Clinical trial NCT02431559
Conditions: Ovarian Cancer
Keywords: Ovarian Cancer Motolimod Immunotherapy PD-L1 MEDI4736 Pegylated Liposomal Doxorubicin PLD TLR-8 Durvalumab
Sponsor: Ludwig Institute for Cancer Research
Start date: 2015-12-02; Completion date: 2021-06-10
Enrollment: 53 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and safety profile, with a secondary objective to evaluate the clinical efficacy as measured by progression-free survival (PFS) rate at 6 months (PFS-6). The primary objective of Phase 2 is the evaluation of clinical efficacy as measured by PFS-6. For both phases, secondary objectives include evaluation of clinical efficacy as measured by overall response rate, PFS, and overall survival (OS), safety and tolerability, and immunological responses.

Detailed description:
In the completed Phase 1 part of the study, eligible subjects were enrolled using a standard 3 + 3 design to identify the MTD (i.e., the highest dose for which fewer than 33% of subjects experienced a dose-limiting toxicity \[DLT\]) of combination study treatment. All dose levels in Phase 1 included intravenous (IV) PLD (40 mg/m\^2) in combination with subcutaneous (SC) motolimod (2.0 or 2.5 mg/m\^2), using a starting dose of 3 mg/kg of IV durvalumab given every 2 weeks (Q2W) or 1500 mg of IV durvalumab given every 4 weeks (Q4W). All subjects in a cohort had their safety data reviewed for DLTs before proceeding with cohort expansion.

After completion of Phase 1 and determination of the durvalumab MTD to be carried forward into Phase 2, availability of data from another study (NCT01666444) indicated a lack of additive efficacy when motolimod was administered with PLD compared with PLD alone. As such, motolimod dosing was discontinued for all subjects in Study LUD2014-001 after completion of Phase 1. Subjects who had initiated treatment may have continued to receive PLD and durvalumab at their respective dose levels but must have discontinued motolimod. Thus, in the fully-accrued but ongoing Phase 2 portion of the study, subjects received only PLD (40 mg/m\^2) in combination with durvalumab at the MTD determined in Phase 1 (1500 mg every 4 weeks \[Q4W\]).

Subjects are treated in the Core Study for an initial 12 cycles (28 days each) according to their treatment assignment. Durvalumab treatment may be extended for subjects who complete the Core Study with stable disease or better and upon agreement among the subject, Sponsor, and Investigator; extended durvalumab monotherapy may continue until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.

Subjects are followed on study for 90 days after the last drug administration and off study every 3 months for 3 years from the date of the first dose of study treatment.

Arms: arm 1: Subjects received PLD (40 mg/m\^2 IV on Day 1 of every cycle) + durvalumab (3 mg/kg Q2W \[equivalent to 450 mg Q4W\] IV on Days 3 and 17 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m\^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Days 3 and 17 of Cycles 4-12. arm 2: Subjects received PLD (40 mg/m\^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.0 mg/m\^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. arm 3: Subjects received PLD (40 mg/m\^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m\^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. arm 4: Subjects received the MTD determined in Phase 1 (Dose Level +1), comprising PLD (40 mg/m\^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment.
Interventions: intervention 1: Durvalumab intervention 2: Pegylated Liposomal Doxorubicin intervention 3: Motolimod
Intervention descriptions: intervention 1: Durvalumab is administered as an IV infusion over 60 ± 5 minutes. intervention 2: PLD was administered as an IV infusion in accordance with local prescribing information. intervention 3: Motolimod was administered as an SC injection. Within 30 minutes prior to each dose of motolimod, subjects were administered 650-1000 mg acetaminophen by mouth to help mitigate potential adverse events (AEs) commonly associated with the administration of motolimod (e.g., fever, myalgia). On days with concurrent motolimod and durvalumab dosing, motolimod administration occurred 30-60 minutes after the end of the durvalumab infusion. After completion of Phase 1, a protocol amendment was implemented to remove motolimod dosing from the study.

Protocol documents:
Prot_000.pdf: 
 
C O N F I D E N T I A L  
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Study Protocol 
LUD2014-001 
US-IND# 125040 
NCT02431559 
Amendment 4 
Final 
08-SEP-2017 
 
Protocol Title 
A Phase 1/2 Study of Chemo-immunotherapy with Toll-like Receptor 8 Agonist Motolimod 
(VTX-2337) and anti-PD-L1 Antibody MEDI4736 in Subjects with Recurrent, Platinum-Resistant 
Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin (PLD) is Indicated. 
 
Objectives and Synopsis 
This is an open-label, non-randomized, multicenter Phase 1/2 study of motolimod and 
MEDI4736 in subjects with recurrent, platinum-resistant ovarian cancer, scheduled to receive 
pegylated liposomal doxorubicin (PLD).   
Subjects will be treated during each 28-day cycle according to the following schedules. 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. At the time of 
Amendment 2, Phase 1 is completed, and Phase 2 will be initiated at the +1 dose level (PLD 
40 mg/m2, MEDI4736 1500 mg Q4W). Subjects who initiated treatment during Phase 1 will 
continue the trial at their respective doses levels for PLD and MEDI4736; however, motolimod 
will be discontinued.  
PER Amendment 2, the treatment schedule for the cohort at dose level 0a will be:  
Day 
CYCLES 1 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) 
17 
MEDI4736 (IV)  
PER Amendment 2, the treatment schedule for all subjects EXCEPT the cohort at dose level 
0a will be: 
Day 
Cycles 1 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) 
Pre Amendment 2 Treatment Schedule for cohort at dose level 0a only (see note below): 
Day 
CYCLES 1 – 3 
CYCLES 4 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
10 
Motolimod (SC) 
n/a 
17 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
Pre Amendment 2 (and Per Amendment 1) Treatment Schedule for all subjects except 
cohort at dose level 0a: 
Day 
Cycles 1 – 3 
Cycles 4 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
10 
Motolimod (SC) 
n/a 
17 
Motolimod (SC) 
n/a 
Phase 1 Cohorts: Dose escalations and de-escalations for the determination of the MTD (or 
highest tolerable dose tested) via assessment of DLTs will be performed based on the 
available dose levels and respective standard 3 + 3 rules, as per table below: 
 
 


 
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Dose Level 
Pegylated liposomal 
doxorubicin 
[mg/m2 IV] 
MEDI4736 
[IV] 
Motolimod 
[mg/m2 SC] 
Pre Amendment 2 only* 
-1 
40 
450 mg Q4W  
2.0 
0a (Starting Level) 
40 
3 mg/kg Q2W 
(equivalent to 450 mg Q4W) 
2.5 
0b 
40 
1500 mg Q4W** 
2.0 
+1 
40 
1500 mg Q4W** 
2.5 
Q2W = every 2 weeks; Q4W = every 4 weeks   
*PER Amendment 2, motolimod dosing will be discontinued for all subjects 
**Note for fixed dose of 1500 mg MEDI4736: If a subject’s body weight drops to ≤ 30 kg while on the study, the MEDI4736 
dose will be weight based as long as the body weight remains ≤ 30 kg (see Section 6.3.3.2) 
Note: Per Amendment 1, dose level 0 was renamed as 0a, and dose level 0b was added to 
Phase 1. Depending on the timing of Amendment 1, dose level 0b cohort could be running 
concurrently with the cohort at dose level 0a, -1, or +1. The dosing for the cohort in dose 
level 0a will continue per the protocol prior to Amendment 1 (i.e., MEDI4736 at 3 mg/kg 
Q2W); however, escalation or de-escalation dosing will be according to Amendment 1. 
The primary objective is to determine the Maximum Tolerated Dose (MTD) and the safety 
profile of the combination.  Secondary objective is the evaluation of clinical efficacy as 
measured by the Progression Free Survival (PFS) rate at 6 months. 
Phase 2 Cohort: The Phase 1 Cohort treated at the MTD (n=6) will become the Phase 2 Cohort 
and expanded to a total of 41 evaluable subjects.  The primary objective is the evaluation of 
clinical efficacy as measured by the Progression Free Survival (PFS) rate at 6 months. 
All Phase 1 and 2 Cohorts: Secondary objectives are the evaluation of clinical efficacy as 
measured by overall response rate, progression-free survival rate at 12 months, overall 
survival and biological activity defined as immunological responses. 
Safety will be assessed by CTCAE v4.03 and clinical efficacy by RECIST 1.1 and irRECIST. 
Per Amendment 3, optional MEDI4736 treatment extension beyond the initial 12-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, and it may continue until confirmed 
disease progression, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.  See Section 8.9 for details regarding treatment extension 
and collection/reporting of adverse events during this period. 
 


