Clinical trial NCT01975831
Conditions: Breast Cancer Ovarian Cancer Colorectal Cancer Cervical Cancer Renal Cell Carcinoma
Sponsor: Ludwig Institute for Cancer Research
Start date: 2013-12-19; Completion date: 2021-07-02
Enrollment: 104 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This was a Phase 1, open-label, nonrandomized, multicenter study of durvalumab and tremelimumab in subjects with advanced cancers who were not eligible for, declined, or failed standard treatment. The primary study objective was to determine the maximum tolerated dose (MTD) and safety profile of the durvalumab and tremelimumab combination. Secondary objectives were to evaluate the pharmacokinetics (PK) and immunogenicity of durvalumab and tremelimumab, and the antitumor activity (tumor response, progression-free survival \[PFS\], and overall survival \[OS\]) of the durvalumab and tremelimumab combination. (Note: Collection of PK and immunogenicity samples was removed by amendment; analysis was not done.) Exploratory objectives were to evaluate the biological activity of the durvalumab and tremelimumab combination.

Detailed description:
The study comprised a 3 + 3 dose escalation phase in which 3 to 6 subjects were enrolled into sequential cohorts until determination of the MTD, followed by an expansion phase in 5 tumor type-specific cohorts (i.e., ovarian cancer, colorectal cancer, non-triple negative breast cancer, renal cell carcinoma, and cervical cancer). Each expansion cohort was to include 15 subjects treated with the identified MTD or maximum dose tested in the dose-escalation phase.

Subjects received durvalumab and tremelimumab over 12 to 13 four-week cycles during the Core Study, with continuous monitoring for safety, clinical efficacy, and biological activity, followed by optional treatment extension with durvalumab for subjects maintaining at least stable disease if agreed upon by the Investigator and Sponsor. After study treatment completion, study assessments were continued for up to 90 days after the last administration of study treatment or until start of alternate therapy, with long-term follow up after study completion for clinical outcomes at least every 6 months for up to 3 years following initiation of treatment.

Study treatment in the Core Study continued for up to 12 months or until confirmed progressive disease (PD), initiation of alternative cancer therapy, observation of unacceptable toxicity, or any other criteria for treatment discontinuation.

Optional treatment extension beyond the Core Study was permitted for subjects who completed the Core Study with a tumor response of stable disease or better and upon agreement by the Sponsor and Investigator. Extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg administered every 4 weeks (Q4W).

Arms: arm 1: Subjects received durvalumab (0.3 mg/kg every 2 weeks \[Q2W\] for 13 cycles) and tremelimumab (3 mg/kg every 4 weeks \[Q4W\] for 6 cycles, then every 12 weeks \[Q12W\]). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 2: Subjects received durvalumab (1 mg/kg Q2W for 13 cycles) and tremelimumab (3 mg/kg Q4W for 6 cycles, then Q12W). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 3: Subjects received durvalumab (3 mg/kg Q2W for 13 cycles) and tremelimumab (3 mg/kg Q4W for 6 cycles, then Q12W). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 4: Subjects received durvalumab (3 mg/kg Q2W for 12 or 13 cycles) and tremelimumab (1 mg/kg Q4W for 6 cycles, then Q12W or Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 5: Subjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 6: Subjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 7: Subjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 8: Subjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W. arm 9: Subjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab
Intervention descriptions: intervention 1: Durvalumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes. intervention 2: Tremelimumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes.

Protocol documents:
Prot_SAP_000.pdf: 
 
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Study Protocol 
LUD2013-003 
NCT01975831 
US IND# 118511 
Amendment 8 
FINAL 
08-JAN-2019 
 
A Phase 1 Study to Evaluate the Safety and Tolerability of anti-PD-L1, 
MEDI4736, in combination with tremelimumab in Subjects With 
Advanced Solid Tumors 
  
Study Synopsis and Objectives  
Prior to Amendment 5, this was an open label Phase 1 study of a MEDI4736 and tremelimumab 
combination, utilizing a 3+3 dose-escalation phase, with doses of MEDI4736 0.3, 1, 3 and 10 
mg/kg and tremelimumab 1, 3 and 10 mg/kg (see Figure 2: Dose-escalation Schema), followed 
by an expansion phase with 6 disease-specific cohorts in subjects with ovarian cancer, colorectal 
cancer (CRC), non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma 
(RCC) and cervical cancer, who are not eligible for, declined or failed standard treatment, 
treated at the identified maximum tolerated dose (MTD or maximum dose tested).   
Per Amendment 5, the disease states of NSCLC and head and neck cancer were removed from 
the study and were replaced by non-triple negative breast cancer for a total of 5 expansion 
cohorts.  Cohort sample sizes were increased from 12 to 15, for a total of 75 subjects in the 
expansion phase. 
Prior to Amendment 5, MEDI4736 was administered every 2 weeks (Q2W) for 13 cycles. 
Tremelimumab was administered every 4 weeks (Q4W) for the first 6 cycles and then at Cycle 7, 
10 and 13 (every 12 weeks (Q12W)).   
 
Per Amendment 5, the study will continue with enrollment into Cohort 3a and possibly Cohort 
4a, with the following modifications: 
• 
Cohort 3a:  
Tremelimumab, 1mg/kg Q4W for 4 four-week cycles; MEDI4736, 
3 mg/kg Q2W for 12 four-week cycles. 
• 
Cohort 4a: 
Tremelimumab, 75 mg Q4W (for subjects > 30 kg) for 4 four-week 
cycles; MEDI4736, 1500 mg Q4W (for subjects > 30 kg) for 12 four-week cycles. (Note: 
fixed dosing will be implemented for Cohort 4a. See Section 3.1.7 for details.) 
• 
Cohorts 4 and 5 were removed from the study 
The primary objective is to determine the MTD and the safety profile of the MEDI4736 / 
tremelimumab combination.  The secondary objectives are to evaluate the pharmacokinetics 
(PK), immunogenicity of MEDI4736 and tremelimumab, and the antitumor activity of the 
treatment. The exploratory objective is to evaluate the biological activity of the MEDI4736 / 
tremelimumab combination. 
Per Amendment 6, optional treatment extension beyond the original 12- or 13-cycle treatment 
period (Core Study) will be available for subjects who complete the Core Study with Stable 
Disease or better; the optional treatment extension will be permitted upon agreement with 
subject, Sponsor and Investigator.  See Section 8.8 for details. 
 


 
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Sponsor: Ludwig Institute for Cancer Research, Ltd 
 
 
 
 
 
 
 
 
Sponsor representative Signature and Date 
Study Chair: Jedd Wolchok, MD, PhD; Memorial 
Sloan-Kettering Cancer Center 
 
 
 
 
 
 
 
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 Information ......................................................................................................... 7 
 
Advanced Solid Tumors and Immunotherapy ................................................................. 7 
 
CTLA-4 .............................................................................................................................. 7 
 
PD-1 and PD-L1 ................................................................................................................ 8 
 
CTLA-4 blocking antibody tremelimumab ....................................................................... 9 
 
PD-L1 blocking antibody MEDI4736 .............................................................................. 10 
2 
Study Rationale ..................................................................................................................... 12 
 
Rationale for Combining MEDI4736 and tremelimumab .............................................. 12 
 
Rationale for MEDI4736 dose selection ........................................................................ 12 
 
Rationale for tremelimumab dose selection ................................................................. 13 
 
Rationale for Study Design ............................................................................................ 13 
3 
Experimental Plan ................................................................................................................. 15 
 
Study Design .................................................................................................................. 15 
3.1.1 
Study Phase ........................................................................................................... 15 
3.1.2 
Enrollment/Randomization ................................................................................... 15 
3.1.3 
Blinding/Unblinding ............................................................................................... 15 
3.1.4 
Subject Population................................................................................................. 15 
3.1.5 
Number of Sites/Subjects ...................................................................................... 15 
3.1.6 
Sample Size Considerations ................................................................................... 15 
3.1.7 
Treatment Cohorts and Treatment Schema .......................................................... 16 
3.1.7.1 
Dose-escalation Phase, 3+3 Design ............................................................... 17 
3.1.7.2 
Expansion Phase ............................................................................................ 19 
3.1.8 
Dosing Adjustments, Delays and Discontinuations ............................................... 20 
3.1.8.1 
MEDI4736 and tremelimumab Dose Modification Due to Toxicity .............. 20 
3.1.8.2 
MEDI4736 and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities .............................................................................................................. 22 
3.1.8.3 
MEDI4736 and Tremelimumab Discontinuation ........................................... 23 
3.1.9 
DLT and MTD ......................................................................................................... 23 
3.1.10 
Subject Withdrawal from Treatment or from Study ............................................. 25 
3.1.10.1 
Treatment Beyond Progression ..................................................................... 25 
3.1.11 
Per-Protocol Subject Evaluability and Replacement ............................................. 26 
3.1.12 
Optional Study Treatment Extension .................................................................... 26 
3.1.13 
Interim Analysis ..................................................................................................... 26 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 26 
3.1.15 
Duration of Study .................................................................................................. 27 
3.1.16 
On Study and Post-Study Follow-up ...................................................................... 27 
3.1.16.1 
End of Study Visit ........................................................................................... 28 
 
Study Flowcharts ........................................................................................................... 29 
4 
Study Objectives and Endpoints ........................................................................................... 36 


 
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Safety and Tolerability ................................................................................................... 36 
4.1.1 
Endpoints & Assessment Methods ........................................................................ 36 
4.1.2 
Subject Evaluation and Statistics ........................................................................... 36 
4.2 
MEDI4736 and tremelimumab pharmacokinetics ........................................................ 37 
4.2.1 
Endpoints and Assessment Methods .................................................................... 37 
4.2.2 
Subject Evaluation and Statistics ........................................................................... 37 
 
MEDI4736 and tremelimumab Immunogenicity ........................................................... 37 
4.3.1 
Endpoints and Assessment Methods .................................................................... 37 
4.3.2 
Subject Evaluation and Statistics ........................................................................... 37 
 
Clinical Efficacy .............................................................................................................. 37 
4.4.1 
Tumor Response Assessment by irRC.................................................................... 38 
4.4.2 
Tumor Response Assessment by RECIST ............................................................... 38 
4.4.3 
Progression-free survival (PFS) .............................................................................. 38 
4.4.4 
Overall Survival (OS) .............................................................................................. 38 
4.4.5 
Subject Evaluation and Statistics ........................................................................... 38 
 
Biological activity of MEDI4736/tremelimumab Combination ..................................... 38 
4.5.1 
Endpoints and Assessment Methods .................................................................... 38 
4.5.2 
Subject Evaluation and Statistics ........................................................................... 39 
5 
Subject Eligibility ................................................................................................................... 40 
 
Inclusion Criteria ............................................................................................................ 40 
 
Exclusion Criteria ........................................................................................................... 41 
 
Restrictions on Concomitant Therapies ........................................................................ 44 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 44 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 44 
6 
Study Drugs ........................................................................................................................... 45 
 
MEDI4736 ...................................................................................................................... 45 
6.1.1 
Study Drug Information for MEDI4736 ................................................................. 45 
6.1.2 
MEDI4736 Preparation .......................................................................................... 45 
6.1.2.1 
Preparation of 0.3 mg/kg dose for administration with a syringe ................ 46 
6.1.2.2 
Preparation of 1 mg/kg, 3 mg/kg and 10 mg/kg dose for administration with 
an IV bag  ....................................................................................................................... 47 
6.1.2.3 
Preparation of 1500 mg dose for administration with an IV bag (Amendment 
5 Cohort 4a subjects and for optional study treatment extension) ................................. 47 
6.1.3 
Administration of MEDI4736 ................................................................................. 48 
 
Tremelimumab .............................................................................................................. 49 
6.2.1 
Study Drug Information for Tremelimumab .......................................................... 49 
6.2.2 
Tremelimumab Preparation .................................................................................. 49 
6.2.2.1 
Preparation of 75 mg dose (Amendment 5, Cohort 4a subjects) .................. 50 
6.2.3 
Administration of Tremelimumab ......................................................................... 51 
 
Assessment of Vital Signs during Administration of Study Drugs ................................. 52 
 
Estimated Study Requirements ..................................................................................... 52 
 
Drug Overdose Management ........................................................................................ 52 


 
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7 
Administrative, Legal and Ethical Requirements .................................................................. 53 
 
Documentation and Reporting of Adverse Events ........................................................ 53 
7.1.1 
Definitions ............................................................................................................. 53 
7.1.2 
Additional SAE Definitions for this Study .............................................................. 54 
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 .......................................................................... 54 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 55 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 55 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 56 
7.1.8.1 
Hepatic Function Abnormality ....................................................................... 56 
7.1.8.2 
Pneumonitis ................................................................................................... 57 
7.1.8.3 
Infusion Reactions ......................................................................................... 57 
7.1.8.4 
Hypersensitivity Reactions ............................................................................ 57 
7.1.8.5 
Gastrointestinal Disorders ............................................................................. 57 
7.1.8.6 
Neurotoxicity (Neuropathy/Neuromuscular toxicity .................................... 57 
7.1.8.7 
Endocrine Disorders ...................................................................................... 57 
7.1.8.8 
Dermatitis/Rash ............................................................................................. 57 
7.1.8.9 
Nephritis and increases in serum creatinine ................................................. 58 
7.1.8.10 
Pancreatic Disorders ...................................................................................... 58 
7.1.8.11 
Uveitis ............................................................................................................ 58 
 
Administrative Sponsor Requirements ......................................................................... 58 
7.2.1 
Pre-Study Requirements........................................................................................ 58 
7.2.2 
Study Master Files ................................................................................................. 58 
7.2.3 
Case Report Form Data Collection ........................................................................ 58 
7.2.4 
Language ................................................................................................................ 59 
7.2.5 
Monitoring ............................................................................................................. 59 
7.2.6 
Protocol Amendments ........................................................................................... 59 
7.2.7 
Premature Subject Withdrawal from Treatment or from Study ........................... 60 
7.2.8 
Early Trial Termination .......................................................................................... 60 
7.2.9 
Study Drug Shipments and Accountability ............................................................ 60 
 
Regulatory, Legal and Ethical Requirements ................................................................. 61 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 61 
7.3.2 
Informed Consent .................................................................................................. 61 
7.3.3 
Institutional Review Board .................................................................................... 61 
7.3.4 
Subject Confidentiality .......................................................................................... 61 
7.3.5 
Inclusion of Women and Minorities ...................................................................... 62 
8 
Appendices ........................................................................................................................... 63 
 
Protocol Version History ................................................................................................ 63 
 
Participating Study Sites, Investigators and Staff .......................................................... 79 
 
Participating Laboratories ............................................................................................. 79 
 
Sponsor Information ...................................................................................................... 80 
 
Tumor Response Assessment by irRC............................................................................ 81 


 
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Tumor Response Assessment by RECIST ....................................................................... 83 
 
Laboratory procedures .................................................................................................. 84 
8.7.1 
sPD-L1 .................................................................................................................... 84 
8.7.2 
Flow Cytometry ..................................................................................................... 84 
8.7.3 
PBMC Banking ....................................................................................................... 84 
8.7.4 
Circulating soluble factors ..................................................................................... 84 
8.7.5 
CTC ......................................................................................................................... 84 
8.7.6 
mRNA/miRNA profiling .......................................................................................... 85 
8.7.7 
Archival Tumor Samples and Tumor Biopsies ....................................................... 85 
8.7.7.1 
Archival Tumor Samples ................................................................................ 85 
8.7.7.2 
Tumor Biopsies .............................................................................................. 86 
8.7.8 
Additional translational and exploratory studies .................................................. 86 
 
Details for Subjects who Continue Treatment beyond the Core Study ........................ 87 
8.8.1 
Study Flowchart for Subjects who Continue Treatment beyond the Core Study . 88 
8.8.2 
Reinduction with MEDI4736 and Tremelimumab for Subjects With Confirmed 
Progression ........................................................................................................................... 89 
 
List of Abbreviations ...................................................................................................... 90 
9 
References ............................................................................................................................ 92 
 
Table of Figures  
Figure 1: Treatment Schema Prior to-Amendment 5 .................................................................... 17 
Figure 2: Dose-escalation Schema ................................................................................................. 18 
Figure 3: Expansion Phase Schema ............................................................................................... 19 
 
 


 
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1 Background Information 
 Advanced Solid Tumors and Immunotherapy 
In the United States of America, cancer is the second most common cause of death after heart 
disease, accounting for nearly 1 in every 4 deaths (American Cancer Society, 2011).  The 5-year 
survival rate for all cancers diagnosed between 1999 and 2006 is 68%, which is 18% higher than 
the rate reported between 1975 and 1977, likely reflecting progress in diagnosing certain 
cancers earlier and improvements in treatment (American Cancer Society, 2011).  
Unfortunately, despite this progress, there continues to be an unmet medical need for more 
effective and less toxic therapies, especially for patients with advanced disease that do not 
respond to or have become refractory to existing therapies. 
Recent advances in immunotherapy offer promise for improving clinical outcomes in patients 
with advanced solid tumors.  It is increasingly appreciated that cancers are recognized by the 
immune system, and under some circumstances, the immune system may control or even 
eliminate tumors.(1)  Studies in mouse models of transplantable tumors have demonstrated 
that manipulation of costimulatory or coinhibitory signals can amplify T cell responses against 
tumors.(2)  This may be accomplished by blocking coinhibitory molecules such as Cytotoxic T-
Lymphocyte-associated Antigen-4 (CTLA-4) or Programmed Death-1 (PD-1) from binding with 
their ligands, B7 or B7-H1 (PD-L1).  Based upon robust preclinical activity in mouse models, 
antibodies targeting these coinhibitory molecules have been developed for treatment of human 
cancers.  The human CTLA-4 blocking antibody ipilimumab has demonstrated an overall survival 
benefit in two Phase 3 studies, and was approved by the FDA for the treatment of advanced 
melanoma in 2011 (3, 4) and approved in Europe for the treatment of advanced (unresectable 
or metastatic) melanoma in adults who have received prior therapy.  Additionally, clinical 
activity for PD-1 blocking and PD-L1 blocking antibodies have been reported from Phase 1 
studies.(5, 6) 
 CTLA-4 
CTLA-4, the canonical coinhibitory receptor, was cloned in 1987. (7)  However, it took several 
years to appreciate the unique role of CTLA-4 in attentuating T cell activation (8-10).  CTLA-4 
engagement on activated T cells inhibits cytokine synthesis and restricts cell proliferation.(8, 10-
13)  Characterization of CTLA-4 -/- knockout mice established a critical negative regulatory 
function for CTLA-4 in vivo.  These mice develop a profound, hyperproliferative lymphocyte 
expansion, which is lethal within 3 weeks after birth.(14-16)  On a cellular level, CTLA-4-
mediated inhibition of T cell activion relies on several overlapping mechanisms.  First, CTLA-4 
competes with CD28 for interaction with the ligands B7-1 and B7-2.  Secondly, CTLA-4 
engagement impacts multiple intracellular pathways.  Inhibitory signaling is thought to be 
mediated by (1) association with intracellular phosphatases like Src homology 2 (SH2) domain-
containing phosphatase-1 (SHP-1), SHP-2, and protein phosphatase 2A (PP2A), (2) blockade of 
lipid-raft expression, and (3) disruption of microcluster formation (reviewed by Rudd et al. 2009 
(17)). 


