  
IM Injection 
IM injections will be given using standard technique into the thighs or upper arms. Injection 
sites may be rotated based on subject and investigator preference and will be recorded in the 
electronic case report form (eCRF). 
Subjects will be monitored before and for at least 1 hour after the first IM injection, including a 
determination of temperature, blood pressure, heart rate, and respiratory rate. 
6.4 Estimated Drug Requirements 
Drug 
Required Quantity (vials) 
Durvalumab 
5703 
Tremelimumab 
713 
PolyICLC 
2326 
 


 
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6.5 Monitoring of Tremelimumab and Durvalumab IV Dose 
Administration 
Subjects will be monitored before, during and after tremelimumab and durvalumab infusions 
with assessment of vital signs according to the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre Dose 
During Infusion 
End of Infusion 
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Tremelimumab 
X 
Every 30 (± 5) 
minutes 
X 
 
 
Durvalumab  
X 
Every 15 (± 5) 
minutes 
X 
X 
X 
Note: When IV durvalumab and IV tremelimumab are to be administered on the same day, 
durvalumab infusion will start at least 60 minutes after the end of tremelimumab infusion even 
though vital signs assessment is not required during the entire 60-minute period post 
tremelimumab. 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions in that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems 
it clinically necessary. 
Vital Signs Assessment on Study Drug Administration Days (after first 4 doses) 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
6.6 Drug Overdose Management 
There are no known antidotes available for tremelimumab, durvalumab, or polyICLC. Any 
overdoses with these drugs should be managed symptomatically. An overdose is defined as a 
subject receiving any dose in excess of that specified in this protocol by > 10%. All such 
overdoses must be reported, with or without associated AEs/serious adverse events (SAEs), 
according to Section 7.1.2.2. 
 
 


 
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7 Administrative, Legal and Ethical Requirements 
7.1 Documentation and Reporting of Adverse Events 
7.1.1 General AE/SAE Definitions per ICH Guidelines 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of LICR studies to include any events, intercurrent diseases and accidents observed 
while the subject is on study, i.e., during the actual treatment period, as well as during drug-
free, pre- and post-treatment periods.,  
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. Results in death, 
2. Is life-threateningA, 
3. Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. Results in persistent or significant disability or incapacity, 
5. Is a congenital anomaly / birth defect or 
6. Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject is 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. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require intervention 
to prevent one of the outcomes listed in the definition above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain). The event itself may be of relatively minor medical 
significance (such as severe headache). This is not the same as “serious”, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to 
subject’s life or vital functions. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 


 
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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (see Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.6) 
3. Hepatic Function Abnormality (as defined in Section 7.1.8). 
4. New cancers 
5. Deaths 
7.1.2.1 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer) (see Section 5.2, #17). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see section 7.1.6).  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, the Investigator or other site personnel 
should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when 
he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.1.2 Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer) (see Section 5.2, #17).   
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last drug 
dose should, if possible, be followed up and documented.   


 
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Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the subject’s partner.  Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.  
7.1.2.2 Overdose 
Any overdose (as defined in Section 6.6) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor. If the 
overdose results in an AE, the AE must also be recorded as an AE according to Section 7.1.5. 
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as an SAE according to Section 7.1.6. There is currently no specific treatment in the 
event of an overdose of the study drugs. The Investigator will use clinical judgment to treat any 
overdose. See Section 6.6 for additional details. 
7.1.2.3 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the Investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.2.4 New Cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after 
the subject’s inclusion in this study. 
7.1.2.5 Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period (On Study Follow-up) after the administration of the last dose of study 
drug, must be reported as follows: 
• Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and should be documented in the 
eCRF. It should be reported as an SAE if it meets SAE reporting criteria per 
Section 7.1.6. 


 
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• Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study 
Monitor/Physician as an SAE within 24 hours. It should also be documented in 
the eCRF. 
• The report should contain a comment regarding the co involvement of PD, if 
appropriate, and should assign main and contributory causes of death. 
• Deaths with an unknown cause should always be reported as an SAE. It should 
also be documented in the eCRF. 
• A post mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results should be forwarded to LICR 
within the usual timeframes. 
Deaths occurring after the protocol-defined safety follow-up period after the 
administration of the last dose of study drug should be documented only in the Post 
Study Follow-up eCRF form. If the death occurred as a result of an event that started 
after the defined safety follow-up period and the event is considered to be due to a late 
onset toxicity to study drug, then it should also be reported as an SAE. 
LICR and AstraZeneca retain the right to request additional information for any subject 
with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship. Information provided in the IB and/or in Section 1 (Background) of this protocol 
may support these evaluations. 


 
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7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on 
the respective section of the CRF, regardless of severity or the assumption of a causal 
relationship.  The documentation includes: dates of onset and resolution, severity, seriousness, 
study drug intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4.  This documentation is required for 
all AEs that occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 90 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE as per Section 7.1.1, irrespective of suspected causation, must 
be reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, 
alternatively, to the Primary Sponsor Contact, within 24 hours of becoming aware of the event 
(see contact information below). SAEs should be reported via the Medidata RAVE data 
capture system (which utilizes “Safety Gateway”), using the respective Adverse Event and 
Safety Case Summary eCRFs.  This includes any deaths that occur after the off-study date, but 
within 30 days of last study drug administration. In the event that the SAE cannot be reported 
via Medidata RAVE, the SAE should be reported using the “Initial Serious Adverse Event 
Report Form,” provided by the Sponsor. 
Note: If an SAE cannot be reported via Medidata RAVE or the “Initial Serious Adverse Event 
Report Form” within 24 hours of becoming aware of the event, the Sponsor’s Drug Safety 
Contact (primarily) or, alternatively, the Primary Sponsor Contact, must be contacted by 
phone or email within 24 hours of becoming aware of the event. In this case, the phone or 
email notification can then be followed up through Medidata RAVE or an “Initial Serious 
Adverse Event Report Form” within one working day of the event. 
If the “Initial Serious Adverse Event Report Form” is being used, the expedited reports should be 
directed by fax or e-mail to the Drug Safety Contact (primarily) or, alternatively, the Primary 
Sponsor Contact.  Studies utilizing Medidata RAVE (and the “Safety Gateway”) built into the 
eCRF, and respective SAE reporting procedures, do not require reporting by fax or email.  
Questions related to Medidata RAVE and “Safety Gateway” procedures should be directed to 
the Drug Safety Contact or Primary Sponsor Contact (see table below for contact information). 


 
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In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave Floor 32 
New York, New York 10016 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@lcr.org 
Primary Sponsor Contact: 
Mary Macri 
Senior Director 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave Floor 32 
New York, New York 10016 
Tel: 
+1 212 450 1546 
Fax: 
+1 212 450 1535 
mmacri@lcr.org  
 
 
Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned a serious adverse event tracking number by the 
Sponsor. Institutional Review Boards may have specific rules on which Adverse Events need to 
be reported expeditiously, as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor. Regulatory authorities and 
other investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered. In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug(s) cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause. Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available, using the “SAE 
Follow-up Report form”, provided by the Sponsor. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is an event of scientific and medical interest specific 
to understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs including AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of the investigational products.  
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
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replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-related adverse event (irAE) is 
defined as an adverse event that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate aetiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Medical Monitor. 
If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and tremelimumab and those considered AESIs for the 
purpose of this study are listed below. Further information on these AESIs (e.g. presenting 
symptoms) can be found in the current versions of the durvalumab (MEDI4736) and 
tremelimumab Investigator’s Brochures. Guidelines for the management of subjects 
experiencing toxicities for durvalumab and tremelimumab can be found in Section 8.3 and in the 
following Medimmune guideline: “Medimmune’s Dosing Modification and Toxicity 
Management Guidelines for Immune- mediated, Infusion Related, and Non Immune-mediated 
Reactions (MEDI4736 (durvalumab) Monotherapy or Combination therapy with 
Tremelimumab or Tremelimumab monotherapy).” 
• 
Diarrhea/Colitis and Intestinal Perforation 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs 
following dosing with study medications.  In rare cases, colon perforation may occur 
that requires surgery (colectomy) or can lead to a fatal outcome, if not properly 
managed. 
• 
Pneumonitis/Interstitial Lung Disease (ILD) 
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-L1 
antibodies (see IB). Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatitis / transaminase increases) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-
1 antibodies (see IB).  Inflammatory hepatitis has been reported in 3% to 9% of subjects 
treated with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical 
manifestations of ipilimumab-treated subjects included general weakness, fatigue, 
nausea and/or mild fever and increased liver function tests such as AST, ALT, alkaline 
phosphatase, and/or total bilirubin. Hepatic function abnormality is defined as any 
increase in ALT or AST to greater than 3 × ULN and concurrent increase in total bilirubin 
to be greater than 2 × ULN.  Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other.  Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a concurrent or pre-existing disease (e.g., 


 
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cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other 
than the investigational product. Cases where a subject shows an AST or ALT ≥ 3 x ULN 
or total bilirubin ≥ 2 x ULN may need to be reported as SAEs. These cases should be 
reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law case or if any 
of the individual liver test parameters fulfill any of the SAE criteria.    
• 
Neurotoxicity (Neuropathy / neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism, and Type 1 diabetes mellitus. 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators 
should obtain an endocrinology consult and institute appropriate management which 
may include the administration of insulin. 
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as 
per current established toxicity management guidelines. 
• 
Nephritis and increases in Serum Creatinine 
A consult with a Nephrologist should be done as well as monitoring for signs and 
symptoms that may be related to changes in renal function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, etc.). Subjects should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections, etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low 
grade events (Grade 2), in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis or labs suggestive of 
pancreatitis (increased serum lipase, increased serum amylase). 
• 
Myocarditis 
Myocarditis, a rare, but severe immune-mediated adverse event, presents with 
signs/symptoms such as decreased ejection fraction, arrhythmias, in particular 
occurrences of atrioventricular block. For patients with suspected myocarditis, 
investigators should obtain a cardiology consult and institute full diagnostic work-up 
(that includes exclusion of other alternate causes such as infection). 
• 
Myositis /Polymyositis 
Myositis or polymyositis should be suspected in patients who present with proximal 
muscle weakness and the evaluation should include an examination of the skin, muscle 
enzyme measurement, antibody testing, any systemic disease manifestations and 
exclusion of other diseases including drug-induced myopathy. Cases of myositis have 
been reported with myocarditis in which immune infiltration has been described in 
skeletal and cardiac muscle (see IB). 


 
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• 
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and 
other events involving the eye, skin, haematological and rheumatological events. 
• 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (see IB).  As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of monoclonal 
antibodies (MAbs) can be caused by various mechanisms, including acute anaphylactic 
(IgE-mediated) and anaphylactoid reactions against the MAb, and serum sickness.  
Acute allergic reactions may occur, may be severe, and may result in death.  Acute 
allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, 
urticaria, pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, 
dizziness, fatigue, headache, hypertension, myalgia, vomiting and unresponsiveness. 
Guidelines and/or literature for the management of subjects experiencing the toxicities for 
durvalumab and tremelimumab can be found in Section 8.3. 
Guidelines for the management of subjects experiencing toxicities for PolyICLC can be found in 
Section 8.4. 
7.2 Administrative Sponsor Requirements 
7.2.1 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities. Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor. No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor. The use of eCRFs encompasses electronic data entry, 
query management and sign-off. Systems used for electronic data capture will be compliant 
with FDA regulations 21 CFR Part 11 and within the constraints of the applicable local regulatory 
agency guidelines (whichever provides the greatest protection to the integrity of the data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigator will sign and date the completed eCRF sections. This signature will indicate a 
thorough inspection of the data in the CRF and will certify its content. 


 
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7.2.3 Language 
The protocol is written in English. All correspondence between the study site and the Sponsor 
should be maintained in English. Case Report Forms must be completed in English. All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood and be in the language appropriate for the trial site. 
7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
qualification, site initiation, routine monitoring and site close-out. Clinical Monitors and/or 
other sponsor staff will meet with the investigator staff and require direct access to source 
data/documents. Such access may also be required for Institutional Review Board review, and 
regulatory inspection/audits. Direct access is defined as permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study. All 
reasonable precautions within the constraints of the applicable regulatory requirement(s) to 
maintain the confidentiality of subjects’ identities and sponsor’s proprietary information will be 
exercised. 
It is the Clinical Monitor’s responsibility to inspect the case report forms at regular intervals 
throughout the trial to verify adherence to the protocol, the completeness, accuracy and 
consistency of the data, and adherence to Good Clinical Practice guidelines. The Clinical Monitor 
should have access to subject charts, laboratory reports and other subject records needed to 
verify the entries on the case report forms (“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities. Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals. However, in this case, approval must be obtained as soon as possible after 
implementation. Implementation of administrative amendments that do not affect the safety of 
the subjects do usually not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the sponsor if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully documented in the 
source documentation. 
7.2.6 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from study treatment or from the study at any time for any reason 
without prejudice to his/her future medical care by the physician or at the study site. Likewise, 
the Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study. Specific subject withdrawal reasons are listed in Section 3.1.10. Should a subject (or a 
subject’s legally authorized representative) decide to withdraw from study treatment or from 
the study, all efforts will be made to complete the required study procedures and report the 
treatment observations as thoroughly as possible. 


 
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A complete final evaluation should be made at the time of the subject’s withdrawal, the 
appropriate form in the case report form should be completed with an explanation of why the 
subject is withdrawing, and an attempt should be made to perform a follow-up evaluation. 
7.2.7 Early Trial Termination 
“End of study” is defined as the last visit of the last subject. Sponsor and Investigator have the 
right to terminate the study early. Specific study stopping rules are listed in Section 3.1.14. In 
such case, one party must notify the other in advance in writing about the intent of and the 
reasons for the termination. The investigator must also notify the appropriate Institutional 
Review Board accordingly. 
7.2.8 Study Drug Shipments and Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably the site’s pharmacy. The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor. The 
Investigator is responsible for the accounting of all used and unused trial supplies. At the end of 
the study, the Clinical Monitor will also collect the original study drug dispensing records. 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable. Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person. At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal, and Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines and 
applicable local laws and regulations, with the understanding that local laws and regulations 
take precedence over respective sections in the Declaration of Helsinki and/or the ICH 
Guidelines. 


 
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7.3.2 Informed Consent 
The investigator must obtain witnessed (if applicable) written informed consent from the 
subject or the subject’s legally authorized representative after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any study-
specific procedures are performed. The subject should be given a copy of the informed consent 
documentation. The original signed and dated informed consent form must be retained in the 
study records at the study site and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Institutional Review Board 
The investigator must obtain written approval from the appropriate Institutional Review Board 
for the protocol and informed consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The investigator must report Serious Adverse Events (SAEs) to the appropriate Institutional 
Review Board in accordance with the Institutional Review Board’s rules and guidelines (see also 
Section 7.1). 
The investigator must assure that continuing review (at least once per year) of the study is 
performed by the Institutional Review Board throughout the duration of the study. If so 
required by the Institutional Review Board, the investigator must provide study reports on an 
annual basis and upon completion of the study. 
All correspondence with, and reports to, the Institutional Review Board must be maintained in 
the study files at the study site and copies must be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The investigator must ensure that the subject’s privacy is maintained. A subject should only be 
identified by their initials, date of birth and subject number on the case report forms or other 
documents submitted to the Sponsor. Documents that are not submitted to the Sponsor (e.g., 
signed informed consent form) should be kept in a strictly confidential section of the study file 
by the Investigator. 
The investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study. As part 
of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 
 


 
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8 Appendices 
8.1 Protocol Version History 
Original issue 
Issue date: 10-NOV-2015 
Summary of Changes: n/a 
 
Amendment 001 
Issue date: 08-FEB-2016 
Summary of Changes:  
The following changes were made: 
1. Administrative changes: General spelling, capitalization, abbreviation, and formatting 
changes, as needed. 
2. Synopsis, Section 3.1 and Section 6.1.3.1: the word “randomized” was deleted, as this is 
not a randomized study. 
3. Synopsis, Table 1, and Section 3.1.7.2: “60 evaluable subjects” was changed to “66 
evaluable subjects” to correct an inconsistency with Section 3.1.5. 
4. Section 3.1.3: “will be” was changed to “is.” 
5. Section 3.1.6: Phase 2 sample size language was clarified by the addition of the following: 
“The expansion phase sample size of 66 subjects is deemed to be sufficient for the assessment of 
safety and tolerability as it provides sufficient precision for estimation of adverse events.  The 
confidence intervals (CI) for estimating the incidence of AEs ranging from 10% to 90% (in 
increments of 10%) are listed below.  The margins of error (half width of the CI) are deemed 
acceptable for the estimation of AE incidences in this early phase trial.”  The following table was 
inserted: 
Number of Subjects 
with Event 
Incidence 
95% Confidence Interval 
(Normal approximation) 
Margin of error (half 
width of the CI) 
7/66 
0.1 
(0.028, 0.172) 
0.072 
14/66 
0.2 
(0.103, 0.297) 
0.097 
20/66 
0.3 
(0.189, 0.411) 
0.111 
27/66 
0.4 
(0.282, 0.518) 
0.118 
33/66 
0.5 
(0.379, 0.621) 
0.121 
40/66 
0.6 
(0.482, 0.718) 
0.118 
47/66 
0.7 
(0.589, 0.811) 
0.111 
53/66 
0.8 
(0.703, 0.897) 
0.097 
60/66 
0.9 
(0.828, 0.972) 
0.072 
 
6. Section 3.1.16: The following clarification was added to the last paragraph: “The first Post 
Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) since the last study visit.  If the first Post Study Follow-up is less 
than 90 days since the last administration of study drug, any irAEs occurring since the last 
study visit will continue to be collected and recorded at the subsequent Post Study 
Follow-up visit.” 