 
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Sponsor: Ludwig Institute for Cancer Research, New 
York, NY 
 
 
 
 
 
 
 
 
Sponsor Representative Signature & Date 
Study Chair: George Coukos, MD, PhD; University 
Hospital of Lausanne 
 
 
 
 
 
 
 
 
Study Chair Signature & Date 
Local Sponsor for Switzerland:  Ludwig Institute for 
Cancer Research Ltd, Zurich, Switzerland 
 
 
 
 
 
 
 
 
 
Local Sponsor for Switzerland Signature & Date 
US Study Chair: Bradley J. Monk, MD; Arizona 
Oncology, Phoenix, AZ 
 
 
 
 
 
 
 
 
 
US Study Chair Signature & 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 ............................................................................................................................. 8 
1.1 
Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer ................................... 8 
1.2 
PEGylated Liposomal Doxorubicin (PLD) ......................................................................... 8 
1.3 
Motolimod (VTX-2337) .................................................................................................... 8 
1.4 
PD-1 and PD-L1 ................................................................................................................ 9 
1.4.1 
MEDI4736 (Durvalumab) ....................................................................................... 10 
2 
Study Rationale ..................................................................................................................... 11 
2.1 
Rationale for Amendment 1 .......................................................................................... 12 
3 
Experimental Plan ................................................................................................................. 14 
3.1 
Study Design .................................................................................................................. 14 
3.1.1 
Study Phase ........................................................................................................... 14 
3.1.2 
Enrollment/Randomization ................................................................................... 14 
3.1.3 
Blinding/Unblinding ............................................................................................... 14 
3.1.4 
Subject Population................................................................................................. 14 
3.1.5 
No. of Sites/Subjects.............................................................................................. 14 
3.1.6 
Sample Size and Statistical Considerations ........................................................... 15 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 15 
3.1.8 
Dosing Adjustments, Delays and Discontinuations ............................................... 17 
3.1.9 
DLT and MTD ......................................................................................................... 18 
3.1.10 
Subject Withdrawal from Treatment or Study ...................................................... 19 
3.1.10.1 
Treatment beyond Progression ..................................................................... 20 
3.1.11 
Subject Evaluability and Replacements ................................................................. 20 
3.1.12 
Optional Study Treatment Extension .................................................................... 20 
3.1.13 
Interim Analysis ..................................................................................................... 21 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 21 
3.1.15 
Duration of Study .................................................................................................. 21 
3.1.16 
On Study and Post Study Follow-up ...................................................................... 21 
3.1.16.1 
End of Study Visit ........................................................................................... 22 
3.2 
Study Flowchart ............................................................................................................. 23 
4 
Study Objectives & Endpoints .............................................................................................. 27 
4.1 
Clinical Efficacy .............................................................................................................. 27 
4.1.1 
Endpoints & Assessment Methods ........................................................................ 27 
4.1.1.1 
Progression-free Survival Rate ...................................................................... 27 
4.1.1.2 
Progression-free Survival Time ...................................................................... 27 
4.1.1.3 
Overall Response Rate ................................................................................... 28 
4.1.1.4 
Overall Disease Control Rate ......................................................................... 28 
4.1.1.5 
Overall Survival Time ..................................................................................... 28 
4.1.2 
Subject Evaluation & Statistics .............................................................................. 28 
4.2 
Safety and Tolerability ................................................................................................... 28 
4.2.1 
Endpoints & Assessment Methods ........................................................................ 29 


 
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4.2.2 
Subject Evaluation & Statistics .............................................................................. 29 
4.3 
Biological Activity........................................................................................................... 30 
4.3.1 
Endpoints & Assessment Methods ........................................................................ 30 
4.3.2 
Subject Evaluation & Statistics .............................................................................. 30 
5 
Subject Eligibility ................................................................................................................... 31 
5.1 
Inclusion Criteria ............................................................................................................ 31 
5.2 
Exclusion Criteria ........................................................................................................... 32 
5.3 
Restrictions on Concomitant Therapies ........................................................................ 35 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 35 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 35 
6 
Study Drug Preparation and Administration ........................................................................ 36 
6.1 
Pegylated Liposomal Doxorubicin (PLD) ........................................................................ 36 
6.2 
Motolimod ..................................................................................................................... 36 
6.2.1 
Motolimod Study Drug Information ...................................................................... 36 
6.2.2 
Motolimod Preparation ......................................................................................... 36 
6.2.3 
Motolimod Administration .................................................................................... 37 
6.3 
MEDI4736 ...................................................................................................................... 38 
6.3.1 
MEDI4736 Study Drug Information ....................................................................... 38 
6.3.2 
MEDI4736 Investigational Product Inspection ...................................................... 38 
6.3.3 
MEDI4736 Preparation .......................................................................................... 38 
6.3.3.1 
MEDI4736 Preparation for Cohort at Dose Level 0a ..................................... 39 
6.3.3.2 
MEDI4736 Preparation for all Subjects except Cohort at Dose Level 0a and 
for Treatment Extension .................................................................................................. 39 
6.3.4 
MEDI4736 Administration ..................................................................................... 40 
6.3.5 
Monitoring of MEDI4736 Dose Administration ..................................................... 41 
6.4 
Estimated Study Drug Requirements for Motolimod and MEDI4736 ........................... 42 
6.5 
Drug Overdose Management ........................................................................................ 42 
7 
Administrative, Legal & Ethical Requirements ..................................................................... 43 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 43 
7.1.1 
General AE/SAE Definitions per ICH Guidelines .................................................... 43 
7.1.2 
Additional Expedited Reporting Requirements for this Study .............................. 44 
7.1.2.1 
Pregnancy ...................................................................................................... 44 
7.1.2.2 
Overdose ....................................................................................................... 44 
7.1.2.3 
Hepatic Function Abnormality ....................................................................... 45 
7.1.3 
Severity of an Adverse Event ................................................................................. 45 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 45 
7.1.5 
General Reporting Requirements .......................................................................... 45 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 46 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 47 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 47 
7.1.8.1 
Additional AESIs for this Study ...................................................................... 49 
7.2 
Administrative Sponsor Requirements ......................................................................... 50 
7.2.1 
Study Master Files ................................................................................................. 50 
7.2.2 
Case Report Form Data Collection ........................................................................ 50 


 
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7.2.3 
Language ................................................................................................................ 50 
7.2.4 
Monitoring ............................................................................................................. 51 
7.2.5 
Protocol Amendments ........................................................................................... 51 
7.2.6 
Premature Subject Withdrawal ............................................................................. 51 
7.2.7 
Early Trial Termination .......................................................................................... 52 
7.2.8 
Study Drug Shipments & Accountability ............................................................... 52 
7.3 
Regulatory, Legal & Ethical Requirements .................................................................... 52 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 52 
7.3.2 
Informed Consent .................................................................................................. 52 
7.3.3 
Institutional Review Board .................................................................................... 53 
7.3.4 
Subject Confidentiality .......................................................................................... 53 
8 
Appendices ........................................................................................................................... 54 
8.1 
Protocol Version History ................................................................................................ 54 
8.2 
Pegylated Liposomal Doxorubicin (PLD) Dose Delays and Adjustments ....................... 68 
8.2.1 
Hematological Toxicity .......................................................................................... 68 
8.2.2 
Hand Foot Syndrome (HFS) ................................................................................... 68 
8.2.3 
Stomatitis ............................................................................................................... 69 
8.2.4 
Subjects with Impaired Hepatic Function.............................................................. 69 
8.3 
Motolimod Toxicity Management and Dose Adjustments ........................................... 70 
8.3.1 
Management of Injection Site Reactions .............................................................. 70 
8.3.2 
Management of Systemic Toxicities ...................................................................... 70 
8.3.3 
Motolimod Dose Modifications due to Toxicities ................................................. 71 
8.3.3.1 
Cytokine Release Syndrome .......................................................................... 71 
8.3.3.2 
Injection Site Reaction ................................................................................... 71 
8.3.3.3 
Non-Hematologic Drug-Related AEs.............................................................. 71 
8.3.3.4 
Hematologic Drug-Related AEs...................................................................... 71 
8.4 
MEDI4736 Toxicity Management and Dose Adjustments ............................................. 72 
8.4.1 
Management of MEDI4736-related Toxicities ...................................................... 72 
8.4.2 
MEDI4736 Dose Modifications due to Toxicities ................................................... 72 
8.4.2.1 
Immune-related Adverse Events (irAEs) ........................................................ 73 
8.4.2.2 
Infusion-related Reactions ............................................................................ 74 
8.4.2.3 
All other Adverse Events ............................................................................... 75 
8.4.3 
MEDI4736 Dose Modifications Not Due to Toxicities ........................................... 75 
8.5 
RECIST 1.1 Guidelines .................................................................................................... 76 
8.5.1 
Disease Parameters ............................................................................................... 76 
8.5.2 
Methods for Evaluation of Measurable Disease ................................................... 77 
8.5.3 
Response Criteria ................................................................................................... 79 
8.5.3.1 
Evaluation of Target Lesions .......................................................................... 79 
8.5.3.2 
Evaluation of Non-Target Lesions .................................................................. 79 
8.5.3.3 
Evaluation of Best Overall Response ............................................................. 79 
8.5.3.4 
Duration of Response .................................................................................... 80 
8.6 
irRECIST Guidelines ........................................................................................................ 81 
8.6.1 
Response in Measurable Lesions ........................................................................... 81 
8.6.2 
Response in Non-measurable Lesions ................................................................... 81 
8.6.3 
Evaluation of Biomarkers ...................................................................................... 82 


 
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8.6.4 
Overall Response ................................................................................................... 82 
8.6.5 
Duration of Response ............................................................................................ 83 
8.7 
Exploratory Assessment of Correlative Immunologic Research .................................... 84 
8.7.1 
Phenotypic Analysis of PBMCs .............................................................................. 84 
8.7.2 
Myeloid Derived Suppressor Cells (MDSC) ............................................................ 84 
8.7.3 
Quantification of Tumor-specific T-cell Responses ............................................... 84 
8.7.4 
Baseline Immune Responsiveness to TLR8 activation ........................................... 85 
8.7.5 
Immune Landscape: TILs and Tumor Microenvironment ..................................... 85 
8.7.6 
TCR sequencing ..................................................................................................... 86 
8.7.7 
Immune biomarkers .............................................................................................. 86 
8.7.8 
Pharmacogenomics ............................................................................................... 86 
8.7.9 
BRCA status of tumors ........................................................................................... 87 
8.7.10 
MEDI4736 PK and Immunogenicity for Anti-drug Antibodies (ADA) .................... 87 
8.7.11 
sPD-L1 .................................................................................................................... 87 
8.7.12 
Circulating soluble factors ..................................................................................... 87 
8.7.13 
Additional translational and exploratory studies .................................................. 87 
8.7.14 
mRNA/miRNA Profiling .......................................................................................... 88 
8.8 
ECOG Performance Status ............................................................................................. 89 
8.9 
Details for Subjects Who Continue Optional MEDI4736 Treatment beyond the Core 
Study  ....................................................................................................................................... 90 
8.9.1 
Study Flowchart for Subjects Who Continue Optional MEDI4736 Treatment 
beyond the Core Study ......................................................................................................... 91 
8.10 
Abbreviations................................................................................................................. 92 
9 
References ............................................................................................................................ 94 
 