 
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 PD-1 and PD-L1 
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.(18)  The structure of PD-1 is composed of one IGSF domain, a transmembrane domain, 
and an intracellular domain containing an immunoreceptor tyrosine-based inhibitory motif 
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).(19-21)  PD-1 has two 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.(22, 23)  It is found on T cell, B cells, macrophages, NK cells, DCs, 
and mast cells.  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.(9, 24-35)  PD-L1 is constitutively expressed on 
many hematopoietic cells, but may be upregulated in hematopoietic and non-hematopoietic 
cells.  Regulation of PD-L1 is mediated, in part, by type I and type II interferons.  PD-L2 was 
identified in 2001.(36, 37)  Its expression is far more restricted and is confined to hematopoietic 
cells.  
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.(23, 38-42)  Inhibitory signaling by PD-1 is thought to depend upon the cytosolic ITSM 
domain, which associates with phosphatases SHP-1 and SHP-2.(43, 44)  While CTLA-4 and PD-1 
are both inhibitory receptors, they fulfill distinct roles and mediate their effects through distinct 
mechanisms.(45)  For example, PD-1 inhibits activation of the serine threonine kinase Akt via its 
effect on the phosphoinositide 3-kinase (PI3K) pathway, whereas CTLA-4 inhibits Akt in a PI3K 
independent manner.(39, 43, 46)  Studies of PD-1 -/- knockout and PD-L -/- knockout mice 
support unique role for PD-1: PD-L interaction in mediating peripheral tolerance and preventing 
autoimmunity.(27)  The phenotype of the PD-1-/- knockout mouse depends upon the genetic 
background, but manifestations of spontaneous autoimmunity have been reported, including 
dilated cardiomyopathy and glomerulonephritis.(47, 48) 
PD-L1 and PD-L2 are expressed on many human tumors including urothelial, ovarian, breast, 
cervical, colon, pancreatic, gastric cancers as well as melanoma glioblastoma, and NSCLC.(9, 24, 
25, 29, 30, 34, 49-54)  In addition, PD-L1 and PD-L2 have been detected on several hematologic 
malignancies including: Hodgkin lymphoma, primary mediastinal B cell lymphoma, 
angioimmunoblastic T-cell lymphoma, multiple myeloma, acute myeloid leukemia chronic 
lymphocytic leukemia, and adult T-cell leukemia/lymphoma.(28, 55-58)  Expression of PD-L has 
been correlated with prognosis in many these malignancies, fueling the hypothesis that PD-L 
expression is a mechanism for tumor immune evasion.(50, 52, 53, 59)  Additionally, PD-1 is 
highly expressed on lymphocytes infiltrating human tumors and circulating tumor-specific T 
cells, a phenotype correlated with impaired T cell function.(60-63)  Together, these findings 
suggest that interrupting PD-1: PD-L interaction could be an effective anti-cancer therapy. 


 
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 CTLA-4 blocking antibody tremelimumab 
Tremelimumab (formerly CP-675,206) is a human immunoglobulin G2 (IgG2) monoclonal 
antibody (mAb) being investigated as a cancer immunotherapeutic agent.  Tremelimumab is 
specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), with no cross-
reactivity to related human proteins. 
Tremelimumab has been administered as single-agent treatment to subjects participating in 9 
clinical studies, 1 of which continues to follow subjects.  In total, more than 1,300 subjects with 
a variety of tumor types have been treated in these studies, including over 1,000 subjects 
treated with tremelimumab.  In addition, 116 subjects with a variety of tumor types have 
received tremelimumab in combination with other anticancer agents in 5 industry sponsored 
clinical trials. 
Across the clinical development program for tremelimumab, and that of the related anti-CTLA-4 
antibody ipilimumab, a pattern of efficacy has emerged that appears to be consistent across 
tumor types for this mechanism of action.  Response rates to anti-CTLA-4 antibodies are 
generally low, approximately 10%.  However, in subjects who respond, the responses are 
generally durable, lasting months to years even in subjects with aggressive tumors, such as, 
refractory metastatic melanoma.  Some subjects may have had progression of their disease 
early in their treatment, with a delayed tumor response or disease stabilization.  The CTLA-4 
blocking antibody ipilimumab has demonstrated a benefit in OS in two Phase 3 studies of 
subjects with advanced melanoma.  Tremelimumab has also been tested in the Phase 3 setting 
for advanced melanoma, but, at a dose of 15 mg/kg every 3 months, it failed to demonstrate 
improved overall survival.  The present study is testing an alternative dosing schedule, 10 mg/kg 
monthly that has been tested in a Phase 2 study.  The profile of 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, which appears to be confined to subjects with melanoma).  
Events reported at a frequency of ≥5% and assessed by the investigator as related to treatment 
(listed in descending order of frequency) were diarrhea, rash, pruritus, fatigue, nausea, 
vomiting, anorexia, headache, abdominal pain, and colitis.  Infusion-related side effects are rare.  
Age, gender, baseline hepatic or renal function, and body mass index do not appear to influence 
the number, type, or severity of AEs observed, although older subjects appear to tolerate 
diarrhea less well.  Acute renal failure was seen in subjects who received the combination of 
tremelimumab and sunitinib in a Phase 1 study; however, acute renal failure has not been an 
expected AE for tremelimumab as a single agent in other tumors, and was not seen in a Phase 2 
study of ipilimumab in RCC.  Of the 132 all-causality deaths among tremelimumab-treated 
subjects that met the reporting criteria for an SAE (120 in single-agent studies, 7 in combination 
studies, and 5 in investigator-led research studies), 13 (10 in single-agent studies, 2 in 
combination studies, and 1 in an investigator-led research study) were due to SAEs judged to be 
related or possibly related to tremelimumab.  The treatment-related deaths were attributed to 
colitis, colonic/intestinal perforation, diverticular perforation/diverticulitis, pulmonary 
embolism, pneumonia, septic shock, cardiac arrest, electrolyte imbalance, sudden death, and 
hemorrhage. 


 
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 PD-L1 blocking antibody MEDI4736 
MEDI4736 is a human monoclonal antibody of the immunoglobulin G1 kappa (IgG1κ) subclass 
that inhibits binding of B7-H1 (PD-L1, cluster of differentiation [CD]274) to programmed death 1 
(PD-1; CD279) and CD80 (B7-1).  MEDI4736 is composed of 2 identical heavy chains and 2 
identical light chains, with an overall molecular weight of approximately 149 kDa.  MEDI4736 
contains a triple mutation in the constant domain of the immunoglobulin (Ig)G1 heavy chain 
that reduces binding to complement protein C1q and the fragment crystallizable gamma (Fcγ) 
receptors involved in triggering effector function. 
Nonclinical data with MEDI4736 suggest that targeting PD-L1 with a biologic agent could be an 
effective antitumor therapy.  MEDI4736 is a human monoclonal antibody that selectively binds 
human PD-L1 with high affinity and blocks its ability to bind to PD-1 and CD80. 
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation.  PD-L1 acts at multiple sites in the body to help regulate normal immune responses 
by delivering inhibitory signals to T cells through the PD-1 and CD80 receptors. 
Blockade of PD-L1 with MEDI4736 relieved PD-L1-mediated suppression of human T-cell 
activation in vitro.  In a xenograft model, MEDI4736 inhibited human tumor growth via a T-cell-
dependent mechanism.  Moreover, an anti-mouse PD-L1 antibody demonstrated improved 
survival in a syngeneic tumor model when given as monotherapy and resulted in complete 
tumor regression in > 50% of treated mice when given in combination with chemotherapy. 
The first-time-in-human (FTIH) study, currently being conducted by MedImmune, is a 
multicenter, open-label study to evaluate the safety, tolerability, and pharmacokinetics of 
MEDI4736 in subjects with advanced solid tumors.  The study includes a standard 3+3 dose-
escalation phase followed by an expansion phase in melanoma, CRC, and NSCLC.  Dose 
escalation began enrollment at 0.1 mg/kg administered by intravenous infusion every 2 weeks.  
Escalation will continue at dose levels of 0.3, 1, 3, and 10 mg/kg or until a maximum tolerated 
dose (MTD) or optimal biologic dose (OBD) is determined.  Once an MTD or OBD is determined, 
20 subjects will be enrolled in each expansion cohort to further evaluate the safety and 
preliminary antitumor activity of MEDI4736.  
The dose-escalation schema of 0.1, 0.3, 1, 3, and 10 mg/kg MEDI4736 in the FTIH monotherapy 
study was designed to achieve dose levels at which clinical activity may be observed while 
maintaining an adequate safety margin.  The starting dose of 0.1 mg/kg is approximately 1/30 of 
the maximum recommended starting dose (MRSD).  The MRSD was determined based on the 
no-observed adverse-effect-level (NOAEL) of 100 mg/kg in nonclinical studies in cynomolgus 
monkeys (US FDA, 2005).  The MRSD in a 70-kg individual is 3.2 mg/kg, calculated by applying an 
allometric scaling factor of 3.1 and a safety factor of 10 to the NOAEL (100 mg/kg).  
Following intravenous dosing MEDI4736 exhibited multiphasic pharmacokinetics (PK) and 
exposure that increased supra proportionally with dose from 0.1 to 1 mg/kg. These findings 
were consistent with the PK observed in preclinical studies in cynomolgus monkeys. Where 
evaluable, exposures following multiple doses demonstrated exposures and limited 
accumulation consistent with the half-lives estimated from the first dose in each group (mean 


 
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half-lives of 1.8 (SD 0.3), 2.8 (SD 1) and 7.8 (SD 1.5) days in the 0.1, 0.3 and to 1 mg/kg dose 
groups respectively). 
The FTIH trial, Study 1108 (NCT01693562), is the first clinical study with MEDI4736.  As of 
09Jun2013, a total of 14 subjects have been enrolled in the dose-escalation phase of the study 
where MEDI4736 is administered Q2W, including 4 subjects in each of the 0.1 and 0.3 mg/kg 
cohorts and 3 subjects in each of the 1.0 and 3.0 mg/kg cohorts.  One subject in the 0.1 mg/kg 
cohort was replaced after receiving her 2nd infusion of MEDI4736 during the DLT evaluation 
period over 4 hours rather than the 60 minutes specified per protocol.  In addition, one subject 
in the 0.3 mg/kg cohort was replaced after discontinuing MEDI4736 treatment due to an 
unrelated intercurrent illness prior to completing the DLT evaluation period.  
Overall, subjects have received from 1 to 16 doses of MEDI4736.  One subject (0.1 mg/kg 
cohort) experienced a dosing interruption due to a Grade 2 infusion-related reaction during 
administration of Dose 1, although the entire dose was ultimately received.  Two additional 
infusion-related reactions were observed for this subject that did not interrupt dosing. 
Subsequent doses for this subject were administered with corticosteroid prophylaxis and the 
subject has received 16 doses of MEDI4736 to date with no further infusion-related reactions.  
Of the 14 subjects enrolled, 12 subjects have reported at least one AE.  The most common AEs 
were diarrhea (4 subjects); cough, fatigue, nausea, pyrexia (3 subjects each); and bronchitis, 
dizziness, dyspnea, headache, peripheral edema, upper-airway cough syndrome, and vomiting 
(2 subjects each).  All AEs were Grade 1 or 2 in severity with the exception of a Grade 5 disease 
progression in a subject in the 0.1 mg/kg cohort (see below).  Five subjects experienced 
treatment-related AEs (i.e., infusion-related reaction, rash, diarrhea, nausea, vomiting, fatigue, 
dizziness, and pruritus).  No subject has experienced a dose-limiting toxicity (DLT) as defined by 
the protocol.  
Three subjects have experienced SAEs; these events were disease progression (0.1 mg/kg 
cohort) in a subject with non-small cell lung cancer, diarrhea and abdominal pain (0.3 mg/kg 
cohort) in a subject with colorectal cancer, and pyrexia and pneumonia (0.3 mg/kg cohort) in a 
subject with non-small cell lung cancer, all of which were assessed by the investigator as not 
related to MEDI4736.  One subject in the 0.1 mg/kg cohort died due to disease progression; a 
white male with non-small cell lung cancer died on 11Nov2012, 18 days after receiving his third 
dose of MEDI4736.  The event was considered not related to investigational product; disease 
progression was confirmed through radiographic assessment.  No other subjects have 
discontinued treatment due to an AE.   
The dose-escalation committee (which includes MedImmune clinical and safety team members 
and all participating investigators) reviewed all of the safety data and agreed to escalate to the 
10.0 mg/kg dose on 06Jun2013.   
Updated safety data for MEDI4736 dose of 10 mg/kg will be made available to the investigators 
prior to starting cohorts at MEDI4736 10 mg/kg dose level in this study.  
See updates per Amendment 5 in Section 2.4. 
 
 


 
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2 Study Rationale 
 Rationale for Combining MEDI4736 and tremelimumab  
There is sound rationale for evaluating the combination of MEDI4736 and tremelimumab for the 
treatment of advanced solid tumors in a Phase 1 dose escalation study.  Firstly, the mechanisms 
of activation of known sites for activity for CTLA-4 and PD-1 are non-redundant, suggesting that 
targeting both pathways may have additive or synergistic activity.(64)  Secondly, preclinical data 
in mouse models of transplantable solid tumors supports the superior anti-tumor activity of 
combination therapy over monotherapy.(65, 66)  Based upon these observations, combination 
therapy may generate superior anti-tumor activity (compared to monotherapy), which may 
translate into high rates of response in tumors known to respond to immunotherapies, or 
increased likelihood of activity in tumors that have previously not shown high levels of 
responsiveness to immunotherapy.  In a recently reported study of the combination of similar 
agents, nivolumab, a PD-1 blocking antibody, with ipilimumab, a CTLA-4 blocking antibody, it 
was demonstrated that the agents could be combined with a manageable safety profile.  Using a 
dosing schedule of nivolumab and ipilimumab of every 3 weeks for 4 doses followed by every 
12 weeks for up to 8 doses, durable tumor regressions were seen.  As this was a Phase 1 dose 
escalation study, doses exceeding the MTD were established (3 mg/kg ipilimumab plus 3 mg/kg 
nivolumab Q3 weeks x 4 doses, followed by maintenance dosing of both drugs on an alternative 
schedule).  Clinical activity of the concurrent combination appeared to exceed that of published 
monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 weeks) 
in 53% (9/17) of subjects treated at the selected dose of 1 mg/kg nivolumab plus 3 mg/kg 
ipilimumab and an objective response rate of 40% (21/53) across all dose levels.(67)  This 
regimen is currently studied in an ongoing Phase 3 study (NCT01844505). 
As was seen in the combination of nivolumab and ipilimumab, the combination of MEDI4736 
and tremelimumab may increase the frequency or severity of toxicities and thus, a Phase 1 dose 
escalation study in the appropriate setting to explore this combination is indicated.   
Tremelimumab has been evaluated in earlier studies and has a well characterized toxicity profile 
and evidence for clinical activity, as outlined above.  The safety, tolerability, pharmacokinetics 
and antitumor activity of MEDI4736 are being evaluated in an ongoing Phase 1 study as 
described in Section 1.5. 
 Rationale for MEDI4736 dose selection 
MEDI4736 dose selection was based upon available clinical, pharmacokinetic, and safety data 
from the ongoing Phase 1 study of MEDI4736.  The range of doses selected was based on 
predicted PD-L1 suppression.  The dose of 0.3 mg/kg is predicted to produce a free PD-L1 level 
of 5 to 10% at Cmax, with a return to greater than 90% of baseline in approximately 10 days. 
The dose of 1 mg/kg MEDI4736 is predicted to achieve free PD-L1 of less than 5% at Cmax, while 
the doses of 10 mg/kg are predicted to achieve free PD-L1 of less than 1% throughout the 
dosing interval.  Safety and tolerability will be established for MEDI4736 monotherapy at each 
dose level prior to combination dosing with tremelimumab.  


 
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The potential of MEDI4736 and tremelimumab to induce cytokine release was tested in a whole 
blood assay system using whole blood from healthy human donors.  In this in vitro study, a 
positive control (mouse anti-human CD3) induced cytokine release in all donors.  However, no 
cytokine induction was observed with either of the isotype negative controls, MEDI4736 or 
tremelimumab as single agents or the combination of MEDI4736 and tremelimumab.  These 
results are consistent with the mechanism of action of MEDI4736 and tremelimumab, and the 
combination is not expected to induce acute cytokine release in humans.  
 Rationale for tremelimumab dose selection 
The target trough concentration of tremelimumab is estimated to be ~ 30 μg/mL based on 
enhanced IL-2 release (in vitro) and antitumor activity (in vivo) in preclinical studies. 
tremelimumab at a dose of 3 mg/kg Q4W is expected to yield a median steady state 
concentration above the target trough level (~30 µg/mL) for about half of the dosing interval 
followed by a decrease in PK exposure with a median steady state trough level of ~17 µg/mL at 
the end of the dosing interval.  Using this schedule, tremelimumab concentrations within an 
individual would be expected to be within the active range, but for a limited period of time, 
thereby providing both an opportunity to elicit biological activity but also a greater safety 
margin as a result of reduced PK exposure.  
Pharmacokinetic simulations indicate that following tremelimumab at a dose of 10 mg/kg Q4W, 
approximately 90% of subjects are expected to be above the target concentration of ~ 30 μg/mL 
compared to ~ 50% with 15 mg/kg Q12W which was used in previous studies.  
Therefore, the starting dose of tremelimumab will be 3 mg/kg Q4W and the highest dose was 
initially chosen as 10 mg/kg Q4W; however, dosing was changed per Amendment 5, as 
described in Section 2.4.   
 Rationale for Study Design 
Current treatment options for advanced ovarian cancer, colorectal cancer (CRC), non-triple 
negative breast cancer, renal cell carcinoma (RCC) and cervical cancer reflect an unmet medical 
need and additional options for treatment are needed.  The current study focuses on evaluating 
the MTD and safety profile of a novel combination of immunotherapies in subjects with 
advanced solid tumors that are not eligible for, declined or failed standard treatment.  There is a 
sound rationale to combine MEDI4736 and tremelimumab supported by preclinical evidence for 
superior antitumor activity in mouse models and clinical data reviewed above.  The results from 
this study will form the basis for decisions for future studies. 
Note: Per Protocol Amendment 5, the disease states of NSCLC and head and neck cancer were 
removed from the study and were replaced by non-triple negative breast cancer. This change 
was made to avoid redundancy with the MedImmune development program.  Cohort sample 
sizes were increased to 15, for a total of 75 subjects in the expansion phase.   
In addition, the dosing regimens for tremelimumab and MEDI4736 were changed according to 
Amendment 5 in order to align with current recommendations from MedImmune. See Section 
3.1.7 for details. 


 
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According to MedImmune, the combination dose selection of 1 mg/kg Q4W for tremelimumab 
and 20 mg/kg Q4W for MEDI4736 was based on the identification of an optimal dose of 
MEDI4736 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 for Cohort 4a is based on information from MedImmune, which indicates that 
the dose and schedule of 1500 mg MEDI4736 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 MEDI4736 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 MEDI4736 is equivalent to 10 mg/kg Q2W, 1500 mg Q4W MEDI4736 is 
equivalent to 20 mg/kg Q4W, and 75 mg Q4W tremelimumab is equivalent to 1 mg/kg Q4W.  
 


 
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3 Experimental Plan 
 Study Design 
3.1.1 Study Phase 
Phase 1 study with a dose-escalation phase followed by an expansion phase. 
3.1.2 Enrollment/Randomization 
Non-randomized, competitive multicenter, sequential enrollment with central subject 
registration.  Enrollment will be under ongoing review by an internal data safety monitoring 
panel (see Section 3.1.14, Safety Monitoring and Study Stopping Rules). 
For each cohort in the dose-escalation phase, the first study drug administration for the first 
subject and the second subject will be separated by at least 24 hours.  All subjects in a cohort 
will have their safety data reviewed for DLTs for at least two cycles of treatment before 
proceeding to a subsequent cohort (see Section 3.1.7).   
 