 
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7. Section 3.2 : Study flowchart was updated to add amylase and lipase to the assessments. 
In addition, Free T3, Free T4, and TSH were moved to a separate line for clarification, as 
these assays are not part of the routine chemistry analysis. 
8. Section 4.1.2: Additional detail was inserted for evaluation and statistics:  
“Adverse events will be coded using the MedDRA dictionary. Incidences of treatment-
emergent adverse events (TEAE, those events that started after dosing or worsened in 
severity after dosing) will be presented overall and by maximum severity (according to 
CTCAE version 4.03) and relationship to study medication. For each continuous 
laboratory parameter, results will be categorized as low, normal, or high based on the 
laboratory normal ranges. Frequencies and percentages will be presented for the shifts in 
these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to each 
post-treatment assessment time point. Additionally, for each continuous hematology and 
chemistry parameter, descriptive statistics will be presented for the changes from 
baseline to each post-treatment assessment time point.  Descriptive statistics will be 
presented for the changes in vital signs from baseline to each post-treatment assessment 
time point.” 
9. Section 4.2.2: The phrase “will be conducted for Cohort 2 and” was deleted from the first 
sentence in order to provide consistency with Section 4.0. 
10. Section 5.1: 
• 
Inclusion Criterion #1 was clarified to require that subjects have unresectable 
disease, have failed at least one standard of care therapy, and do not have curative 
options. Changes in bold: “Subjects must have histologic confirmation of advanced 
unresectable disease, have failed at least one standard of care therapy, and do not 
have curative options. Tumors should be biopsy-accessible, measurable cancers of 
the following histologies:…” 
• 
# 4 – “ECOG” was added to Performance Status 
11. Section 8.3.1: 
• 
Paragraph 3: deleted the reference to “Tremelimumab Guidelines for the 
Management of Diarrhea and Colitis” as this guideline is currently included in 
“Medimmune’s Dosing Modification and Toxicity Management Guidelines.” 
• 
Paragraph 4, which referenced the package inserts for ipilimumab, nivolumab, and 
pembrolizumab, was deleted. 
 
Amendment 002 
Issue date: 12-APR-2016 
Summary of Changes:  
The following changes were made: 
1. Changed IND # from 118511 to 130529. 
2. Section 3.1.6:  The following text was added:  “The primary endpoint for the Phase 1 
portion of the study is safety. The objective for Phase 1 is to determine the 
recommended combination dose (RCD). In each of the Phase 1 cohorts, a 3+3 design is 
used.  Each cohort will be evaluated on its own.  The only modification to the design is 
that the protocol evaluates up to 2 dose levels and starts at the desired dose level (Level 
0). As only one drug is being modified in each cohort, the principles of a 3+3 design are 
applicable.  The RCD for each cohort is defined as the highest dose level at which no 
more than 1 of 6 subjects experience DLTs.  The Cohort 1A doublet (durvalumab + 


 
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polyICLC) will be enrolled first, starting at Level 0. Dose Level -1 will only be evaluated if 
Level 0 exceeds the RCD. Once safety is demonstrated for the subjects in the Cohort 1A 
doublet, the Cohort 1B triplet (durvalumab + polyICLC + tremelimumab IV) and the 
Cohort 1C triplet (durvalumab + polyICLC + intratumoral tremelimumab) will open to 
enrollment.  Based on the DLT assessment, the starting dose Level 0 will either be 
expanded to 6 subjects or the dose level will be reduced to Level -1. This is in accordance 
with a standard 3+3 design, whereby a dose level may be reduced as well as escalated 
based on the DLTs observed. The table below gives the probabilities of dose expansion 
of dose Level 0 or de-escalation to dose Level -1 based on true DLT rate in the 3+3 
design. 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of de-escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
Adverse events will be summarized by maximum toxicity grade for each dose level 
cohort. Phase 1 will enroll up to 36 subjects to determine the RCD. Once the RCD of the 
triplet dosing regimen has been determined in Cohort 1C, up to 66 subsequent subjects 
will be enrolled into the Phase 2 cohort at the RCD according to Cohort 1C. If Cohort 1C 
is not cleared, the RCD of the previously cleared cohort will be used for Phase 2. For the 
Cohort 1A doublet, if dose Level -1 is too toxic, the RCD cannot be determined and the 
study will stop.  Otherwise, Cohorts 1B and 1C triplets will open in parallel at the 
doublet RCD of Cohort 1A, and the triplet RCD will be determined in both Cohorts 1B 
and 1C. If no triplet RCD can be determined, Phase 2 of the study will be done at the 
Cohort 1A doublet RCD. If triplet RCDs are determined for both Cohorts 1B and 1C, the 
triplet RCD of Cohort 1C will be used in Phase 2. If a triplet RCD can only be determined 
in Cohort 1B, that triplet RCD will be used in Phase 2. Phase 2: The phase 2 portion of 
the study is intended to indicate proof of concept regarding the activity of the 
combination selected in Phase 1, in a study of 8 disease types. The goal is to determine 
if there is any evidence to support future larger clinical trials of specific tumor targets. 
Enrollment of 6 subjects per tumor type will be allowed initially, with enrollment of an 
additional 6 subjects being contingent on at least one response among the initial 6 
subjects. Response is defined in this protocol as achieving a partial response (PR) or 
complete response (CR) by immune-related RECIST or RECIST 1.1, or stable disease (SD) 
for at least 6 months. PD-1 receptors and PD-1 ligand have been previously investigated 
in Phase 1 and 2 studies. Response rates range from 8% to 25% overall, and from 10% to 
35% in the squamous subpopulation (44). This combination therapy trial seeks to 
improve on these response rates. The stopping rule for lack of sufficient efficacy in the 
initial 6 subjects for each tumor type, results in a rejection rate of <20% if the true 
response rate for a particular tumor type is 25%. A total of (8)(6)= 48 subjects will be 
initially enrolled for the Phase 2 portion plus a potential additional (3)(6)= 18 subjects 
for three tumor types having at least one response in the initial group (total of 48+18= 
66 subjects). For tumor types accruing 6+6= 12 subjects, an exact 90% confidence 
interval for response rate will be computed.  The safety of the regimen taken into Phase 
2 will be evaluated by the Medical Monitor on an ongoing basis. When 6 subjects have 
been enrolled and treated in a disease cohort, a review of the data from the cohort will 
be conducted by the internal data safety monitoring panel and a decision (based on 


 
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efficacy as well as safety) will be made whether to expand the disease cohort to 12 
subjects. At any time during the study, the Medical Monitor and/or the internal data 
safety monitoring panel may stop the cohort or the study if the toxicity seen is not 
acceptable.  Respective study stopping rules are described in Section 3.1.14 of the 
protocol. If more than one subject in the initial group of 6 subjects in a disease type 
have a DLT, then accrual to that disease type cohort will be terminated.” 
3. Section 3.1.7.2:  Added phrases (changes in bold): Cohort 2 will expand the cohort that 
was treated at the RCD from the dose-finding phase.  Up to 6 subjects per tumor type 
will be initially enrolled into Cohort 2.  Data from all subjects who are treated with the 
dosing regimen in either the cleared dose-finding cohort or Cohort 2 will be reviewed for 
safety/efficacy to select up to 3 tumor types that demonstrate an efficacy signal, defined 
as at least 1 of 6 subjects within a tumor type who achieve a partial response (PR) or 
complete response (CR) by immune-related RECIST (irRECIST) or RECIST 1.1, or stable 
disease (SD) for at least 6 months (See Section 3.1.6 regarding DLT assessment during 
expansion). 
4. Section 3.1.10:   
• 
Treatment withdrawal criterion #6 “Initiation of alternative anti-cancer therapy 
including another investigational agent” was moved to Study withdrawal criterion 
#2 and changed to “Initiation of alternative anti-cancer therapy (marketed or 
investigational).” 
• 
The following phrase was removed from Study withdrawal criterion #1: “e.g., start 
of new treatment.” 
5. Section 3.1.13: Deleted “No formal interim analysis will be performed.”  Added “(see 
Section 3.1.6)” for analysis of Cohort 2. 
6. Section 3.1.15.2:  updated as follows: 
Duration of Study per 
Subject: 
Up to 12 months treatment + 3 months On Study Follow-up 
Enrollment Period: 
24 months 
Length of Study: 
39 months (not including Post Study Follow-up as described in 
Section 3.1.16) 
7. Section 3.1.16:  Next to last paragraph was changed FROM: “The first Post Study Follow-
up will include a query to determine if there were any immune-related adverse events 
(irAEs) since the last study visit.  If the first Post Study Follow-up is less than 90 days since 
the last administration of study drug, any irAEs occurring since the last study visit will 
continue to be collected and recorded at the subsequent Post Study Follow-up visit.”  
TO: “The Post Study Follow-up will include a query to determine if there were any 
immune-related adverse events (irAEs) during the 90 days since the last administration 
of study drug.” 
8. Section 3.2, Flowchart: 
• 
“pre-existing symptoms” was deleted from the Medical History line 
• 
“Procedures” was added to the Concomitant medications line 
• 
Mg was added to the list of chemistry analytes 
• 
Vital signs assessments were added to all intratumoral polyICLC and first IM polyICLC 
injections 
• 
The following assessments were deleted: IV tremelimumab PK, IV durvalumab PK, 
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• 
Footnote 6 (collected pre-dose and end of infusion) was deleted 
• 
New Footnote 6 was added for AEs:  “See section 7.1.5 for details regarding 
collection of AEs for 90 days after last study drug administration.” 
• 
Footnote 9 (optional) was deleted and a new Footnote 9 was added: “Standard of 
Care procedures may be used for eligibility assessments provided they meet the 
criteria specified in either the inclusion criteria or flowchart.” 
• 
Footnote 10 was added for Vital signs: “See Section 6.5 for assessment 
before/during/after IV infusions; Section 6.1.3.1 for intratumoral tremelimumab 
vitals assessments; Section 6.3.3 for intratumoral and IM polyICLC vitals 
assessments.” 
9. Section 4.3, Pharmacokinetics:  all language pertaining to durvalumab and 
tremelimumab PK assessments pre and post respective IV infusions was deleted.  PK 
assessments pre and post intratumoral tremelimumab were retained. 
10. Section 4.4, Durvalumab and tremelimumab immunogenicity was deleted; other sections 
were re-numbered accordingly.   
11. Section 5, Subject Eligibility: the following was added “NOTE:  Standard of Care 
procedures may be used for eligibility assessments provided they meet the criteria 
specified in either the inclusion criteria or flowchart.” 
12. Section 5.2: 
• 
Exclusion Criterion #17: updated contraception language according to current 
language provided by AstraZeneca. 
• 
contraception requirements were changed from 6 months after last dose of drug to 
“90 days after last dose of durvalumab or 6 months after the last dose of 
tremelimumab (whichever is longer) 
13. Section 5.3.1:  
• 
Added bold phrase to #2: “Wash-out period: 4 weeks or 5 half-lives (whichever is 
shorter) prior to Day 1.” 
• 
Added the following as #5: “Drugs with laxative properties and herbal or natural 
remedies for constipation should be avoided through 90 days post last dose of 
tremelimumab because of the potential for exacerbation of diarrhea.” 
14. Section 6.1.3.1: 
• 
2nd paragraph, 5th sentence was changed as follows (changes in bold): “If the injected 
lesion regresses completely before all of the priming intratumoral injections are 
administered, no further intratumoral injections will be given.” 
• 
4th paragraph was changed as follows (changes in bold): The subjects will be 
monitored before and for at least 1 hour after the intratumoral injections, including 
a determination of temperature, blood pressure, heart rate, and respiratory rate. 
before and after injection 
15. Sections 6.1.4.2 and 6.2.4: infusion time for tremelimumab and durvalumab, 
respectively, were changed from 60 ± 10 minutes to 60 ± 5 minutes. The following 
statement was added: “An infusion time of less than 55 minutes is considered a 
deviation.” 
16. Section 6.3.3: 
• 
Intratumoral injection, 1st paragraph, last sentence was changed as follows (changes 
in bold): “If the injected lesion regresses completely before all of the priming 
Intratumoral injections are administered, no further intratumoral injections will be 


 
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given unless the lesion grows again during the intratumoral injection period or until 
Cycle 2 if the lesion regresses during Cycle 1.  
• 
Intratumoral injection, last paragraph was changed as follows (changes in bold): “The 
subjects will be monitored before and for at least 1 hour after each of the first two 
intratumoral injections in each cycle, including a determination of temperature, 
blood pressure, heart rate, and respiratory rate before and after injection. 
• 
IM injection, 2nd paragraph was changed as follows (changes in bold): “Subjects will 
be monitored before and for at least 1 hour after the first IM injection, including a 
determination of temperature, blood pressure, heart rate, and respiratory rate 
before and after the injection. 
17. Section 6.5: The following was added:  “If a subject tolerates treatment well for the first 
4 doses of MEDI4736 (i.e., no infusion reactions), subsequent infusions in that subject 
can be monitored according to the table below.  A longer duration of observation after 
the end of infusion can be used if the Investigator deems it clinically necessary. 
Vital Signs Assessment on Study Drug Administration Days (after first 4 doses) 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
18. Section 7.1.2: updated language according to current recommendations from 
MedImmune/AstraZeneca.  Defined additional expedited reporting requirements for 
study, specifically pregnancy, overdose, and hepatic function abnormality 
19. Section 7.1.5: language for documenting AEs was changes FROM: “Documentation of 
serious and non-serious adverse events includes: dates of onset and resolution, severity, 
seriousness, study drug intervention, treatment and outcome, as well as the causal 
relationship between the event and the study drug in accordance with Section 7.1.4. All 
serious and non-serious adverse events occurring between the date of signing the 
informed consent and the off-study date must be documented in the source records and 
on the respective section of the CRF, regardless of the assumption of a causal 
relationship.  During the On Study Follow-up period, all AEs will continue to be 
documented for 90 days after the last dose of study drug.” TO: ““All serious and non-
serious adverse events must be documented in the source records and on the respective 
section of the CRF, regardless of severity or the assumption of a causal relationship.  The 
documentation includes: dates of onset and resolution, severity, seriousness, study drug 
intervention, treatment and outcome, as well as, the causal relationship between the 
event and the study drug in accordance with Section 7.1.4.  This documentation is 
required for all AEs that occur: a) from the date of signing the informed consent, and b) 
until the off-study date or 90 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment).Immune Related Adverse Events (irAEs) will be collected 
from the time of informed consent through 90 days after the last dose of the last study 
treatment (regardless of initiation of another therapy).” 
20. Section 7.1.6: Additional detail and clarification were added regarding reporting of SAEs 
to the Sponsor within 24 hours.  


 
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21. Section 7.1.8: Updated AESI language in the entire section according to current 
recommendations from MedImmune/AstraZeneca. 
22. Section 7.2.2: the following statement was added: “All subjects who sign an informed 
consent form, regardless of study procedures performed, will be assigned a screening 
number and have their data entered into the eCRF.” 
23. Section 8.3.1: Durvalumab and tremelimumab dose modifications for all other AEs (last 
portion of table) was changed as follows: 
• 
Grade 3 was separated from Grade 2 modifications 
• 
Grade 3 modifications were added:  "Hold M and T. If AEs downgrade to ≤ Grade 2 
within 7 days or resolve to ≤ Grade 1 or baseline within 14 days, resume M and T 
administration at next scheduled dose. Otherwise, discontinue M and T 
permanently.” 
• 
Grade 4, bullet 2: the phrase ”in consultation with the Sponsor” was added. 
24. Section 8.3.2:  
• 
For Point 2, “7 days or less” was changed to “≤ half the planned dosing interval.” 
• 
For Point 3, “7 days“ was changed to “half the planned dosing interval.” 
25. Added a new Section 8.7, ECOG PS; other sections were re-numbered accordingly. 
26. Administrative:  
• 
Spelling, grammar and typographical errors were corrected.  
• 
Formatting/administrative changes were implemented, as applicable. 
• 
Updated List of abbreviations 
• 
Monitor and Study Monitor were standardized as “Clinical Monitor” in Sections 
7.2.4 and 7.2.8. 
 