 
 


 
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1 Background 
1.1 Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer 
Approximately 24,000 new cases are diagnosed and 15,000 women die of ovarian cancer 
annually in the US, and approximately ten times as many worldwide.  No significant advances 
have been made in chemotherapy over the past three decades, and no molecular drugs appear 
promising.  Initial response rates of advanced ovarian cancer to standard upfront paclitaxel / 
carboplatin approach 75%, with complete clinical response rates near 55%. 
Unfortunately, over 80% of patients progress, and response rates to second line chemotherapy 
for platinum-resistant patients are significantly lower, usually 15-20%.  Once ovarian cancer has 
recurred, it is incurable with available therapies.  These facts elucidate the enormous unmet 
need for the development of alternate therapies in ovarian cancer. 
1.2 PEGylated Liposomal Doxorubicin (PLD) 
PEGylated liposomal doxorubicin (PLD, known commercially as Doxil, Caelyx or Lipodox) is a 
formulation of doxorubicin encapsulated in polyethylene-glycol (PEG)-coated liposomes, which 
leads to dramatic improvement in pharmacokinetics, characterized by a prolonged circulation 
time, reduced clearance, and a small volume of distribution.(1)  It is approved for the treatment 
of ovarian cancer after failure of platinum-based chemotherapy and is considered standard of 
care for these patients. 
The approved clinical dose of PLD is 50 mg/m2.  However, based on an improved tolerability 
profile without a perceived loss of efficacy, 40 mg/m2 of PLD has become the community 
standard dose and will thus be used in this study.(2) 
Refer to the current PLD (Doxil, Caelyx, Lipodox) prescribing information for complete and 
current information. 
1.3 Motolimod (VTX-2337) 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
Motolimod (VTX-2337) is briefly described in this section below.  Refer to the current motolimod 
Investigator’s Brochure for complete and current information. 
Motolimod is a small molecule agonist of TLR8 that stimulates specific immune cell populations.  
TLR8 is primarily expressed by monocytes, myeloid dendritic cells (mDCs), and NK cells.  
Engagement of TLR8 with single-stranded RNA (its natural ligand) or a pharmacologic agonist, 
such as motolimod, stimulates an inflammatory immune response, in part, via the activation of 
NF-κB pathway.  In vivo, TLR8 stimulation induces the production of multiple cytokines and 
chemokines including: G-CSF, MCP-1, MDC, MIP-1β, TNFα, IL-1α, IL-8, IL-6, IL-12, IL-18 and IFNγ.  
Production of these mediators is hypothesized to enhance the efficacy of standard-of-care (SOC) 
chemotherapy and monoclonal antibody therapy in the oncology setting via modulation of the 
tumor microenvironment and augmentation of both innate and adaptive immune responses. 
Motolimod has been evaluated in 4 open-label trials: as monotherapy in a Phase 1 dose 
escalation study (3) and in Phase 1b trials of combination regimens utilizing cytotoxic 


 
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chemotherapy (PLD and paclitaxel) (4) and two studies in combination with the monoclonal 
antibody cetuximab.(5)  Across these trials, 79 subjects have received motolimod, which has 
been shown to be safe and well tolerated as a single agent or in combination, with no significant 
drug-related hematologic, gastrointestinal, neurologic, or cardiac toxicities observed. 
Motolimod is currently being evaluated in 2 double-blind, randomized Phase 2 studies: in 
combination with PLD in women with recurrent ovarian cancer and in combination with the 
EXTREME regimen (platinum chemotherapy + 5-flourouracil + cetuximab) in subjects with 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).  A total of 297 
subjects with ovarian cancer and 195 subjects with SCCHN have been enrolled as of 02 
December 2015.  Preliminary blinded safety data indicate that the combinations appear to be 
safe and well tolerated. 
1.4 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.(6)  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).(7-9)  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.(10-12)  It is found on T-cells, B cells, macrophages, NK cells, DCs, 
and mast cells (13).  It has also been described on peripheral tissues including cardiac endo-
thelium, lung, small intestine, keratinocytes, islet cells of the pancreas, and syncytiotrophoblasts 
in the placenta as well as a variety of tumor cell types.(13-24)  PD-L1 is constitutively expressed 
on many hematopoietic cells, but may be upregulated in hematopoietic and non-hematopoietic 
cells.(25)  Regulation of PD-L1 is mediated, in part, by type I and type II interferons.  PD-L2 was 
identified in 2001.(26, 27)  Its expression is far more restricted and is confined to hematopoietic 
cells.(28) 
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.(29-33)  Inhibitory signaling by PD-1 is thought to depend upon the cytosolic ITSM 
domain, which associates with phosphatases SHP-1 and SHP-2.(34, 35) 
Tumors employ the programmed cell death 1 (PD-1) inhibitory pathway to paralyze the 
antitumor immune response.  PD-1 is expressed by activated T-cells, but not by resting T-cells.  
PD-1 binds two ligands, PD-L1 and PD-L2, also called B7-H1 (CD274) and B7-DC (CD273), 
respectively.  Upregulation of PD-L1 occurs in most ovarian cancers, suggesting that cancer cells 
utilize the PD-1/PD-L1 inhibitory pathway to escape the host immune response.  Thus, although 
anti-tumor immunity can be elicited against ovarian cancer through in situ vaccination, it could 
be counterbalanced by immunosuppressive factors in the tumor microenvironment.  In fact, 
recent studies showed that tumor-infiltrating T-cells express PD-1 in ovarian cancer, and 
survival in ovarian cancer patients inversely correlates with PD-L1 expression.(15, 36)  PD-1 
blockade could enhance the reactivity and cytokine response of NY-ESO-1 specific tumor-derived 
T-cells from ovarian cancers.(37)  PD-L1 blockade in mice bearing intraperitoneal ID8 ovarian 
cancer tumors (which express PD-L1) can restore antitumor immunity and synergize with 


 
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whole tumor antigen vaccine (GVAX) to produce tumor rejections.  Vaccine alone was 
completely ineffective, while PD-L1 antibody monotherapy produced half the cure rate than 
GVAX plus PD-L1 blockade combination.(38) 
1.4.1 MEDI4736 (Durvalumab) 
MEDI4736 is briefly described in this section below.  Refer to the current Investigator’s Brochure 
(IB) for complete and current information. 
MEDI4736 is a human immunoglobulin G1 kappa monoclonal antibody (MAb) directed against 
human PD-L1.  MEDI4736 has an overall molecular weight of approximately 149 kDa, including 
N-linked oligosaccharides.  The antibody is composed of 2 identical heavy chains of approxi-
mately 49,670 Da each, and 2 identical light chains of approximately 23,390 Da each.  The 
fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant 
domain of the IgG1 heavy chain that reduces binding to the complement component C1q and 
the Fcm receptors, responsible for mediating antibody-dependent cell-mediated cytotoxicity 
(ADCC).(39)  Subsequent to this triple mutation, the anticipated lack of MEDI4736-mediated 
ADCC and complement-dependent cytotoxicity were confirmed using cell based functional 
assays.  MEDI4736 is selective for recombinant PD-L1 and blocks the binding of recombinant PD-
L1 to the PD-1 and cluster of differentiation (CD) 80 receptors. 
As of the data cutoff dates in the IB (15Apr2015 to 12Jul2015), a total of 1,883 subjects have 
been enrolled and treated in 30 ongoing MEDI4736 clinical studies, including 20 sponsored 
(6 monotherapy and 14 combination therapy) and 10 collaborative studies. Of the 1,883 
subjects, 1,279 received MEDI4736 monotherapy, 440 received MEDI4736 in combination with 
tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), 
and 150 have been treated with blinded investigational product. No studies have been 
completed or terminated prematurely due to toxicity. 
The safety profile of MEDI4736 as monotherapy and combined with other anticancer agents was 
consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
MEDI4736 and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy / 
neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an 
important potential risk particularly with MEDI4736 and tremelimumab combination therapy. 
These events are manageable by available/established treatment guidelines as described in the 
study protocols. 
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 


 
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2 Study Rationale 
It is evident that ovarian tumors are spontaneously recognized and controlled by the immune 
system in some patients.  For example, in ovarian cancer, CD8+ tumor infiltrating lymphocytes 
(TIL) are associated with favorable prognosis,(40) while, conversely, tumor infiltrating T 
regulatory (T reg) cells predict for reduced survival.(41)  Research also suggests that natural 
immune surveillance can be associated with a lower risk of developing ovarian cancer.(42)  The 
finding of spontaneous antitumor immune responses in some patients with ovarian cancer 
suggests that immunotherapy, if delivered in the right context, could produce substantial clinical 
benefit. 
Nevertheless, for the most part, immunotherapy trials have been unsuccessful in ovarian cancer 
patients, suggesting that there are potent immune suppressing mechanisms at play in the 
majority of patients.  It is notable that PD-1/PD-L1 inhibitor therapy has not demonstrated 
significant single agent activity in ovarian cancer despite reports of PD-L1 expression on ovarian 
tumor cells.  There are a variety of potential reasons for this diminished immune activity, 
including defects in T-cell access to tumors (T-cell-poor tumors), the presence of potent immune 
suppressive cells such as T reg and myeloid derived suppressor cells (MDSC) in the tumor 
microenvironment, and defects in the generation of activated cancer-specific T-cells.(43-45)  
Motolimod and PLD have been combined safely (without dose limiting toxicities) in Phase 1, and 
a Phase 2 study is ongoing in subjects with recurrent ovarian cancer without significant 
toxicities.  Given the background above, there is strong rationale for adding a PD-L1 inhibitor to 
this combination. 
Based on its mechanism of action, the administration of motolimod and PLD may have in situ 
vaccination effects, which may be enhanced with the addition of MEDI4736.  Motolimod 
stimulation of the innate immune system may alter the tumor microenvironment to drive T-cell 
infiltration into T-cell-poor tumors, and create an inflamed microenvironment poised for anti-
tumor immunity.  Stimulation of the TLR8 receptor on immunosuppressive MDSCs may promote 
their differentiation into non-suppressive mDCs and macrophages (unpublished data and (26, 
46)).  The novel tumor antigens exposed on tumor cells that are immunogenically killed by PLD 
may then be captured and processed by motolimod-stimulated mDCs.  These mature mDCs 
have the capacity to cross-present a large repertoire of potential tumor rejection antigens to 
CD8+ and CD4+ T-cells, both in the tumor and in draining lymph nodes.  The summation of these 
steps may result in an increase in the population of PD-1 expressing activated CD8+ effector 
cells, infiltrating tumors that will destroy cognate antigen expressing tumor cells not expressing 
PD-L1, and will be unleashed by the PD-L1 inhibitor to destroy antigen expressing tumor cells 
that do express PD-L1. 
NOTE: PER Amendment 2, motolimod dosing will be discontinued for all subjects.  This 
decision was based upon the results from a Phase 2 study of motolimod and PLD (GOG-3003) 
that was being conducted by VentiRx. Although the combination of motolimod with PLD was 
safe and well-tolerated in GOG-3003, the combination did not significantly improve overall 
survival or progression free survival (as determined using irRECIST) in the ITT population 
compared to PLD alone. 
At the time of Amendment 2, Phase 1 is completed, and Phase 2 will be initiated at the +1 dose 
level (PLD 40 mg/m2, MEDI4736 1500 mg Q4W). Subjects who initiated treatment during 