In the expansion phase, eligible subjects will be enrolled in parallel into each of the disease-
specific cohorts. 
3.1.3 Blinding/Unblinding 
Open label. 
3.1.4 Subject Population 
For complete subject eligibility criteria, see Section 5. 
Prior to Amendment 5, subjects with ovarian cancer, CRC, non-small cell lung cancer, head and 
neck cancer, RCC and cervical cancer who were not eligible for, declined or failed standard 
treatment, were included in the study.   
Per Amendment 5, the disease states of NSCLC and head and neck cancer were removed from 
the study and were replaced by non-triple negative breast cancer, for a total of 5 disease-
specific cohorts.  Cohort sample sizes were increased from 12 to 15, for a total of 75 subjects in 
the expansion phase. 
3.1.5 Number of Sites/Subjects 
Up to 10 sites for the dose-escalation phase and up to 10 sites for the expansion phase; up to 
105 subjects. 
3.1.6 Sample Size Considerations 
The dose-escalation phase of the study will enroll 3-6 subjects in each cohort, based on a 3+3 
dose-escalation design to assess the MTD level.  
The table below gives the probabilities of dose-escalation based on true DLT risk in the 3+3 design. 


 
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True DLT rate 
 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
 
The expansion phase sample size of 75 subjects is not based on a formal sample size calculation.  
Fifteen (15) subjects in each of the 5 disease-specific cohorts are deemed to be sufficient for the 
assessment of safety and tolerability as the primary objective and the exploration of clinical anti-
tumor activity and other secondary and exploratory endpoints.  Within each cohort of 
15 subjects, the confidence interval of estimating the incidence of AE of special interest (i.e., 
symptomatic and/or irreversible treatment-related grade 4 pneumonitis, colitis, dermatitis, or 
hepatitis or any symptomatic treatment-related related grade ≥3 neurological toxicity or uveitis) 
are provided in the table below: 
Number of Subjects 
with Event 
Incidence 
95% Exact Confidence Interval 
(Clopper Pearson) 
1/15 
0.067 
 (0.002, 0.320) 
2/15 
0.133 
 (0.017, 0.405) 
3/15 
0.200 
 (0.043, 0.481) 
4/15 
0.267 
 (0.078, 0.551) 
5/15 
0.333 
 (0.118, 0.616) 
6/15 
0.400 
 (0.163, 0.677) 
 
3.1.7 Treatment Cohorts and Treatment Schema 
MEDI4736 and tremelimumab will be administered intravenously according to Section 6. 
Subjects will be treated for up to 12 months or until confirmed PD, initiation of alternative 
cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment prematurely 
occur as defined in Section 3.1.10.   
Per Amendment 6, optional treatment extension beyond the Core Study will be available for 
subjects who complete the Core Study with Stable Disease or better; the optional treatment 
extension will be permitted upon agreement with subject, Sponsor and Investigator.  See 
Section 8.8 for details. 
As shown in Figure 1, each cycle consists of 4 weeks.  
Prior to Amendment 5, MEDI4736 was administered every 2 weeks (Q2W) for 13 cycles, and 
tremelimumab was administered every 4 weeks (Q4W) for the first 6 cycles and then at cycle 7, 
10 and 13 (every 12 weeks (Q12W)).   
Per Amendment 5, the study will continue with enrollment into Cohort 3a and possibly Cohort 
4a, with the following modifications: 
• 
Cohort 3a:  
Tremelimumab, 1mg/kg Q4W for 4 four-week cycles; MEDI4736 
3 mg/kg, Q2W for 12 four-week cycles (previously: tremelimumab 1mg/kg Q4W for the 
first 6 cycles and then Q12W; MEDI4736 3 mg/kg, Q2W for 13 cycles) 


 
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• 
Cohort 4a: 
Tremelimumab, 75mg Q4W for 4 four-week cycles; MEDI4736 1500 mg 
Q4W for 12 four-week cycles (previously: tremelimumab 1mg/kg Q4W for the first 6 
cycles and then Q12W; MEDI4736 10 mg/kg, Q2W for 13 cycles). (Note: Per 
Amendment 5, fixed dosing will be implemented for Cohort 4a.) 
• 
Cohorts 4 and 5 were removed from the study. 
Note: The MEDI4736 and tremelimumab fixed doses are for subjects > 30 kg.  
• 
MEDI4736 dose:1500 mg for subjects > 30 kg.  If a subject’s body weight drops to ≤ 30 
kg while on the study, the subject will be dosed at 600 mg Q4W as long as the body 
weight remains ≤ 30 kg. 
• 
Tremelimumab dose: 75 mg for subjects > 30 kg. If a subject’s body weight drops to ≤ 
30 kg while on the study, the subject will be dosed at 30 mg Q4W for tremelimumab as 
long as the body weight remains ≤ 30 kg.   
 
On the days when MEDI4736 and tremelimumab are to be administered, MEDI4736 infusion will 
start at least 60 minutes after the end of tremelimumab infusion.  
 
Screening
(3weeks)
Cycle 1 to 6 
(4 weeks/cycle)
MEDI4736 Q2W
tremelimumab Q4W
Up to 6 months or until 
confirmed PD
Cycle 7 to 13 
(4 weeks/cycle)
MEDI4736 Q2W
tremelimumab Q12W
Up to 6 months or until 
confirmed PD
Survival follow-up up to 3 
years from initiation of 
treatment
Treatment
Up to 12 months or until 
confirmed PD
 
Figure 1: Treatment Schema Prior to-Amendment 5 
End of study is defined as the date of the last protocol-specified visit/assessment for the last 
subject in the study or the date the study is closed by the Sponsor, whichever occurs first (see 
Section 3.2). 
3.1.7.1 Dose-escalation Phase, 3+3 Design 
In each cohort, as a safety precaution, the first study drug administration for the first subject 
and the second subject will be separated by at least 24 hours.  All subjects in a cohort will have 
their safety data reviewed for DLTs for at least two cycles of treatment before proceeding to a 
subsequent cohort. Thereafter, the following dose-escalation schema will be applied: 
 


 
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Cohort 1 (n=3-6)
tremelimumab 3 mg/kg 
+ MEDI4736  0.3 mg/kg
Cohort 2 (n=3-6)
tremelimumab 3 mg/kg 
+ MEDI4736  1 mg/kg
Cohort 3 (n=3-6)
Tremelimumab 3 mg/kg 
+ MEDI4736  3 mg/kg
Cohort 4 (n=3-6)
tremelimumab 3 mg/kg 
+ MEDI4736  10 mg/kg
Cohort 1a (n=3-6) 
tremelimumab 1 mg/kg 
+ MEDI4736  0.3 mg/kg
Cohort 2a (n=3-6)
tremelimumab 1 mg/kg 
+ MEDI4736  1 mg/kg
Cohort 3a (n=3-6)
tremelimumab 1 mg/kg 
+ MEDI4736  3 mg/kg
See Note
Cohort 5 (n=3-6)
tremelimumab 10 mg/kg 
+ MEDI4736  10 mg/kg
Cohort 4a (n=3-6)
tremelimumab 75 mg + 
MEDI4736  1500 mg
See Note
≥ 2  DLTs
0/3 or 1/6 DLT
0/3 or 1/6 DLT
0/3 or 1/6 DLT
0/3 or 1/6 DLT
0/3 or 1/6 DLT
0/3 or 1/6 DLT
0/3 or 1/6 DLT
≥ 2  DLTs
≥ 2  DLTs
 
Figure 2: Dose-escalation Schema 
Note: Per Amendment 5, dosing regimens for Cohorts 3a and 4a were modified according to 
Section 3.1.7; Cohorts 4 and 5 were removed from the study and are no longer applicable in 
the following evaluation. 
• 
If 0 out of the 3 subjects have a DLT, the next dose-escalation cohort may be started. 
• 
If exactly 1 out of the 3 subjects has a DLT, an additional 3 subjects will be enrolled in the 
same cohort.  If none of these 3 additional subjects has a DLT after being observed for at 
least 2 cycles of treatment, the next dose-escalation cohort may be started. 
• 
If 2 or more subjects in Cohort 1, 2, 3, or 4 develop a DLT, all further subjects will be 
enrollment in Cohorts 1a, 2a, 3a, or 4a, respectively. 
• 
In Cohort 1a, if 2 or more subjects develop a DLT, enrollment will cease immediately and the 
study will be halted.  No MTD can be determined. 


 
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• 
In Cohort 2a, 3a, and 4a, if 2 or more subjects develop a DLT, enrollment into the cohort will 
cease immediately, and the previous cohort with fewer than 2 DLTs will be determined as 
the MTD (Cohort 1 or 1a, 2 or 2a, and 3 or 3a, respectively). 
• 
In Cohort 5, if 2 or more subjects develop a DLT, enrollment into the cohort will cease 
immediately, and the previous cohort with fewer than 2 DLTs will be determined as the MTD 
(Cohort 4). 
• 
If fewer than 2 subjects in Cohort 4a or 5 develop a DLT, the respective Cohort 4a or 5 dose 
level will be declared the MTD level. 
 
Accordingly, the MTD of the combination is defined as the highest dose of tremelimumab and 
MEDI4736 studied, for which the observed incidence of DLT is less than 33%.   
 
Late onset DLTs that could not be taken into consideration prior to scheduled dose-escalations 
will be evaluated on a case-by-case basis, and may lead to enrollment of additional subjects in 
the previous cohort, or to new determination or revision of the MTD. 
3.1.7.2 Expansion Phase  
Subjects in the expansion phase (Cohorts A to E) will be treated at the MTD level determined in 
the dose-escalation phase. 
MTD 
dose-escalation Phase
Cohort A (n=15) 
ovarian cancer 
Cohort C (n=15)
non-triple negative 
breast cancer 
Cohort D (n=15)
renal cell carcinoma
Cohort E (n=15)
cervical cancer
Cohort B (n=15)
colorectal cancer
Up to 12 months or 
until confirmed PD
 
Figure 3: Expansion Phase Schema 
NOTE: Per Amendment 5, the disease states of NSCLC and head and neck cancer were 
removed from the study and were replaced by non-triple negative breast cancer. 
Per Amendment 6, optional treatment extension beyond the Core Study will be available for 
subjects who complete the Core Study with Stable Disease or better; the optional treatment 
extension will be permitted upon agreement with subject, Sponsor and Investigator.  See 
Section 8.8 for details. 
 


 
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3.1.8 Dosing Adjustments, Delays and Discontinuations 
3.1.8.1 MEDI4736 and tremelimumab Dose Modification Due to Toxicity 
MEDI4736 and tremelimumab administration may be modified or discontinued as a result of 
toxicities as described in Table 3.1.8-1.  
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 MEDI4736 or 
tremelimumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. 
Table 3.1.8-1 
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(s) 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. 
Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease, consider holding M and T dosing as clinically 
appropriate and during diagnostic work-up for other etiologies.  
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. 


 
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Table 3.1.8-1 
MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
• 
For pneumonitis/interstitial lung disease, 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, 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, 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. 
• 
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 peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), 
apply respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For pneumonitis/interstitial lung disease, diarrhea/enterocolitis, 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. 
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. 
 


 
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Table 3.1.8-1 
MEDI4736 (M) and Tremelimumab (T) Dose Modification Due to Toxicity 
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of M and T may be decreased 50% or temporarily interrupted until 
resolution of the event; total infusion time not to exceed 4 hours. 
• 
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; total infusion time not to exceed 4 hours. 
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. 
3.1.8.2 MEDI4736 and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities 
MEDI4736 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. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may 


 
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be made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 10 days for Q2W dosing or no less than 21 days for Q4W dosing. 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 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. 
3.1.8.3 MEDI4736 and Tremelimumab Discontinuation  
Subjects who permanently discontinue treatment as defined in Section 3.1.8.1 and Section 
3.1.8.2, and who are not withdrawn from study as defined in Section 3.1.10 and/or Section 
7.2.7, will proceed to the Post Treatment Follow-up (On Study Follow-up) for 90 days after the 
last study drug treatment according to Section 3.1.16.  
Thereafter, the subjects will be taken off study and they will enter the Post Study Follow-up as 
per Section 3.1.16. 
3.1.9 DLT and MTD  
The MTD is defined as the highest dose studied, for which the observed incidence of DLT is less 
than 33%.  Frequencies of toxicities will be tabulated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
A DLT is any event that: 
a) occurs during the DLT Evaluation Period (as described in Section 3.1.7.1); and  
b) is possibly, probably, or definitely related to the administration of MEDI4736 or 
tremelimumab; and 
c)  fulfills 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 exception of those 
that downgrade 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 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.). 


 
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• 
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. 
• 
Liver transaminase elevation ≤ 8 times upper limit of normal (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, 
and (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. 
• 
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. 
• 
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. 
Immune-related adverse events (irAEs) are defined as 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 the rules for adjudicating DLTs in the context of dose escalation / dose expansion phase 
are specified above, an AE that is Grade < 3 or listed as exempt above may also be defined as 
DLT after consultation with the Sponsor and Investigators, based on the emerging safety profiles 
of MEDI4736 and tremelimumab.  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 treatment and will be followed 
as described in Section 3.1.8.3.  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. 
The MTD will be determined in accordance with Section 3.1.7.1.   


 
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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) Any dose-limiting toxicity as defined in Section 3.1.9. 
(4) Confirmation of symptomatic progressive disease or objective progression by Immune-
related Response Criteria (irRC). 
(5) Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal; e.g., refusal to adhere to study visits. 
(6) Development of intercurrent, non-cancer related illness 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) 
 
See also Section 3.1.8 for subject withdrawal from study treatment due to necessary dosing 
interruptions or discontinuations. 
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 Post Treatment Follow-up (On Study Follow-up) procedures (see Section 3.2) 
followed by the Post Study Follow-up (see Section 3.1.16).  
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 (e.g., start of 
new treatment) 
(2) Initiation of alternative anticancer therapy (marketed or investigational) 
(3) Withdrawal of consent for all follow-up 
(4) Lost to follow-up 
(5) Death 
 
General subject withdrawal criteria are outlined in the Administrative, Legal and Ethical 
Requirements section of the protocol, Section 7.2.7. 
3.1.10.1 Treatment Beyond Progression 
Subjects meeting criteria for progression 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. 


 
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See Section 8.5 and Section 8.6 regarding tumor response assessment by irRC and RECIST 1.1, 
respectively. 
3.1.11 Per-Protocol Subject Evaluability and Replacement  
In the dose escalation phase, subjects are fully evaluable for DLT if they fulfill the criteria for the 
Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). Subjects who are not 
considered fully evaluable for DLT per Section 4.1.2 will be replaced. 
3.1.12 Optional Study Treatment Extension 
Optional treatment extension beyond the original 12- or 13-cycle treatment period (Core Study) 
will be available for subjects who complete the Core Study with Stable Disease or better; the 
optional treatment extension will be permitted upon agreement with subject, Sponsor and 
Investigator.  See Section 8.8 for details. 
3.1.13 Interim Analysis 
No formal interim analysis is currently planned.  Analyses will be performed to assess safety and 
tolerability in the context of dose-escalations (see Section 3.1.7.1). 
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements section of the protocol, 
Safety Monitoring will be performed by an internal data safety monitoring panel, consisting of 
the Principal Investigators (and co-investigators as needed), the sponsor medical monitor, and 
drug safety personnel from Medimmune, the provider of the two 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 and possibly stopped for any of the following reasons: 
(1) Death in any subject in which the cause of death is unexpected and assessed as at least 
probably related to MEDI4736 and/or tremelimumab. 
(2) Severe anaphylactic reaction to MEDI4736 and/or tremelimumab (i.e., with respiratory 
and cardiovascular failure) in any subject. 
(3) Any events that, in the judgment of the medical monitor, are deemed serious enough to 
warrant immediate review by the internal 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 related grade ≥3 
neurological toxicity or uveitis. 
(4) Any other safety finding assessed as related to MEDI4736 and/or tremelimumab that, in 
the opinion of the internal data safety monitoring panel, contraindicates further dosing 
of study subjects. 
General criteria for premature trial termination are outlined in the Administrative, Legal and 
Ethical Requirements section of the protocol. 


 
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3.1.15 Duration of Study 
During the dose escalation phase, due to the safety assessments after the first subjects and the 
end of cohort assessments, 1 cohort is estimated to take 2 months to complete, on average.  
During the expansion phase, enrollment of 1 subject per site per month is assumed. 
Enrollment Period: 
38months (24 months dose escalation + 14 months expansion) 
Duration of Treatment  
12 months  
See Section 3.1.12 for optional treatment extension. 
Length of Study: 
50 months (not including long term follow-up) 
3.1.16 On Study and Post-Study Follow-up 
All subjects, whether they complete treatment as planned, discontinue treatment prematurely 
as per Section 3.1.8.3, or prematurely withdraw from the study as per Sections 3.1.10 and/or 
Section 7.2.7, will be followed as per institutional guidelines in accordance with the usual 
standard of care principles.   
Subjects who complete study treatment or discontinue treatment prematurely will enter the 
Post Treatment Follow-up (On Study Follow-up), which will be conducted for 90 days after the 
last administration of study drug according to the flowchart in Section 3.2  Refer to Section 7.1.5 
for information on collection of adverse events during the Post Treatment Follow-up (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 Post Treatment Follow-up (On Study Follow-up), any assessments required in 
the first Post Treatment Follow-up (On Study Follow-up) 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 first Post Treatment Follow-up (On Study Follow-up)  visit should not be 
repeated. 
In addition to the Post Treatment Follow-up (On Study Follow-up), there will be a Post Study 
Follow-up, where clinical outcomes data (dates of progression/relapse, and survival) will be 
collected at least every 6 months for up to 3 years from the initiation of the treatment.   
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. 
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 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician. 
See Section 3.1.12 for optional study treatment extension. 


 
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3.1.16.1 End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End 
of Study visit must be conducted at the time of withdrawal. For subjects not yet in Post 
Treatment Follow-up (On Study Follow-up), this End of Study visit will be the first planned visit 
of the Post Treatment Follow-up (On Study Follow-up). For subjects already in Post Treatment 
Follow-up (On Study Follow-up), this End of Study visit will be the next planned visit of the Post 
Treatment Follow-up (On Study Follow-up). However, any procedures/assessments that were 
done within 7 days of the End of Study visit need not be repeated. All subjects of childbearing 
potential who withdraw from study must have a serum pregnancy test done at the End of Study 
visit, unless it was done within 7 days prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up).  
 