Amendment 2.1 (Administrative Change) 
Issue date: 05-MAY-2016 
Summary of Changes:  
1. Section 3.1.6: Typographical errors were corrected in the table showing probability of 
de-escalation. Specifically, the text and table were changed as follows:  
FROM: 
The table below gives the probabilities of dose expansion of dose Level 0 or de-escalation to 
dose Level -1, based on true DLT rate in the 3+3 design. 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of de-escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
TO: 
The table below gives the probabilities of de-escalation to dose Level -1, based on true DLT 
rate in the 3+3 design. 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
Probability of de-escalation 
0.09 
0.29 
0.51 
0.69 
0.83 
0.92 
0.97 
 


 
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2. Section 7.1.6: Changed Primary Sponsor Contact from Lisa Shohara to Mary Macri. 
 
Amendment 3 
Issue date: 16-May-2016 
Summary of Changes: 
1. An administrative change was incorporated and documented as Amendment 2.1 (see 
above).  
2. Section 3.1.2: Clarified that alternating enrollment will be used for Cohorts 1B and 1C 
(changes in bold): “After safety is demonstrated in the first 3-6 subjects in Cohort 1A, 
Cohorts 1B and 1C will open to with alternating enrollment.” 
3. Sections 3.1.7, 6.1.3.1, and 6.3.3: clarified that a maximum of 3 lesions may be injected 
with intratumoral tremelimumab and intratumoral polyICLC per patient per dose. 
4. Section 3.1.7: The following statement was added: “See Section 6 for the sequence of 
drug administration on dosing days when multiple drugs are given.” 
5. Section 3.1.9, Dose limiting toxicity: Deleted the last 2 exceptions for item #3 (i.e., 
deleted “Isolated Grade 3 electrolyte abnormalities that are not associated with clinical 
signs or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days.” and “Any pre-existing laboratory abnormality that deteriorates to Grade 
3/4, but where the increment of deterioration is considered not clinically significant by 
both investigator and sponsor.”  
6. Section 3.1.10: added the following NOTE to provide criteria that must be met to 
continue treatment until confirmation of progression of disease: “ NOTE: Subjects 
meeting criteria for radiographic progression by RECIST 1.1 (Section 8.5) will be allowed 
to continue on therapy until confirmation of progression if the subject agrees and signs 
an appropriate informed consent form regarding continuation of treatment and as long 
as the following criteria are met at the discretion of the Investigator: 
a. Absence of symptoms and signs (including worsening of laboratory values) 
indicating disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention. 
7. Section 3.2, Study Flowchart: 
1. Added Footnote 11 for disease assessments: “Subsequent imaging at 4 to 6 weeks 
after first documentation of RECIST v1.1-defined progression must be performed.” 
2. ECOG PS as a single assessment at baseline was deleted and ECOG PS assessments 
were added to Physical Examination assessments.  
8. Section 4.2.1: added the following: “Disease assessments will be done in accordance with 
the flowchart in Section 3.2.  Subsequent imaging at 4 to 6 weeks after first 
documentation of RECIST v1.1-defined progression must be performed.” 
9. Section 4.2.1.1: Clarified the ORR definition (changes in bold): “ORR is defined as the 
percentage of evaluable subjects meeting criteria of CR or PR by the end of 1 year, 
confirmed at a subsequent time point (≥ 4 weeks). 
10. Section 5.1, Inclusion Criteria, added the definition of biopsy-accessible tumor to #1: 
• 
NOTE 1: A biopsy-accessible lesion is defined as a tumor lesion which can be, in the 
opinion of the Investigator or that of consulting physicians, safely accessed for 


 
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biopsy or for injection by means of physical examination or imaging guided means 
such as ultrasound or CT scan (e.g., cutaneous lesions, inguinal nodes, 
supraclavicular or cervical nodes, superficial abdominal lesions, and lesions that are 
accessible by ultrasound guidance and not impacting vital organs/structures). 
• 
References were added to Sections 1.1, 3.1 and 3.1.4 regarding the definition for a 
biopsy-accessible tumor/lesion. 
11. Section 5.1, Inclusion Criteria: added the following to #5: 
• 
International normalized ratio (INR) or prothrombin time (PT) AND activated partial 
thromboplastin time (aPTT)/PTT ≤1.5 X ULN. NOTE: for subjects on therapeutic 
anticoagulation, subject must be stable on current regimen, as determined by the 
Investigator 
 
Amendment 4 
Issue date: 20-AUG-2018 
Summary of Changes: 
1. Synopsis: the following footnote was added to the table: “Q4W = every 4 weeks; IV = 
intravenous; ITM = intratumoral; IM= intramuscular. Note: See Section 3.1.7.1 for 
durvalumab doses for instances when a subject’s body weight drops to ≤ 30 kg while on the 
study.” 
2. Section 2 (Study Rationale): The following paragraph was added to address the added 
requirement of weight-based durvalumab dosing for subjects whose body weight drops to 
≤ 30 kg while on the study: “The 1500 mg Q4W dosing of durvalumab is recommended only 
for subjects with > 30 kg body weight in order to limit endotoxin exposure.  See Section 
3.1.7.1 for details regarding durvalumab dose requirements for instances when a subject’s 
body weight drops to ≤ 30 kg while on the study. See Section 3.1.7.1 for additional details 
regarding the dose de-escalation cohorts for durvalumab and tremelimumab.” 
3. Section 3.1.7.1 (Phase 1: Dose-finding Cohorts): 
• 
Table 2: added clarification that the RCD for Cohorts 1B and 1C is the RCD from Cohort 
1A; added footnote. This change was also implemented in the Synopsis. 
• 
The durvalumab dosing requirements were added for subjects whose body weight drops 
to ≤ 30 kg while on the study. 
4. Section 3.1.8 (Dosing Adjustments, Delays and Discontinuations). The following paragraph 
was added: “If a toxicity occurs that requires toxicity management in accordance with 
Sections 8.3 or 8.4, and the toxicity causing drug can be clearly identified, then the respective 
guideline should be followed. If the toxicity causing drug cannot be identified, then the more 
conservative guideline (i.e., the guideline that provides for the greatest dose reduction, dose 
delays or holds) should be followed. “ 
• 
This paragraph was also added to Sections 8.3 and 8.4. 
5. Section 3.1.9 (dose-limiting Toxicity). The following exception was added to criterion #3:  
“Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which appropriate 
evaluation shows no clinical evidence of pancreatitis.” This was done to align with the 
amylase/lipase information in Section 8.3.1 dose modifications. 
6. Section 3.1.11 (Evaluability and Subject Replacement) was updated for clarification (changes 
in bold):  


 
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“Phase 1: Subjects in Cohorts 1A through 1C are fully evaluable for DLT if they fulfill the 
criteria for the Per-Protocol Population for DLT Assessment.  The Per-Protocol (PP) 
Population for DLT Assessment includes: 
(1) All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9. They experience a DLT, or 
(2)  In the absence of a DLT, they All subjects with no DLT who receive at least 75% of the 
total dose of each study drug and undergo respective safety assessments, without major 
protocol violations, over the entire DLT evaluation period. 
Subjects who are not fully evaluable for DLT will be replaced. 
Phase 2: Subjects in Cohort 2 who receive at least 1 dose of each study drug and undergo 
respective disease assessments, without major protocol violations, are considered fully 
evaluable and will be included in the Per-Protocol (PP) Analysis Population for Clinical 
Efficacy.” 
7. Section 3.1.16 (On Study and Post Study Follow-up), 3rd paragraph was clarified (changes in 
bold): “If the determination is made to remove a subject from treatment at a visit that 
coincides with the first visit of the On-Study Follow-up Period (which is 28 days after the last 
dose of study treatment), any assessments required in the 28 day post-last treatment visit 
that are not covered as part of the last on-treatment visit (usually correlative labs) should be 
done as soon as possible.  If these assessments cannot be done on the same day, the subject 
should be brought back in at the earliest opportunity.  Any assessments or correlative 
samples required by both the protocol last on-treatment visit and the 28 day post-last 
treatment visit should not be repeated.” 
8. Section 3.2 (Flowchart): 
• 
Visit name was clarified (changes in bold): 
Withdrawal Visit for 
Subjects who Discontinue 
Treatment Prematurely  
• 
Hemoglobin A1c was added to screening procedures to align with requirement in 
Inclusion criteria. 
• 
Sample collection was deleted for Intratumoral tremelimumab PK. This was to align with 
removal of Section 4.3 (Tremelimumab PK) from protocol.  
• 
The following note was added to Footnote 3: ““It is strongly recommended that 
hematology, chemistry and pregnancy test (when applicable) results are reviewed before 
dosing.” 
• 
The following notes were added to Footnote 5: “See Sections 4.3.1.1 and 5.1 (#2) for 
details on biopsies” and “Note: the Screening/Baseline biopsy may be done on the Cycle 
1/Day 1 Visit as long as it is done prior to start of any treatment.” 
• 
Footnote 8 (regarding tremelimumab PK) was deleted. 
• 
Footnote 11 was renumbered as #8 
• 
Collection of blood for all biological markers was added to First On Study Follow-up Visit 
with newly added Footnote 11, which says “There is no need to repeat these assessments 
if they were done at the Premature Discontinuation Visit.” 


 
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9. Section 4.0 (Study Objectives and Endpoints): pharmacokinetics was removed from 
secondary objectives (see change for Section 4.3, Tremelimumab PK).  This was also changed 
in the Synopsis. 
10. Section 4.1.2 (Subject Evaluation and Statistics for Safety): the following clarifications were 
added (changes in bold):  “See Section 3.1.11 for subject evaluability and replacement for DLT 
assessments and for description of the Per-Protocol (PP) Population for DLT Assessment.   
In addition, all subjects who receive at least 1 dose of tremelimumab, durvalumab, or 
polyICLC will be assessed for safety and tolerability, regardless of whether or not they are 
fully evaluable per protocol as defined in Section 3.1.11; this is the Safety Population. 
Appropriate summaries of AEs, SAEs, DLTs, laboratory data, and vital sign data will be 
presented. AEs will be listed individually per subject according to the NCI CTCAE, Version 
4.03, and the number of subjects experiencing each AE will be summarized using descriptive 
statistics.” 
11. Section 4.3 (Tremelimumab PK) was deleted. Rationale: Systemic levels of tremelimumab 
after low intratumoral doses are not of interest. Other sections were re-numbered 
accordingly. 
12. Section 5.1 (Inclusion Criteria) #1 was modified based on PI requests for clarification (changes 
in bold): “Subjects must have histologic confirmation of advanced unresectable disease, have 
failed at least one standard of care therapy, and do not have curative options. Tumors should 
be biopsy-accessible (see NOTE 1), measurable cancers of the following histologies: 
- 
Non-viral-associated head and neck squamous cell carcinoma (HNSCC) or HPV-associated 
HNSCC after failure of prior therapy 
- 
Locally recurrent or metastatic breast cancer 
- 
Sarcoma 
- 
Merkel Cell Carcinoma (MCC) 
- 
Cutaneous T cell Lymphoma (CTCL) 
- 
Melanoma after failure of available therapies 
- 
GU cancers with accessible metastases (e.g., bladder, renal)  
- 
Any solid tumors with masses that are accessible without imaging  
NOTE 1: A biopsy-accessible lesion is defined as a tumor lesion which can be, in the opinion of 
the Investigator or that of consulting physicians, safely accessed for biopsy or for injection by 
means of physical examination or imaging guided means, preferably such as ultrasound or CT 
scan (e.g., cutaneous lesions, inguinal nodes, supraclavicular or cervical nodes, superficial 
abdominal lesions, and lesions that are accessible by ultrasound guidance and not impacting 
vital organs/structures). NOTE 2: CTCL may respond very differently than solid tumors; 
therefore, the study will primarily focus on solid tumors, but a “signal-seeking” approach to 
including some subjects with CTCL will be supported.  There will be a limit of < 10-20% CTCL 
for total enrollment.” 
13. Section 5.1 (Inclusion Criteria) #2 was changed FROM: 
“Subjects with measurable disease as defined by irRECIST and RECIST 1.1: at least 1 lesion 
that can be accurately measured in at least 1 dimension (longest diameter to be recorded), 
where each lesion must be ≥ 10 mm when measured by computed tomography (CT), 
magnetic resonance imaging (MRI), or caliper measurement by clinical examination, or ≥ 20 
mm when measured by chest x-ray. To be considered measurable, lymph nodes must be ≥ 15 
mm in short axis when measured by CT or MRI. Additionally, subjects must have at least 
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(approximately 2 cm or more) amenable to multiple core biopsies; multiple small lesions of 
comparable volume may be biopsied on a single date. Subjects must have at least 2 lesions 
that can be biopsied or 1 lesion that can be biopsied at least twice.” 
TO: “Subjects need to have at least 2 lesions, as follows: 
(1) 1 lesion considered measurable disease as defined by irRECIST and RECIST 1.1, i.e., that 
can be accurately measured in at least 1 dimension (longest diameter to be recorded), 
where each lesion must be ≥ 10 mm when measured by computed tomography (CT), 
magnetic resonance imaging (MRI), or caliper measurement by clinical examination, or ≥ 
20 mm when measured by chest x-ray. To be considered measurable, lymph nodes must 
be ≥ 15 mm in short axis when measured by CT or MRI. These lesions should not be 
injected with study drug or biopsied. 
(2) 1 larger lesion (approximately 2 cm or more) amenable to repeated multiple core 
biopsies or at least 3 smaller lesions of at least 6 mm diameter amenable to repeated 
single core biopsy, measured by clinical examination. Multiple small lesions of 
comparable volume may be biopsied on a single date. These lesions must also be 
suitable for repeated injections of study drug, either as single injection in larger lesions 
(preferred) or multiple injections in up to 3 smaller lesions. 
Ideally, subjects should have at least 1 additional lesion amenable to biopsy. This/these 
lesion(s) should not be injected with study drug.” 
Rationale: The criterion was reworded to provide clarification for the lesions that are 
needed for the study. 
14. Section 5.2 (Exclusion Criteria): 
• 
#1 was modified per PI request (changes in bold): “Prior treatment with combination 
CTLA-4 and PD-1/PD-L1 blockade, with the exception of subjects with melanoma.” 
• 
#7 was updated as follows (changes in bold): 
“Active, suspected or prior documented autoimmune disease (including but not 
restricted to inflammatory bowel disease, celiac disease, irritable bowel syndrome, 
Wegner’s granulomatosis and Hashimoto’s thyroiditis, etc.). Participants with vitiligo, 
alopecia, type I diabetes mellitus, residual hypothyroidism (e.g., following Hashimoto 
syndrome) due to autoimmune condition only requiring hormone replacement, psoriasis 
or any chronic skin condition not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. Subjects 
without active disease in the last 5 years may be included but only after consultation 
with the study physician. Subjects with celiac disease controlled by diet alone may also 
be included.” 
Rationale: irritable bowel syndrome was deleted from the list of examples for 
autoimmune diseases, as it should not have been included in this category. The 
remaining changes were clarifications and updates per standard language in current 
protocols. 
• 
#17 - contraception language was updated according to current recommendations from 
MedImmune. 
• 
#18 was updated for clarification (changes in bold): “Any condition that, in the clinical 
judgment of the treating physician, is likely to interfere with the interpretability of the 
data or to prevent the subject from complying with any aspect of the protocol or that 
may put the subject at unacceptable risk.” 


 
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• 
#19 and #20 were added per current recommendations from Medimmune. 
15. Section 5.3.1 (Non permitted Concomitant Therapies): # 2 was updated for clarification 
(changes in bold): “Other cancer therapy (e.g., drug, radiation, or immunotherapy). Wash-
out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1. (6 weeks for 
nitrosoureas and 12 weeks for antibodies other than anti-CTLA-4 or anti-PD-1/PD-L1 
antibodies). 
16. Section 5.3.2 (Permitted Concomitant Therapies): 
• 
#6 was clarified as follows (changes in bold): “Hormone or hormone-related anti-cancer 
therapy, and cancer supportive therapy such as bone modifying agents 
(bisphosphonates/RANK-L inhibitors).” 
• 
Footnote was corrected (changes in bold): “All prescription and nonprescription drugs 
must be recorded in the concomitant medications section of the case report form, listing 
generic (preferably) or brand name, indication, dose, route, and dates of administration. 
All non-drug therapies must be recorded in the respective sections of the case report 
form or as AEs. 
17. Section 6 (Study Drug Preparation and Administration): A title header was added to second 
paragraph: "Order of Drug Administration.”  A reference was provided to this paragraph in 
Sections 6.1, 6.2, and 6.3. Also, the following correction was made (changes in bold): 
“…durvalumab infusion will start at least 60 minutes after the end of the tremelimumab 
infusion.” 
18. Section 6.1 (Tremelimumab) and Section 6.2 (Durvalumab): the entire sections were 
updated and reorganized according to current language for IV infusions from Medimmune / 
AstraZeneca. 
• 
Dextrose was added as an option to be used as a diluent for IV bag. 
• 
Infusion pump requirement was deleted 
• 
Emphasized that 0.22 or 0.2 μm in-line filter must be used 
• 
The following statement was added or clarified: “After the contents of the IV bag are fully 
administered, the IV line will be flushed with a volume of IV diluent equal to the priming 
volume of the infusion set used.  Alternatively, the infusion will be completed according 
to institutional policy to ensure the full dose is administered; documentation is required 
if the line was not flushed.” 
• 
The following statement was added “See Section 8.3.1 for guidelines for infusion-related 
reactions.” 
• 
The following statement was added for each respective section: 
“Tremelimumab/durvalumab solution should not be infused with other solutions or 
medications.” 
• 
Weight restriction for fixed doses of durvalumab was added.  Dose 
calculations/preparation were added or clarified. 
• 
The following statement was clarified for durvalumab: ”The total time between needle 
puncture of the durvalumab vial to start of administration should not exceed 4 hours at 
room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). Standard infusion time is 60 ± 
5 minutes. However, if there are interruptions during infusion, the total allowed time 
should not exceed 8 hours. In the event that either preparation time or infusion time 
exceeds the time limits, a new IV bag must be prepared from new vials and the remaining 
dose is given.” 