 
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Phase 1 will continue the trial at their respective doses levels for PLD and MEDI4736; however, 
motolimod will be discontinued. 
2.1 Rationale for Amendment 1 
Per Amendment 1, the following changes will be implemented (refer to Section 8.1 for a 
complete description of all changes): 
1. The starting dose level cohort was renamed as dose level 0a. The dosing for the cohort 
in dose level 0a will continue per the protocol prior to Amendment 1 (i.e., MEDI4736 at 
3 mg/kg Q2W); however, escalation or de-escalation dosing will be conducted according 
to Amendment 1. 
 
2. Dose level 0b was added to Phase 1. See table below: 
Dose Level 
PLD 
[mg/m2 IV] 
MEDI4736 
[IV] 
Motolimod 
[mg/m2 SC] 
-1 
40 
450 mg Q4W 
2.0 
0a (Starting Level) 
40 
3 mg/kg Q2W 
(equivalent to 450 mg Q4W) 
2.5 
0b 
40 
1500 mg Q4W 
2.0 
+1 
40 
1500 mg Q4W 
2.5 
 
3. A fixed dosing schedule for MEDI4736 was added for all subjects except for those in the 
cohort that was already started prior to Amendment 1 (i.e., dose level 0a).   
Rationale for fixed dosing of MEDI4736: 
Currently, the recommended dosing schedule for MEDI4736 is 20 mg/kg every 4 weeks (Q4W).  
The fixed dosing in this protocol for MEDI4736 (1500 mg Q4W for the +1 and 0b dose levels) is 
based on data from PK models. Using population PK models, simulations indicated that both 
body weight-based and fixed dosing regimens of MEDI4736 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, it is considered feasible 
to switch to fixed dosing regimens. Based on an average body weight of 75 kg, a fixed dose of 
1500 mg Q4W MEDI4736 is equivalent to 20 mg/kg Q4W or 10 mg/kg Q2W. 
The 1500 mg dosing of MEDI4736 is recommended only for subjects with > 30 kg body weight 
due to endotoxin exposure.  Subjects with a body weight ≤ 30 kg are not eligible for enrollment 
in the current study. If a subject’s body weight drops to ≤ 30 kg while on the study, the 
MEDI4736 dose will be weight based as long as the body weight remains ≤ 30 kg (see Section 
6.3.3.2). 
Rationale for addition of dose level 0b:  
If the starting dose level 0a does not clear and dosing de-escalates to -1, dose level 0b will 
continue to accrue subjects according to the 3 + 3 design (in addition to the cohort at the dose 
level -1) because it represents a de-escalation of motolimod from 2.5 to 2.0 mg/m2.  The 1500 
mg of MEDI4736 is supported by the fact that there is no dose response for toxicity for anti-PD-1 
and anti-PD-L1 antibodies, and even half the clinical dose of MEDI4736 would be above 


 
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saturation of the receptor. Therefore, it would be safe to reduce the motolimod dose (from 2.5 
to 2.0) but maintain the currently recommended 1500 mg dose for MEDI4736.  
If dose level 0a does clear and dosing escalates to +1, dose level 0b will also continue to accrue 
subjects according to the 3 + 3 design (in addition to the cohort at the dose level +1). 
Depending on the timing of Amendment 1, dose level 0b cohort could be running concurrently 
with the cohort at dose level 0a, -1, or +1.  Thus, subject enrollment will occur as follows: 
a) when only 1 cohort is open: sequential enrollment; 
b) when 2 parallel cohorts are open: preferential sequential enrollment into the cohort 
with the higher motolimod dose level or into the cohort with the higher MEDI4736 dose 
level if both cohorts have the same motolimod dose level. 
 


 
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3 Experimental Plan 
3.1 Study Design 
3.1.1 Study Phase 
Phase 1/2. 
3.1.2 Enrollment/Randomization 
Subjects will be enrolled in a non-randomized, competitive multicenter, sequential enrollment 
manner with central subject registration.  Subject enrollment and the safety of the combination 
regimen will be reviewed on an ongoing basis by an internal data safety monitoring panel (see 
Section 3.1.14, Safety Monitoring and Study Stopping Rules). 
For each cohort in Phase 1, the start of the Cycle 1 Day 3 study drug administration (MEDI4736 + 
motolimod) for the first and second subject will be separated by at least 24 hours.  All subjects 
in a cohort will have their safety data reviewed for DLTs as per Section 3.1.9, before proceeding 
with a cohort expansion or to a dose-escalated/de-escalated cohort (see section 3.1.7). 
Per Amendment 1, the cohort at dose level 0b will be added to Phase 1.  Depending on the 
timing of Amendment 1, dose level 0b cohort could be running concurrently with the cohort at 
dose level 0a, -1, or +1.  Thus, subject enrollment will occur as follows: 
a) when only 1 cohort is open: sequential enrollment; 
b) when 2 parallel cohorts are open: preferential sequential enrollment into the cohort 
with the higher motolimod dose level or into the cohort with the higher MEDI4736 dose 
level if both cohorts have the same motolimod dose level. 
 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
Subject enrollment will be centrally administered. 
Enrollment in Phase 2 will begin after the MTD has been established in Phase 1. 
3.1.3 Blinding/Unblinding 
This is an open label study. 
3.1.4 Subject Population 
Subjects must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal 
carcinoma with measureable disease (as defined by RECIST 1.1.) after first or second line 
platinum-based chemotherapy, for which treatment with PLD is indicated. 
See Section 5 for complete eligibility criteria. 
3.1.5 No. of Sites/Subjects 
Approximately 6 to 9 sites; and 6 to 53 evaluable subjects are estimated for this study. 
Phase 1: 6-18 evaluable subjects will be needed to identify the MTD. 


 
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Phase 2: 41 evaluable subjects, including the 6 subjects treated in Phase 1 at the MTD. 
3.1.6 Sample Size and Statistical Considerations 
Phase 1 of this trial will employ the 3+3 design as described in Section 3.1.7. The maximum 
tolerated dose (MTD) is defined as the highest dose for which fewer than 33% of subjects 
experience a dose-limiting toxicity (DLT). 
Phase 2 of this trial will expand the Phase 1 cohort that was treated at the MTD.  For the subject 
population to be enrolled, standard of care treatment with PLD alone has been reported to 
result in a 25% 6-months PFS rate.(47-50)  A true 6-months PFS rate of ≥45% in the current 
study, using motolimod + MEDI4736 with standard of care, would be of interest and represent a 
clinically meaningful improvement, while ≤25% would be of no interest.  Therefore, the study 
will test the hypotheses H0: p≤0.25 versus H1: p≥0.45, with p being the proportion of subjects 
who have survived and not progressed at 6 months, based on RECIST v1.1 criteria.  Expansion of 
the Phase 1 MTD cohort to 41 evaluable subjects will yield 80% power to test the null hypothesis 
of 6-months PFS rate of ≤25% against the alternative hypothesis of a PFS rate of ≥45% at an 
alpha level of 0.05 (one-sided) based on exact test for single proportion. 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
3.1.7 Treatment Arms and Treatment Schema 
All subjects will be treated with pegylated liposomal doxorubicin (PLD) intravenously, MEDI4736 
intravenously and motolimod (pre Amendment 2 only) subcutaneously during each 28-day cycle 
according to the treatment schedule below.  On days with concurrent motolimod and MEDI4736 
dosing, motolimod administration will occur 30-60 minutes after the end of the MEDI4736 
infusion (pre Amendment 2 only). 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. At the time of 
Amendment 2, Phase 1 is completed, and Phase 2 will be initiated at the +1 dose level (PLD 
40 mg/m2, MEDI4736 1500 mg Q4W). Subjects who initiated treatment during Phase 1 will 
continue the trial at their respective doses levels for PLD and MEDI4736; however, motolimod 
will be discontinued. 
PER Amendment 2 Treatment Schedule 
for Cohort at Dose Level 0a only 
DAY 
CYCLES 1 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV)  
17 
MEDI4736 (IV)  
 
PER Amendment 2 Treatment Schedule 
for all Subjects Except Cohort at Dose Level 0a 
DAY 
CYCLES 1 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) 
 
 
 


 
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Pre Amendment 2 Treatment Schedule for Cohort at Dose Level 0a only (see note below) 
DAY 
CYCLES 1 – 3 
CYCLES 4 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
10 
Motolimod (SC) 
n/a 
17 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
 