 


 
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 Study Flowcharts 


 
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Last Study Drug 
Administration
+ 14±3 days 
Last Study Drug 
Administration
+ 28±3 days 
Last 
Tremelimumab 
Administration
+ 90±7  days 
Last MEDI4736 
administration 
+ 90±7 days 
Study weeks
Week 
25
Week 
27
Week 
29
Week 
31
Week 
33
Week 
35
Week 
37
Week 
39
Week 
41
Week 
43
Week 
45
Week 
47
Week 
49
Week 
51
Week 53
Week 55
Week 62 
Week 64 
Study days
169±3 183±3 197±3 211±3 225±3 239±3 253±3 267±3 281±3 295±3 309±3 323±3 337±3 351±3
365±3
379±3
428±7
442±7
MEDI4736 (pre Amendment 5)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tremelimumab (pre Amendment 5)
x
x
x
Disease Assessment by RECIST  (including appropriate 
imaging) 
x
x
x
x
Disease Assessment by irRC (including appropriate 
imaging)
x
x
x
x
Physical Exam (incl. weight and ECOG Perf Status)
x
x
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.3)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medication (name, indication, dose, 
route, start & end dates) /Concomitant Procedures
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after consent)1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential, Mean Corpuscular Hemoglobin, Mean 
Corpuscular Volume, Mean Corpuscular HGB 
Concentration, Red Cell Distribution Width, Platelets 
and Mean Platelet Volume)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
x
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
x
Chemistry cont. (Amylase, lipase)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
x
Serum Pregnancy test
x2
x2
x2
x2
x
x
Flow cytometry (immune monitoring)
x2
x2
x2
x
PBMC collection (immunodiversity, flow cytometry, 
functional assays)
x2
x2
x2
x2
x2
x2
x2
x
x
x
x
PAXgene RNA tube
x2 
x2 
x2
x
x
Tumor Biopsy (expansion phase only)
Overall Survival
x
Progression Free Survival 3
x
+56 ± 7 days from last disease assessment
+56 ± 7 days from last disease assessment
Other Labs & Assays 
3 For subjects who did not experience progression while on study
Long-Term Follow-up
x
2 Collected pre-dose  (prior to first drug administration). Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable)  results are reviewed before dosing.
1 See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
4  Cycle 13 pertains to cohorts 3 and ealier in pre Amendment 5 only
Post Study 
Follow-up 
(Done at 
least every 6 
months for 
up to 3 years 
from start of 
treatment)
Study Drugs Administration
Tumor & Disease Assessments
Study Procedures & Examinations
Labs & Assays
End of Study 
Post Treatment Follow-up (On Study Follow-up)
Cycle 12 
(4 weeks)
Cycle 13 
(4 weeks)4
 
Pre Amendment 5 Study 
Flowchart - Cohorts 3 and 
earlier (continued - 2 of 2)
Treatment
Cycle 7 
(4 weeks)
Cycle 8 
(4 weeks)
Cycle 9 
(4 weeks)
Cycle 10 
(4 weeks)
Cycle 11 
(4 weeks)


 
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Treatment  weeks
-3 to 0 
Week 5 Week 7 Week 
9
Week 
11
Week 
13
Week 
15
Week 
17
Week 
19
Week 
21
Week 
23
Treatment days
-21 to 0 
1
2
8±1
15±1
29±3
43±3
57±3
71±3
85±3
99±3
113±3
127±3
141±3
155±3
MEDI4736 (Post Amendment 5 Cohort 3a)
x
x
x
x
x
x
x
x
x
x
x
x
Tremelimumab (Post Amendment 5 Cohort 3a)
x
x
x
x
Disease Staging (date/stage at 1st diagnosis & at 
study entry)
x
Disease Assessment by RECIST  (including appropriate 
imaging) 
x
x
x
x
Disease Assessment by irRC (including appropriate 
imaging)
x
x
x
x
Eligibility Assessment and Informed Consent3
x
Demographics (incl. DoB; sex; height; race; ethnicity)
x
Physical Exam (incl. weight and ECOG Perf Status)
x
x
 x
x
x
x
x
x
x
Medical history and Pre-Existing Symptoms
x
Vital Signs (T, HR, BP, RR) (see Section 6.3)
x
x
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) / Concomitant Procedures
x
x
x
 x
x
x
x
x
x
x
x
x
x
x
x
Brain MRI repeated as clinically indicated
x
Adverse Events (starting or worsening after consent)1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential, Mean Corpuscular Hemoglobin, Mean 
Corpuscular Volume, Mean Corpuscular HGB 
Concentration, Red Cell Distribution Width, Platelets 
and Mean Platelet Volume)
-7 to 0
x2
x
x
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
-7 to 0
x2
x
x
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
Chemistry cont. (Amylase, lipase)
-7 to 0
x2
x
x
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
Serum pregnancy test (urine test only on Day 1)
-7 to 0
x2
x2
x2
Flow cytometry (immune monitoring)
x
x2
x2 
x2 
x2 
x2 
x2 
PBMC collection (immunodiversity, flow cytometry, 
functional assays)
x
x2
x2
x2
x2
x2
x2
PAXgene RNA tube
x2
x
x
x2
x2
x2
Archived tumor sample
-7 to 0
Tumor Biopsy (expansion phase only)
-14 to 0
1 See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
3 Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
Week 1
Week 2-3
Study Drugs Administration
Tumor & Disease Assessments
Post Amendment 5
Study Flowchart - Cohort 3a
(1 of 2)
Screening / 
Baseline
Treatment 
Cycle 1 
(4 weeks)
Cycle 2 
(4 weeks)
Cycle 3 
(4 weeks)
Cycle 4 
(4 weeks)
Cycle 5 
(4 weeks)
Cycle 6 
(4 weeks)
2 Collected pre-dose  (prior to first drug administration). Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable)  results are reviewed before dosing.
Labs
Other Labs & Assays
x
Study Procedures & Examinations
Day -7 to 1 (pre-dose)
Day -7 to 1 (pre-dose)


 
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Last Study Drug 
Administration
+ 14±3 days 
Last Study Drug 
Administration
+ 28±3 days 
Last Study Drug 
Administration
+ 90±7 days 
Study weeks
Week 
25
Week 
27
Week 
29
Week 
31
Week 
33
Week 
35
Week 
37
Week 
39
Week 
41
Week 
43
Week 
45
Week 
47
Week 49
Week 51
Week 58
Study days
169±3 183±3 197±3 211±3 225±3 239±3 253±3 267±3 281±3 295±3 309±3 323±3
337±3
351±3
399±7
MEDI4736 (Post Amendment 5 Cohort 3a)
x
x
x
x
x
x
x
x
x
x
x
x
Tremelimumab (Post Amendment 5 Cohort 3a)
Disease Assessment by RECIST  (including appropriate 
imaging) 
x
x
x
Disease Assessment by irRC (including appropriate 
imaging)
x
x
x
Physical Exam (incl. weight and ECOG Perf Status)
x
x
x
x
x
x
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.3)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medication (name, indication, dose, 
route, start & end dates) /Concomitant Procedures
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (starting or worsening after consent)1 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Hematology (complete blood count with 
differential, Mean Corpuscular Hemoglobin, Mean 
Corpuscular Volume, Mean Corpuscular HGB 
Concentration, Red Cell Distribution Width, Platelets 
and Mean Platelet Volume)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
Chemistry cont. (Amylase, lipase)
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x2
x
x
x
Serum Pregnancy test
x2
x2
x2
x
x
Flow cytometry (immune monitoring)
x2
x2
x
PBMC collection (immunodiversity, flow cytometry, 
functional assays)
x2
x2
x2
x2
x2
x2
x
x
x
PAXgene RNA tube
x2 
x2 
x
x
Tumor Biopsy (expansion phase only)
Overall Survival
x
Progression Free Survival 3
x
3 For subjects who did not experience progression while on study
Cycle 12 
(4 weeks)
 Post Amendment 5
Study Flowchart - Cohort 3a
 (continued 2 of 2)
Treatment
 End of Study 
Post Treatment Follow-up (On Study Follow-up)
Post Study 
Follow-up 
(Done at 
least every 6 
months for 
up to 3 years 
from start of 
treatment)
Cycle 7 
(4 weeks)
Cycle 8 
(4 weeks)
Cycle 9 
(4 weeks)
Cycle 10 
(4 weeks)
Cycle 11 
(4 weeks)
Study Drugs Administration
Tumor & Disease Assessments
2 Collected pre-dose  (prior to first drug administration). Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable)  results are reviewed before dosing.
Long-Term Follow-up
+56 ± 7 days from last disease assessment
+56 ± 7 days from last disease assessment
Study Procedures & Examinations
Labs & Assays
Other Labs & Assays 
x
1 See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.


 
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Treatment  weeks
-3 to 0 
Treatment days
-21 to 0 
1
2
8±1
15±1
MEDI4736 (Post Amendment 5 Cohort 4a)
x
Tremelimumab  (Post Amendment 5 Cohort 4a)
x
Disease Staging (date/stage at 1st diagnosis & at 
study entry)
x
Disease Assessment by RECIST  (including appropriate 
imaging) 
x
Disease Assessment by irRC (including appropriate 
imaging)
x
Eligibility Assessment and Informed Consent3
x
Demographics (incl. DoB; sex; height; race; ethnicity)
x
Physical Exam (incl. weight and ECOG Perf Status)
x
x
 x
x
Medical history and Pre-Existing Symptoms
x
Vital Signs (T, HR, BP, RR) (see Section 6.3)
x
x
x
x 
x
12-Lead ECG
x
Concomitant Medication (name, indication, dose, 
route, start & end dates) /Concomitant Procedures
x
x
x
 x
x
Brain MRI repeated as clinically indicated
x
Adverse Events (starting or worsening after consent)1
x
x
x
x
x
Blood Hematology (complete blood count with 
differential, Mean Corpuscular Hemoglobin, Mean 
Corpuscular Volume, Mean Corpuscular HGB 
Concentration, Red Cell Distribution Width, Platelets 
and Mean Platelet Volume)
-7 to 0
x2
x
x
x2
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
-7 to 0
x2
x
x
x2
Chemistry cont. (Amylase, lipase)
-7 to 0
x2
x
x
x2
Serum pregnancy test (urine test only on Day 1)
-7 to 0
x2
Flow cytometry (immune monitoring)
x
x2
PBMC collection (immunodiversity, flow cytometry, 
functional assays)
x
x2
PAXgene RNA tube
x2
x
x
Archived tumor sample
-7 to 0
Tumor Biopsy (expansion phase only)
-14 to 0
1 See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
3 Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
Day -7 to 1 (pre-dose)
Day -7 to 1 (pre-dose)
Week 1
Week 2-3
Study Drugs Administration
Tumor & Disease Assessments
Study Procedures & Examinations
Week 13
85±3
x
x
x
x
Week 9
57±3
Other Labs & Assays
Week 5
29±3
x
x
Post Amendment 5
Study Flowchart - Cohort 4a
(1 of 2)
Screening / 
Baseline
Treatment 
Cycle 1 
(4 weeks)
Cycle 2 
(4 weeks)
Cycle 3 
(4 weeks)
Cycle 4 
(4 weeks)
Cycle 5 
(4 weeks)
Cycle 6 
(4 weeks)
x2 
x2
x2
Labs
x
x2
x2
x
x
x2
x2
x
x
x
x
x
x
x
x2
x2
x2
x
x
x2
Week 17
113±3
x
x
x
x2 
x
x
x2
x2
x
x
x
x
x
x
Week 21
141±3
x
x2 
x2
x
x
x2
x2
2 Collected pre-dose  (prior to first drug administration). Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable)  results are reviewed before dosing.
x2
x2 
x
x
x2
x2
x2
x2
x2
x2
x2
x
x2 
x2
x2


 
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Last Study Drug 
Administration
+28±3 days 
Last Study Drug 
Administration
+ 56±3 days 
Last Study Drug 
Administration
+ 90±7 days 
Study weeks
Week 49
Week 53
Week 58
Study days
337±3
365±3
399±7
MEDI4736 (Post Amendment 5 Cohort 4a)
Tremelimumab (Post Amendment 5 Cohort 4a)
Disease Assessment by RECIST  (including appropriate 
imaging) 
Disease Assessment by irRC (including appropriate 
imaging)
Physical Exam (incl. weight and ECOG Perf Status)
x
x
x
Vital Signs (T, HR, BP, RR) (see Section 6.3)
x
x
x
Concomitant Medication (name, indication, dose, 
route, start & end dates) /Concomitant Procedures
x
x
x
Adverse Events (starting or worsening after consent)1 
x
x
x
Blood Hematology (complete blood count with 
differential, Mean Corpuscular Hemoglobin, Mean 
Corpuscular Volume, Mean Corpuscular HGB 
Concentration, Red Cell Distribution Width, Platelets 
and Mean Platelet Volume)
x
x
x
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x
x
x
Chemistry cont. (Amylase, lipase)
x
x
x
Serum Pregnancy test
x
x
Flow cytometry (immune monitoring)
x
PBMC collection (immunodiversity, flow cytometry, 
functional assays)
x
x
x
PAXgene RNA tube
x
x
Tumor Biopsy (expansion phase only)
Overall Survival
x
Progression Free Survival 3
x
+56 ± 7 days from last disease assessment
+56 ± 7 days from last disease assessment
End of Study  
Post Treatment Follow-up (On Study Follow-up)
Post Study 
Follow-up 
(Done at 
least every 6 
months for 
up to 3 years 
from start of 
treatment)
Cycle 7 
(4 weeks)
Cycle 8 
(4 weeks)
Cycle 9 
(4 weeks)
Cycle 10 
(4 weeks)
Cycle 11 
(4 weeks)
Cycle 12 
(4 weeks)
Week 45
Week 25
169±3
Week 29
197±3
309±3
Week 33
225±3
Week 37
253±3
Week 41
281±3
x
x
x
x
Study Procedures & Examinations
x
x2
Post Amendment 5 
Study Flowchart - Cohort 4a 
(continued - 2 of 2) 
Treatment
x
x
x2
x2
x
x2
x
x
x
x
x
x
x
x
x2
x2
x2
x2
x
x2
x2
x
x
x
x
x2
x2
Labs & Assays
x
x2
x2
x2
x
x2
Study Drugs Administration
x
x
x
x
x2
x
x
x
x
x
x
x
x
x
Tumor & Disease Assessments
x
Long-Term Follow-up
x2
x2 
x2
x2
2 Collected pre-dose  (prior to first drug administration). Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable)  results are reviewed before dosing.
1 See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
3 For subjects who did not experience progression while on study
x2
x2
x2
x2
x2
x2
x2
x2
x2 
x2
Other Labs & Assays 


 
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4 Study Objectives and Endpoints 
Primary Objectives 
Safety/Tolerability (Endpoint: MTD, CTCAE version 4.03) 
Secondary Objectives  Pharmacokinetics and immunogenicity (MEDI4736/tremelimumab) 
Clinical efficacy (Tumor Response by RECIST and irRC, progression-
free survival and overall survival) 
Exploratory objective Biological activity of MEDI4736/tremelimumab Combination 
In order to be fully evaluable (per protocol) for the primary endpoint, major protocol violations 
that interfere with the assessment of the primary endpoint must be absent. 
 Safety and Tolerability 
Assessment of safety and tolerability will be performed 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 & Assessment Methods 
Laboratory tests, vital sign measurements, physical exams and subject interviews will be 
performed to detect new abnormalities and deteriorations of any pre-existing conditions.  All 
“treatment-emergent” clinically significant abnormalities and deteriorations that begin or 
worsen in severity after initial administration of MEDI4736 and/or tremelimumab should be 
recorded in the Case Report Forms as Adverse Events and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
4.1.2 Subject Evaluation and Statistics 
All subjects who receive at least the first two cycles of treatment (i.e., DLT evaluation period; 
approx. 8 weeks) and respective safety assessments, as well as, all subjects who discontinue the 
study prematurely due to DLT are considered fully evaluable per protocol for DLT (see Section 
3.1.11 for subject replacement).  Subjects must also have received at least 75% of the planned 
dose during the DLT evaluation period (except for subjects who discontinued prematurely due 
to DLT) to be evaluable for DLT.   
All subjects who received at least one dose of MEDI4736 and/or tremelimumab will be 
evaluated for safety and tolerability.  Appropriate summaries of AEs, laboratory data and vital 
sign data will be presented.  AEs will be listed individually per subject according to CTCAE 
version 4.03, and the number of subjects experiencing each AE will be summarized using 
descriptive statistics.   
The MTD will be determined in accordance with Section 3.1.9. 
 
 


 
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4.2 
MEDI4736 and tremelimumab pharmacokinetics  
4.2.1 Endpoints and Assessment Methods 
A validated enzyme-linked immunosorbent assay (ELISA) will be used for the quantitative 
determination of tremelimumab in human serum.  A validated electrochemiluminescence assay 
(ECLA) using a Meso Scale Discovery (MSD) platform will be used for the quantitative 
determination of MEDI4736 in human serum. 
NOTE: Per Amendment 6, samples will no longer be collected for analysis of MEDI4736 and 
tremelimumab pharmacokinetics, as sufficient samples have already been collected. The 
collection time points for these assays have been removed from the flowchart in Section 3.2. 
4.2.2 Subject Evaluation and Statistics 
Only subjects, who received at least one dose of MEDI4736 and tremelimumab and provided the 
baseline and at least one post-treatment sample, will be evaluated.  The PK of MEDI4736 and 
tremelimumab will be assessed using parameters including peak concentration (Cmax), trough 
concentration (Cmin) and time to peak concentration (Tmax) and area under the concentration-
time curve (AUC) after the first dose.  MEDI4736 and tremelimumab steady-state PK parameters 
including peak concentration (Cmax,ss), trough concentration (Cmin,ss), and time to peak 
concentration (Tmax,ss) will be estimated.  All PK parameters will be estimated by non-
compartmental analysis.  Accumulation to steady state will be assessed as the ratio of 
Cmax,ss:Cmax and Cmin,ss:Cmin. 
 MEDI4736 and tremelimumab Immunogenicity 
4.3.1 Endpoints and Assessment Methods 
Validated electrochemiluminescence assays using the MSD platform will be used for the detection 
of anti-tremelimumab and anti-MEDI4736 antibodies in human serum. 
NOTE: Per Amendment 6, samples will no longer be collected for the assessment of anti-
tremelimumab and anti-MEDI4736 anti-drug antibodies (ADA), as sufficient samples have already 
been collected. The collection time points for these assays have been removed from the flowchart 
in Section 3.2. 
4.3.2 Subject Evaluation and Statistics 
Only subjects who received at least one dose of both MEDI4736 and tremelimumab, and 
provided the baseline and at least one post-treatment sample, will be evaluated. 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of subjects who develop detectable anti-MEDI4736 or tremelimumab antibodies. 
The immunogenicity titer will be reported for samples confirmed positive for the presence of 
anti-MEDI4736 or tremelimumab antibodies.   
 Clinical Efficacy  
Clinical efficacy evaluation will include tumor response assessed by irRC and RECIST, 
Progression-free Survival and overall survival. 


 
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4.4.1 Tumor Response Assessment by irRC 
Tumor Response will be assessed by the Immune-related Response Criteria (irRC) as published 
by Wolchok et al., 2009.(68)  Tumor Response by irRC is defined as irPR or irCR over a period of 
at least 4 weeks.  Disease Control by irRC is defined as irSD or irPR or irCR.  Disease control by 
irRC will be used to determine eligibility for the maintenance treatment phase (see Section 
3.1.7). 
4.4.2 Tumor Response Assessment by RECIST 
Tumor Response will also be evaluated using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Committee.  Tumor Response by 
RECIST is defined as PR or CR over a period of at least 4 weeks.  Disease Control by RECIST is 
defined as SD or PR or CR. 
4.4.3 Progression-free survival (PFS) 
Progression-free Survival will be determined for each subject with time origin at the start of the 
treatment (Day 1) until the first occurrence of confirmed progression by irRC or date of death if 
the subject dies from any causes before progression.  Every effort will be made to follow 
subjects for progression after they discontinue the study. 
4.4.4 Overall Survival (OS) 
Overall survival (OS) will be measured for each subject with time origin at the start of the 
treatment (Day 1) until recorded date of death.  Every effort will be made to follow subjects for 
overall survival after they discontinue the study. 
4.4.5 Subject Evaluation and Statistics 
All subjects who received at least one dose of MEDI4736 and/or tremelimumab, as well as 
baseline and at least one post-baseline disease assessments, will be evaluated for clinical 
efficacy.  Tumor Responses by irRC and RECIST, progression free survival and overall survival will 
be summarized and analyzed descriptively. 
 Biological activity of MEDI4736/tremelimumab Combination 
4.5.1 Endpoints and Assessment Methods 
Samples for exploratory pharmacodynamic assessments at each visit and time points as noted in 
Section 3.2). 