 
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• 
The following statement was clarified for IV tremelimumab (changes in bold): “The total 
time from needle puncture of the tremelimumab vial to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C (36°F to 46°F). If 
there are no requirements to slow, interrupt, or permanently stop the infusion, the 
anticipated infusion time to deliver each dose (250 mL) is anticipated to be 60 
(± 5) minutes. However, if there are interruptions during infusion, the total allowed 
should not exceed 8 hours. In the event that either preparation time or infusion time 
exceeds the time limits, a new IV bag must be prepared from new vials and the 
remaining dose is given.” 
• 
The following statement was added for tremelimumab: “No incompatibilities between 
tremelimumab and polyvinylchloride or polyolefin have been observed.” The following 
statement was deleted: “lines containing cellulose based filters should not be used with 
tremelimumab.” 
• 
The following statement was added for tremelimumab: “The IV bag size should be chosen 
such that the final concentration of tremelimumab after dilution in the bag is between 
0.10 mg/mL and 10 mg/mL. The appropriate IV bag size should be chosen for the 
respective dose. For the 75 mg dose only, tremelimumab may be administered using a 
250 mL IV bag.” 
• 
The following statement was deleted for tremelimumab only: “An infusion time of less 
than 55 minutes is considered a deviation.” 
• 
The following statement was added for durvalumab: “The IV bag size should be chosen 
such that the final durvalumab concentration after dilution in the bag must be 1 mg/mL 
to 15 mg/mL. The appropriate IV bag size should be chosen for the respective dose.” 
• 
The removal of a volume of IV diluent equal to the volume of durvalumab or 
tremelimumab being added to the bag was deleted as it is an unnecessary step as long 
the defined concentration ranges for the doses in the IV bags are maintained. 
19. Section 6.3.1 (PolyICLC Study Drug Information): table was updated to reflect concentration 
of different lots of PolyICLC (changes in bold): 
Manufacturer 
Oncovir 
Expiration/Retes
t Date 
Expiration/retest dates are documented on the Certificate of 
Conformance. 
Container 
Description 
Type: 
Single-use unpreserved 
vial 
Material: 
 
Size: 
1 mL 
Formulation 
PolyICLC is supplied in vials containing 1 mL of 2 mg/mL opalescent 
white suspension (approximately 2 mg/mL). Each mL of polyICLC for 
injection contains approximately 2 mg/mL poly-IC, 1.5 mg/mL poly-L-
lysine, and 5 mg/mL sodium carboxymethylcellulose in 0.9% sodium 
chloride solution and adjusted to pH 7.6-7.8 with sodium hydroxide. 
Active Ingredient 
Content 
Mass/Weight: 
approximately 2 mg 
Volume: 
1 mL 
Concentration: 
approximately 
2 mg/mL 
Storage 
Conditions 
+2°C to +8°C (approximately 40°F) Do not freeze 
Labeling 
Product name, concentration, lot number, date of manufacture, 
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20. Section 6.3.3 (PolyICLC Preparation and Administration):  
• 
The first sentence was updated (changes in bold): “PolyICLC is supplied by the Ludwig 
Institute for Cancer Research in vials containing 1 mL of 2 mg/mL opalescent white 
suspension (approximately 2 mg/mL).” 
• 
The following note was added: 
“NOTE:  Lot PJ215-1-10-01 of PolyICLC has a labeled concentration of 2 mg/mL. As the 
PolyICLC dose is 1 mg, this corresponds to 0.5mL. Lot PJ215-1-10-01 expired on 28 FEB 
2018 and was replaced by Lot PJ215B03.  Lot PJ215B03 has a concentration of 1.8 
mg/mL. For a 1 mg dose using this lot, the volume to be administered is 0.556 mL (this 
number may be rounded according to institutional practice). The volume administered for 
subsequent lots should be adjusted accordingly so that the administered dose is 1 mg.” 
• 
In the subsequent paragraphs for PolyICLC, reference to these directions was provided 
for volume required. 
21. Section 6.5 (Monitoring of Tremelimumab and Durvalumab IV Dose Administration). The 
following note was added for clarification: “Note: When IV durvalumab and IV tremelimumab 
are to be administered on the same day, durvalumab infusion will start at least 60 minutes 
after the end of tremelimumab infusion even though vital signs assessment is not required 
during the entire 60-minute period post tremelimumab.” 
22. Section 7.1.6 (Expedited Serious Adverse Event Reporting Requirements). The following 
statement was added: “Serious adverse event reporting to AstraZeneca/Medimmune is 
described in a separate agreement.” 
23. Section 7.1.8 (AESIs). The section was updated and reorganized based on updated 
recommendations from Medimmune in the updated IB. Specifically: 
• 
Additional information was added to the description of the AESIs 
• 
Myocarditis, myositis/polymyositis, other inflammatory responses, and hypersensitivity 
and infusion reactions were added. 
• 
The following sentence was added “Guidelines for the management of subjects 
experiencing toxicities for PolyICLC can be found in Section 8.4.” 
24. Section 8.3.1 (Durvalumab and Tremelimumab Dose Modification Due to Toxicity): Immune-
related AEs were updated based on updated Toxicity Mgt Guidelines from Medimmune 
(Dated 01Nov2017). Specifically, myocarditis, myositis/polymyositis were added; 
Diarrhea/colitis, elevated creatinine, rash, and endocrinopathies were updated. 
25. Section 8.3.2 (Durvalumab and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities): Section was changed  
FROM: Durvalumab and tremelimumab administration may be modified or discontinued as a 
result of events other than toxicity, e.g., intercurrent illness or logistical/administrative 
reasons, whereby the following rules should apply: 1. If the subject misses 2 consecutive 
planned doses, the subject should be discontinued from treatment; 2. If the dosing 
interruption is ≤ half the planned dosing interval, the originally planned drug administration 
should be given.  Any respective protocol deviation should be documented, if applicable; 3. If 
the dosing interruption is greater than half the planned dosing interval, the dosing should be 
skipped, and the next scheduled drug administration should be performed.  The respective 
protocol deviation should be documented. 
TO: Durvalumab and tremelimumab administration may be modified or discontinued as a 
result of events other than toxicity, e.g., intercurrent illness or logistical/administrative 


 
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reasons, whereby the following rules should apply: 1. The originally planned visit/treatment 
schedule should be maintained in general, i.e., dosing interruptions should not reset the 
original treatment schedule. Exceptions may be made only for individual dosing days, 
whereby the interval between any two doses shall be no less than 21 days. All resulting 
protocol deviations should be documented; 2. If the dosing interruption causes 2 consecutive 
planned doses to be missed, the treatment should be discontinued; 3. If the dosing 
interruption is ≤ half the planned dosing interval, the originally planned dose should be given 
and the timing of the next dose(s) should be adjusted in accordance with #1, if necessary; 4. If 
the dosing interruption is greater than half the planned dosing interval, the dose should be 
skipped and the next dose(s) should be adjusted in accordance with #1, if necessary. 
26. Administrative Changes:  
• 
“IT” was changed to “intratumoral” throughout the document to provide clarification.  
ITM was used in the tables due to space constraints. 
• 
Spelling, grammar and typographical errors were corrected.  
• 
Formatting/administrative changes were implemented, as applicable. 
• 
Updated List of abbreviations 
 
Amendment 5 
Issue date: 13-MAY-2019 
Summary of Changes: 
1. Section 3.1.10 (Subject Withdrawal from Treatment or from Study).  The following note was 
changed (changes in bold). Rationale: For this study, irRECIST is the primary method for 
determining response and progression rather than RECIST 1.1. 
“NOTE: Subjects meeting criteria for radiographic progression by RECIST 1.1 irRECIST (Section 
8.5) will be allowed to continue on therapy until confirmation of progression by irRECIST if the 
subject agrees and signs an appropriate informed consent form regarding continuation of 
treatment and as long as the following criteria are met at the discretion of the Investigator: 
a. Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.” 
2. In accordance with the change in Section 3.1.10, the following change from RECIST 1.1 to 
irRECIST was made to Section 3.2 (Flowchart – footnote 8) and Section 4.2.1 (Clinical Efficacy- 
Endpoints and Assessment Methods). In addition, the change in time period (“4 to 6 weeks” 
to “4 to 8 weeks” was done to align with the visits in the study. (Changes in bold.) 
“Subsequent imaging at 4 to 6 8 weeks after first documentation of RECIST 1.1 irRECIST-
defined progression must be performed.” 
3. Section 3.1.11 (Evaluability and Subject Replacement). The PP definition for subjects in Phase 
2 was clarified to provide better guidance for minimum drug requirements (changes in bold): 
“Phase 2: Subjects in Cohort 2 who receive at least 1 dose of each study drug and undergo 
respective disease assessments, without major protocol violations, are considered fully 
evaluable and will be included in the Per-Protocol (PP) Analysis Population for Clinical Efficacy if 
they meet the following criteria: 
• 
Receive at least the following minimum quantities of study drugs over the subject’s 
entire treatment period: 


 
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o 2 durvalumab administrations  
o 3 tremelimumab administrations 
o 10 polyICLC administrations (regardless of route) 
• 
Undergo appropriate disease assessments (radiological or clinical) 
• 
Have no major protocol violations that would have an effect on the efficacy evaluation. 
Subjects who are not fully evaluable for PP population for Clinical Efficacy may be 
replaced.” 
4. Section 5.2 (Exclusion Criteria) #4 was changed to provide clarification regarding the 
intention of the criterion regarding brain metastases (change in bold): 
“Subjects with history or evidence upon physical examination of central nervous system 
(CNS) disease, including primary brain tumor, seizures not controlled with standard medical 
therapy, any active brain metastases, or, within 6 months of the first date of treatment on 
this study, history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or 
subarachnoid hemorrhage.” 
5. Formatting/administrative changes were implemented, as applicable. 
6. Section 6.1.1 (Tremelimumab study drug information). The following was added: 
Tremelimumab is also available in a 25 mg/vial format; the concentration remains 20 mg/mL. 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented on the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: Single-use vial 
Material: Clear glass 
Size: 2 mL 
Formulation 
Liquid solution containing 25 mg tremelimumab per vial.  
The solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 
mM disodium edetate dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 5.5. 
Active Ingredient 
Content 
Mass/Weight: 
25 mg/vial 
Volume: 
1.25 mL/vial 
Concentration: 
20 mg/mL 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Allowable Short Term Temperature Variation: 2°C to 25°C for 7 days 
Labeling 
Product name, lot number, and storage conditions 
 
Amendment 5.1 
Issue date: 23-JUL-2019 
Summary of Changes: 
1. Section 6.1.1 (Tremelimumab study drug information) The highlighted line was deleted from 
the 25 mg/vial table.  The deleted information was inadvertently included in Amendment 5. 
Storage Conditions 
+2°C to +8°C (36°F to 46°F). Do not freeze. 
Allowable Short Term Temperature Variation: 2°C to 25°C for 7 days 
2. Section 5.3.1 (Non-permitted concomitant therapies). Criterion # 5 was clarified as follows 
(changes in bold):  “Drugs with laxative properties and herbal or natural remedies for 
constipation should generally be avoided through 90 days post last dose of tremelimumab 
because of the potential for exacerbation of diarrhea, but, for example, opiate-induced 
constipation may be treated with laxatives at the Investigator’s discretion.” 
 


 
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Amendment 6.0 
Issue date: 02-NOV-2021 
Summary of Changes: 
1. All subjects have completed treatment, and by the date of implementation of this 
amendment, all subjects will have completed On Study Follow-up. This amendment provides 
that the Post Study Follow-up for the collection of survival data will be discontinued as of 
28 February 2022, and the study will be completed. (This note was added to the synopsis.) 
a. The following note was added to Sections 3.1.15.2 (Duration of Study), 3.1.16 (On Study 
and Post Study Follow-up), and 4.2.1.3 (Overall Survival): “NOTE: Per Amendment 6.0, all 
post study follow-up for the collection of survival data will be discontinued as of 
28 February 2022 (see rationale in Section 8.1, Amendment 6.0 on Page 80).” 
b. Section 3.2 (Study Flowchart): Footnote 12 was added, “Per Amendment 6.0, all post 
study follow-up for the collection of survival data will be discontinued as of 28Feb2022 
(see Section 8.1, Amendment 6.0).”   
2. AstraZeneca provided updated language for Section 7.1.2 (Additional expedited reporting 
requirements for this study). Section 7.1.2.4 (New Cancers) and Section 7.1.2.5 (Deaths) were 
added.   
3. Section 7.1.6 (Expedited SAE Reporting Requirements): updated address for Drug safety 
Contact and Primary Sponsor Contact due to office move.  
 
4. Administrative edits: In Section 7.1.6, the title of Primary Sponsor Contact was changed from 
Director to Senior Director. 
 
 
 
8.2 Participating Study Sites, Investigators and Staff, Laboratories, and 
Sponsor Information 
This information is maintained in the Clinical Study File. 
 
 


 
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8.3 Dose Adjustments and Delays for Durvalumab and Tremelimumab 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
(i.e., the guideline that provides for the greatest dose reduction, dose delays or holds) should be 
followed. 
8.3.1 Durvalumab and Tremelimumab Dose Modifications due to Toxicity 
Durvalumab (MEDI4736) and tremelimumab administration may be modified or discontinued as 
a result of toxicities as described in the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from Medimmune in the following guideline: 
Medimmune’s Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 Monotherapy 
or Combination therapy with Tremelimumab or Tremelimumab monotherapy). 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab or 
tremelimumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. 
MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
Note: If M and T dosing is held temporarily until resolution of the event as per instructions 
below, treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology.  Maximum supportive care, including 
immunosuppressive medications, such as high dose steroids, is allowed to induce resolution 
of the event.  However, infliximab should not be used for management of immune-related 
hepatitis. 
In addition to the criteria for permanent discontinuation of M and T depicted below, 
permanently discontinue M and T also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
• Any Grade biopsy-proven immune-mediated myocarditis. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease and myocarditis, consider holding M and T dosing as 
clinically appropriate and during diagnostic work-up for other etiologies. 


 
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Grade 2 
• 
In general, hold M and T until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue M and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities).  Criteria for temporary hold or permanent discontinuation of M and T may differ 
by event as detailed below. 
• 
For myositis/polymyositis, hold M and T until resolution to ≤ Grade 1; permanently discontinue M 
and T if it does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory 
insufficiency. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate M and T upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event does not 
meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow 
general instructions above, but always discontinue M and T permanently if there are signs of 
respiratory insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism and isolated Type 1 diabetes mellitus, 
follow general instructions above, but patients may be retreated if the endocrinopathy is 
controlled and the patient is clinically stable while requiring steroid doses of ≤ 10 mg/day 
prednisone equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, isolated Type 1 
diabetes mellitus treated with appropriate diabetic therapy, and for sensory 
neuropathy/neuropathic pain, holding M and T is at the discretion of the Investigator. 
• 
For elevated creatinine or rash, M and T should be held until resolution to ≤ Grade 1 or baseline 
and after completion of steroid taper 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold M and T until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue M and T permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash).  Criteria for permanent discontinuation of M and T may differ by event 
as detailed below. 
• 
For myositis/polymyositis, follow Grade 2 instructions above. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For diarrhea/colitis, permanently discontinue M and T if toxicity does not improve to ≤ Grade 1 
within 14 days. 
• 
For pneumonitis/interstitial lung disease, myocarditis, and elevated serum creatinine (e.g., 
nephritis or renal dysfunction), always discontinue M and T permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold M and T, and if complete work up 
shows no evidence of pancreatitis, M and T may be continued. 
• 
For hepatitis, discontinue M and T permanently for (1) transaminases or bilirubin not resolving to ≤ 
Grade 1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or 
bilirubin > 5 × ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document 
“Drug-Induced Liver Injury”). 
• 
For rash, M and T should be held until resolution to ≤ Grade 1 or baseline. 
 


 
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MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
Grade 4 
• 
In general, discontinue M and T permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold M and T, and if complete work up 
shows no evidence of pancreatitis, M and T may be continued.  
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of M and T may be decreased 50% or temporarily interrupted until resolution of 
the event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2  
• 
Hold M and T until resolution to ≤ Grade 1 or baseline, and discontinue M and T permanently if 
such resolution does not occur within 60 days. 
Grade 3 
• 
Hold M and T. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume M and T administration at next scheduled dose. Otherwise, discontinue M 
and T permanently. 
Grade 4 
• 
In general, discontinue M and T permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment in consultation with the Sponsor. 
 