Pre Amendment 2 Treatment Schedule for all Subjects Except Cohort at Dose Level 0a 
DAY 
CYCLES 1 – 3 
CYCLES 4 – 12 
1 
Pegylated liposomal doxorubicin (IV) 
Pegylated liposomal doxorubicin (IV) 
3 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
10 
Motolimod (SC) 
n/a 
17 
Motolimod (SC) 
n/a 
Phase 1 Dose escalations and de-escalations for the determination of the MTD (or highest 
tolerable dose tested) will be performed based on the available dose levels and the respective 
rules for a standard 3 + 3 study design, as per Dose Level Table and Schema below: 
Dose Level Table 
Dose Level 
Pegylated liposomal 
doxorubicin 
[mg/m2 IV] 
MEDI4736 
[ IV] 
Motolimod 
[mg/m2 SC] 
Pre Amendment 2 
only* 
-1 
40 
450 mg Q4W 
2.0 
0a (Starting Level) 
40 
3 mg/kg Q2W 
(equivalent to 450 mg Q4W) 
2.5 
0b 
40 
1500 mg Q4W** 
2.0 
+1 
40 
1500 mg Q4W** 
2.5 
Q2W = every 2 weeks; Q4W = every 4 weeks 
**Note for fixed dose of 1500 mg MEDI4736: If a subject’s body weight drops to ≤ 30 kg while on the 
study, the MEDI4736 dose will be weight based as long as the subject’s body weight remains ≤ 30 kg. 
See Section 6.3.3.2.  
*PER Amendment 2, motolimod dosing will be discontinued for all subjects 
 
Note: Per Amendment 1, dose level 0 was renamed as 0a, and dose level 0b was added to 
Phase 1. Depending on the timing of Amendment 1, dose level 0b cohort could be running 
concurrently with the cohort at dose level 0a, -1, or +1. The dosing for the cohort in dose level 
0a will continue per the protocol prior to Amendment 1 (i.e., MEDI4736 at 3 mg/kg Q2W); 
however, escalation or de-escalation dosing will be conducted according to Amendment 1. 
 


 
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Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is unsafe
DL is safe
Is DL + 1 available
and not
previously declared unsafe?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared unsafe?
Yes
DL is MTD
No
Is DL - 1 
available?
No
MTD cannot be 
determined
Was DL - 1 
previously declared 
safe?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is MTD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         MTD = Maximum Tolerated Dose (per DL Table)
 
For detailed definitions of DLT and MTD see Section 3.1.9. 
Phase 2 subjects will be treated at the MTD level determined in Phase 1.  See Sections 3.1.5 and 
3.1.6 for the number of subjects to be enrolled. 
Subjects will be followed on study for 90 days after the last drug administration and off-study 
every 3 months thereafter for 3 years from initiation of treatment (see Section 3.1.16). 
3.1.8 Dosing Adjustments, Delays and Discontinuations 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
Dose adjustment and management guidelines for toxicity related to the standard PLD regimen, 
motolimod, and MEDI4736 are outlined in Sections 8.2, 8.3, 8.4, respectively. 
In the event of a delay in PLD dosing due to drug-related toxicity, doses of motolimod and 
MEDI4736 should also be delayed, so that the relative timing of the administration of each drug 
within each cycle is not altered.  That is, the administration of PLD always constitutes cycle Day 
1, and the dose dates of motolimod and MEDI4736 are determined relative to this date (see 
Section 3.1.7). Note that delays in the dosing of motolimod or MEDI4736 due to drug-related 
toxicity should not delay the 28-day dosing cycle of PLD, if possible.  Likewise, any delay in 
MEDI4736 should not delay the administration of motolimod, and vice versa.   
If PLD has to be discontinued due to PLD-related toxicities, the treatment with motolimod 
and/or MEDI4736 may continue, provided that the subject had received at least 2 doses of PLD 
(i.e., 2 cycles). 


 
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Irrespective of delay(s) in the dosing of the combination treatment, the disease assessments 
(CT, MRI) should not be delayed and must be conducted on the days originally scheduled, as 
calculated from the first study dose of PLD (Cycle 1 Day 1). 
If a toxicity occurs that requires toxicity management in accordance with the toxicity 
management guidelines referenced above, and the toxicity causing drug can be clearly 
identified, then the respective guideline should be followed. If the toxicity causing drug cannot 
be identified, then the more conservative guideline should be followed. 
3.1.9 DLT and MTD 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
DLTs will be observed over a period of the first cycle including the pre-dose assessment for 
Cycle 2, defined as the “DLT Evaluation Period”.  The decisions for dose escalations, de-
escalations and MTD, as described in Section 3.1.7, will primarily be based on the number of 
subjects with DLTs occurring during the DLT Evaluation Period.  DLTs occurring outside the DLT 
Evaluation Period will also be evaluated and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of MEDI4736, motolimod or PLD, and fulfill any of the following criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event, or uveitis. 
2. Any Grade 2 pneumonitis, neurological event, or uveitis with the following exception: 
• 
Grade 2 pneumonitis, neurological event, or uveitis that downgrades to Grade ≤ 1 
within 3 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade ≥ 3 PLD-related toxicities, manageable according to the dose modification 
instructions in the package insert/product information (see Section 8.2.) 
• 
Grade 3 irAEs (see definition below) that downgrade to Grade ≤ 2 within 3 days, or 
to Grade ≤ 1 or baseline within 14 days after onset, whereby maximal supportive 
care, including systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times ULN that downgrades to Grade ≤ 2 (≤ 5 times 
ULN) within 7 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) within 7 
days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, (2) 
does not require medical intervention, and (3) improves to Grade 2 within 7 days. 
• 
Grade 3 or Grade 4 lymphopenia. 


 
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• 
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 AEs (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 rules for adjudicating DLTs 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 motolimod, and in combination with PLD.  
Likewise, subjects who become not evaluable for DLT, because they discontinued or interrupted 
treatment due to toxicities other than DLTs, may be counted as DLT subjects, if the toxicities 
cannot be managed in accordance with the dosing modifications described in Section 3.1.8. 
Subjects who experience a DLT will be discontinued from study therapy and will enter the On 
Study Follow-up phase of the study (see Sections 3.1.16 and 3.2).  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 of combination treatment is defined as the highest dose of MEDI4736 + motolimod + 
PLD studied, for which the observed incidence of DLT is less than 33% (based on n=6).  
3.1.10 Subject Withdrawal from Treatment or 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. Dose-limiting toxicity at any time (see Section 3.1.9 for definition of DLT and permitted 
continuation). 
4. Confirmation of progressive disease by irRECIST criteria requiring alternative treatment. 
5. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal. 
6. Development of intercurrent, non-cancer related illnesses or complications that prevent 
either continuation of therapy or regular follow-up. 
7. Best medical interest of the subject (at the discretion of the Investigator) 
 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study.  If feasible, subjects who are withdrawn from study treatment should enter the 
On Study Follow-Up, followed by the Post Study Follow-up (see Sections 3.1.16 and 3.2).   


 
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Subjects who begin other anti-cancer therapy should immediately be considered off-study and 
proceed to 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. 
2. Initiation of alternative anti-cancer therapy including marketed or another 
investigational agent. 
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 (see Section 7.2.6). 
See also Sections 8.2, 8.3, and 8.4 for subject withdrawal from treatment due to necessary 
dosing interruptions or discontinuations. 
3.1.10.1 Treatment beyond Progression 
Subjects meeting criteria for progression by RECIST 1.1 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. 
See Section 8.5 for additional information regarding RECIST 1.1. 
3.1.11 Subject Evaluability and Replacements 
Phase 1: Subjects are fully evaluable for DLT if they fulfill the criteria for the Per-Protocol 
Population for DLT Assessment as defined in Section 4.2.2. 
Subjects who are not fully evaluable for DLT will be replaced. 
Phase 2: Subjects are fully evaluable for the primary endpoint of clinical efficacy, if they fulfill 
the criteria for the Per-Protocol Population (as defined in Section 4.1.2).  Subjects who are not 
fully evaluable per protocol may be replaced. 
3.1.12 Optional Study Treatment Extension 
Optional MEDI4736 treatment extension beyond the initial 12-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, and it may continue until confirmed disease progression, unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  See 


 
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Section 8.9 for details regarding treatment extension and collection / reporting of adverse 
events during this period.  
3.1.13 Interim Analysis 
Interim safety reviews will be performed to assess DLTs in Phase 1 (see Section 3.1.7).  Interim 
analyses may be performed to analyze the endpoints of progression free survival at 6 and 12 
months and/or as specified in the statistical analysis plan. 
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and Co-investigators as needed), the Sponsor Medical 
Monitor, and drug safety personnel from Medimmune and VentiRx, providers of the study 
drugs.  Additional investigators and staff, or additional sponsor personnel and consultants, shall 
participate in reviews as indicated.  An Independent Data Monitoring Board (IDMB) will not be 
utilized for this open label study. 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 
1. A death that is unexpected and at least probably related to MEDI4736, motolimod, or to 
the combination of MEDI4736 and motolimod and PLD. 
2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to 
MEDI4736 or motolimod. 
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 Grade ≥3 
neurological toxicity. 
4. Any other safety finding assessed as related to MEDI4736 or motolimod that, in the 
opinion of the internal data safety monitoring panel, contraindicates further dosing of 
study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the Sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
3.1.15 Duration of Study 
Duration of Treatment: 
Up to 12 months for individual subjects 
See Section 3.1.12 for optional treatment extension. 
Duration of On Study Follow-up 
3 months 
Enrollment Period: 
24 months 
Length of Study: 
39 months 
Post Study Follow-up 
3 years from initiation of treatment 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment prematurely, 
or withdraw from the study as per Section 3.1.10, will be followed as per institutional guidelines 
in accordance with the usual standard of care principles.   