 
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Exploratory pharmacodynamic assessments may include but not be limited to: 
• 
Serum sPD-L1 levels before and after treatment. 
• 
PBMCs will be collected to assess immune cell phenotypes that may include T cell 
phenotype and activation markers, B cells, myeloid derived suppressor cells and/or 
immune diversity. 
• 
Levels of Circulating soluble factors (cytokine profiling) 
• 
Flow cytometry (immune monitoring) 
• 
Circulating Tumor Cell (CRC, ovarian cancer, and SCCHN) 
• 
Immunologic changes in the tumor microenvironment  
• 
mRNA/miRNA profiling 
 
NOTE: Per Amendment 6, samples will no longer be collected for analysis of sPD-L1, circulating 
soluble factors, and circulating tumor cells (CTC), as sufficient samples have already been 
collected. The collection time points for these assays have been removed from the flowchart in 
Section 3.2. 
4.5.2 Subject Evaluation and Statistics 
Only subjects who received at least one dose of both MEDI4736 and tremelimumab, and 
provided the baseline and at least one post-treatment sample (if applicable), will be evaluated.   
The exploratory pharmacodynamic assessment of the immunologic changes in the tumor 
microenvironment will include the correlation between clinical activity and the expression level 
of PD-L1 and tumor-infiltrating lymphocytes (TILs) changes in biopsies pre and post treatment. 
Subjects will be classified as responders or non-responders based on irRC.  Within each response 
group, subject tumors will be assessed as positive or negative for PD-L1 expression.  For the 
purpose of this exploratory analysis, and to maximize power, the 5 disease-specific cohorts will 
be combined and a Cochran-Mantel-Haenszel test stratified by cohort will be used to test 
whether there is a significant association between responder-status and PD-L1 
expression.  Assuming tumor biopsies are available for at least 48 subjects and approximately 
equal numbers of responders and non-responders, if there are 80% and 40% of subjects with 
positive PD-L1 expression in the two groups, respectively, there will be at least 80% power to 
detect a significant difference.  The association between response and PD-L1 expression within 
each disease-specific cohort will be assessed descriptively.  Confidence intervals for the overall 
odds ratio and the odds ratio within each cohort will be presented.  The association between 
response and TILs changes (increase, decrease, or no change) will be evaluated similarly. 
All other 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 
 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1.  
Histologically- or cytologically-confirmed ovarian cancer, colorectal cancer, non-triple 
negative breast cancer, renal cell carcinoma and cervical cancer, with at least one lesion 
measurable by irRC not previously irradiated. 
NOTE: Per Amendment 5, the disease states of non-small cell lung cancer and head 
and neck cancer were removed from the study and were replaced by non-triple 
negative breast cancer. 
2. 
Failed to respond to or relapsed following standard treatment, or declined or was not 
eligible for standard treatment. 
3. 
ECOG performance status of 0-2. 
4. 
Anticipated lifespan greater than 6 month. 
5. 
At the time of day 1 of the study, subjects with brain metastases must be asymptomatic 
for at least 4 weeks and: 
• 
at least 8 weeks without tumor progression after any whole brain radiotherapy 
• 
at least 4 weeks since craniotomy and resection or stereotactic radiosurgery 
• 
at least 3 weeks without new brain metastases as evidenced by MRI/CT 
6. 
Adequate organ and marrow function, as defined below: 
• 
Hemoglobin ≥ 9 g/dL 
• 
Absolute Neutrophil Count ≥ 1500/mm3 
• 
Platelet count ≥ 100,000/mm3 
• 
Total bilirubin within normal ranges unless associated with hepatobiliary 
metastases or Gilbert syndrome, then total bilirubin ≤ 2 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN unless associated with hepatic metastases, then ALT and AST ≤ 5 x ULN 
• 
Creatinine ≤ 2.0 mg/dL 
7. 
Have been informed of other treatment options. 
8. 
Age ≥18 years. 
9. 
Able and willing to give valid written informed consent. 
10. 
Able and willing to give valid written consent for archival tumor samples 
11. 
Able and willing to give valid written consent for biopsy samples (subjects with 
biopsiable tumors, and if clinically appropriate, in the expansion phase only). 
 
 


 
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 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Prior exposure to tremelimumab or MEDI4736 or other anti-CTLA-4, anti-PD-1, anti-PD-
L1 antibodies 
2. 
History of severe allergic reactions to any unknown allergens or any components of the 
study drugs. 
3. 
Active or prior autoimmune disease except for autoimmune thyroiditis or vitiligo. 
4. 
Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-
refractory irAE. 
5. 
Known active or chronic viral hepatitis or history of any type of hepatitis within the last 
6 months. 
6. 
History of sarcoidosis syndrome. 
7. 
Active or history of inflammatory bowel disease (colitis, Crohn’s), diverticulitis, irritable 
bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions 
associated with diarrhea. Active or history of systemic lupus erythematosus or 
Wegener’s granulomatosis. 
8. 
Metastatic disease to the central nervous system for which other therapeutic options, 
including radiotherapy, may be available. 
9. 
Known immunodeficiency or active HIV. 
10. 
Other active serious illnesses (e.g., serious infections requiring antibiotics). 
11. 
If a subject previously received investigational treatment, the last dose of 
investigational treatment was administered within 4 weeks of Day 1 of the study or 
adverse event(s) attributable to investigational treatment have not resolved to Grade 1 
or better. 
12. 
Major surgical procedure (as defined by the investigator) within 30 days prior to Day 1 
or still recovering from prior surgery. 
13. 
Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study. 
14. 
Lack of availability for immunological and clinical follow-up assessments. 
15. 
Women who are breast feeding or pregnant as evidenced by positive serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG)  
16. 
Females subjects of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of  contraception (see table 
below) from the time of screening, and must agree to continue using such precautions 
for 90 days after last dose of MEDI4736 or for 6 months after the final dose of 
MEDI4736 + tremelimumab (whichever is longer). Non-sterilized 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 is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control. 


 
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Female subjects should also refrain from breastfeeding 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 
post-menopausal 
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.  
Non-sterilized 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 MEDI4736 or through 6 months after receipt of the final dose 
of MEDI4736 + 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”: 
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 
17. 
Any condition that, in the clinical judgment of the treating physician, is likely to prevent 
the subject from complying with any aspect of the protocol or that may put the subject 
at unacceptable risk. 
18. 
Subjects must not donate blood while on study and for at least 90 days following the 
last MEDI4736 treatment or 6 months after the last tremelimumab treatment, 
whichever is longer. 
 


 
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 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subjects may not receive the following concomitant therapies during the study 
1. 
Systemic treatment with high dose corticosteroids (greater than Prednisone 10 mg daily 
or equivalent) or other immunosuppressive treatments (e.g. methotrexate, 
chloroquine, azathioprine).  See Section 5.3.2 for exceptions. 
Wash-out period: 2 weeks prior to day 1. 
2. 
Other cancer therapy (chemotherapy, radiation or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1; 6 weeks 
for nitrosoureas. 
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 
be avoided through 90 days post last dose of tremelimumab because of the potential 
for exacerbation of diarrhea. 
5.3.2 Permitted Concomitant Therapies 
Subjects may receive the following concomitant therapies during the study: 
1. 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical 
steroids for localized (< 5% of body surface area) dermatitis. 
2. 
NSAIDs, acetylsalicylic acid and specific COX-2 inhibitors. 
3. 
Antihistamines and other non-steroidal anti-allergy medication. 
4. 
Hormone or hormone-related anti-cancer therapy. 
5. 
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 and TNF-α 
inhibitors to treat adverse reactions. 
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 Drugs  
All study drugs are manufactured in accordance with Good Manufacturing Practices (GMP). 
When MEDI4736 and tremelimumab are to be administered on the same day, MEDI4736 
infusion will start at least 60 minutes after the end of tremelimumab infusion. 
 MEDI4736 
6.1.1 Study Drug Information for MEDI4736 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification or in the in the QA 
Disposition of Investigational Medicinal Product (IMP) Report. 
Container Description 
Type: 
Single use vial  
Material: 
 
Size: 
 
Formulation 
Lyophilized powder containing 200 mg MEDI4736. When 
reconstituted with 4 mL of water for injection (WFI), the 
solution contains 50 mg/mL MEDI4736, 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: 
200 mg 
Volume: 
n/a 
Concentration: 
n/a 
Storage Conditions 
+2°C to +8°C 
Stability after 
reconstitution 
24h at 2 to 8°C and 4h at 25°C/ambient 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
 
6.1.2 MEDI4736 Preparation  
Each vial of MEDI4736 selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator, Site Monitor, and Sponsor 
should be notified immediately. 
Preparation of MEDI4736 and preparation of the intravenous (IV) bag are to be performed by 
the IP Manager or designated personnel using aseptic technique.  . No incompatibilities between 
MEDI4736 and polyvinylchloride or polyolefin copolymers have been observed. 
MEDI4736 does not contain preservatives and any unused portion must be discarded. 
MEDI4736 requires reconstitution prior to use.  The reconstitution should be performed with 
4 mL sterile water for injection (WFI) for each vial with the liquid added gently to the side of the 
vial to minimize product foaming.  The vial should be gently rotated or swirled for 5 minutes or 
until dissolution is complete.  The vial should not be shaken or vigorously agitated.  
Reconstituted MEDI4736 should stand undisturbed at room temperature for a minimum of 5 


 
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minutes or until the solution clarifies.  The reconstituted solution should appear clear or slightly 
opalescent.  A thin layer of bubbles on the liquid surface is considered normal. 
6.1.2.1 Preparation of 0.3 mg/kg dose for administration with a syringe 
For an IV dose equal to 0.3 mg/kg, administration will be performed using a polypropylene 
syringe and IV administration set.  Each dose will be administered as an admixture of MEDI4736 
and 0.9% (w/v) saline prepared to a set volume.  The delivery volume for the dose level of 
0.3 mg/kg is 12 mL.  The preparation volume will include additional volume of admixture to 
allow for purging the lines of the administration set. 
The dose preparation procedure is as follows: 
1. Calculate the amount of admixture to prepare using the formula below: 
Preparation 
Volume (mL) 
= 
Delivery Volume (mL) 
+ 
Hold-up Volume of Administration Set (mL) 
 
 
2. Calculate the concentration of MEDI4736 in the admixture using the formula below:  
Final Dose 
Concentration 
(mg/mL) 
= 
Dose (mg/kg) 
X 
Subject Weight (kg) 
 
÷ 
 
Delivery Volume (mL) 
 
 
3. Determine the volume of reconstituted MEDI4736 (mL) to be prepared in 0.9% (w/v) 
saline required for the calculated concentration: 
Volume of 
MEDI4736 to be 
Diluted (mL) 
= 
Final Dose 
Concentration 
(mg/mL) 
X 
Preparation 
Volume (mL) 
 
÷ 
Drug Product 
Concentration 
(nominal 50 mg/mL) 
 
4. Determine the volume of 0.9% (w/v) saline (mL) used to dilute MEDI4736: 
Volume of 0.9% (w/v) 
Saline (mL) 
= 
Preparation Volume (mL) 
- 
Volume of MEDI4836 to 
be Diluted (mL) 
 
The admixture should be prepared in a separate sterile container. Following preparation, the 
admixture must be mixed by gentle swirling or inversion. The admixture should then be 
inspected to ensure the solution is clear and then drawn up into the syringe. Intravenous lines 
are then purged and the specified delivery volume is administered, using a 0.2-μm in-line filter. 
Subjects will receive the infusion over 60 minutes (± 5 minutes) in duration. Disconnect the IV 
line when the correct volume has been delivered. See Section 6.1.3 for details regarding 
administration of MEDI4736. 
Example: 
1. The administration lines to be used have a hold-up volume of approximately 10 mL. The 
volume of admixture to prepare is 22 mL (12 mL + 10 mL) 
2. The Final Dose Concentration of MEDI4736 for a subject weighing 100 kg and dosed at 
0.3 mg/kg will be 2.5 mg/mL.  (0.3 mg/kg × 100 kg ÷ 12 mL) 
3. The volume of reconstituted MEDI4736 required will be 1.1 mL. (2.5 mg/mL × 22 mL ÷ 50 
mg/mL) 


 
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4. The volume of 0.9% (w/v) saline required to dilute MEDI4736 will be 20.9 mL. (22 mL - 1.1 
mL). After gentle mixing the admixture in the syringe by gentle inversion the lines are 
purged and 12 mL is administered over the specified infusion time. 
 
6.1.2.2 Preparation of 1 mg/kg, 3 mg/kg and 10 mg/kg dose for administration with 
an IV bag 
Doses greater than or equal to 1 mg/kg will be administered using a 250 mL 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 volume of reconstituted MEDI4736 to add to the IV bag is 
calculated as follows: 
Volume of 
MEDI4736 (mL) 
= Dose (mg/kg) 
X 
Subject Weight 
(kg) 
 
÷ 
MEDI4736 Concentration 
(nominal 50 mg/mL) 
 
A volume of diluent equal to the calculated volume of MEDI4736 to be added to the IV bag must 
be removed from the bag prior to addition of MEDI4736. The calculated volume of MEDI4736 is 
then added to the IV bag, and the bag is mixed by gentle inversion to ensure homogeneity of the 
dose in the bag.   
Example: For a subject weighing 80 kg and dosed at 10 mg/kg, 16 mL [10 mg/kg × 80 kg divided 
by 50 mg/mL] of MEDI4736 is to be diluted in a 250 mL IV bag . First, 16.0 mL of diluent is 
removed from the IV bag, and then 16 mL of MEDI4736 is added to the bag. The bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag and the diluted MEDI4736 is 
administered as described below. 
NOTE: Per Amendment 5, Fixed dosing will be used for Cohort 4a (See Section 6.1.2.3).  Per 
Amendment 6, fixed dosing will be used for the optional study treatment extension as 
described in Section 3.1.12 and Section 8.8. 
6.1.2.3 Preparation of 1500 mg dose for administration with an IV bag (Amendment 
5 Cohort 4a subjects and for optional study treatment extension) 
Beginning with Amendment 5, subjects enrolled to Cohort 4a will receive a fixed dose of 
MEDI4736: 1500 mg Q4W for subjects > 30 kg.   
Beginning with Amendment 6, subjects who receive optional study treatment extension per 
Section 3.1.12 will receive a fixed dose of MEDI4736 (1500 mg Q4W for subjects > 30 kg), unless 
a lower dose is agreed upon by Investigator and Sponsor.   
NOTE: If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will be dosed at 
600 mg Q4W for MEDI4736 as long as the body weight remains ≤ 30 kg. 
The volume of reconstituted MEDI4736 required for 1500 mg is 30 mL (see calculation below). 
This will require approximately 8 vials of MEDI4736, depending on the extractable volume from 
the vials. 


 
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Volume of 
MEDI4736 (mL) 
= 
Dose (1500 mg) 
 
÷ 
MEDI4736 Concentration 
(nominal 50 mg/mL) 
 
Doses will be administered using a 250 mL 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.  A 
volume of 30 mL diluent must be removed from the bag, and then, the 30 mL reconstituted 
MEDI4736 is added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity of 
the dose in the bag and the diluted MEDI4736 is administered as described below.   
6.1.3 Administration of MEDI4736 
Following preparation of the dose, MEDI4736 will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product(s). Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV contents must be at room temperature to avoid 
an infusion reaction due to the administration of the solution at low temperatures. 
• 
MEDI4736 must not be administered via IV push or bolus, but as an IV infusion.  
• 
MEDI4736 solution should not be infused with other solutions or medications. 
• 
MEDI4736 must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
Subjects will receive the dose of MEDI4736 as an IV infusion over 60 (± 5) minutes.  An 
infusion time of less than 55 minutes is considered a deviation.   
• 
When a syringe is used for the infusion, the syringe should be disconnected when the 
correct volume has been infused.  See Section 6.1.2.1 for details. 
• 
When an IV bag is used for the infusion, the entire contents of the IV bag should be 
administered as an IV infusion, using a 0.2- or 0.22-μm in-line filter.  
• 
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. If the line was not flushed, documentation is required. 
• 
The total time between reconstitution of MEDI4736 to start of administration should 
not exceed 4 hours at room temperature or 24 hours at 2 to 8°C (36°F to 46°F). Standard 
infusion time is 60 ± 5 minutes. However, if there are interruptions during infusion (total 
infusion time not to exceed 4 hours), the total allowed time for preparation and 
administration should not exceed 8 hours at room temperature. In the event that either 
preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. 
• 
The date, start time, interruption, and completion time of MEDI4736 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 6.3. 
• 
See Section 3.1.8.1 for guidelines for infusion-related reactions. 


 
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Tremelimumab 
6.2.1 Study Drug Information for Tremelimumab 
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification or in 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, route of administration, and storage 
conditions 
6.2.2 Tremelimumab Preparation 
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. 
The dose of tremelimumab for administration must be prepared by the IP manager or 
designated personnel using aseptic technique. No incompatibilities between tremelimumab and 
polyvinylchloride or polyolefin have been observed. However, administration sets containing 
cellulose-based filters should not be used with tremelimumab. 
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
Dose Calculation: 
Subject weight measurements can be taken in street clothes without shoes and a calibrated 
scale must be used for all measurements. 
The dose will be calculated at each dosing visit using the following formula: 
Tremelimumab 
Dose (mL) 
= 
subject 
weight (kg) 
X 
dose level (mg/kg) 
÷ 
Tremelimumab 
concentration  
(20 mg/mL) 
 
The corresponding volume of investigational product should be rounded according to 
institutional practice.  Each vial contains a small amount of overage and the overage should be 
utilized as much as possible before using another vial. 


 
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The number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
Number of vials 
= Tremelimumab Dose (mL) 
÷ 
20 (mL/vial) 
 
Dose Preparation: 
Tremelimumab will be administered using a 250 mL 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.  To prepare the IV bag: 
• 
First, calculate the dose volume of tremelimumab required.  
• 
Second, remove the volume of IV diluent equivalent to the calculated dose volume of 
tremelimumab from the IV bag.   
• 
Lastly, add the calculated dose volume of tremelimumab to the IV bag.   
• 
Gently mix the solution in the bag by inverting up and down.  Avoid shaking the IV bag 
to prevent foaming. 
Example for a 10 mg/kg dose: A subject weighing 85 kg will require 42.5 mL (3 vials) of 
tremelimumab. Remove 42.5 mL of diluent from the  IV bag. Add the 42.5 mL of tremelimumab 
to the IV bag and gently mix by inverting up and down. 
NOTE: Per Amendment 5, Fixed dosing will be used for Cohort 4a (See Section 6.2.2.1). 
6.2.2.1 Preparation of 75 mg dose (Amendment 5, Cohort 4a subjects) 
Dose Calculation: 
Beginning with Amendment 5, subjects enrolled to Cohort 4a will receive a fixed dose of 
tremelimumab: 75 mg for subjects > 30 kg.   
Note: If a subject’s body weight drops to ≤ 30 kg while on the study, the subject will be dosed at 
30 mg for tremelimumab as long as the body weight remains ≤ 30 kg. 
The volume of tremelimumab required for a 75 mg dose is 3.75 mL (see calculation below).  
Tremelimumab 
Dose (mL) 
= 
dose level (75 mg) 
 
÷ 
Tremelimumab 
concentration (20 mg/mL) 
 
The corresponding volume of tremelimumab should be rounded according to institutional 
practice. 
Dose Preparation: 
Tremelimumab will be administered using a 250 mL 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.  To prepare the IV bag (for a 75 mg dose), remove 3.75 mL of diluent.  Then, add 3.75 mL 
of tremelimumab to the IV bag.  Gently mix the solution in the bag by inverting up and down.  
Avoid shaking the IV bag to prevent foaming. 