8.3.2 Durvalumab and Tremelimumab Dose Modification Not Due to Toxicities 
Durvalumab and tremelimumab administration may be modified or discontinued as a result of 
events other than toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby 
the following rules should apply: 


 
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1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 
be made only for individual dosing days, whereby the interval between any two IV doses 
of durvalumab or tremelimumab shall be no less than 21 days. All resulting protocol 
deviations should be documented. 
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the timing of the next dose(s) should be adjusted in 
accordance with #1, if necessary. 
4. If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
. 
 


 
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8.4 PolyICLC Toxicity Management, Dose Delays and Adjustments 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.3 or 8.4, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
(i.e., the guideline that provides for the greatest dose reduction, dose delays or holds) should be 
followed. 
8.4.1 Management of Injection Site Reactions  
Intratumoral Injection 
Some degree of inflammatory response in the injected lesion is expected as part of the therapy. 
Prior to each intratumoral injection, the maximal diameter of peritumoral inflammation will be 
recorded in millimeters and photographically, if appropriate in the judgment of the investigator, 
as a baseline for subsequent post-injection measurements. 
Pain medication to be administered includes, if needed, acetaminophen, diphenhydramine, 
benzodiazepines, and/or opiates. Other analgesics may be given at the discretion of the 
investigator.  
IM administration 
PolyICLC IM injections are usually well tolerated, with few issues (general fatigue and malaise). 
8.4.2 Management of Systemic Toxicities 
The most common systemic drug-related AEs—Grade 1 or 2 chills, flu-like symptoms and fever—
typically resolve in < 48 hours and do not require dose reductions or a delay in the dosing 
regimen. 
Anti-emetics 
Prophylactic anti-emetics will be administered at the discretion of the study physician. 
Anti-inflammatory and Pain Medication 
Corticosteroids and other immunosuppressant drugs should not be used to control 
polyICLC-associated AEs unless indicated in the opinion of the study physician and sponsor. 
Acetaminophen will be used to treat fever or flu-like side effects of polyICLC. Subjects may be 
pretreated with acetaminophen as warranted by previous side effects, at the discretion of the 
local investigator. NSAIDS may be given if necessary at the discretion of the study physician. 
8.4.3 PolyICLC Dose Modifications due to Toxicities 
PolyICLC will be dosed as defined in Section 3.1.7. Delays or skipped doses of polyICLC should 
not delay or shift the timing of other treatment agents. 
In the event that steroids are administered to treat tremelimumab or durvalumab irAEs, dosing 
of polyICLC should be withheld during the time period that steroid administration is given. 


 
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8.5 RECIST 1.1 and irRECIST Guidelines 
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines were revised in 2009 as 
RECIST 1.1.(55) These guidelines have been the widely accepted criteria to assess response and 
progression in solid tumors; however, limitations have been noted in the use of RECIST 1.1 for 
immunotherapy trials. With immunotherapeutic agents, clinical trials have shown that complete 
response, partial response, or stable disease status can still be achieved after an initial increase 
in overall tumor burden, and regression of initial lesions may occur despite development of new 
lesions. The Immune-related Response Criteria (irRC) were developed to address the need for 
response criteria in an immunotherapy setting.(56)  The main difference with irRC was that it 
considered the subject's total tumor burden at each subsequent assessment and required 
confirmation of suspected disease progression with subsequent imaging, approximately four 
weeks later.  In addition, a greater number of lesions (10 vs. 5) were measured in a 
bidimensional manner instead of unidimensionally as in RECIST 1.1.  In 2013, Nishino et al. 
demonstrated that immune-related response criteria using unidimensional measurements were 
highly concordant with the bidimensional results of irRC, but with less measurement 
variability.(57)  Based on these findings and in order to utilize both the established criteria of 
irRC and RECIST 1.1, the two systems have been adapted, modified, and combined into the 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).(58)  The adapted 
irRECIST criteria are modifications to the irRC, incorporating the findings of Nishino et al. and the 
advantages of RECIST 1.1 while overcoming the shortcomings of each of the other guidelines. 
The guidelines for RECIST 1.1 are summarized below, followed by a summary for irRECIST. 
RECIST 1.1 
The following section outlines the RECIST 1.1 guidelines as published (55) and as summarized by 
National Cancer Institute for CTEP-involved clinical trials.   
I. 
Disease Parameters for RECIST 1.1 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria. 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).  Note:  Tumor lesions that are 
situated in a previously irradiated area might or might not be considered measurable.  If the 
investigator thinks it appropriate to include them, the conditions under which such lesions should 
be considered must be defined in the protocol. 
NOTE for irRECIST: During target lesion selection the radiologist will consider information on the 
anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, etc.). 
Lesions undergoing prior intervention will not be selected as target lesions unless there has been a 
demonstration of progress in the lesion. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 


 
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recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for selection 
as target lesions. 
NOTE for irRECIST: Lesions that are partially cystic or necrotic can be selected as target lesions. The 
longest diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with a non-liquid/non-necrotic component are present, those 
should be preferred. 
Brain lesions detected on brain scans can be considered as both target or non-target lesions depending 
on the protocol definition. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any non-measureable as well 
as measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
II. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 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. 


 
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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 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.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, 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).   
Use of MRI remains a complex issue.  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.  Furthermore, the availability of 
MRI is variable globally.  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.  It is 
beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases.  Ideally, the same type of scanner should be used, and 
the image acquisition protocol should be followed as closely as possible to prior scans.  Body 
scans should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, 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 identical 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.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 


 
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response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published.(59-61)  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer.(62)  
Cytology, 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. 
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:  
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b) 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. 
c) 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 protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
III. 
Response Criteria for RECIST 1.1 
A. Evaluation of Target Lesions 


 
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Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.   
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
B. 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 short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
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). 
C. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


 
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1. For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
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 the objective progression even after discontinuation of 
treatment. 
 
2. 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 end-
point for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
 
D. 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 (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
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. 
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.  


 
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irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. (58) are presented 
below. 
I. 
Baseline Assessments in irRECIST 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1.  One new definition is 
added: If a subject has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-up time 
points unless new measurable lesions are identified and contribute to the total measured tumor 
burden (TMTB).  irND is a valid assessment in studies with adjuvant setting where the protocol 
and study design allow the inclusion of subjects with no visible disease 
II 
Follow-up Assessments in irRECIST 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not automatically 
indicate progression.  Instead, all measured lesions (baseline-selected target lesions and new 
measurable lesions) are combined into the total measured tumor burden (TMTB) at follow up.  
Baseline-selected target lesions and new measurable lesions are NOT assessed separately. 
Measurements of those lesions are combined into the TMTB, and one combined assessment 
provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
time point), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions should be prioritized 
according to size, and the largest lesions elected as new measured lesions.  
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non-target 
lesions primarily contributes to the overall response assessments of irCR and irNon-CR/Non-PD 
(irNN). Non-target lesions do not affect irPR and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions alone, even without progress in the TMTB is 
indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target lesions can never 
convert to measurable lesions, not even if they increase in size at subsequent time points and 
become measurable. Only true new lesions can be measured and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions  
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new non-
measurable lesions leads to an overall assessment of irPD for the time point. Persisting new 
non-measurable lesions prevent irCR.  


 
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III 
Overall Assessments for irRECIST 
The irRECIST overall tumor assessment is based on TMTB of measured target and new lesions, 
non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment, the SumD of 
the target lesions and of new, measurable lesions (up to 2 new lesions per organ, total 5 new 
lesions) are added together to provide the total measurable tumor burden (TMTB). 
Overall Assessments by irRECIST 
Complete Response 
(irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, 
and no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no target lesions at 
baseline, irPD will be assessed. That irPD time point will be considered a 
new baseline, and all subsequent time points will be compared to it for 
response assessment. irPR is possible if the TMTB of new measurable 
lesions decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the adjuvant setting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. 
These subjects can achieve a response if the TMTB decreases at follow-up, 
as a sign of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease (irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive Disease 
(irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time-
window of the first 12 weeks of treatment, depending on the compound 
efficacy expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal massive 
worsening 
Other 
irNE: used in exceptional cases where insufficient data exist.  
irND: in adjuvant setting when no disease is detected 
irNN:, no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 


 
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8.6 Exploratory Assessment of Correlative Immunologic Research 
Please refer to the laboratory manual for additional instructions and information on specimen 
handling and logistics.  
8.6.1 Effects on the Tumor Microenvironment 
Tumor biopsies will be obtained at Baseline (pretreatment), Day 15, and, provided there is 
sufficient tumor to biopsy, at Day 29 (Cycle 2, Day 1), and optionally at the time of progression 
and at the end of treatment. 
Endpoints include induction of a favorable immune signature and increased T-cell infiltration, as 
well as pre-treatment and post-treatment immune signatures that predict clinical response. 
8.6.2 Circulating Soluble Factors 
Blood samples will be collected for analyses of circulating soluble factors as outlined in Section 
3.2. This includes cytokines, chemokines, and antibodies. The timing of the collection of these 
samples will match the timing of collection of tumor biopsy samples so that the effects in the 
blood and tumor can be correlated. 
8.6.3 Peripheral blood mononuclear cells (PBMC) 
Samples will be collected for analyses at the time points designated in the study flowchart 
(Section 3.2).  
Peripheral blood populations before and after treatment will be assessed numerically and 
functionally by flow cytometry and other assays (e.g., ELIspot).  Measures will include immune 
cell phenotypes, numbers of immune cells (T cells, T cell subsets, NK cells, B cells, myeloid 
derived suppressor cells), Immune cell activation and function, Immune diversity, and functional 
cellular immune responses. These will be assessed by flow cytometry to evaluate the association 
with treatment and subject responses. 
8.6.4 RNA Profiling 
Samples will be collected for analyses at the time points designated in the study flowchart 
(Section 3.2). 
 
 


 
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8.7 ECOG Performance Status 
ECOG Performance Status: Developed by the Eastern Cooperative Oncology Group, Robert L. 
Comis, MD, Group Chair. * 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655 
 
 


 
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8.8 List of Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
CD 
Cluster of differentiation 
Cmax 
peak concentration 
CRF 
Case report form 
CTC 
Circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4  
DC 
Dendritic cell 
DLT 
dose-limiting toxicity 
ECLA 
Electrochemiluminescence assay 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FTIH 
First time in human 
GCP 
Good Clinical Practice 
GMP 
Good manufacturing practice 
HLA 
Human Leukocyte Antigen 
HNSCC 
Head and neck squamous cell carcinoma 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGSF 
Immunoglobulin superfamily 
IHC 
Immunohistochemistry 
IL 
interleukin 
IMiD 
Immune modulatory drug 
IND 
Investigational new drug 
irAE 
Immune-related adverse event 
irRC 
immune-related response criteria 
irRECIST 
Immune-related Response Evaluation Criteria In Solid Tumors 
IM 
Intramuscular 


 
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ITM 
intratumoral 
IV 
intravenous 
IRB 
Institutional Review Board 
LICR 
Ludwig Institute for Cancer Research 
M 
MEDI4736 (durvalumab) 
mAb 
Monoclonal antibody 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSD 
Meso Scale Discovery 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-small cell lung cancer 
NK 
Natural killer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD-1 
Programmed death-1  
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PolyIC 
Polyinosinic-polycytidylic acid 
PolyICLC 
polyIC stabilized with polylysine and carboxymethylcellulose as 
polyICLC (Hiltonol®, Oncovir Inc.). 
Q4W 
Every 4 weeks 
RCD 
Recommended combination dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
T 
Tremelimumab 
TME 
Tumor microenvironment 
TIL 
tumor-infiltrating lymphocyte 
TLR 
Toll like receptor 
ULN 
Upper limit of normal 
WFI 
Water for Injection 
 
 


 
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9 References  
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Ludwig Institute for Cancer Research  
(LICR) 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 1/2 Study of In Situ Vaccination with Tremelimumab and IV Durvalumab 
(MEDI4736) Plus the Toll-like Receptor Agonist PolyICLC in Subjects with 
Advanced, Measurable, Biopsy-accessible Cancers 
 
Clinical Trial Protocol LUD2014-011 
 
 
 
SAP Version: 
Date of Statistical Analysis Plan: 
 
 
Version 1.0 
29 March 2019 
 
 
Version 2.0 
 
 
21 December 2020 
 
 
Version 3.0 
 
 
18 May 2021 
 


 
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LUD2014-011 
 
 
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          Page 2 of 41 
 
SIGNATURE PAGE 
 
 
 
 
 
Date 
 
Prepared by:  
Patricia Feeney, MS, MA 
Senior Manager Biostatistics 
PROMETRIKA, LLC 
 
 
 
Date 
 
Reviewed by:  
Nicole LaVallee, PhD 
Senior Director, Biostatistics 
PROMETRIKA, LLC 
 
 
 
 
 
 
 
 
 
Date 
 
Reviewed and Approved by:  
Kristen Aufiero Ramirez 
Senior Clinical Project Manager 
Ludwig Institute for Cancer Research 
 
 
 
Date 
 
Reviewed and Approved by:  
Ralph R. Venhaus, MD 
Vice President & Chief Medical Officer 
Ludwig Institute for Cancer Research 
 
 
 
 


 
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LUD2014-011 
 
 
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          Page 3 of 41 
 
Table of Contents 
1 
INTRODUCTION ................................................................................................ 8 
2 
STUDY SUMMARY............................................................................................ 8 
2.1 
STUDY OBJECTIVES .................................................................................. 8 
2.2 
STUDY DESIGN ........................................................................................... 8 
2.2.1 Number of Subjects................................................................................... 9 
2.2.2 Randomization Procedures ....................................................................... 9 
2.2.3 Efficacy Assessments.............................................................................. 10 
2.2.4 Safety Assessments ................................................................................. 10 
2.2.5 Biological Activity Assessments ............................................................ 11 
2.2.6 Other Assessments .................................................................................. 11 
3 
STATISTICAL METHODS ............................................................................... 15 
3.1 
General Methods .......................................................................................... 15 
3.1.1 Computing Environment ......................................................................... 15 
3.1.2 Presentation of Data Summaries ............................................................. 15 
3.1.3 Reporting of Numerical Values .............................................................. 15 
3.1.4 Baseline Value and Change from Baseline ............................................. 16 
3.1.5 Pre-Dose Value and Change from Pre-Dose .......................................... 16 
3.1.6 Handling of Missing/Incomplete Values ................................................ 16 
3.1.7 Handling of Repeated Assessments ........................................................ 16 
3.1.8 Handling of Missing/Incomplete Date/Time .......................................... 16 
3.2 
Analysis Populations and Subgroups ........................................................... 17 


 
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3.2.1 Intent-to-Treat Population ....................................................................... 17 
3.2.2 Per-Protocol Population for DLT Assessment in Phase 1 ...................... 17 
3.2.3 Per-Protocol Population for Phase 2 Clinical Efficacy ........................... 18 
3.3 
Analysis Variables........................................................................................ 18 
3.3.1 Efficacy Variables ................................................................................... 18 
3.3.1.1 Objective Response Rate .......................................................... 19 
3.3.1.2 Overall Disease Control Rate ................................................... 19 
3.3.1.3 Progression-Free Survival Time............................................... 19 
3.3.1.4 Overall Survival Time .............................................................. 20 
3.3.2 Safety Variables ...................................................................................... 20 
3.3.2.1 Adverse Events ......................................................................... 20 
3.3.2.2 Clinical Laboratory Evaluations............................................... 20 
3.3.2.3 Vital Signs ................................................................................ 21 
3.3.3 Biological Activity Variables ................................................................. 21 
3.4 
Subject Disposition and Evaluability ........................................................... 21 
3.4.1 Subject Disposition ................................................................................. 21 
3.4.2 Protocol Deviations ................................................................................. 21 
3.5 
Demographics and Baseline Characteristics ................................................ 21 
3.5.1 Demographics and Baseline Characteristics ........................................... 22 
3.5.2 Baseline Disease Characteristics ............................................................. 22 
3.5.3 Non-Oncological Medical History .......................................................... 22 
3.5.4 Oncological Medical History .................................................................. 22 
3.6 
Prior and Concomitant Medications/Procedures .......................................... 22 
3.7 
Treatment Exposure ..................................................................................... 23 