 
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For all subjects who complete study treatment or discontinue treatment prematurely, there will 
be an On Study Follow-up Period (see Section 3.2) for 90 days after the last study drug 
administration, which will include collection of AE data (see Section 7.1.5 for details on 
collection of AEs). 
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first visit of the On Study Follow-up Period, any assessments required in the first 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 On Study Follow-up 
visit should not be repeated. 
Following the 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 every 3 months for 3 years 
from initiation of 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 Investigator, 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. 
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 On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For 
subjects already in On Study Follow-up, this End of Study visit will be the next planned visit of 
the 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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3.2 Study Flowchart 
 
Study Flowchart for Subjects in 
Dose Level 0a Cohort Only
Screening / 
Baseline
Cycle week
3
3
3
3
3
3
Visit Day per Cycle
-28 to -1
1
3±1
17±2
1±3
3±1
17±2
1±3
3±1
17±2
1±3
3±1
17±2
1±3
3±1
17±2
1±3
3±1
17±2
Target Cumulative Visit Day
1
3
17
29
31
45
57
59
73
85
87
101
113
115
129
141
143
157
Phase 1 & 2 STUDY DRUG ADMINISTRATION
Pegylated liposomal doxorubicin - PLD (IV)
X
X
X
X
X
X
MEDI4736 (IV)
X
X
X
X
X
X
X
X
X
X
X
X
Tumor & Disease Assessments
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
X
Disease Assessment  by RECIST 1.1 and irRECIST 
(including appropriate imaging)
-14 to -1
X
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)i
X
Demographics (incl. DoB; sex; race; ethnicity) 
X
Medical history
X
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
X
X
X
X
Height
X
Vital Signs (T, HR, BP, RR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
X
Echocardiogram or MUGA
X
X
X
Concomitant Medication / Procedure 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, PO4, 
Mg, prot., alb., Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testa,f
-7  to  -1
X
X
CA-125a 
-14 to -1
X
X
X
X
X
Urine Pregnancy Testa,f
Xa
Specimens for Correlative Assessments
PBMC/Plasma Collection & Banking a,g
X 
X
X
MDSC (Serametrix)a,g  (US sites only)
X
X
Tumor Biopsy (Tumor microenvironment, PD-L1 
expression, TCR sequencing)e
X
X
Pharmacogenomics (including BRCA1 and BRCA2 
tumor status)c
Xg
PAX RNAa,g
X
X
g- Screening/Baseline specimens for correlative assessments may be collected up to Cycle 1/Day 1 prior to the PLD dose.
h - See Section 3.1.16 regarding assessments scheduled for  both the last on treatment visit and the first post-last treatment visit.
i - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart.
1
Treatment
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
1
1
1
1
1
e - Biopsy is optional for Phase 1.  Refer to Criterion 4 in Section 5.1.  Archival tissue will be requested for all subjects, preferably from primary tumor site 
prior to cancer treatment; however, archival tissue is not a requirement  for study entry.
f - Pregnancy tests are not required for subjects who are not of child-bearing potential as defined in Section 5.2, # 17
X (at disease progression: optional)
X (at disease progression: optional)
a - pre-dose (when applicable) Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing.
b - See Section 6.3.5 for assessment of vital signs before/during/after MEDI4736 infusion
c - An aliquot of the PBMC and/or Tumor Biopsy/Archival Tissue will be used for pharmacogenomics – a separate sampling is not needed
d - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.


 
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Study Flowchart for Subjects in 
Dose Level 0a Cohort Only (Cont)
Cycle week
3
3
3
3
3
3
Visit Day per Cycle
1±3
3±1
17±2
1 ±3
3 ±1
17 ±2
1 ±3
3 ±1
17 ±2
1 ±3
3 ±1
17 ±2
1 ±3
3±1
17 ±2
1 ±3
3 ±1
17 ±2
Target Cumulative Visit Day
169
171
185
197
199
213
225
227
241
253
255
269
281
283
297
309
311
325
Phase 1  & 2 STUDY DRUG ADMINISTRATION
Pegylated liposomal doxorubicin - PLD (IV)
X
X
X
X
X
X
MEDI4736 (IV)
X
X
X
X
X
X
X
X
X
X
X
X
Tumor & Disease Assessments
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
Disease Assessment  by RECIST and irRECIST 
(including appropriate imaging)
X
X
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)i
Demographics (incl. DoB; sex; race; ethnicity)
Medical history 
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
X
X
X
X
X
X
Height
Vital Signs (T, HR, BP, RR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
X
Concomitant Medication / Procedure (name, 
indication, dose, route, start & end dates)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, PO4, 
Mg, prot., alb., Tbili., AST, ALT,  ALP,LDH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testa,f
X
X
X
X
X
CA-125a 
X
X
X
X
X
X
X
Urine Pregnancy Testa,f
Specimens for Correlative Assessments
PBMC/Plasma Collection & Banking a,g
X
X
X
MDSC (Serametrix)a,g  (US sites only)
X
X
Tumor Biopsy (Tumor microenvironment, PD-L1 
expression, TCR sequencing)e
Pharmacogenomics (including BRCA1 and BRCA2 
tumor status)c
PAX RNAa,g 
g- Screening/Baseline specimens for correlative assessments may be collected up to Cycle 1/Day 1 prior to the PLD dose.
h - See Section 3.1.16 regarding assessments scheduled for  both the last on treatment visit and the first post-last treatment visit.
i - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
Treatment
On Study Follow-up
Post 
Study 
Follow-Up
Cycle 7
Cycle 8
Cycle 9
Cycle 10
Cycle 11
Cycle 12
Last Study Drug 
Administration 
+14 +3 daysh
b - See Section 6.3.5 for assessment of vital signs before/during/after MEDI4736 infusion
Last Study Drug 
Administration 
+42 +7 days
 Last Study Drug 
Administration 
+ 90 +7 days      
End of  Study
1
1
1
1
1
1
Every 3 months for 3 years from initiation of treatment. 
Clinical outcomes data (dates of progression/relapse and survival) will be recorded (See Section 3.1.16).
+84 ± 7 days from last disease assessment
X (at disease progression: optional)
X (at disease progression: optional)
a - pre-dose (when applicable) Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing.
c - An aliquot of the PBMC and/or Tumor Biopsy/Archival Tissue will be used for pharmacogenomics – a separate sampling is not needed
d -See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
e - Biopsy is optional for Phase 1.  Refer to Criterion 4 in Section 5.1.  Archival tissue will be requested for all subjects, preferably from primary tumor site 
prior to cancer treatment; however, archival tissue is not a requirement  for study entry.
f - Pregnancy tests are not required for subjects who are not of child-bearing potential as defined in Section 5.2, # 17


 
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Study Flowchart for All Subjects 
Except Dose Level 0a Cohort
Screening / 
Baseline
Cycle week
Visit Day per Cycle
-28 to -1
1
3±1
1±3
3±1
1±3
3±1
1±3
3±1
1±3
3±1
1±3
3±1
Target Cumulative Visit Day
1
3
29
31
57
59
85
87
113
115
141
143
Phase 1 & 2 STUDY DRUG ADMINISTRATION
Pegylated liposomal doxorubicin - PLD (IV)
X
X
X
X
X
X
MEDI4736 (IV)
X
X
X
X
X
X
Tumor & Disease Assessments
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
X
Disease Assessment  by RECIST 1.1 and irRECIST 
(including appropriate imaging)
-14 to -1
X
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)i
X
Demographics (incl. DoB; sex; race; ethnicity) 
X
Medical history
X
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
X
X
X
X
Height
X
Vital Signs (T, HR, BP, RR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
X
Echocardiogram or MUGA
X
X
X
Concomitant Medication / Procedure 
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, PO4, 
Mg, prot., alb., Tbili., AST, ALT,  ALP, LDH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
Serum pregnancy testa,f
-7  to  -1
X
X
CA-125a 
-14 to -1
X
X
X
X
X
Urine Pregnancy Testa,f
Xa
Specimens for Correlative Assessments
PBMC/Plasma Collection & Banking  a,g
X 
X
X
MDSC (Serametrix)a,g  (US sites only)
X
X
Tumor Biopsy (Tumor microenvironment, PD-L1 
expression, TCR sequencing)e
X
X
Pharmacogenomics (including BRCA1 and BRCA2 
tumor status)c
Xg
PAX RNAa,g
X
X
a - pre-dose (when applicable) Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing.
e - Biopsy is optional for Phase 1.  Refer to Criterion 4 in Section 5.1.  Archival tissue will be requested for all subjects, preferably from primary tumor site 
h - See Section 3.1.16 regarding assessments scheduled for  both the last on treatment visit and the first post-last treatment visit.
i - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
1
Treatment
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
1
1
1
1
1
prior to cancer treatment; however, archival tissue is not a requirement  for study entry.
f - Pregnancy tests are not required for subjects who are not of child-bearing potential as defined in Section 5.2, # 17
g- Screening/Baseline specimens for correlative assessments may be collected up to Cycle 1/Day 1 prior to the PLD dose.
X (at disease progression: optional)
X (at disease progression: optional)
b - See Section 6.3.5 for assessment of vital signs before/during/after MEDI4736 infusion
c - An aliquot of the PBMC and/or Tumor Biopsy/Archival Tissue will be used for pharmacogenomics – a separate sampling is not needed
d - See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.