 
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6.2.3 Administration of Tremelimumab 
Following preparation of the dose,  tremelimumab will be administered according to the 
following guidelines: 
• 
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 must not be administered via IV push or bolus but as a controlled IV 
infusion.   
• 
Tremelimumab solution should not be infused with other solutions or medications. 
• 
Tremelimumab 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 by IV infusion over 60 (±5) 
minutes, using a 0.2, or 0.22-μm in-line filter. An infusion 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 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). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion (total infusion time not to exceed 4 hours), the total 
allowed time for preparation and administration should not exceed 8 hours at room 
temperature.  In the event that either preparation time or infusion time exceeds the 
time limits, a new dose must be prepared from new vials. 
• 
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 6.3. 
• 
See Section 3.1.8.1 for guidelines for infusion-related reactions. 


 
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 Assessment of Vital Signs during Administration of Study Drugs 
Subjects will be monitored before, during and after tremelimumab and MEDI4736 infusion 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 
 
 
MEDI4736  
X 
Every 15 (± 5) 
minutes 
X 
X 
x 
Note: When MEDI4736 and tremelimumab are to be administered on the same day, MEDI4736 
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 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 
MEDI4736 
X 
Every 30 (± 5) 
minutes 
X 
X 
 
 Estimated Study Requirements 
Drug 
Required Quantity 
MEDI4736 
9200 vials 
Additional MEDI4736 for optional study 
treatment extension per Section 3.1.12 
1000 vials 
tremelimumab  
1550 vials  
 
 Drug Overdose Management 
An overdose is defined as a subject receiving a dose of investigational product in excess of that 
specified in this protocol by >10%.  There are no known antidotes available for MEDI4736 or 
tremelimumab.  Any overdoses with these drugs should be managed symptomatically and 
reported, with or without associated AEs/SAEs, according to Section 7.1.5 and Section 7.1.6. 


 
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7 Administrative, Legal and Ethical Requirements 
 Documentation and Reporting of Adverse Events 
7.1.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient 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 patient/subject is on study, i.e., during the actual treatment period, as well as during 
drug-free, pre- and post-treatment periods, under placebo or in a reference group receiving 
drug or non-drug therapy or no treatment. 
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 
patient/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 patient/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 SAE Definitions for this Study 
For the purpose of this study, the following events are considered medically important conditions 
and must be treated as SAEs: 
1. 
Pregnancy 
2. 
Overdose (as defined in Section 6.5) 
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 “Background” of this protocol may 
support these evaluations. 
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 Section7.1.4.  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). 


 
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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 Sections 7.1.1 and 7.1.2, 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. This should be done using the “Initial Serious Adverse Event Report 
Form,” provided by the Sponsor, or, if Medidata RAVE data capture is utilized, using the 
respective Adverse Event and Safety Case Summary eCRFs (and indicated as an SAE).  This 
includes any deaths that occur after the off-study date, but within 30 days of last study drug 
administration. Note: If an SAE cannot be reported through the “Initial Serious Adverse Event 
Report Form” or through Medidata RAVE 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 by an “Initial Serious Adverse Event 
Report Form” or through Medidata RAVE 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, as specified in “Sponsor Information”, Section 8.4.  Studies utilizing the 
Medidata “Safety Gateway”, built into the eCRF, and respective SAE reporting procedures, do 
not require reporting by fax or email.  Questions related to “Safety Gateway” procedures should 
be directed to the Drug Safety Contact or Primary Sponsor Contact. 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 
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 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. 


 
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7.1.8 Adverse Events of Special Interest (AESIs) 
An AESI is an event of scientific and medical interest specific to the understanding of the 
investigational product(s) 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 product(s).   
AESIs for MEDI4736 and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with MEDI4736 
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 MEDI4736 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 MEDI4736 and tremelimumab 
Investigator Brochures. Guidelines for the management of subjects experiencing the toxicities 
listed below can be found in Section 3.1.8.1 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).”. 
7.1.8.1 Hepatic Function Abnormality  
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 disease (e.g., 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. 


 
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7.1.8.2 Pneumonitis 
Adverse events of pneumonitis are also of interest for the Sponsor, as pneumonitis has been 
observed with anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies.(69)  Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary 
consultation is highly recommended.  
7.1.8.3 Infusion Reactions  
Adverse events of infusion reactions (also termed infusion-related reactions) are of special 
interest to the sponsor and are defined, for the purpose of this protocol, as all AEs occurring 
from the start of the study treatment infusion up to 48 hours after the infusion start time.  For 
all infusion reactions, the eCRF should be completed as described above, and all SAEs should be 
reported to the Sponsor as described in Section 7.1.6. 
7.1.8.4 Hypersensitivity Reactions 
Hypersensitivity reactions have been reported with anti-PD-L1 and anti-PD-1 therapy.(69)  As 
with the administration of any foreign protein and/or other biologic agents, reactions following 
the infusion of 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.  
7.1.8.5 Gastrointestinal Disorders  
Diarrhea and colitis are the most commonly observed treatment-emergent SAEs.  In rare cases, 
colon perforation may occur that requires surgery (colectomy) or can lead to a fatal outcome if 
not properly managed.   
7.1.8.6 Neurotoxicity (Neuropathy/Neuromuscular toxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. 
7.1.8.7 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. 
7.1.8.8 Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines. 


 
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7.1.8.9 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. 
7.1.8.10 Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis); increased serum lipase, increased serum amylase). 
7.1.8.11 Uveitis 
Uveitis is among the clinically significant, immune-mediated adverse reactions that occurred in 
less than 1% of subjects treated with agents targeting the PD-1 / PD-L1 pathway.  Physicians 
should initiate ophthalmologic evaluation should symptoms develop. 
 
Administrative Sponsor Requirements 
7.2.1 Pre-Study Requirements 
The following are required before study drug can be shipped to the study site: 
• 
Satisfactory Site Validation (conducted by Sponsor, if applicable) 
• 
Signed Statement of Investigator 
• 
Regulatory Approval (e.g., active IND or IMPD) 
• 
Institutional Review Board approval of Protocol and Informed Consent Form 
• 
Executed Clinical Trial Agreement (if applicable) 
7.2.2 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. 
7.2.3 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 


 
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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. 
7.2.4 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. 
7.2.5 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
validation, 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 patient charts, laboratory reports and other patient records 
needed to verify the entries on the case report forms (“source data verification”). 
7.2.6 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 usually do 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. 


 
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7.2.7 Premature Subject Withdrawal from Treatment or from Study 
A subject may withdraw from 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 criteria are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw, all efforts will be made to 
complete the required study procedures and report the treatment observations as thoroughly 
as possible. 
A complete final evaluation should be made at the time of the subject’s withdrawal from 
treatment or from the study. 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. 
7.2.8 Early Trial Termination 
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. 
7.2.9 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 seeing to it that all used and unused trial supplies are accounted 
for.  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 
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 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. 
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 
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 


 
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part of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
7.3.5 Inclusion of Women and Minorities 
Both men and women and members of all ethnic groups are eligible for this trial.  The expected 
distribution of men and women enrolled is based on the experience with other clinical trials at 
the study sites included in this study.  The anticipated study population will be about 50% male 
and 50% female. 
 
 


 
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8 Appendices 
 Protocol Version History 
 
Version 000 
Issue date: 27-June-2013 
Summary of Changes: n/a 
 
Version  001 (Amendment 001) 
Issue Date: 26-July-2013 
Summary of Changes: 
 
Following FDA comments, updates for this amendment are outlined below: 
• 
Section 3.1.9, DLT and MTD: second bullet: all Grade 4 irAEs are now considered as DLTs. 
• 
Section 3.1.14 Safety Monitoring and Study Stopping Rules: reason (3) was updated to 
include specific toxicities. 
• 
Section 5.1 Inclusion Criteria 6: adequate marrow function  is now defined as hemoglobin 
≥ 9 g/dl absolute neutrophil ≥ 1500/m3 
 
Version 002 (Amendment 002)  
Issue Date: 06-September-2013 
Summary of Changes: 
 
Following Roswell Park Cancer Center 
SRC review,  Dana-Farber Cancer Institute 
SRC pre-review and Memorial Sloan-Kettering Cancer Center Medicine Steering review, updates 
for this amendment are outlined below: 
 
• 
Section 3.1.6 Sample Size Considerations was updated to include confidence intervals 
indicating the degree of precision that can be expected when estimating AE of special 
interest incidence rates within each cohort  
• 
Section 3.1.7 Treatment Cohorts and Treatment Schema & section 6 Study Drugs, 
MEDI4736 and tremelimumab administration was updated to a 60 minutes (± 10 
minutes) infusion. 
• 
Section 3.1.8.1 MEDI4736 and tremelimumab Dose Modification Due to Toxicity, 
footnote c was added to define  maximum allowable time for decrease or interruption of  
MEDI4736 or tremelimumab infusion rate 
• 
Section 3.1.9: the definition of a DLT was clarified 
• 
Section 3.1.11 Per-Protocol Subject Evaluability and Replacement was updated to 
confirm that patient in the dose-escalation phase  not evaluable for DLT will be replaced 
as defined  as defined in Section 4.1.2 
• 
Section 3.2 Study Flowchart was updated to specify that “other Labs and Assays” should 
be performed at screening only if patient is deemed eligible. Tumor biopsies time points 
were updated to ensure consistency with section 8.7.7.2 Tumor Biopsies 


 
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• 
Section 4 Study Objectives and Endpoints sections were re-ordered to ensure consistency 
across the document 
• 
Section 5.1 Inclusion Criteria, Inclusion criterion 5 was updated to correct creatinine unit. 
• 
Section 6 Study Drugs and Section 8.5 Study Drug Information were merged.  
• 
Section 6 Study Drugs: 
o Formatting was updated 
o MEDI4736 and tremelimumab stability after reconstitution were added 
o Maximum allowable time for decrease or interruption of  MEDI4736 or 
tremelimumab infusion rate was added 
o Rounding rules for tremelimumab dose calculation  were updated  
o Specifications for  tremelimumab via a central line were added 
• 
Section 8.2 Participating Study Sites, Investigators and Staff Patrick Ott, MD, PhD replace 
Stephen Hodi, MD as principal investigator  
• 
8.7.7.2 Tumor Biopsies was updated to state that tumor biopsies will be obtained for all 
biopsiable tumors in the expansion phase 
 
 
Version 003 (Amendment 003) 
Issue Date : 11-October-2013 
Summary of Changes: 
 
Following Dana-Farber Cancer Institute IRB  comments updates for this amendment are outlined 
below: 
• 
Section 3.1.8.1 MEDI4736 and tremelimumab Dose Modification Due to Toxicity was 
updated to mention that MEDI4736 and tremelimumab should not be held for 
dermatologic irAEs 
• 
Section 4.5.2 Subject Evaluation and Statistics and  Section 8.7.7.2 Tumor Biopsies were 
updated to clarify collection of  biopsiable tumors in the expansion phase and include a 
statistical justification for the sample size 
 
 
Version  004 (Amendment 004) 
Issue Date:  18-February-2015 
Summary of Changes: 
 
Based on updated information from Medimmune and to provide clarifications for the protocol, 
updates for this amendment are outlined below.  Due to the extent of changes made in this 
amendment, a separate document (Amendment 4 Summary of Changes) was generated.  Outline 
of changes: 
• 
Section 3.1.8.1 (MEDI4736 and tremelimumab Dose Modification Due to Toxicity): Table 
3.1.8-1 was modified and replaced with an updated table based on the most recent 
recommendations from Medimmune.  The 2 guidelines from Medimmune for 
management of toxicity and for management of diarrhea and colitis were referenced in 
Section 3.1.8.1. 
• 
Section 3.1.9 (DLT and MTD): The DLT definition and criteria were updated to be 
consistent with Medimmune recommendations 


 
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• 
Section 3.1.10 (Patient Withdrawal): Item 3 was updated to indicate that either objective 
progression, per irRC, or symptomatic progressions is sufficient cause for patient 
withdrawal. 
• 
Section 3.1.14 (Safety Monitoring and Study Stopping Rules): Item 2 was changed to add 
clarification that anaphylactic reaction refers to severe reactions such as those 
associated with respiratory and cardiovascular failure. 
• 
Section 3.1.16 (Post Study Follow-up): Clarification was added regarding the distinction 
between  Post Treatment Follow-up and Post Study Follow-up (which will be done at 
least every 6 months for up to 3 years from the initiation of the treatment)  
• 
Section 3.2.1: Changes were made to flowchart to add pregnancy tests to Weeks 9, 17, 
33. 41 and 49 
• 
Section 3.2.1and Section 3.2.2:  
o Clarifications for hematology testing and addition of free T3 and free T4 to blood 
chemistry panel were added to flowcharts. 
o Clarification was added regarding the distinction between Post Treatment 
Follow-up and Post Study Follow-up (which will be done at least every 6 months 
for up to 3 years from the initiation of the treatment). 
• 
Section 4.1.2 (Patient Evaluation and Statistics) was modified to clarify that patients will 
be considered evaluable for a DLT if they receive at least75% of the planned dose during 
the DLT evaluation period (except for patients who discontinued prematurely due to 
DLT) 
• 
Section 5.2 (Exclusion criteria): Number 16 was modified to provide more detailed 
guidance regarding contraception use. 
• 
Section 6.5 (Drug Overdose Management) was modified to provide clarification on what 
is considered an overdose as well as treatment and reporting procedures.  
• 
Section 7.1 (Documentation and Reporting of AEs): 
o A new section was added as Section 7.1.2, Additional SAE Definitions for this 
Study: Pregnancy and Overdose 
o Other sections were re-numbered as appropriate 
o Section 7.1.4 (General Reporting Requirements) was re-numbered to Section 
7.1.5.  
o Section 7.1.8 (Adverse Events of Special Interest) was added. 
• 
Section 8.3 (Participating Laboratories): the address for Quintiles Laboratories was 
changed. 
• 
Section 8.4 was updated to include the new Project Manager for this study. 
• 
Section 8.5 (Tumor Response Assessment by irRC): The antitumor response based on 
total measurable tumor burden was updated to define a minimum size requirement for 
considering lesions measurable. 
• 
Section 8.7.7.1 (Archival Tumor Samples) was revised to define the availability, quantity 
and quality of archival tumor samples during the screening period. The section was also 
updated to allow patients who are otherwise eligible to obtain fresh biopsies prior to 
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Amendment 005 
Issue Date: 27-OCT-2015 
Summary of Changes 
 
In order to align the protocol with current recommendations from MedImmune, the following 
changes were made: 
• 
Synopsis, Sections 2.4, 3.1.2, 3.1.4, 3.1.7.2, and 5.1 and Figure 3 were changed (or notes 
were added) to indicate:  
o Disease states of non-small cell lung cancer and head and neck cancer were 
removed from the study and were replaced by non-triple negative breast cancer, 
for a total of 5 expansion cohorts.  Cohort sample sizes were increased to 15, for 
a total of 75 subjects in the expansion phase. 
• 
Synopsis, Sections 2.3, 2.4, 3.1.7, Figure 1, and Figure 2:  Dosing for Cohorts 3a and 4a 
were changed (or notes were added): 
o Cohort 3a:  
Tremelimumab, 1mg/kg Q4W for 4 cycles; MEDI4736 3 mg/kg, 
Q2W for 12 four-week cycles (previously: tremelimumab 1mg/kg Q4W for the 
first 6 cycles and then Q12W; MEDI4736 3 mg/kg, Q2W for 13 cycles) 
o Cohort 4a: 
Tremelimumab, 75 mg Q4W for 4 cycles; MEDI4736 1500 mg, 
Q4W for 12 four-week cycles (previously: tremelimumab 1mg/kg Q4W for the 
first 6 cycles and then Q12W; MEDI4736 10 mg/kg, Q2W for 13 cycles).  Fixed 
dosing was added for Cohort 4a. 
o Cohorts 4 and 5 were removed from the study 
• 
Section 3.1.5: Number of sites and subjects were updated 
• 
Section 3.1.6: Sample size considerations were updated to reflect change in sample size 
of 15 per disease cohort, with a total of 75 subjects in the expansion phase. 
• 
Section 3.1.7.1: clarification was added for review of DLTs 
• 
Section 3.1.8.1:  
o Added references for Yervoy™, Opdivo®, and Keytruda® to provide additional 
guidance for dose modifications. 
o For Table 3.1.8-1, the Note for temporary hold of MEDI4736 and tremelimumab 
until resolution of event was moved from the irAE section to the top of the table 
to indicate that the note refers to all sections. 
o Table 3.1.8-1 was updated based on the most recent dose modification 
guidelines from Medimmune.  The following additions were made: 
- 
In addition to the criteria for permanent discontinuation of M and T depicted 
below, permanently discontinue M and T also for:  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; and recurrence of a 
previously experienced Grade 3 treatment-related AE following resumption 
of dosing. 
- 
Under irAE Grade 2: For pneumonitis/interstitial lung disease, 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) 
- 
Under irAE Grade 3: recommendations were provided for elevated serum 
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- 
Under irAE Grade 4: recommendations were provided for asymptomatic 
increases in amylase or lipase 
• 
Section 3.1.8.2 (MEDI4736 and tremelimumab Discontinuation) was re-numbered as 
Section 3.1.8.3; and a new Section 3.1.8.2 (MEDI4736 and Tremelimumab Dose 
Modification Not Due to Toxicities) was added.  Cross references were updated as 
needed. 
• 
Section 3.1.8.3: clarification was provided to indicate that the Follow up every 8 weeks, 
not to exceed week 64, would start 8 weeks after the Last Study Drug +90 day visit. 
• 
Section 3.1.9 
o #3, 2nd bullet: “Grade 3 asymptomatic endocrinopathy” was changed to “Grade 3 
endocrinopathy that becomes asymptomatic.” 
o #3, 8th bullet: Grade ≥ 3 neutropenia was clarified to indicate that (1) is not 
associated with fever or systemic infection, and (2) does not require medical 
intervention, and (3) improves to Grade 2 within 7 days (changed from 3 days). 
o #3, 10th bullet: for thrombocytopenia, the criterion for improvement to Grade 2 
was changed from 3 to 7 days. 
o The rules for adjudicating DLTs were clarified and expanded 
o A sentence was added to indicate that subjects who experience a DLT will be 
discontinued from study treatment and will be followed as described in Section 
3.1.8.3.  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. 
• 
Section 3.1.10:  
o Section was clarified to indicate reasons for withdrawal from treatment vs. 
withdrawal from study. 
o The withdrawal criteria from Section 7.2.7 were deleted and combined with 
those in Section 3.1.10. 
o Additional cross reference to Section 3.1.8 was added regarding patient 
withdrawal due to necessary dosing interruptions or discontinuations 
• 
Section 3.1.15: duration of study was updated based on changes of Amendment 5. 
• 
Section 3.1.16: additional clarification was added for Post Treatment Follow-up (On 
Study Follow-up) versus Post Study Follow-up. 
• 
Section3.2 1: 
o Updated flowchart to show pre and post Amendment 5 dosing for MEDI4736 and 
tremelimunab.  
o Created flowcharts specific for pre Amendment 5, Cohort 3a Post Amendment 5, 
and Cohort 4a Post Amendment 5; additional flowcharts were included to 
provide details specific to Cohorts 3a and 4a as a result of Amendment 5. 
o Cycle 13 was deleted for Cohorts 3a and 4a 
o Clarified that ECG is 12-lead ECG 
o Footnote was added to clarify that all AEs will be reported for 90 days following 
last study drug dose. 
o For Cohorts 3a and 4a, SCCHN was removed from CTC assessment 
o For Cohorts 3a and 4a, tremelimumab PK assessment was removed from Cycle 
10 and from Post Treatment Follow-up; and total volume blood drawn was 
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o For Cohort 4a, disease assessment by RECIST and irRC were moved from Week 7 
to Week 9 to coincide with Study visit for new dosing schedule in Amendment 5.  
All other assessments for Weeks 7, 11, 15, 19, 23, 27, 31, 35, 39, 43 and 47 were 
removed. 
• 
Section 3.2.2: Flowchart for subjects who discontinue treatment per Section 3.1.8.3: 
o Clarification was provided to flowchart to indicate that the 8 week follow-up for 
up to 64 weeks is part of the On Study Follow-up. 
o Additional flowcharts were included to provide details specific to Cohorts 3a and 
4a as a result of Amendment 5; created flowcharts specific for pre Amend 5, 
Cohort 3a Post Ament 5, and Cohort 4a Post Amend 5. 
o Footnote was added to clarify that all AEs will be reported for 90 days following 
last study drug dose or until subject enters the Post Study Follow-up. 
o For Cohorts 3a and 4a, SCCHN was removed from CTC assessment 
• 
Section 4.1.2: Clarification was added (see bold).  All subjects who receive at least the 
first two cycles of treatment (i.e., approx. 8 weeks) and respective safety assessments, 
as well as, all subjects who discontinue the study prematurely due to DLT are considered 
fully evaluable per protocol for DLT. 
• 
Section 5.2 
o #11: Clarification was provided to indicate “If a patient previously received 
investigational treatment, the last dose of investigational treatment was 
administered within 4 weeks of Day 1 of the study or adverse event(s) 
attributable to investigational treatment have not resolved to Grade 1 or better.” 
o #16: For females of childbearing potential and non sterilized males, the period 
for continuation of contraception after final dose of investigational product was 
changed from 90 days to 6 months.  This is a requirement for tremelimumab. 
• 
Section 6.1.2.3: Additional section was added for instructions on the preparation of the 
fixed dose of 1500 mg MEDI4736. 
• 
Section 6.2.2: In the calculation example, clarification was added that the example is for 
a 10mg/kg dose.  
• 
Section 6.2.2.1;  Additional section was added for instructions on the preparation of the 
fixed dose of 75 mg tremelimumab 
• 
Section 6.3: estimated study requirements were updated. 
• 
Section 7.1.6: additional detail and clarification were added regarding reporting of SAEs 
to the Sponsor within 24 hours. 
• 
Section 7.1.8: clarification was added regarding recording of AESIs. Expedited reporting 
by the Investigator to the Sponsor within 24 hours is not required. 
• 
Section 7.1.8.6, Uveitis, was added. 
• 
Section 7.2.7:  Section was updated to be aligned with Section 3.1.10.  Study Status 
Outcome form was changed to the “appropriate form.” 
• 
Section 8.1 (Protocol Version History):  
o The format of the table was changed to allow more space for recording the 
Summary of Changes.  
o The Issue date for Amendment 4 was corrected to 18-February-2015 (previously 
06-February-2015)  
• 
Section 8.4: Primary Sponsor Contact was changed from Linda Pan to Andrew Park, who 
was already listed in this section as the Clinical Project Manager. 