 
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3.8 
Efficacy Analysis ......................................................................................... 23 
3.8.1 Tumor Response ..................................................................................... 23 
3.8.2 Progression-Free Survival ....................................................................... 24 
3.8.3 Overall Survival ...................................................................................... 25 
3.9 
Safety Analysis ............................................................................................. 26 
3.9.1 Adverse Events ....................................................................................... 26 
3.9.1.1 Summary of TEAEs ................................................................. 26 
3.9.1.2 Incidence of TEAEs ................................................................. 26 
3.9.1.3 TEAEs by Maximum CTCAE Grade....................................... 27 
3.9.1.4 Treatment-Related TEAEs ....................................................... 27 
3.9.1.5 Treatment-Related TEAEs by Maximum CTCAE Grade........ 27 
3.9.1.6 CTCAE Grade ≥ 3 TEAEs ....................................................... 27 
3.9.1.7 CTCAE Grade ≥ 3 TRAEs ....................................................... 27 
3.9.1.8 Serious Adverse Events ............................................................ 27 
3.9.2 Clinical Laboratory Evaluation ............................................................... 27 
3.9.3 Vital Signs ............................................................................................... 28 
3.9.4 ECG......................................................................................................... 28 
3.9.5 Physical Examination.............................................................................. 28 
3.10 
Biological Activity Analysis ................................................................... 28 
4 
List of Tables, Figures and Listings .................................................................... 29 
5 
Appendix ............................................................................................................. 38 
5.1 
Confirmation of Response in irRECIST ...................................................... 38 
5.2 
Confirmation of Response in RECIST 1.1 ................................................... 39 
5.3 
Censoring Rules for PFS .............................................................................. 40 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
AE  
adverse event  
ATC 
Anatomical Therapeutic Class 
BMI 
body mass index 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events  
DLT  
dose-limiting toxicity  
ECG  
electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
IM  
intramuscular  
irRECIST  
Immune-related Response Evaluation Criteria In Solid Tumors  
ITM  
intratumoral  
ITT 
Intent-to-Treat 
IV  
intravenous  
MedDRA  
Medical Dictionary for Regulatory Activities  
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
ODCR 
overall disease control rate 
ORR  
objective response rate  
OS  
overall survival  
PFS  
progression-free survival  
PP 
Per-Protocol 
PR 
partial response 
PT 
Preferred Term 


 
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RCD  
recommended combination dose  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
serious adverse event  
SAP 
statistical analysis plan 
SD  
stable disease  
SOC 
System Organ Class 
TEAE 
treatment emergent adverse event 
TLR 
toll like receptor 
TME 
tumor microenvironment 
TRAE 
treatment-related treatment-emergent adverse event 
 


 
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1 INTRODUCTION 
LUD2014-011 is an open-label, multicenter, Phase 1/2 study of the CTLA-4 
antibody, tremelimumab, and the PD-L1 antibody, durvalumab (MEDI4736), in 
combination with the tumor microenvironment (TME) modulator polyICLC, a TLR3 
agonist, in subjects with advanced, measurable, biopsy-accessible cancers.  
The statistical analysis plan (SAP) contains a detailed description of the data 
presentations and statistical analyses that will be included in the clinical study report 
for Protocol LUD2014-011. The statistical methods and analyses described here are 
based on those presented in the study protocol (Amendment 5.1 dated 23July2019). 
2 STUDY SUMMARY 
2.1 STUDY OBJECTIVES 
For Phase 1, the primary objective is to determine the recommended combination 
dose (RCD) of the dosing regimen, based on assessment of toxicity and tolerability. 
The secondary objective is to obtain preliminary evidence of clinical efficacy as 
measured by objective response rate (ORR) by Immune-related Response Evaluation 
Criteria In Solid Tumors (irRECIST) and Response Evaluation Criteria In Solid 
Tumors (RECIST) 1.1, progression-free survival (PFS), and overall survival (OS). 
For Phase 2, the primary objective is the evaluation of clinical efficacy as measured 
by ORR, PFS, and OS. 
For all Phase 1 and 2 cohorts, safety and tolerability will be evaluated based on 
adverse events, laboratory tests, vital sign measurements, and physical examinations. 
An exploratory objective is the evaluation of biological activity, including effects on 
the TME and immunological responses.  
2.2 STUDY DESIGN 
This is an open-label, multicenter, Phase 1/2 study to evaluate the CTLA-4 antibody, 
tremelimumab, and the PD-L1 antibody, durvalumab, in combination with the TME 
modulator polyICLC, a TLR3 agonist, in subjects with advanced, measurable, biopsy-
accessible cancers. The study will be conducted at up to 8 sites in the US. 
Subjects will receive intratumoral (ITM) and intramuscular (IM) administration of 
polyICLC and intravenous (IV) administration of durvalumab, together with either IV 


 
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or ITM administration of tremelimumab. The study will be conducted in 2 phases. 
There will be enrollment to 3 subject cohorts (1A, 1B, and 1C) in Phase 1. 
Dose de-escalations for determination of the RCDs through the assessment of dose-
limiting toxicities (DLTs) will be performed based on the available dose levels and 
respective standard 3 + 3 rules. 
Once determined, the RCD of the dosing regimen will then be expanded in the Phase 
2 portion of the study. If Cohort 1C is not cleared, the RCD of the previously cleared 
cohort will be used for Phase 2. 
Subjects may receive study drug until withdrawn from treatment or the study per 
Protocol Section 3.1.10 or until the completion of Cycle 12. Treatment extension 
beyond 12 cycles is not planned. 
2.2.1 Number of Subjects 
Up to 102 subjects will be enrolled in the study. 
Phase 1 will enroll up to 36 subjects to determine the RCDs of durvalumab or 
durvalumab and tremelimumab within each cohort (3-6 subjects per dose level for 
each of the 3 cohorts). Subjects in Phase 1 who are not fully evaluable for DLT, as 
defined in Protocol Section 3.1.11, will be replaced. 
Phase 2 will evaluate up to 66 subjects treated with the RCDs of the dosing regimen. 
A total of (8 disease types)(6 subjects per disease type) = 48 subjects will be initially 
enrolled for the Phase 2 portion plus a potential additional (3 disease types)(6 
subjects) = 18 subjects for three disease types having at least one response or stable 
disease for 24 weeks in the initial group (total of 48+18= 66 subjects). 
2.2.2 Randomization Procedures 
This is not a randomized study. For Phase 1 of the study, there will be enrollment to 3 
subject cohorts, with staggered initiation of enrollment:  
• Cohort 1A: IV Durvalumab + ITM/IM PolyICLC.  
• Cohort 1B: IV Durvalumab + IV Tremelimumab + ITM/IM PolyICLC.  
• Cohort 1C: IV Durvalumab + ITM Tremelimumab + ITM/IM PolyICLC.  
 
After safety is demonstrated in the first 3-6 subjects in Cohort 1A, Cohorts 1B and 1C 
will open with alternating enrollment. Cohort 2 will expand the Phase 1 cohort treated 
at the RCD for Phase 2, and enrollment will occur without randomization. 
The study will be under ongoing review by an internal data safety monitoring panel. 


 
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2.2.3 Efficacy Assessments 
Tumor response disease assessments will be done in accordance with Table 1: Study 
Flowchart. The primary method for tumor response disease assessments will be by 
irRECIST, and the secondary method will be by RECIST 1.1 (see Protocol Section 
8.5). Confirmation of response (CR/PR ≥ 4 weeks) is required for RECIST 1.1 and 
irRECIST. Confirmation of progression is recommended a minimum of 4 weeks after 
the first irPD assessment, when appropriate, per irRECIST.  
Additionally, date of death or last follow-up will be recorded for each subject. Every 
effort will be made to follow subjects for overall survival after they discontinue the 
study. 
2.2.4 Safety Assessments 
Safety assessments include clinical laboratory tests, vital sign measurements, physical 
examinations, and subject interviews to detect new abnormalities and deteriorations 
of any pre-existing conditions and will be conducted according to Table 1: Study 
Flowchart. 
Clinical laboratory tests will be conducted pre-dose and include: 
• Hematology: CBC, differential, platelets 
• Chemistry: glucose, BUN, creatinine, Na, K, Cl, CO2, Ca, Mg, protein, alb, 
Tbili, AST, ALT, ALP, LDH, Free T3, Free T4, TSH, Amylase, lipase 
• Coagulation: PT, aPTT, INR 
• Urinalysis 
• Serum pregnancy test 
Vital sign measurements include: 
• Oral temperature 
• Heart rate 
• Respiratory rate 
• Systolic and diastolic blood pressure 
The investigator will evaluate any laboratory abnormalities for clinical significance, 
and clinically significant abnormalities will be recorded as adverse events (AEs). All 
treatment-emergent, clinically significant abnormalities and deteriorations from the 
time of informed consent to the End of Study Visit will be recorded as AEs and 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.03. 


 
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2.2.5 Biological Activity Assessments 
Tumor biopsies for TME assessments and blood samples for exploratory 
pharmacodynamic assessments will be collected as specified in Table 1: Study 
Flowchart. Additional biopsies may be obtained as appropriate. 
Protocol Section 4.3 contains comprehensive information on the biological activity 
assessments to be completed during the study. 
2.2.6 Other Assessments 
Medical history and demographics will be collected, and 12-lead electrocardiogram 
(ECG) and serum pregnancy test will be performed in accordance with Table 1: Study 
Flowchart. 
 
 


 
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Table 1.  Study Flowchart
 


 
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3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS Version 9.4 or higher for 
Windows. 
3.1.2 Presentation of Data Summaries 
Unless otherwise specified, tables for Phase 2 subjects will be presented by specific 
disease type (which may include Head and Neck Squamous Cell Carcinoma, Locally 
Recurrent Breast Cancer, Sarcoma, Merkel Cell Carcinoma, Cutaneous T-cell 
Lymphoma, Metastatic Melanoma, Genitourinary Cancers with Accessible 
Metastases, or any solid tumors with masses that are accessible) within analysis 
population. Only disease types for which at least one subject was enrolled will be 
presented. An “All Subjects” column will be included as appropriate. When Phase 1 
is presented as a separate table, “All Subjects” will include total for Phase 1 only. 
When Phase 2 is presented, this column will include the total for all subjects in Phase 
1 + all subjects in Phase 2 and will be labeled “All Subjects (Phase 1/Phase 2). This 
will also be footnoted. 
Subjects from Cohort 1C who are treated at the RCD will be included in expansion; 
thus, the subjects in the Phase 1 cohort treated at the RCD will be included in both the 
Phase 1 and Phase 2 tables.  
All clinical study data will be presented in subject data listings. 
3.1.3 Reporting of Numerical Values 
Relevant descriptive statistics (n, mean, standard deviation, 25th percentile, median, 
75th percentile, minimum, and maximum) will be calculated for continuous variables. 
Confidence intervals (CIs) will be provided where appropriate. 
Frequencies and percentages will be presented for categorical and ordinal variables. If 
there are missing values, the number missing will be presented, but without a 
percentage. 
Means, medians, and confidence intervals will be reported to one decimal place more 
than the data reported on the case report form (CRF) or by the laboratory/vendor. 
Standard deviations will be reported to two decimal places more than the data 


 
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reported. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the laboratory/vendor. 
3.1.4 Baseline Value and Change from Baseline 
Baseline value is defined as the most recent non-missing value obtained prior to 
administration of first dose of study treatment. Change from baseline will be 
calculated by subtracting the baseline value from the relevant post-baseline 
assessment for each subject (i.e., post-baseline – baseline). 
3.1.5 Pre-Dose Value and Change from Pre-Dose 
Pre-dose value is defined as the last non-missing value obtained prior to dosing at a 
particular visit. Change from pre-dose will be calculated by subtracting the pre-dose 
value from the post-dose assessment for each subject at the visit (i.e., post-dose – pre-
dose). 
3.1.6 Handling of Missing/Incomplete Values 
Unless otherwise explicitly specified, missing data will not be imputed; observed 
cases will be used in the analyses. 
3.1.7 Handling of Repeated Assessments 
If multiple results are available for a post-dose assessment at the same scheduled time 
point, then the earliest result recorded for that time point will be used in all 
descriptive summaries. All results will be displayed in subject data listings, and 
abnormal values will be flagged, where applicable. 
3.1.8 Handling of Missing/Incomplete Date/Time 
All analyses of AEs will be based on the principle of treatment emergence. An AE is 
considered to be treatment emergent if it has a start date/time on or after the date/time 
of first dose of study treatment; if the AE is missing start time, it is considered to be 
treatment emergent if it has a start date on or after the date of first dose of study 
treatment. For missing or incomplete AE start date, the following criteria will be used 
to determine whether an AE is treatment emergent: 
Missing AE start day: 
• If the partial date contains a different month from the date of first 
study dose, then impute it as the first day of the month. 
• If it contains the same month as the date of first dose, then impute it as 
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Missing AE start day and month: 
• If the partial date contains a different year from the date of first dose, 
then impute the missing day and month as Dec 31. 
• If it contains the same year as the date of first dose, then impute the 
missing day and month as day and month of first dose. 
Completely missing AE date: 
• Impute the missing date as the date of first dose. 
A medication or procedure is considered to be concomitant if it has a start or end date 
on or after the date of first dose of study treatment and on or before the last day of On 
Study Follow-Up. In order to determine whether a medication or procedure with an 
incomplete or missing start or end date is concomitant, the following criteria will be 
used:  
• If both the start and stop dates of a particular medication are missing, 
that medication will be considered concomitant. 
• If the start date of a medication is missing and the stop date of that 
medication falls on or after the first dose date, that medication will be 
considered concomitant. 
• If the start date of a medication is missing and the stop date of the 
medication is prior to the first dose date, that medication is considered 
not concomitant. 
• If the start date of a medication is prior to the first dose date and the 
stop date of the medication is missing, that medication is considered 
concomitant. 
3.2 Analysis Populations and Subgroups 
3.2.1 Intent-to-Treat Population 
The Intent-To-Treat (ITT) Population and the Safety Population are the same for this 
study and are defined as all subjects who receive at least one dose of tremelimumab, 
durvalumab, or polyICLC. All tables, listings, and figures will identify this group of 
subjects as the ITT Population. 
3.2.2 Per-Protocol Population for DLT Assessment in Phase 1  
The Per-Protocol Population for DLT Assessment includes subjects in Cohorts 1A 
through 1C who fulfill the criteria below.   
(1) All subjects who experience a DLT at any time during the DLT Evaluation 
Period (as defined in Protocol Section 3.1.9).  


 
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(2) All subjects with no DLT who receive at least 75% of the total dose of each 
study drug and undergo respective safety assessments, without major protocol 
violations, over the entire DLT evaluation period.  
 
Subjects who fulfill the criteria will be identified by the Sponsor.  
3.2.3 Per-Protocol Population for Phase 2 Clinical Efficacy 
Subjects in the Phase 1 cohort treated at the RCD and in Phase 2 who receive the 
minimum required dose of each study drug and undergo appropriate disease 
assessments (radiological or clinical), without major protocol violations that could 
impact assessments of efficacy, are considered fully evaluable and will be included in 
the Per-Protocol (PP) Analysis Population. The minimum required dose of each study 
drug that a subject must receive to be fully evaluable is: 
• 2 durvalumab infusions (including partial infusions over 50%) 
• 3 of 5 tremelimumab administrations 
• 10 of 14 polyICLC administrations (regardless of route) 
The Sponsor will provide a list of the subjects who meet the above criteria, which will 
be cross-checked with the treatment exposure data collected on the CRF. Subjects in 
Phase 2 who do not meet these requirements may be replaced. The PP Population will 
be used for analysis of clinical efficacy, in addition to the ITT Population. Subjects 
will be analyzed by disease type. 
3.3 Analysis Variables 
3.3.1 Efficacy Variables 
The evaluation of clinical efficacy is the primary objective of Phase 2 and the 
secondary objective of Phase 1. Clinical efficacy will be determined by tumor 
response, PFS, and OS, using irRECIST as the primary method and RECIST 1.1 as 
the secondary method (see Protocol Section 8.5). 
Subsequent imaging at a minimum of 4 weeks after first documentation of 
progression is recommended as per irRECIST.  
If there is clinical progression or progressive disease resulting in the subject 
discontinuing treatment (defined as the last dose date occurring no more than 7 days 
after the date of progression), confirmation of progression would not be expected.  
Confirmation is also not expected for progressions identified in the post-study follow-
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Post-study follow-up visits collect the investigator’s assessment of disease 
progression via both irRECIST and RECIST. A post-study assessment of “No 
Progressive Disease” will assume that subject’s previous irRECIST/RECIST 
assessment remains in effect. A post-study assessment of “Progressive Disease Not 
Previously Reported” will be considered as a confirmed Disease Progression. 
Appendices 5.1-5.2 contain the general algorithms for confirming response using 
irRECIST and RECIST 1.1.  
3.3.1.1 Objective Response Rate 
ORR is defined as the percentage of evaluable subjects meeting criteria of complete 
response (CR) or partial response (PR), confirmed at a subsequent time point (≥ 4 
weeks). In calculating ORR, subjects who drop out prior to meeting the responder 
criteria will be considered as non-responders. Tumors injected and/or biopsied during 
the study will not be considered measurable for ORR but will be assessed as non-
measureable lesions to the extent that marked progression of a non-measurable lesion 
is inconsistent with an objective response. 
3.3.1.2 Overall Disease Control Rate 
Overall Disease Control Rate (ODCR) is defined as the percentage of subjects who 
have stable disease (SD) for at least 6 months, or PR or CR over a period of at least 4 
weeks. In calculating ODCR, subjects who drop out prior to meeting the responder 
criteria will be considered as non-responders. 
3.3.1.3 Progression-Free Survival Time 
PFS will be defined as the number of days from the date of first dose of study drug to 
the date of earliest disease progression based on irRECIST, clinical progression or to 
the date of death, if disease progression does not occur. PFS based on RECIST 1.1 
will also be presented but will not be the primary method. If a subject does not 
experience progression or death by the last on study follow-up or is lost to follow-up, 
then the subject will be censored at the date of the last adequate tumor assessment. 
One exception to this is a subject who completes the study or discontinues the study 
for reasons other than progression (e.g., AE) and did not receive any alternate anti-
cancer treatment. In these cases, the post study follow-up visits will be examined for 
disease assessments until progression is noted. If progression is not noted, then the 
subject will be censored at the date of the last “No Progressive Disease” assessment 
in the post study follow-up, using the same criteria (RECIST 1.1, irRECIST, or 
“Unequivocal Clinical Progression”, as applicable). See Section 3.8.2 for additional 
details. Subjects with no relevant tumor response assessment will be censored at the 
start of treatment. Appendix 5.3 contains complete details regarding censoring for 
PFS. 