 
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Page 26 of 97 
 
 
Study Flowchart for All Subjects 
Except Dose Level 0a Cohort (Cont)
Cycle week
Visit Day per Cycle
1±3
3±1
1 ±3
3 ±1
1 ±3
3 ±1
1 ±3
3 ±1
1 ±3
3±1
1 ±3
3 ±1
Target Cumulative Visit Day
169
171
197
199
225
227
253
255
281
283
309
311
Phase 1  & 2 STUDY DRUG ADMINISTRATION
Pegylated liposomal doxorubicin - PLD (IV)
X
X
X
X
X
X
MEDI4736 (IV)
X
X
X
X
X
X
Tumor & Disease Assessments
Disease Staging (date/stage at 1st diagnosis and at 
study entry)
Disease Assessment  by RECIST and irRECIST 
(including appropriate imaging)
X
X
Study Procedures & Examinations
Eligibility Assessment and Informed Consent (IC)i
Demographics (incl. DoB; sex; race; ethnicity)
Medical history
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
X
X
X
X
X
X
Height
Vital Signs (T, HR, BP, RR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGa
X
X
X
X
X
X
X
Echocardiogram or MUGA
X
X
Concomitant Medication / Procedure (name, 
indication, dose, route, start & end dates)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Specimens for Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, PO4, 
Mg, prot., alb., Tbili., AST, ALT,  ALP,LDH)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Amylase and lipase)a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry cont. (Free  T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
X
Serum pregnancy testa,f
X
X
X
X
X
CA-125a 
X
X
X
X
X
X
X
Urine Pregnancy Testa,f
Specimens for Correlative Assessments
PBMC/Plasma Collection & Banking a,g
X
X
X
MDSC (Serametrix)a,g  (US sites only)
X
X
Tumor Biopsy (Tumor microenvironment, PD-L1 
expression, TCR sequencing)e
Pharmacogenomics (including BRCA1 and BRCA2 
tumor status)c
PAX RNAa,g
Treatment
On Study Follow-up
Post 
Study 
Follow-Up
Cycle 7
Cycle 8
Cycle 9
Cycle 10
Cycle 11
Cycle 12
Last Study Drug 
Administration 
+28 +3 daysh
b - See Section 6.3.5 for assessment of vital signs before/during/after MEDI4736 infusion
Last Study Drug 
Administration 
+56 +7 days
 Last Study Drug 
Administration 
+ 90 +7 days      
End of  Study
1
1
1
1
1
1
Every 3 months for 3 years from initiation of treatment. 
Clinical outcomes data (dates of progression/relapse and survival) will be recorded (See Section 3.1.16).
+84 ± 7 days from last disease assessment
X (at disease progression: optional)
X (at disease progression: optional)
a - pre-dose (when applicable) Note: It is strongly recommended that hematology, chemistry and pregnancy test (when applicable) results are reviewed before dosing.
h - See Section 3.1.16 regarding assessments scheduled for  both the last on treatment visit and the first post-last treatment visit.
i - Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
c -An aliquot of the PBMC and/or Tumor Biopsy/Archival Tissue will be used for pharmacogenomics – a separate sampling is not needed
d -  See section 7.1.5  for details regarding collection of AEs for 90 days after last study drug administration.
e - Biopsy is optional for Phase 1.  Refer to Criterion 4 in Section 5.1.  Archival tissue will be requested for all subjects, preferably from primary tumor site 
prior to cancer treatment; however, archival tissue is not a requirement  for study entry.
f - Pregnancy tests are not required for subjects who are not of child-bearing potential as defined in Section 5.2, # 17
g- Screening/Baseline specimens for correlative assessments may be collected up to Cycle 1/Day 1 prior to the PLD dose.


 
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4 Study Objectives & Endpoints 
Phase Primary Objectives [Endpoints] 
Secondary Objectives [Endpoints] 
1 
Safety and tolerability 
[DLT/MTD by CTCAE v4.03] 
Clinical Efficacy 
[PFS Rate at 6 and 12 months by RECIST v1.1 and irRECIST] 
[Median PFS by RECIST v1.1 and irRECIST] 
[ORR by RECIST v1.1 and irRECIST] 
[Median Overall Survival (OS)] 
Biological Activity 
[Immunological Response] 
2 
Clinical Efficacy 
[PFS Rate at 6 months by RECIST 
v1.1] 
Clinical Efficacy 
[PFS rate at 6 months by irRECIST] 
[PFS Rate at 12 months by RECIST v1.1 and irRECIST] 
[Median PFS by RECIST v1.1 and irRECIST] 
[ORR by RECIST v1.1 and irRECIST] 
[Median Overall Survival (OS)] 
Safety and tolerability 
[Toxicity by CTCAE v4.03] 
Biological Activity 
[Immunological Response] 
4.1 Clinical Efficacy 
The assessment of Clinical Efficacy is the Primary Objective of Phase 2 and the Secondary 
Objective of Phase 1 of the study and will be performed by RECIST 1.1 and irRECIST. 
4.1.1 Endpoints & Assessment Methods 
Clinical Efficacy is determined by measuring the Progression-free Survival (PFS), Overall Response 
Rate (ORR), and Overall Survival (OS).  Every attempt should be made to use whichever imaging 
technique(s) and test(s) are used initially for repeat evaluations throughout the study, whereby 
the last tumor assessment will be at least 4 weeks from the prior assessment. 
4.1.1.1 Progression-free Survival Rate 
The proportion of subjects who survive and do not progress - Progression Free Survival (PFS) rate- 
within the first 6 months of treatment based on RECIST v1.1 evaluated for the per-protocol 
analysis population constitutes the primary endpoint in Phase 2 of the study. PFS rate at 6 
months will be based on disease assessments at the scheduled visit at the start of Cycle 7. 
4.1.1.2 Progression-free Survival Time 
Progression-free survival time will be defined as the number of days from the date of first dose to 
the date of earliest disease progression based on RECIST v1.1 and irRECIST, or to the date of 
death, if disease progression does not occur. 


 
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4.1.1.3 Overall Response Rate 
Overall Response Rate is defined as the percentage of subjects meeting criteria of CR or PR over a 
period of at least 4 weeks. 
4.1.1.4 Overall Disease Control Rate 
Disease Control is defined as SD, PR or CR over a period of at least 4 weeks.   
4.1.1.5 Overall Survival Time 
Overall survival (OS) time will be measured for each subject with time origin at the date of study 
Day 1 until recorded date of death or last follow-up.  Subjects lost to follow-up will be censored 
on the date when they were last known to be alive.  Every effort will be made to follow subjects 
for overall survival after they complete or discontinue the study. 
4.1.2 Subject Evaluation & Statistics 
The Per-Protocol (PP) Population for clinical efficacy is defined as all subjects who received at 
least 75% of the scheduled doses of MEDI4736, motolimod (pre Amendment 2), and PLD over the 
first 2 cycles, as well as respective disease assessments, without major protocol violations.  The 
Intent-To-Treat (ITT) Population for clinical efficacy is defined as all subjects who receive at least 
one dose of PLD, motolimod (pre Amendment 2) or MEDI4736. 
The analysis of clinical efficacy will be based on both the intent-to-treat (ITT) and the per-
protocol (PP) populations.  
The PFS Rate at 6 months based on RECIST v1.1 evaluated for the per-protocol analysis 
population constitutes the primary endpoint in Phase 2 of the study.  This PFS rate along with its 
one sided 95% Confidence Interval (CI) based on binomial distribution will be estimated and 
reported.  The one-sided null hypothesis of 6-month PFS ≤0.25 will be rejected at 0.05 level of 
significance if the 95% one-sided CI does not contain 0.25. The 12-months PFS rate along with its 
95% one-sided CI will be calculated and reported as a secondary endpoint. 
Tumor Response will be summarized and analyzed descriptively for each cohort and analysis 
population.  A 95% Confidence Interval based on binomial distribution will be constructed for the 
estimated ORR. 
Median OS will be calculated using the Kaplan-Meier method.  The analysis of PFS and OS will be 
updated based on data collected during the Post Study Follow-up (see Section 3.1.16). 
4.2 Safety and Tolerability 
The assessment of safety and tolerability is the Primary Objective of Phase 1 and Secondary 
Objective of Phase 2 of the study.  It 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.  In Phase 1, formal safety reviews will be performed and documented for the 
purpose of dose escalation / de-escalation in the context of the 3+3 study design. 


 
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4.2.1 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.  The 
investigator will evaluate any laboratory abnormalities for clinical significance, and clinically 
significant abnormalities will be recorded as adverse events.  All clinically significant 
abnormalities and deteriorations from time of signing of informed consent to the end of study 
visit 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. 
4.2.2 Subject Evaluation & Statistics 
The Per-Protocol (PP) Population for DLT Assessment includes: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) 
• 
All subjects with no DLT who receive at least 75% of the scheduled doses of MEDI4736, 
motolimod (pre Amendment 2), and PLD as well as respective safety assessments, 
without major protocol violations, over the entire DLT Evaluation Period (as defined in 
Section 3.1.9).   
Refer to Section 3.1.11 for subject replacements. 
The Intent-To-Treat (ITT) Population for safety and tolerability is defined as all subjects who 
receive at least one dose of PLD, motolimod (pre Amendment 2) or MEDI4736. 
In Phase 1, for the primary endpoint of determining DLTs and the MTD, the analysis of safety and 
tolerability will be based on the PP Population for DLT Assessment.   
In both Phases 1 and 2, the overall analysis of safety and tolerability will be based on the ITT 
Population for safety and tolerability. 
Appropriate summaries of AEs, laboratory data and vital sign data will be presented.  Adverse 
events will be coded using the MedDRA dictionary.  Incidences of treatment-emergent adverse 
events (TEAE, those events that started after dosing or worsened in severity after dosing) will be 
presented overall and by maximum severity (according to CTCAE version 4.03) and relationship to 
study medication. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges.  Frequencies and percentages will be presented by 
treatment arm for the shifts in these categories (i.e., low to normal, low to high, high to low, etc.) 
from baseline to each post-treatment assessment time point.  Additionally, for each continuous 
hematology and chemistry parameter, descriptive statistics will be presented by treatment arm 
for the changes from baseline to each post-treatment assessment time point.  Descriptive 
statistics will be presented by cohort for the changes in vital signs from baseline to each post-
treatment assessment time point. 