 
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• 
Section 8.7.7.2: for tumor biopsy collections, added “(or Cycles 8 to 12 post Amendment 
5)”. 
• 
Administrative Changes 
o The term “patient(s) was changed to “subjects(s)” throughout the document, 
where appropriate. 
o General spelling and capitalization changes, as needed 
o Added IND # and signature line to Synopsis page 
o Updated abbreviations list 
o Updated footer and synopsis page with new protocol format and logo 
 
Amendment 006 
Issue Date: 04-JUN-2016 
Summary of Changes: 
 
• 
Synopsis: The following statement was added: “Per Amendment 6, optional treatment 
extension beyond the original 12- or 13-cycle treatment period (Core Study) will be 
available for subjects who complete the Core Study with Stable Disease or better; the 
optional treatment extension will be permitted upon agreement with subject, Sponsor 
and Investigator.  See Section 8.8 for details. 
• 
Sections for Participating Study Sites and Participating Laboratories were deleted from 
the Synopsis, as these sections are not included in the current protocol template. 
• 
Section 3.1.7. The infusion time for MEDI4736 and tremelimumab was changed from 60 
(± 10) minutes to 60 (± 5) minutes, and the following statement was added: “An infusion 
of less than 55 minutes is considered a deviation.” In addition, the following change was 
made (change in bold): “On the days when MEDI4736 and tremelimumab are to be 
administered, MEDI4736 infusion will start at least 60 (±10) minutes after the end of 
tremelimumab infusion.” 
• 
Section 3.1.8.1: 
o The statement, which referenced guidelines for ipilimumab, nivolumab, and 
pembrolizumab was deleted. 
o The reference to tremelimumab guideline was deleted, as this guideline is now 
included in Medimmune’s Dosing Modification and Toxicity Management 
Guidelines (also referenced in this section). 
o MEDI4736 and Tremelimumab Dose Modifications due to toxicity were updated 
according to current recommendations from MedImmune/AstraZeneca (Dated 
02-OCT-2015). 
• 
Section3.1.8.2: 
o For Point 2, “7 days or less” was changed to “≤ half the planned dosing interval.” 
o For Point 3, “7 days“ was changed to “half the planned dosing interval.” 
• 
Section 3.1.8.3: The section was changed FROM: “Subjects who permanently discontinue 
treatment as defined in Section 3.1.8.1 and Section 3.1.8.2, and who are not withdrawn 
from study as defined in Section 3.1.10 and/or Section 7.2.7, will remain on study on a 
modified/reduced study schedule without study drug administrations as per Section 
3.2.2 for the remainder of the planned study or until withdrawn from study as per 
Section 3.1.10 and/or Section 7.2.7.  For example, if a subject permanently discontinues 
treatment due to toxicity, then the subject will be followed on study according to the 


 
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schedule defined in Section 3.2.2 until disease progression or initiation of alternative 
anticancer therapy including another investigational product. Under the 
modified/reduced study schedule as per Section 3.2.2 subjects will be followed up for up 
to 64 weeks according to the following assessments: 
o Disease assessments (including appropriate imaging), as per the original schedule 
(see Section 3.2.1), up to Week 64. 
o End of Study Post treatment Follow-up (On Study Follow-up) scheduled to match 
the required time frames from the last study drug administrations (Section 
3.2.2). 
o Follow up every 8 weeks, not to exceed week 64, starting 8 weeks after the Last 
Study Drug +90 day visit (Section 3.2.2). 
Thereafter, the subjects will be taken off study and they will enter the Post Study Follow-
up as per Section 3.1.16.”  
TO: “Subjects who permanently discontinue treatment as defined in Section 3.1.8.1 and 
Section 3.1.8.2, and who are not withdrawn from study as defined in Section 3.1.10 
and/or Section 7.2.7, will proceed to the Post Treatment Follow-up (On Study Follow-up) 
for 90 days after the last study drug treatment according to Section 3.1.16.  Thereafter, 
the subjects will be taken off study and they will enter the Post Study Follow-up as per 
Section 3.1.16.” 
• 
Section 3.1.10: 
o 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).” 
o The following paragraph was changed FROM: “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 procedures according to Section 3.1.8.3.” TO: “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 Post Treatment Follow-up (On Study Follow-up) procedures 
(see Section 3.2) followed by the Post Study Follow-up (see Section 3.1.16).” 
• 
Section 3.1.11 was changed FROM: “Subjects who are not considered fully evaluable per 
protocol for the primary objective of safety and tolerability per Section 4.1.2 may be 
replaced. In the dose-escalation phase, subjects who are not evaluable for DLT will be 
replaced.“ TO: “In the dose escalation phase, subjects are fully evaluable for DLT if they 
fulfill the criteria for the Per-Protocol Population for DLT Assessment (as defined in 
Section 4.1.2). Subjects who are not considered fully evaluable for DLT per Section 4.1.2 
will be replaced.” 
• 
Section 3.1.12 was updated to indicate that optional treatment extension beyond initial 
study is permitted.  The following statement was added: “Optional treatment extension 
beyond the original 12- or 13-cycle treatment period (Core Study) will be available for 
subjects who complete the Core Study with Stable Disease or better; the optional 
treatment extension will be permitted upon agreement with subject, Sponsor and 
Investigator.  See Section 8.8 for details.” 


 
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• 
Section 3.1.13: “No formal interim analysis will be performed” was changed to “No 
formal interim analysis is currently planned.”  
• 
Section 3.1.15 and Section 3.1.16: reference was provided to Section 3.1.12 regarding 
optional study treatment extension. 
• 
Section 3.1.16: 
o Paragraph 2 was changed FROM: “Post Treatment Follow-up (On Study Follow-
up) will be conducted according to Section 3.2.1 (for subjects who complete the 
study) and Section 3.2.2 (for subjects who discontinue treatment prematurely 
according to Section 3.1.8.3.” TO: “Subjects who complete study treatment or 
discontinue treatment prematurely will enter the Post Treatment Follow-up (On 
Study Follow-up), which will be conducted for 90 days after the last 
administration of study drug according to the flowchart in Section 3.2  Refer to 
Section 7.1.5 for information on collection of adverse events during the Post 
Treatment Follow-up (On Study Follow-up).” 
o The following was added: “If the determination is made to remove a subject 
from treatment at a visit that coincides with the first visit of the Post Treatment 
Follow-up (On Study Follow-up) Period, any assessments required in the post-last 
treatment visit that are not covered as part of the 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 visit and the post-last treatment visit should not be repeated.” 
o The following correction was made (change in bold): In addition to the Post 
Treatment Follow-up (On Study Follow-up), there will be a Post Study Follow-up, 
where clinical outcomes data (dates of progression/relapse, subsequent 
therapy, and survival) will be collected at least every 6 months for up to 3 years 
from the initiation of the treatment. 
o The following was added: “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.” 
• 
Section 3.2 
o For each of the 3 major flowcharts in Section 3.2.1, parts 1 and 2 were 
consolidated into one section and parts 3 and 4 were consolidated into a second 
section. 
o Deleted the flowcharts related to “Subjects discontinuing treatment per Section 
3.1.8.3” to provide alignment with update to Section 3.1.8.3 
o Footnote related to PK collections was deleted and other footnotes were re-
numbered as appropriate. 
o Added a Note to Indicate “It is strongly recommended that hematology, 
chemistry and pregnancy test (when applicable) results are reviewed before 
dosing.” 
o ECOG Perf Status was deleted as a single assessment at baseline and added to 
Physical Exam assessments. 
o For the Cohorts 3 and earlier flowchart, pregnancy test was added to Last study 
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o Added the footnote: “Standard of Care procedures may be used for eligibility 
assessments provided they meet the criteria specified in either the inclusion 
criteria or flowchart.”  
o Added (or clarified) the AE footnote: “See section 7.1.5 for details regarding 
collection of AEs for 90 days after last study drug administration.”  The footnote 
was re-numbered as appropriate for each flowchart. 
o Added amylase and lipase assessments to Chem cont., as these are required for 
monitoring pancreatitis. 
o Deleted MEDI4736 and tremelimumab PK, sPD-L1, ADA, circulating soluble 
factors, and CTC sample collections.  Medimmune has determined that they have 
adequate data, and samples are no longer needed. 
o Deleted blood volume for blood collections, as this information is provided in the 
Lab Manual. 
o Added concomitant procedures to concomitant medications line in flowchart 
o Added reference to Section 6.3 for vital signs assessment. 
o Disease assessment during Post Treatment Follow-up (On Study Follow-up) was 
changed from a specific study visit to “'+56 ± 7 days from last disease 
assessment.” This allows the frequency of disease assessments to remain 
constant for subjects who complete the study as well as those who discontinue 
early. 
o Collection for flow cytometry and PBMC at baseline and Day 1 were merged as 
“Day -7 to 1 (pre-dose)” 
o Updated formatting, as appropriate 
• 
Section 4.2.1: the following statements were added: “NOTE: Per Amendment 6, samples 
will no longer be collected for analysis of MEDI4736 and tremelimumab 
pharmacokinetics, as sufficient samples have already been collected. The collection time 
points for these assays have been removed from the flowchart in Section 3.2.” 
• 
Section 4.3.1: the following statements were added: “NOTE: Per Amendment 6, samples 
will no longer be collected for the assessment of anti-tremelimumab and anti-MEDI4736 
anti-drug antibodies (ADA), as sufficient samples have already been collected. The 
collection time points for these assays have been removed from the flowchart in Section 
3.2.” 
• 
Section 4.5.1: the following statements were added: “NOTE: Per Amendment 6, samples 
will no longer be collected for analysis of sPD-L1, circulating soluble factors, and 
circulating tumor cells (CTC), as sufficient samples have already been collected. The 
collection time points for these assays have been removed from the flowchart in Section 
3.2.” 
• 
Section 4.5.2: “6 disease-specific cohorts” was changed to “5 disease-specific cohorts” to 
align with other changes made in Amendment 5. 
• 
Section 5, Subject Eligibility: The following note 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.” 
• 
Section 5.1: Criterion #11 was changed FROM: “Able and willing to give valid written 
consent for biopsy samples (subjects in the expansion phase only).” 
TO: “Able and willing to give valid written consent for biopsy samples (subjects with 
biopsiable tumors, and if clinically appropriate, in the expansion phase only).” 


 
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• 
Section 5.2: contraception requirements were changed from 6 months after last dose of 
drug to “90 days after last dose of MEDI4736 or 6 months after the final dose of 
tremelimumab (whichever is longer).” 
• 
Section 5.3.1: 
o Added bold phrase: “Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) 
prior to day 1; 6 weeks for nitrosoureas.” 
o 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.” 
• 
Section 5.3.2: The last statement was modified as follows (changes in bold: “All non-drug 
therapies must be recorded in the respective sections of the case report form, or as 
adverse events”. 
• 
Section 6: second paragraph was changed FROM: “On the days when MEDI4736 and 
tremelimumab are to be administered (first day of Cycles 1-7, 10, and 13), MEDI4736 
infusion will start 60 minutes after the end of tremelimumab infusion.“ TO:  “When 
MEDI4736 and tremelimumab are to be administered on the same day, MEDI4736 
infusion will start at least 60 minutes after the end of tremelimumab infusion.” 
• 
Section 6.1, Medi4736:  
o MEDI4736 Preparation and Administration sections were re-organized to remove 
redundancy and to improve clarity. 
o The following statements were added:  
 
Each vial of MEDI4736 selected for dose preparation should be 
inspected.  If there are any defects noted with the investigational 
product, the Investigator, Site Monitor, and Sponsor should be notified 
immediately. 
 
Preparation of MEDI4736 is to be performed aseptically. 
 
Per Amendment 6, fixed dosing will be used for the optional study 
treatment extension as described in Section 3.1.12 and Section 8.8. 
 
Beginning with Amendment 6, subjects who receive optional study 
treatment extension per Section 3.1.12 will receive a fixed dose of 
1500 mg MEDI4736, regardless of weight, unless a lower dose is agreed 
upon by Investigator and Sponsor. 
 
Each dose of investigational product should be administered using the 
following guidelines: 
 
A physician must be present at the site or immediately available to 
respond to emergencies during all administrations of investigational 
product(s). Fully functional resuscitation facilities should be available. 
Investigational product(s) must not be administered via IV push or bolus 
but as an IV infusion. 
 
Investigational product(s) must be administered at room temperature by 
controlled infusion via an infusion pump into a peripheral vein or central 
line.  Prior to the start of the infusion, ensure that the bag contents are 
at room temperature to avoid an infusion reaction due to the 
administration of the solution at low temperatures. 
 
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hours at 2-8°C.  If administration time exceeds these limits, a new dose 
must be prepared from new vials.  MEDI4736 does not contain 
preservatives and any unused portion must be discarded. 
 
Subjects will be monitored before, during and after infusion with 
assessment of vital signs according to Section 6.3. 
o Infusion time window was changed from 60 ±10 minutes to 60 ± 5 minutes, and 
the following statement was added: “An infusion of less than 55 minutes is 
considered a deviation.” 
• 
Section 6.2, Tremelimumab: The following statements were added 
o Each vial of tremelimumab 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. 
o The infusion should be administered by IV infusion over 60 (±5) minutes, using a 
0.2, or 0.22-μm in-line filter. An infusion of less than 55 minutes is considered a 
deviation. 
o Subjects will be monitored before, during and after infusion with assessment of 
vital signs according to Section 6.3. 
• 
Section 6.3 was added to replace Table 3.2-1 for the assessment of vital signs during 
study drug administration; a second table was added to provide assessment vital signs 
frequency that may be used if a subject tolerates treatment well for the first 4 doses of 
MEDI4736 (i.e., no infusion reactions).  Other sections were re-numbered accordingly.  
The following note was added: “Note: When MEDI4736 and tremelimumab are to be 
administered on the same day, MEDI4736 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.” 
• 
Section 6.4: Additional estimated MEDI4736 requirements (1000 vials) for optional study 
treatment extension was added. 
• 
Section 7.1.5: language for documenting AEs was changed 
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.” 
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 
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days after the last dose of the last study treatment (regardless of initiation of another 
therapy).” 
• 
Section 7.1.6: The following phrase was added to the beginning of the second paragraph: 
“If the Initial Serious Adverse Event Report Form” is being used...” 
• 
Section 7.2.3: 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.” 
• 
Sections 8.2 and 8.3: Tables for Participating Study Sites and Participating Laboratories, 
respectively, were deleted. The following statement was added: “This information is 
provided in the Clinical Study File.” 
• 
Section 8.7.1: The following statement was added: “NOTE: Per Amendment 6, samples 
will no longer be collected for analysis of sPD-L1, as sufficient samples have already been 
collected. The collection time points for these assays have been removed from the 
flowchart in Section 3.2.” 
• 
Section 8.7.4: The following statement was added: “NOTE: Per Amendment 6, samples 
will no longer be collected for analysis of circulating soluble factors, as sufficient samples 
have already been collected. The collection time points for these assays have been 
removed from the flowchart in Section 3.2.” 
• 
Section 8.7.5: the following statement was added: “NOTE: Per Amendment 6, samples 
will no longer be collected for analysis of CTC, as sufficient samples have already been 
collected. The collection time points for these assays have been removed from the 
flowchart in Section 3.2.” 
• 
Section 8.8 was added to provide additional details and flowchart for subjects who 
receive optional treatment extension according to Section 3.1.12. 
• 
Administrative:  
o Spelling, grammar and typographical errors were corrected; formatting changes 
were implemented, as applicable. 
o Monitor and Study Monitor were standardized as “Clinical Monitor” in Sections 
7.25 and 7.2.9. 
o Updated abbreviation list 
 


 
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Amendment 7 
Issue Date: 02-FEB-2017 
Summary of Changes: 
1. Synopsis: Clarification was provided that fixed dosing of 1500 mg for MED4737 and 75 mg for 
tremelimumab is for subjects >30 kg. 
2. Section 3.1.7, Treatment Cohorts and Treatment Schema:  
a. Clarification was provided regarding administration of MEDI4736 and tremelimumab 
(reference to Section 6 was provided).   
b. Clarification was also added that, per Amendment 6, optional treatment extension 
beyond the Core Study is available.  
c. The following text was added: 
Note: The MEDI4736 and tremelimumab fixed doses are for subjects > 30 kg.  
• 
MEDI4736 dose: 1500 mg for subjects > 30 kg.  If a subject’s body weight drops to 
≤ 30 kg while on the study, the subject will be dosed at 600 mg Q4W as long as the 
body weight remains ≤ 30 kg. 
• 
Tremelimumab dose: 75 mg for subjects > 30 kg. If a subject’s body weight drops to 
≤ 30 kg while on the study, the subject will be dosed at 30 mg Q4W for 
tremelimumab as long as the body weight remains ≤ 30 kg.   
3. Section 3.1.8.1, MEDI4736 and tremelimumab Toxicity Management Guidelines: Section was 
updated to correspond with current Medimmune/AZ guidelines (19August2016). 
4. Section 3.1.8.2, MEDI4736 and Tremelimumab Dose Modification Not Due to Treatment-
related Toxicities: Section was changed FROM: MEDI4736 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: MEDI4736 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. 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 10 days for Q2W dosing or 
no less than 21 days for Q4W dosing. 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 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. 
5. Section 3.1.10.1, Treatment Beyond Progression, was added. 
6. Section 3.1.16.1, End of Study Visit, was added. 
7. Section 5.2, Exclusion Criteria: 


 
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a. #16: Requirements for Contraception: updated entire section for agreement with current 
Medimmune guidelines. 
b. #18 was added: “Subjects must not donate blood while on study and for at least 90 days 
following the last MEDI4736 treatment or 6 months after the last tremelimumab 
treatment, whichever is longer.” 
8. Section 6.1 (MEDI4736) and Section 6.2 (Tremelimumab): the entire sections were updated 
and reorganized according to current language from Medimmune/AstraZeneca. 
a. Dextrose was added as an option to be used as a diluent. 
b. Infusion pump requirement was deleted 
c. Weight restriction for fixed doses of MEDI4736 and tremelimumab were added 
d. The following statement was added “See Section 3.1.8.1 for guidelines for infusion-
related reactions.” 
e. The following statement was clarified for MEDI4736: ”The total time between 
reconstitution of MEDI4736 to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2 to 8°C (36°F to 46°F). Standard infusion time is 60 ± 5 
minutes. However, if there are interruptions during infusion (total infusion time not to 
exceed 4 hours), the total allowed time for preparation and administration should not 
exceed 8 hours at room temperature. In the event that either preparation time or 
infusion time exceeds the time limits, a new dose must be prepared from new vials.” 
f. The following statement was clarified for tremelimumab: “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). Standard infusion time 
is 60 ± 5 minutes. However, if there are interruptions during infusion (total infusion time 
not to exceed 4 hours), the total allowed time for preparation and administration should 
not exceed 8 hours at room temperature.  In the event that either preparation time or 
infusion time exceeds the time limits, a new dose must be prepared from new vials.” 
g. The following statement was added for tremelimumab: “No incompatibilities between 
tremelimumab and polyvinylchloride or polyolefin have been observed. However, 
administration sets containing cellulose-based filters should not be used with 
tremelimumab.” 
9. Section 7.1.6: The following statement was added; “Serious adverse event reporting to 
AstraZeneca/Medimmune is described in a separate agreement.” 
10. Section 7.1.8 (AESIs). Additional information was added to the description of the AESIs per 
the updated guidelines provided by Medimmune/AstraZeneca. The following AESIs were 
added: neurotoxicity, endocrine disorders (including Type 1 diabetes mellitus), 
dermatitis/rash, nephritis, and pancreatic disorders. 
11. Section 8.8, Details for Subjects Who Continue Treatment Beyond Core Study: Weight 
restriction for fixed dose of MEDI4736 was added 
12. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable.  Sections were numbered as appropriate when 
additional sections were added. 
 