 
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3.3.1.4 Overall Survival Time 
OS time will be based on data collected during the study and Post Study Follow-Up 
and is defined as the number of days from the date of first dose until the recorded date 
of death due to any cause, or last follow-up. Subjects who are still alive and subjects 
lost to follow-up will be censored on the date when they were last known to be alive. 
Every effort will be made to follow subjects for OS after they complete or discontinue 
the study.  
3.3.2 Safety Variables 
The evaluation of safety and tolerability is a secondary objective for all cohorts. 
Safety variables include clinical laboratory results, vital signs, physical examinations, 
and AEs. Clinically significant abnormalities on the ECG or noted during the physical 
examination are reported as AEs on the CRF. 
3.3.2.1 Adverse Events 
All AEs will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA) Version 19.0 and will be classified by MedDRA System Organ Class 
(SOC) and Preferred Term (PT). Analyses of AEs will be based on the principle of 
treatment emergence. An AE is considered to be treatment-emergent if it has a start 
date/time on or after the date/time of first dose of study drug. Please reference Section 
3.1.8 for the handling of partial date/time in determining treatment emergence. 
3.3.2.2 Clinical Laboratory Evaluations 
For each continuous laboratory parameter, results will be categorized as low, normal, 
or high based on the laboratory normal ranges. Change and shift in chemistry, 
hematology, and coagulation parameters from baseline to relevant time points will be 
calculated. 
Clinical laboratory tests include: 
• Hematology: WBC, Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, RBC, Hemoglobin, Hematocrit, Platelets 
• Chemistry: glucose, BUN, creatinine, Na, K, Cl, CO2, Ca, Mg, protein, alb, 
Tbili, AST, ALT, ALP, LDH, Free T3, Free T4, TSH, Amylase, lipase 
• Coagulation: PT, aPTT, INR 
• Urinalysis 
• Serum pregnancy test 


 
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3.3.2.3 Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral temperature. Change from baseline to relevant time points will be calculated. 
3.3.3 Biological Activity Variables 
The exploratory objective for all cohorts is to evaluate biological activity. Biological 
activity variables will be analyzed by another entity and are not included in the 
analysis sections below. 
3.4 Subject Disposition and Evaluability 
3.4.1 Subject Disposition 
Subject disposition will be summarized by cohort and overall in Phase 1, by disease 
type in Phase 2 (including the Phase 1 cohort treated at the RCD), and overall (all 
subjects). The number of subjects enrolled, and the numbers and percentages of 
subjects in the ITT Population and the relevant PP Populations will be presented. The 
numbers and percentages of Phase 1 subjects evaluable for DLT, experiencing a DLT, 
completing and not completing treatment and the reasons for treatment 
discontinuation, and completing and not completing the study (including the 90 day 
On Study Follow-Up period) and reasons for study discontinuation will also be 
summarized. All percentages will be based on the number of subjects in the ITT 
Population. 
All subject disposition data will be presented in listings. Subject disposition during 
Post Study Follow-Up will also be listed. 
3.4.2 Protocol Deviations 
All protocol deviations will be shown in a subject listing. Protocol deviations that 
exclude Phase 1 subjects treated at the RCD or Cohort 2 subjects from the PP 
Population will be flagged. 
3.5 Demographics and Baseline Characteristics 
Summaries of subject demographics and baseline characteristics will be provided for 
Phase 1 by cohort (and total for Phase 1), for Phase 2 by disease type (including the 
Phase 1 cohort treated at the RCD), and overall for all subjects in the ITT Population 
for Phase 1 and Phase 2 combined. 


 
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3.5.1 Demographics and Baseline Characteristics 
Descriptive statistics will be provided for age (years), height (cm), weight (kg), and 
body mass index [BMI (kg/m2)]. Frequencies and percentages will be tabulated for 
sex, primary race, and ethnicity. 
Demographics will be presented in a subject listing. 
3.5.2 Baseline Disease Characteristics 
Frequencies and percentages will be presented for Eastern Cooperative Oncology 
Group (ECOG) performance status, TNM(B) classification, tumor staging at initial 
diagnosis, tumor staging at study entry, and whether a subject had prior oncological 
treatment, radiation, and surgery. 
Baseline disease characteristics will be presented in a subject listing. 
3.5.3 Non-Oncological Medical History 
Medical history will be coded by body system and preferred term using MedDRA 
Version 19.0. Frequency and percentage of subjects having a non-oncological 
medical condition in each body system will be summarized for Phase 2 by disease 
type (including the Phase 1 cohort treated at the RCD) and overall for all subjects in 
the ITT population combined. 
Non-oncological medical history will be presented in a subject listing. 
3.5.4 Oncological Medical History 
Prior cancers not under study, oncological treatment, radiation, and surgical history 
will be presented in subject listings. 
3.6 Prior and Concomitant Medications/Procedures 
A concomitant medication is defined as any drug or substance administered between 
the date of the first dose of study treatment and the last day of On Study Follow-Up. 
This includes medications that were started prior to screening, if their use continued 
during or after dosing. Similarly, a concomitant procedure is any medical 
procedure/surgery undergone between the date of the first dose of study treatment and 
the last day of On Study Follow-Up. Refer to Section 3.1.8 for the handling of 
incomplete/partial dates in determining whether a medication or procedure is 
concomitant. 
Concomitant medications will be coded using the World Health Organization Drug 
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(ATC) Level 4 and PT. Frequencies and percentages of subjects using each 
concomitant medication will be presented for Phase 2 by disease type (including the 
Phase 1 cohort treated at the RCD) and overall for all subjects in the ITT population 
combined. The summary will be sorted alphabetically by ATC level 4 term, and 
within ATC level 4 term, by decreasing PT frequency for all subjects. 
Concomitant procedures/surgeries will be coded based on MedDRA Version 19.0 
using SOC and PT. All prior and concomitant medications and procedures/surgeries 
will be presented in subject listings. 
3.7 Treatment Exposure 
Descriptive statistics will be displayed for treatment duration (weeks), total number of 
cycles treated, total number of doses received, and cumulative dose of each study 
treatment [Durvalumab (MEDI4736), PolyICLC, Tremelimumab (IV), and 
Tremelimumab (ITM)] for Phase 1 by cohort (and total for Phase 1), for Phase 2 by 
disease type (including the Phase 1 cohort treated at the RCD), and overall for all 
subjects in the ITT Population for Phase 1 and Phase 2 combined. Treatment duration 
will be calculated as follows: [(date of last dose of any study drug – date of first dose 
of any study drug + 1)/7]. Subjects will be counted as treated for a cycle if they 
received any study drug during that cycle. 
All treatment exposure data will be presented in subject listings. 
3.8 Efficacy Analysis 
Each analysis of clinical efficacy (tumor response, PFS, and OS) will be performed as 
indicated within each population: 
• Cohorts 1A-1C, ITT Population – by cohort and overall 
• Phase 1 cohort treated at the RCD + Cohort 2, ITT Population – by disease 
type 
• Phase 1 cohort treated at the RCD + Cohort 2, PP Population – by disease 
type 
Efficacy analysis variables are defined in Section 3.3. 
3.8.1 Tumor Response 
ORR is defined as the percentage of evaluable subjects meeting criteria of CR or PR, 
confirmed at a subsequent time point (≥ 4 weeks). ODCR is defined as the percentage 
of subjects who have SD for at least 6 months, or PR or CR over a period of at least 4 
weeks. 


 
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The ORR, ODCR, and number and percentage of subjects meeting the best overall 
response criteria of CR, PR, SD, and PD based on irRECIST and RECIST 1.1 will be 
displayed, as well as the number and percentage of subjects not evaluable or with 
missing response. Subjects who had no disease assessment based on irRECIST or 
RECIST 1.1 but had clinical progression will be considered as having a best response 
of PD. 
For disease types accruing 6+6=12 subjects, an exact 90% CI for ORR will be 
computed. In calculating ORR and ODCR, subjects who drop out prior to meeting the 
responder criteria will be considered as non-responders. For responders, descriptive 
statistics (n, median, minimum, and maximum) will be presented for duration of 
response, defined as the time from the first response of PR or CR to the date of 
disease progression or death. 
All irRECIST and RECIST 1.1 target lesions, non-target lesions, tumor response, and 
new lesions will be presented in subject listings. 
3.8.2 Progression-Free Survival 
PFS is defined as the number of days from the date of first dose of study drug to the 
date of earliest disease progression based on irRECIST or clinical progression, or to 
the date of death, if disease progression does not occur during treatment and/or on-
study follow-up. PFS based on RECIST 1.1 will also be presented but will not be the 
primary method. Appendix 5.3 contains complete details regarding censoring for 
PFS. 
Tumor response progressions reported during the post-study follow-up period will be 
included in the derivation of PFS if: 
(1) The frequency of the tumor assessment was performed according to standard 
of care and preferably using irRECIST and/or RECIST 1.1 or was 
“Unequivocal Clinical Progression”, with the method recorded in the eCRF; 
and 
(2) The subject a) did not start any alternative anti-cancer therapy; b) did not have 
any prior follow-up visits which were missing or where disease progression 
status was ‘Unknown’ (the sponsor will manually review and confirm these 
cases), and c) was not lost to follow-up during the post-study follow-up 
period.  
Progressions based on irRECIST require confirmation at a subsequent assessment at 
least 4 weeks after the first documentation of progression (exceptions for clinical 
progressions and post-study follow-up progressions, as described in Section 3.3.1). 
When confirmation is required, the date of progression is the date of the first 
documentation of progression. 


 
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The number and percentage of subjects who experienced disease progression, died 
without progression, survived without progression, discontinued from treatment or 
the study, initiated alternate therapy, progressed or died following two or more 
missed tumor assessments, were lost to follow-up (unknown survival and/or 
progression status), and are missing baseline or post-baseline tumor response 
assessments will be presented. Subjects are considered as having baseline tumor 
assessments if they have at least one target lesion at baseline. Descriptive statistics 
(minimum, maximum, 25th percentile, median, 75th percentile, and the corresponding 
95% CIs) will be presented for PFS time using the Kaplan-Meier method. 
Additionally, the Kaplan-Meier PFS curve will be displayed graphically by disease 
type using both irRECIST and RECIST 1.1 response criteria. 
3.8.3 Overall Survival 
OS time is defined as the number of days from the date of first dose until the recorded 
date of death due to any cause, or last follow-up.  
The number and percentage of subjects who died, survived, and were lost to follow-
up at the end of the study will be presented. Subjects who are still alive or who were 
lost to follow-up will be censored on the date when they were last known to be alive. 
Descriptive statistics (minimum, maximum, 25th percentile, median, and 75th 
percentile, and the corresponding 95% CIs) will be presented for OS time using the 
Kaplan-Meier method. Median duration of follow-up and the 95% CI for the median 
will be calculated using a reverse Kaplan-Meier analysis. 
Additionally, the Kaplan-Meier OS curve will be displayed graphically by disease 
type. 


 
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3.9 Safety Analysis 
All safety analyses will be performed using the ITT Population and presented by 
Phase 2 disease type (including the Phase 1 cohort treated at the RCD) and overall 
(all subjects in Phase 1 and Phase 2 combined), unless otherwise indicated. 
3.9.1 Adverse Events 
All adverse events will be coded using MedDRA Version 19.0 and will be classified 
by MedDRA SOC and PT. 
Analyses of AEs will be based on the principle of treatment emergence. A treatment-
emergent AE (TEAE) is an AE occurring or worsening in severity on or after the 
date/time of first dose of study drug. Please reference Section 3.1.8 for the handling 
of partial date/time in determining treatment emergence. 
For the presentation of AE incidences, the SOCs will be sorted alphabetically, and 
within SOC, the PTs will be presented by decreasing frequency in all subjects and 
then alphabetically. Summaries by PT alone will be presented by decreasing 
frequency in all subjects and then alphabetically. If a subject has more than one 
occurrence of the same PT, then the PT will be counted only once for that subject. 
Similarly, if a subject has more than one PT within the same SOC, the subject will be 
counted only once in that SOC. AE summaries will be presented for Phase 2 by 
disease type (including the Phase 1 cohort treated at the RCD) and overall for all 
subjects (Phase 1 + Phase 2) in the ITT population. 
All AEs, TEAEs, treatment-related TEAEs (TRAEs), TEAEs leading to study 
treatment discontinuation, serious adverse events (SAEs), DLTs, and deaths will be 
displayed in subject listings. 
3.9.1.1 Summary of TEAEs 
The numbers and percentages of subjects who experienced any TEAE, treatment-
related TEAEs (TRAEs), DLTs, TEAE with Common Terminology Criteria for 
Adverse Events (CTCAE) grade 3 or higher, TRAE with CTCAE grade 3 or higher, 
SAEs, treatment-related SAEs, TEAEs leading to treatment discontinuation, and 
death will be presented. TRAE is defined as a TEAE with a relationship to any study 
treatment (tremelimumab, durvalumab, or PolyICLC) of “Possibly Related”, 
“Probably Related”, or “Definitely Related”. This summary will also be displayed for 
Phase 1 by cohort and overall within Phase 1. 
3.9.1.2 Incidence of TEAEs 
The number and percentage of subjects who experienced any TEAE as well as the 
number and percentage of subjects who experienced any TEAE within each specific 


 
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SOC and PT will be presented. A summary table of TEAEs by PT will also be 
presented.  
3.9.1.3 TEAEs by Maximum CTCAE Grade 
The incidence of TEAEs will be presented by maximum CTCAE grade for each SOC 
and PT. If a subject experiences more than one occurrence of the same PT, the subject 
will be counted only once under the maximum severity grade at which it was 
experienced. TEAEs with missing severity will be classified as missing. 
3.9.1.4 Treatment-Related TEAEs 
TEAEs with a relationship to any study treatment (tremelimumab, durvalumab, or 
PolyICLC) of “Possibly Related”, “Probably Related”, or “Definitely Related” will be 
classified as treatment-related and presented by SOC and PT. TEAEs with missing 
relationship will be classified as treatment-related. Additionally, TRAEs should be 
broken out by relationship to each individual study drug. 
3.9.1.5 Treatment-Related TEAEs by Maximum CTCAE Grade 
The incidence of TRAEs will be presented by maximum CTCAE grade for each SOC 
and PT. If a subject experiences more than one occurrence of the same PT, the subject 
will be counted only once under the maximum severity grade at which it was 
experienced. TRAEs with missing severity will be classified as missing. 
3.9.1.6 CTCAE Grade ≥ 3 TEAEs 
The incidence of TEAEs with CTCAE grade ≥ 3 will be presented by SOC and PT.  
3.9.1.7 CTCAE Grade ≥ 3 TRAEs 
The incidence of TRAEs with CTCAE grade ≥ 3 will be presented by SOC and PT.  
3.9.1.8 Serious Adverse Events 
The incidence of SAEs will be summarized by SOC and PT. 
3.9.2 Clinical Laboratory Evaluation 
The clinical laboratory parameters that will be collected are listed in Section 3.3.2.2 
and will be analyzed using the ITT Population, for Phase 2 by disease type (including 
the Phase 1 cohort treated at the RCD), and overall (all subjects in Phase 1 and Phase 
2 combined). 
For each continuous laboratory parameter, results will be categorized as low, normal, 
or high based on the laboratory normal ranges. For hematology, coagulation, and 


 
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chemistry parameters, frequencies and percentages will be presented for the shifts in 
these categories (i.e., low to normal, low to high, high to low, etc.) from baseline to 
each post-treatment assessment time point. Additionally, for each continuous 
hematology, coagulation, and chemistry parameter, descriptive statistics will be 
presented for the observed value and change from baseline at each post-baseline 
assessment time point. 
All clinical laboratory values will be presented in subject listings. Out of normal 
range values will be flagged. 
3.9.3 Vital Signs 
Oral temperature, heart rate, systolic and diastolic blood pressure, and respiratory rate 
will be measured at baseline and at select time points before, during, and after 
tremelimumab and durvalumab infusions, according to Protocol Section 6.5. Vital 
signs before, during, and after durvalumab infusions and tremelimumab infusions will 
be analyzed for all subjects combined in the ITT Population. 
Descriptive statistics will be presented for the observed value and change from pre-
dose assessment in the first four cycles. Line plots of mean ± standard error over time 
will be displayed for the first four cycles. 
All vital sign data will be presented in a subject data listing. 
3.9.4 ECG 
Clinically significant ECG abnormalities are reported as AEs on the CRF. 
3.9.5 Physical Examination 
Clinically significant abnormalities noted during the physical examination are 
reported as AEs on the CRF. 
3.10  Biological Activity Analysis 
The analysis of biological activity data will be performed by a separate entity and will 
be described in a separate document. 
 