 
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Amendment 8 
Issue Date: 08-JAN-2019 
Summary of Changes: 
 
Section 8.8.2, Reinduction with MEDI4736 and Tremelimumab for Subjects With Confirmed 
Progression, was added. 
 
 
 
 


 
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Participating Study Sites, Investigators and Staff 
This information is provided in the Clinical Study File. 
 
 
Participating Laboratories 
This information is provided in the Clinical Study File  
 
 


 
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Sponsor Information 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel:  212-450-1500 
 
Drug Safety Contact: 
Gary O’Donnell, MS 
Assistant Director, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel: 212-450-1551 
Fax: 212-450-1535 
godonnell@licr.org  
 
Primary Sponsor Contact: 
Andrew Park, Pharm.D. 
Senior Clinical Project Manager 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave 28th Floor 
New York, New York 10017 
Tel: 212-450-1587 
Fax: 212-450-1535 
apark@licr.org  
 
 


 
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Tumor Response Assessment by irRC  
Tumor Response will be assessed by the Immune-related Response Criteria (irRC) as published 
by Wolchok et al.(68)  Response is defined as irCR, irPR or irSD over a period of at least 4 weeks.  
A condensed/abbreviated summary of the irRC is provided is provided below:  
Antitumor response based on total measurable tumor burden: 
Only index and measurable new lesions are taken into account when evaluating total 
measurable tumor burden.  The longest diameter and longest perpendicular diameter should be 
recorded in millimeters (mm).  At the baseline tumor assessment, the sum of the products of 
the two largest perpendicular diameters (SPD) of all index lesions (≥ 10 x 10 mm; five lesions per 
organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated.  At each 
subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions 
(≥ 5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are 
added together to provide the total tumor burden. 
Time-point response assessment: 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear.  At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change 
in tumor burden (after ruling out irPD).  Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). 
irCR 
Disappearance of all lesions in two consecutive observations not less than 4 
weeks apart. 
irPR 
≥50% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart. 
irSD 
50% decrease in tumor burden compared with baseline cannot be 
established nor 25% increase compared with nadir. 
irPD 
At least 25% increase in tumor burden compared with nadir (at any single 
time point) in two consecutive observations at least 4 weeks apart. 


 
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Overall response assessment: 
The overall response is derived from time-point response assessments (based on tumor burden) 
as follows: 
Index and new 
Measurable Lesions (Tumor 
Burden) 
Non-index 
Non-measurable 
Lesions 
New 
Non-measurable 
Lesions 
Overall 
Response 
100% 
Absent 
Absent 
irCR 
100% 
Stable 
Any 
irPR 
100% 
Unequivocal 
Progression 
Any 
irPR 
≥50% 
Absent/Stable 
Any 
irPR 
≥50% 
Unequivocal 
Progression 
Any 
irPR 
<50% TO <25% 
Absent/Stable 
Any 
irSD 
<50% TO <25% 
Unequivocal 
Progression 
Any 
irSD 
≥25% 
Any 
Any 
irPD 
 
 
 


 
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Tumor Response Assessment by RECIST  
Response and progression will be evaluated using the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Committee.(70) 
Objective responses will be measured by serial CT scans of the chest, abdomen, pelvis, and brain 
MRI if malignant brain lesion(s) were present at time of pre-treatment evaluation.  Overall 
tumor response, based on CT scan results, will be based on observation of measurable and non-
measurable disease as compared to baseline in target and non-target lesions every 4 to 12 
weeks.   
 
 


 
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Laboratory procedures 
8.7.1 sPD-L1   
The association of sPD-L1 with response to treatment and clinical outcome will be evaluated. 
NOTE: Per Amendment 6, samples will no longer be collected for analysis of sPD-L1, as sufficient 
samples have already been collected. The collection time points for these assays have been 
removed from the flowchart in Section 3.2. 
8.7.2 Flow Cytometry 
Samples will be collected for analyses at time points designated in the study flowchart (Section 
3.2). 
Peripheral blood populations before and after treatment, including absolute lymphocyte counts, 
numbers of T cells, T-cell subsets, NK cells, and B cells as well as their cellular phenotypes will be 
assessed by FLOW cytometry to evaluate the association with treatment and subject responses. 
8.7.3 PBMC Banking 
Peripheral Blood Mononuclear Cells (PBMCs) will be isolated and banked as described below at 
time points designated in the study flowchart (Section 3.2) 
These samples may be used to address several key questions: 
- 
The diversity of the immune cell repertoire may be assessed in PBMCs based on VDJ 
coding region analysis to determine if clinical responses are correlated with 
immunodiversity and if repertoire changes occur in response to treatment.   
- 
Functional assays such as ELISPOT or tetramer staining or intracellular cytokine analysis 
may be employed to assess the activation state or antigen specificity of immune cell 
populations in the periphery.  
- 
Flow cytometric analyses to examine additional markers not included in our primary 
panel may be performed on banked samples to supplement our understanding of a 
subject’s immune status.     
8.7.4 Circulating soluble factors 
Analyses of circulating levels of soluble factors such as CRP, cytokines and chemokines may 
include but are not limited to markers such as soluble CD80/86, soluble IL-6R, VEGF, FGF, IL-1 IL-
2, IL-4, IL-6, IL-8, IL-10, soluble CTLA-4, cancer biomarkers (AFP, CEA, CA125, PSA), granzyme B, 
IFN, LARGE, CXCL10, SOCS3, APRIL, BAFF, IGF-1, IGF-2, and autoantibodies to host and tumor 
antigens and exploration of their association with tremelimumab treatment and clinical outcome. 
NOTE: Per Amendment 6, samples will no longer be collected for analysis of circulating soluble 
factors, as sufficient samples have already been collected. The collection time points for these 
assays have been removed from the flowchart in Section 3.2. 
8.7.5 CTC  
Samples for Circulating Tumor Cell (CTC) analysis will only be collected from subjects with CRC, 
ovarian cancer and SCCHN. 


 
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CTC numbers and the PD-L1-expressing CTC subset will be examined in subjects with CRC, ovarian 
cancer, and SCCHN to explore their relationship to treatment effects with MEDI4736 and 
tremelimumab. 
NOTE: Per Amendment 6, samples will no longer be collected for analysis of CTC, as sufficient 
samples have already been collected. The collection time points for these assays have been 
removed from the flowchart in Section 3.2.  
8.7.6 mRNA/miRNA profiling 
Whole blood samples (pre- and post- MEDI4736/tremelimumab treatment) will be collected and 
preserved in PAXgene tubes to prepare miRNA/mRNA samples for future analyses of transcript 
and/or miRNA expression mRNA levels of selected inflammatory/immune and cytokine 
pathways which may include but are not limited to IL-6, IL-8, TIMP1, FCRG2B, LIF, IFN, LARGE, 
CXCL10, SOCS3 may be measured, as well as their association with tremelimumab/MEDI-4736 
treatment outcome.  RNA analyses may be conducted to generate hypotheses associated with 
the mechanisms of action of immunotherapy and/or to identify subsets of subjects responsive 
to MEDI4736 and tremelimumab. 
8.7.7 Archival Tumor Samples and Tumor Biopsies 
Consent for archival tumor samples is mandatory (all subjects) and consent for tumor biopsies is 
mandatory in the expansion phase for all subjects with biopsiable tumors (if clinically 
appropriate). 
Tumor samples will be examined to evaluate biomarkers by immunohistochemistry (IHC) and 
mRNA/miRNA expression profiling.  This may include but is not limited to, the expression level 
and localization of immunosuppressive proteins such as PD-L1 on tumor cells, tumor infiltrating 
lymphocytes (TILs), and/or markers of inflammatory/immune cell signatures, e.g. CTLA-4 CD3, 
CD4, CD8, CD45RO, IFN-gamma, FoxP3, and granzyme B and OX40.  Any relationships between 
biomarker expression with subject response to treatment with MEDI4736 and tremelimumab 
will be evaluated.  Additionally, analyses of tumor mutations and polymorphisms using archival 
tumor tissue may be performed through relevant methodologies in order to assess genetic 
alterations and their potential relationships with treatment outcome to MEDI4736 and 
tremelimumab.  Further, selected gene sequencing of samples may be employed to evaluate 
genetic alterations and relationships with treatment outcome with MEDI4736 and 
tremelimumab. 
8.7.7.1 Archival Tumor Samples 
Archival tumor samples are required for all subjects and must be deemed available during the 
screening period. If the availability, quantity (25 unstained slides: 12 slides with tissue sections 
of 4 microns thick and 13 slides with tissue sections of 10 microns thick), and quality of archival 
tumor samples during screening period cannot be confirmed, then baseline fresh tumor biopsies 
will be obtained prior to Day 1.  Formalin-fixed paraffin-embedded tumor samples will be 
collected for immunohistochemistry (IHC) and additional correlative markers. 


 
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8.7.7.2 Tumor Biopsies 
In the expansion phase, tumor biopsy samples are required for all subjects with biopsiable 
tumors (if clinically appropriate). Tumor biopsy samples will be examined to evaluate the 
correlation between clinical activity and the expression level of PD-L1 and tumor-infiltrating 
lymphocytes changes in biopsies pre and post treatment (Section 4.5.2). 
Tumor biopsy will be performed according to institutional practice during screening, 30 to 60 
days after initiation of treatment (if clinically appropriate), and during Cycles 8 to 13 (or Cycles 8 
to 12 post Amendment 5) or time of progression (if clinically appropriate) for subjects in the 
expansion phase of the study (Section 3.2).   
Tumor lesions planned for biopsy must not be used as index lesions for assessment of disease 
and tumor response.  Excisional biopsies are preferred where clinically appropriate.  Otherwise, 
subjects will undergo 4 core biopsies (18 g or larger, if clinically appropriate).  Two tissue cores 
will be placed in formalin and processed to FFPE.  The remaining 2 cores will be immediately 
frozen in liquid nitrogen and then stored at -80°C.  Additional details for sample collection, 
processing, storage, and shipment will be provided in the Laboratory Manual. 
8.7.8 Additional translational and exploratory studies 
Optional research studies may only be performed for subjects who voluntarily gave their 
consent for additional correlative research on the informed consent document.  Patients who 
declined consent to participate in additional translational studies will have their samples 
destroyed at the end of the study.  Refusal to participate in this optional research will involve no 
penalty or loss of benefits to which the subject would otherwise be entitled.   Based on the data 
generated during the study and/or in other studies, not all samples from subjects consenting to 
this optional research may be utilized. 


 
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 Details for Subjects who Continue Treatment beyond the Core Study  
According to Section 3.1.12, optional treatment extension with MEDI4736 beyond the Core 
Study is available for subjects who complete the Core Study with Stable Disease or better; the 
optional treatment extension will be permitted upon agreement with subject, Sponsor and 
Investigator.   
Subjects who receive optional study treatment extension will receive the currently 
recommended fixed dose of 1500 mg MEDI4736,  unless a lower dose is agreed upon by 
Investigator and Sponsor.   
Note: the fixed dose of MEDI4736 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 be dosed at 600 mg Q4W for 
MEDI4736 as long as the body weight remains ≤ 30 kg. 
The following procedures will be implemented for subjects who receive optional study 
treatment: 
1. Fixed dose of 1500 mg MEDI4736 will be used; preparation details are provided in 
Section 6.1.2.3.   
2. Administration of MEDI4736 will proceed according to Section 6.1.3.   
3. Subjects will be monitored by assessment of vital signs before, during and after each 
MEDI4736 dose administration according to Section 6.3. 
4. First MEDI4736 dose during optional treatment extension will be administered as 
follows: 
a. Last dose in Core Study + 2 weeks (± 3 days) for subjects on Q2W regimen in 
Core Study, OR 
b. Last dose in Core Study + 4 weeks (± 3 days) for subjects on Q4W regimen in 
Core Study 
5. After first dose, MEDI4736 dosing will continue Q4W. 
6. The flowchart for optional treatment extension, which is provided in Section 8.8.1 will 
be followed. 
 


 
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8.8.1 Study Flowchart for Subjects who Continue Treatment beyond the Core Study  
 
 
 
MEDI4736
1500 mg
Disease Assessment by RECIST  (including appropriate 
imaging) 
SOC
Disease Assessment by irRC (including appropriate imaging)
SOC
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
X
Vital Signs (T, HR, BP, RR)4 
X
X
X
X
Concomitant Medications and Procedures
X
X
X
X
Adverse Events (starting or worsening after consent)5
X
X
X
X
Blood Hematology (CBC, differential, platelets)
x3
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, prot., 
alb., Tbili., AST, ALT, LDH, ALP, Free T3, Free T4, TSH)
x3
X
X
X
Chemistry cont. (Amylase, lipase)
x3
X
X
X
Serum pregnancy test
at first optional study 
treatment visit, then Q8W3
x
x
Overall Survival
x
Progression Free Survival
x
3 - Collected pre-dose. Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing.
Optional 
Study Treatment1,2
(Q4W following first 
optional study treatment 
dose)
Study Flowchart for Subjects who Continue 
Optional Study Treatment after Core Study 
Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; SOC = Standard of Care
Last Study Drug 
Administration 
+28 (± 3) days
On Study Follow-up5
Last Study Drug 
Administration 
+56 (± 5) days
Last Study Drug 
Administration 
+90 (± 7) days 
Post Study 
Follow-up 
(Done at least 
every 6 months for 
up to 3 years from 
start of treatment)
Laboratory Assessments
Long-Term Follow-up
Tumor & Disease Assessments 
Study Procedures & Examinations
Treatment 
+56 ± 7 days from last disease assessment
+56 ± 7 days from last disease assessment
4 - See Section 6.3 for assessment of vital signs before, during and after administration of MEDI4736 dose.
5 - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
1 - First MEDI4736 dose during optional treatment extension will be administered: 
   a) Last dose in Core Study + 2 weeks (± 3 days) for subjects on  Q2W regimen in Core Study OR 
   b) Last dose in Core Study + 4 weeks (± 3 days) for subjects on  Q4W regimen in Core Study
2 - After first dose, MEDI4736 dosing will continue Q4W


 
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8.8.2 Reinduction with MEDI4736 and Tremelimumab for Subjects With Confirmed 
Progression  
Upon agreement between the Investigator and the Sponsor and if the subject agrees and signs 
an appropriate informed consent form, a subject with confirmed progression may be reinduced 
with MEDI4736 and tremelimumab. The reinduction will consist of 4 doses (Q4W) of 75 mg 
tremelimumab and 1500 mg MEDI4736 (Q4W). There should be no other intervening therapy 
prior to reinduction with MED4736 and tremelimumab. Reinduction is permitted only once. 
The following procedures will be implemented for reinduction: 
1. Fixed doses of 1500 mg MEDI4736 and 75 mg trememlimumab will be used; 
preparation details are provided in Sections 6.1.2.3 and 6.2.2.1, respectively.  
NOTE: the MEDI4736 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 
as described in Section 6.1.2.3. When tremelimumab 75 mg is given with MEDI4736 
1500 mg Q4W, if a subject’s body weight drops to ≤ 30 kg while on the study, the 
subject will receive weight-based dosing for both drugs as described in Sections 6.1.2.3 
and 6.2.2.1, respectively. 
2. Administration of MEDI4736 and tremelimumab will proceed according to Sections 
6.1.3 and 6.2.3, respectively. 
NOTE: When MEDI4736 and tremelimumab are to be administered on the same day, 
MEDI4736 infusion will start at least 60 minutes after the end of tremelimumab 
infusion. 
3. Subjects will be monitored by assessment of vital signs before, during and after each 
MEDI4736 and tremelimumab dose administration according to Section 6.3. 
4. The assessments and procedures identified in the Flowchart in Section 8.8.1 will be 
followed during the reinduction period. 
 
After reinduction, MEDI4736 dosing may be continued as outlined in the flowchart in Section 
8.8.1. 
 
 


 
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List of Abbreviations 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
CBC 
Complete Blood Chemistry 
CRC 
Colorectal Cancer  
CTLA-4 
Cytotoxic T-Lymphocyte-associated Antigen-4  
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting Toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FFPE 
Formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HLA 
Human Leukocyte Antigen 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IP 
Investigational product 
IRB 
Institutional Review Board 
irCR 
Immune-Related Complete Response 
irPD 
Immune-Related Progressive Disease 
irPR 
Immune-Related Partial Response 
irRC 
Immune-Related Response Criteria 
irSD 
Immune-Related Stable Disease 
LICR 
Ludwig Institute for Cancer Research 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-Small Cell Lung Cancer  
PD-1 
Programmed Death-1  
Q2W 
Every 2 weeks 
RCC 
Renal Cell Carcinoma  
RECIST 
Response Evaluation Criteria In Solid Tumors 


 
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SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SPD 
Sum of Perpendicular Diameters  
sPD-L1 
soluble programmed death ligand 1 
WFI 
Water for Injection 
 


 
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