 


 
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4 List of Tables, Figures and Listings 
 
Table Number  
Title  
Table 14.1.1.1 
Subject Disposition – Dose Escalation Phase – All Subjects  
Table 14.1.1.2 
Subject Disposition – Cohort 1C and Expansion Phase – All 
Subjects 
Table 14.1.2.1 
Demographics and Baseline Characteristics – Dose Escalation 
Phase – Intent-to-Treat Population 
Table 14.1.2.2 
Demographics and Baseline Characteristics – Cohort 1C and 
Expansion Phase – Intent-to-Treat Population 
Table 14.1.3.1 
Baseline Disease Characteristics – Dose Escalation Phase – 
Intent-to-Treat Population 
Table 14.1.3.2 
Baseline Disease Characteristics – Cohort 1C and Expansion 
Phase – Intent-to-Treat Population 
Table 14.1.4  
Non-Oncological Medical History – Cohort 1C and Expansion 
Phase – Intent-to-Treat Population  
Table 14.1.5  
Concomitant Medication – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population 
Table 14.1.6.1 
Treatment Exposure – Dose Escalation Phase – Intent-to-Treat 
Population  
Table 14.1.6.2 
Treatment Exposure – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population 
Table 14.2.1.1 
Tumor Response Based on irRECIST – Dose Escalation Phase 
– Intent-To-Treat Population  
Table 14.2.1.2 
Tumor Response Based on irRECIST – Cohort 1C and 
Expansion Phase – Intent-To-Treat Population 
Table 14.2.1.3 
Tumor Response Based on irRECIST – Cohort 1C and 
Expansion Phase – Per-Protocol Population for Phase 2 
Clinical Efficacy 


 
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Table 14.2.1.4 
Tumor Response Based on RECIST 1.1 – Dose Escalation 
Phase – Intent-To-Treat Population  
Table 14.2.1.5 
Tumor Response Based on RECIST 1.1 – Cohort 1C and 
Expansion Phase – Intent-To-Treat Population 
Table 14.2.1.6 
Tumor Response Based on RECIST 1.1 – Cohort 1C and 
Expansion Phase – Per-Protocol Population for Phase 2 
Clinical Efficacy 
Table 14.2.2.1  
Summary of Progression-Free Survival (PFS) Based on 
irRECIST – Dose Escalation Phase – Intent-to-Treat 
Population  
Table 14.2.2.2 
Summary of Progression-Free Survival (PFS) Based on 
irRECIST – Cohort 1C and Expansion Phase – Intent-to-Treat 
Population 
Table 14.2.2.3 
Summary of Progression-Free Survival (PFS) Based on 
irRECIST – Cohort 1C and Expansion Phase – Per-Protocol 
Population for Phase 2 Clinical Efficacy 
Table 14.2.2.4 
Summary of Progression-Free Survival (PFS) Based on 
RECIST 1.1 – Dose Escalation Phase – Intent-to-Treat 
Population  
Table 14.2.2.5 
Summary of Progression-Free Survival (PFS) Based on 
RECIST 1.1 – Cohort 1C and Expansion Phase – Intent-to-
Treat Population 
Table 14.2.2.6 
Summary of Progression-Free Survival (PFS) Based on 
RECIST 1.1 – Cohort 1C and Expansion Phase – Per-Protocol 
Population for Phase 2 Clinical Efficacy 
Table 14.2.3.1 
Summary of Overall Survival (OS) – Dose Escalation Phase – 
Intent-to-Treat Population  
Table 14.2.3.2 
Summary of Overall Survival (OS) – Cohort 1C and 
Expansion Phase – Intent-to-Treat Population 


 
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Table 14.2.3.3 
Summary of Overall Survival (OS) – Cohort 1C and 
Expansion Phase – Per-Protocol Population for Phase 2 
Clinical Efficacy 
Table 14.3.1.1.1 
Summary of Adverse Events – Dose Escalation Phase – Intent-
to-Treat Population 
Table 14.3.1.1.2 
Summary of Adverse Events – Cohort 1C and Expansion 
Phase – Intent-to-Treat Population 
Table 14.3.1.2 
Incidence of Treatment Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – Cohort 
1C and Expansion Phase – Intent-to-Treat Population  
Table 14.3.1.3  
Incidence of Treatment Emergent Adverse Events by 
MedDRA Preferred Term – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population 
Table 14.3.1.4 
Incidence of Treatment Emergent Adverse Events by 
Maximum CTCAE Grade, MedDRA System Organ Class and 
Preferred Term – Cohort 1C and Expansion Phase – Intent-to-
Treat Population  
Table 14.3.1.5.1  
Incidence of Treatment-Related Treatment Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– Cohort 1C and Expansion Phase – Intent-to-Treat Population  
Table 14.3.1.5.2 
Incidence of Tremelimumab-Related Treatment Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term – Cohort 1C and Expansion Phase – Intent-to-
Treat Population 
Table 14.3.1.5.3 
Incidence of Durvalumab-Related Treatment Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term – Cohort 1C and Expansion Phase – Intent-to-
Treat Population 
Table 14.3.1.5.4 
Incidence of PolyICLC-Related Treatment Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– Cohort 1C and Expansion Phase – Intent-to-Treat Population 


 
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Table 14.3.1.6  
Incidence of Treatment-Related Treatment Emergent Adverse 
Events by Maximum CTCAE Grade, MedDRA System Organ 
Class and Preferred Term – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population  
Table 14.3.1.7 
CTCAE Grade ≥ 3 Treatment Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – Cohort 
1C and Expansion Phase – Intent-to-Treat Population  
Table 14.3.1.8 
CTCAE Grade ≥ 3 Treatment-Related Treatment Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term – Cohort 1C and Expansion Phase – Intent-to-
Treat Population 
Table 14.3.1.9 
Incidence of Serious Treatment Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – Cohort 
1C and Expansion Phase – Intent-to-Treat Population  
Table 14.3.2.1 
Hematology Parameters – Change from Baseline – Cohort 1C 
and Expansion Phase – Intent-to-Treat Population  
Table 14.3.2.2 
Hematology Parameters – Shift from Baseline to Post-Baseline 
Limits of Normal by Visit – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population  
Table 14.3.2.3 
Chemistry Parameters – Change from Baseline – Cohort 1C 
and Expansion Phase – Intent-to-Treat Population  
Table 14.3.2.4 
Chemistry Parameters – Shift from Baseline to Post-Baseline 
Limits of Normal by Visit – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population  
Table 14.3.2.5 
Coagulation Parameters – Change from Baseline – Cohort 1C 
and Expansion Phase – Intent-to-Treat Population  
Table 14.3.2.6 
Coagulation Parameters – Shift from Baseline to Post-Baseline 
Limits of Normal by Visit – Cohort 1C and Expansion Phase – 
Intent-to-Treat Population  


 
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Table 14.3.3.1 
Vital Signs for Tremelimumab Infusions in the First 4 Cycles 
– Change from Pre-Dose – Cohort 1B – Intent-to-Treat 
Population  
Table 14.3.3.2 
Vital Signs for Durvalumab Infusions in the First 4 Cycles – 
Change from Pre-Dose – Dose Escalation and Expansion 
Phases Combined – Intent-to-Treat Population  
 
 
 


 
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Listing Number  
Title  
Listing 16.2.1  
Subject Disposition 
Listing 16.2.2 
Protocol Deviations  
Listing 16.2.3 
Demographics and Baseline Characteristics  
Listing 16.2.4 
Baseline Disease Characteristics  
Listing 16.2.5.1  
Non-Oncological Medical History  
Listing 16.2.5.2 
Other Oncological Medical History  
Listing 16.2.5.3 
Oncological Drug History for Disease Under Study 
Listing 16.2.5.4 
Oncological Radiation History for Disease Under Study 
Listing 16.2.5.5  
Oncological Surgery History for Disease Under Study 
Listing 16.2.6.1 
Prior and Concomitant Medications 
Listing 16.2.6.2 
Prior and Concomitant Procedures/Surgeries 
Listing 16.2.7  
Study Drug Administration  
Listing 16.2.8 
Post Study Follow-up  
Listing 16.2.9.1.1 
RECIST 1.1/irRECIST Target Lesions  
Listing 16.2.9.1.2 
RECIST 1.1/irRECIST Non-Target Lesions  
Listing 16.2.9.2.1 
irRECIST Tumor Response 
Listing 16.2.9.2.2 
RECIST 1.1 Tumor Response 
Listing 16.2.9.3 
New Lesions 
Listing 16.2.9.4 
irRECIST and RECIST 1.1 Best Overall Response 
Listing 16.2.9.5 
Progression-Free and Overall Survival  
Listing 16.2.10.1 
Adverse Events  


 
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Listing 16.2.10.2  
Treatment-Related Treatment Emergent Adverse Events  
Listing 16.2.10.3 
Treatment Emergent Adverse Events Leading to Study 
Treatment Discontinuation  
Listing 16.2.10.4 
Serious Adverse Events 
Listing 16.2.10.5 
Dose Limiting Toxicities 
Listing 16.2.10.6  
Deaths 
Listing 16.2.11.1  
Laboratory Findings – Hematology  
Listing 16.2.11.2  
Laboratory Findings – Chemistry  
Listing 16.2.11.3 
Laboratory Findings – Urinalysis 
Listing 16.2.11.4 
Laboratory Findings – Coagulation 
Listing 16.2.12 
Vital Signs  
 
 
 


 
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Figure Number  
Title  
Figure 14.2.2.1 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on irRECIST – Dose Escalation Phase – Intent-To-Treat 
Population 
Figure 14.2.2.2 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on irRECIST – Cohort 1C and Expansion Phase – 
Intent-To-Treat Population 
Figure 14.2.2.3 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on irRECIST – Cohort 1C and Expansion Phase – Per-
Protocol Population for Phase 2 Clinical Efficacy 
Figure 14.2.2.4 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on RECIST 1.1 – Dose Escalation Phase – Intent-To-
Treat Population 
Figure 14.2.2.5 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on RECIST 1.1 – Cohort 1C and Expansion Phase – 
Intent-To-Treat Population 
Figure 14.2.2.6 
Kaplan Meier Estimate of Progression-Free Survival (PFS) 
Based on RECIST 1.1 – Cohort 1C and Expansion Phase – 
Per-Protocol Population for Phase 2 Clinical Efficacy 
Figure 14.2.3.1  
Kaplan Meier Estimate of Overall Survival (OS) – Dose 
Escalation Phase – Intent-To-Treat Population 
Figure 14.2.3.2 
Kaplan Meier Estimate of Overall Survival (OS) – Cohort 1C 
and Expansion Phase – Intent-To-Treat Population 
Figure 14.2.3.3 
Kaplan Meier Estimate of Overall Survival (OS) – Cohort 1C 
and Expansion Phase – Per-Protocol Population for Phase 2 
Clinical Efficacy 
Figure 14.3.3.1 
Line Plot of Vital Signs for Tremelimumab Infusions in the 
First 4 Cycles – Cohort 1B – Intent-To-Treat Population 


 
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Figure 14.3.3.2 
Line Plot of Vital Signs for Durvalumab Infusions in the First 
4 Cycles – Dose Escalation and Expansion Phases Combined – 
Intent-To-Treat Population 
 
 
 


 
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5 Appendix 
5.1 Confirmation of Response in irRECIST 
The following table displays the general algorithm for confirming response using 
irRECIST. Confirmation of more complex cases, such as a NE from an unscheduled 
visit between two irCRs, will be programmed appropriately. 
Overall 
Response First 
Time Point  
Overall Response 
Subsequent Time Point  
(at least 4 weeks apart)  
Visit Response at First Time Point  
irCR  
irCR  
irCR  
irCR  
irPR  
irSD, irPD, or irPR 
irCR  
irSD  
irSD provided minimum criteria for irSD 
duration are met at the first time point. 
Otherwise irPD  
irCR  
irPD  
irSD provided minimum criteria for irSD 
duration are met at the first time point. 
Otherwise irPD  
irCR  
NE  
irSD provided minimum criteria for irSD 
duration are met at the first time point. 
Otherwise NE  
irPR  
irCR  
irPR  
irPR  
irPR  
irPR  
irPR  
irSD  
irSD  
irPR  
irPD  
irSD provided minimum criteria for irSD 
duration are met at the first time point. 
Otherwise irPD  
irPR  
NE  
irSD provided minimum criteria for irSD 
duration are met at the first time point. 
Otherwise NE  
NE  
NE  
NE  
Abbreviations: CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, NE=Not Estimable 
In addition, irPD is recommended to be confirmed as appropriate by consecutive 
assessment ≥4 weeks after the first documentation. If there is clinical progression or 
progressive disease resulting in the subject discontinuing treatment (defined as the 
last dose date occurring no more than 7 days after the date of progression), 
confirmation of progression would not be expected. Confirmation is also not expected 
for progressions identified in the post-study follow-up period. In the case of irSD, 


 
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measurements must have met the irSD criteria at least once after the first dose of 
study treatment. 
5.2 Confirmation of Response in RECIST 1.1 
The following table displays the general algorithm for confirming response using 
RECIST 1.1. Confirmation of more complex cases, such as a NE from an 
unscheduled visit between two CRs, will be programmed appropriately. 
Overall 
Response First 
Time Point  
Overall Response 
Subsequent Time Point  
Visit Response at First Time Point  
CR  
CR  
CR  
CR  
PR  
SD, PD, or PR  
CR  
SD  
SD  
CR  
PD  
SD  
CR  
NE  
SD  
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD  
PR  
NE  
SD  
NE  
NE  
NE  
Abbreviations: CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, NE=Not Estimable 
*In the case of SD, measurements must have met the SD criteria at least once after 
the first dose of study treatment. 
 


 
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5.3 Censoring Rules for PFS 
The following censoring rules aim to follow the Food and Drug Administration 
guidance on Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
and will be used for PFS analysis. 
Situation  
Date of Progression or Censoring  
Outcome  
No baseline tumor assessments  
Date of first dose 
Censored  
No post-baseline tumor 
assessments, in the absence of 
documented progression or death 
Date of first dose 
Censored 
Documented Progression 
Earliest date of progression 
Event  
No progression  
Date of last scan* 
Censored  
Treatment or study 
discontinuation  
Date of last scan* 
Censored 
Lost to follow-up without 
documented progression 
Date of last scan* 
Censored 
New anticancer treatment started  Date of last scan* prior to new 
anticancer treatment started  
Censored  
Death without documented 
progression and is not after two 
or more missed tumor 
assessment visits  
Date of death  
Event  
Death or progression after two or 
more missed tumor assessment 
visits 
Date of last scan* 
Censored 
[source: https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf] 
*Scheduled or unscheduled visit with a disease assessment of [irCR, irPR, irSD, or 
unconfirmed irPD (for irRECIST)] or [CR, PR, or SD (for RECIST 1.1)]. 
As subjects may have more than one criteria apply for censoring, the following 
hierarchy will implemented: 
(1) If the subject had no baseline tumor assessment, censor at date of first dose. 
(2) Otherwise, if the subject started a new anti-cancer therapy (prior to 
progression), censor at the date of the last adequate tumor assessment on or 
prior to the new therapy. 
(3) Otherwise, if the subject had progression: 
a) If the subject missed two or more tumor assessments prior to progression, 
censor at the later of the date of first dose and the date of the last adequate 
tumor assessment prior to the first missed assessment.† 
b) Otherwise count as an event. 


 
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(4) Otherwise, if the subject died: 
a) If the subject had no post-baseline disease assessment and the death date 
occurred after study day 88 (first scheduled assessment on Day 85 + 3 day 
window), censor at date of first dose. 
b) Otherwise, if the subject missed two or more tumor assessments prior to 
death, censor at the later of the date of first dose and the date of the last 
adequate tumor assessment prior to the first missed assessment.† 
c) Otherwise, count as an event. 
(5) Otherwise, if the subject discontinued treatment or study, censor at the later of 
date of first dose and the date of the last adequate tumor assessment. 
(6) Otherwise, if the subject had no post-baseline tumor assessment and was on 
study after study day 88 (first scheduled assessment on Day 85 + 3 day 
window), censor at date of first dose. 
(7) Otherwise, if the subject was lost to follow-up, censor at the later of the date 
of first dose and the date of the last adequate tumor assessment. 
(8) Otherwise, if the subject is ongoing, censor at the later of the date of first dose 
and the date of the last adequate tumor assessment. 
†The occurrence of two or more missed tumor assessments is not expected on study 
and will be identified by LICR should it occur.