 
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4.3 Biological Activity  
Samples for exploratory assessment of correlative immunologic research will be collected 
according to the Study Flowchart in Section 3.2.  Assessments include, but are not limited to: 
Phenotypic analysis of PBMCs, Characterization of MDSCs, Quantification of tumor-specific T-cell 
responses, Immune Landscape: Tumor Infiltrating Lymphocytes and Tumor Microenvironment, 
TCR sequencing, Immune Biomarkers, Pharmacogenomics, and BRCA status of tumors. 
A comprehensive list of variables to be analyzed for the exploratory assessment of correlative 
immunologic research is located in Section 8.7. 
4.3.1 Endpoints & Assessment Methods 
Subjects who received at least one dose of PLD, motolimod (pre Amendment 2) or MEDI4736, 
and provide baseline and at least one post-treatment sample, will be evaluated.  The assessment 
methods are described in the respective appendices for each assay. 
4.3.2 Subject Evaluation & Statistics 
The association of clinical activity with tumor markers will be assessed based on PD-L1 expression 
level and changes in tumor-infiltrating lymphocytes (TIL) from mandatory pre- and post-
treatment biopsies in the Phase 2 cohort.  Subjects will be classified as responders or non-
responders based on RECIST v1.1 and irRECIST criteria.  Within each response group, subject 
tumors will be assessed as positive or negative for PD-L1 expression.  Fisher’s Exact test will be 
used to test whether there is a significant association between responder-status and PD-L1 
expression.  Assuming evaluable tumor biopsies are available for at least 36 subjects and 
approximately equal numbers of responders and non-responders, if there are 80% and 30% of 
subjects with positive PD-L1 expression in the two groups, respectively, there will be at least 80% 
power to detect a significant difference.  A 95% confidence interval for the odds ratio for positive 
PD-L1 expression will be presented.  The association between response and TIL changes 
(increase, decrease, or no change) will be evaluated similarly. 
Results from the remaining correlative studies will be summarized descriptively and evaluated in 
relation to outcome.  All data will be provided in subject data listings. 
  
 


 
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5 Subject Eligibility 
Note: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
5.1 Inclusion Criteria 
Eligible subjects must fulfill all of the following criteria: 
1. 
Subjects must have recurrent or persistent platinum-resistant epithelial ovarian, 
fallopian tube, or primary peritoneal carcinoma with measureable disease (as defined 
by RECIST 1.1.) after first or second line platinum-based chemotherapy, for which 
treatment with PLD is indicated. 
Platinum-based therapy is defined as treatment with carboplatin, cisplatin or another 
organoplatinum compound. 
Platinum-resistant is defined as having a platinum-free interval (PFI) of < 12 months 
after first- or second-line platinum-based chemotherapy, or having disease progression 
while receiving second-line platinum-based chemotherapy. 
Subjects are allowed to have received, but are not required to have received: 
• 
one additional cytotoxic regimen and/or PARP inhibitor for management of 
recurrent or persistent disease. 
• 
biologic therapy (e.g., bevacizumab) as part of their primary treatment regimen 
or as part of their treatment for management of recurrent or persistent disease. 
2. 
Histologic documentation of the original primary tumor.  
3. 
Documented radiographic disease progression < 12 months after the last dose of first- 
or second-line platinum-based chemotherapy.  
4. 
Subjects in Phase 2 must have disease amenable to biopsy and must be willing to 
undergo pre- and post-treatment tumor biopsies (see Section 3.2 for biopsy time 
points).  Optional for Phase 1. 
NOTE: Archival tissue will be requested for all subjects, preferably from primary tumor 
site prior to cancer treatment; however, archival tissue is not a requirement for study 
entry. 
5. 
ECOG performance status of 0 or 1. 
6. 
Laboratory parameters for vital functions should be in the normal range.  Laboratory 
abnormalities that are not clinically significant are generally permitted, except for the 
following laboratory parameters, which must be within the ranges specified, regardless 
of clinical significance: 
Hemoglobin 
≥ 9 g/dL 
Neutrophil count 
≥ 1.5 x 109/L 
Platelet count 
≥ 100,000/mm3 
Serum creatinine, or 
Creatinine Clearance 
≤ 1.5x Institutional Upper Limit of Normal (ULN), or 
≥ 50 mL/min (by Cockcroft-Gault formula) 
Serum bilirubin 
≤ 1.2 mg/dL  
AST/ALT 
≤ 2.5 x ULN 
Alkaline phosphatase 
≤ 2.5 x ULN 
 
 
7. 
Age ≥18 years. 


 
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8. 
Able and willing to give valid written informed consent. 
9. 
Body weight > 30 kg 
 
 
5.2 Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Prior exposure to doxorubicin, PLD or any other anthracycline, motolimod and other 
TLR agonists (pre Amendment 2), MEDI4736 or checkpoint inhibitors, such as anti-
CTLA4 and anti-PD1/anti-PD-L1 antibodies. 
2. 
Subjects with platinum-refractory disease, defined as disease progression while 
receiving first line platinum-based therapy. 
3. 
Clinically significant persistent immune-related adverse events following prior therapy. 
4. 
Subjects with history or evidence upon physical examination of CNS disease, including 
primary brain tumor, seizures not controlled with standard medical therapy, any brain 
metastases, or, within six months prior to Day 1 of this study, history of 
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid 
hemorrhage. 
5. 
Subjects with clinically significant cardiovascular disease. This includes: 
a. Resistant hypertension. 
b. Myocardial infarction or unstable angina within 6 months prior to Day 1 of the 
study. 
c. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications, except 
for atrial fibrillation that is well controlled with anti-arrhythmic medication. 
d. Baseline ejection fraction ≤ 50% as assessed by echocardiogram or MUGA. 
e. New York Heart Association (NYHA) Class II or higher congestive heart failure. 
f. Grade 2 or higher peripheral ischemia, except for brief (< 24 hrs) episodes of 
ischemia managed non-surgically and without permanent deficit. 
6. 
History of pneumonitis or interstitial lung disease. 
7. 
Active, suspected or prior documented autoimmune disease (including inflammatory 
bowel disease, celiac disease, Wegner’s granulomatosis, active Hashimoto’s thyroiditis, 
rheumatoid arthritis, lupus, scleroderma and its variants, multiple sclerosis, 
myasthenia gravis).  Vitiligo, type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted. 
8. 
Other malignancy within 2 years prior to Day 1 of the study, except for those treated 
with surgical intervention only. 
9. 
Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who 
require drainage gastrostomy tube and/or parenteral hydration or nutrition. 
10. 
Known immunodeficiency or HIV, Hepatitis B or Hepatitis C positivity. 
11. 
History of severe allergic reactions to any unknown allergens or components of the 
study drugs. 


 
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12. 
Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding 
disorders). 
13. 
Prior treatment in any other interventional clinical trial within 4 weeks prior to Day 1 
of the study. 
14. 
Mental impairment that may compromise compliance with the requirements of the 
study. 
15. 
Lack of availability for immunological and clinical follow-up assessment. 
16. 
Women of child bearing potential who are found to be pregnant as evidenced by 
positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
or nursing. NOTE: Pregnancy tests are not required for subjects who are not of child-
bearing potential as defined in #17. 
17. 
Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from screening, and must agree to continue using such precautions for 90 days 
after the final dose of investigational product (MEDI4736). Male partners of a female 
subject must use male condom plus spermicide throughout this period (from screening 
and for 90 days after subject’s receipt of the final dose of investigational product). 
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. 
Female subjects should refrain from breastfeeding throughout the period described 
above. 
NOTE: For the standard of care, pegylated liposomal doxorubicin (PLD, Doxil®, Caelyx®), 
the package insert advises females of reproductive potential to use effective 
contraception during and for 6 months after last treatment with the drug.  Therefore, 
all subjects of childbearing potential on this study should continue contraception use 
for 6 months after the last PLD administration. 
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 
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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: 
Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing intrauterine 
system (e.g., Mirena®)b 
• 
Implants: Etonogestrel implants: e.g. 
Implanon or Norplan 
• 
Intravaginal device:  ethinylestradiol and 
etonogestrel- releasing intravaginal 
devices: e.g. NuvaRing® 
• 
Injection: Medroxyprogesterone 
injection: e.g. Depo-Provera  
• 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• 
Patch: 
Norelgestromin/ethinylestradiol-
releasing transdermal system e.g. 
Ortho Evra®   
• 
“Minipillc”: Progesterone based oral 
contraceptive pill using desogestrel e.g., 
Cerazette®  
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill 
18. 
Any condition that, in the clinical judgment of the treating physician, is likely to 
prevent the subject from complying with any aspect of the protocol or that may put 
the subject at unacceptable risk. 
19. 
Subjects must not donate blood while on study and for at least 90 days following the 
last MEDI4736 treatment. 
20. 
History of allogeneic organ transplant 


 
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5.3 Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with glucocorticosteroids 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 (e.g., drug, radiation or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1; 6 weeks 
for nitrosoureas. 
3. 
Live/attenuated vaccines 1 month prior to Day 1 and for at least 6 months after the 
last dose of treatment. 
The wash-out period prior to Day 1 of the study for all non-permitted drugs should be at least 
1 week, unless stated otherwise above. 
5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Intranasal or inhaled steroids for treating mild to moderate asthma or allergies, 
physiological steroid replacement, intra-articular steroids, or topical steroids for 
localized dermatitis (<5% of BSA). 
2. 
NSAIDs, acetylsalicylic acid and specific COX-2 inhibitors. 
3. 
Antihistamines and other non-steroidal anti-allergy medication. 
4. 
Hormone replacement therapy. 
5. 
Palliative radiation of non-target and/or non-index lesions, or for symptom 
management. 
6. 
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 or anti-TNF 
agents (e.g. infliximab) to treat immune-mediated adverse reactions.  Subjects should 
receive full supportive care, including transfusions of blood and blood products, and 
treatment with antibiotics, anti-emetics, anti-diarrheal, and analgesics, and other care 
as deemed appropriate, and in accordance with their institutional guidelines. Use of 
anticoagulants such as warfarin is permitted however, caution should be exercised and 
additional International Normalized Ratio (INR) monitoring is recommended. 
[Note: Motolimod should not be dosed within 24 hours of systemic corticosteroid 
use.  Doses of motolimod should be delayed or skipped as appropriate.  See Sections 
8.2, 8.3, and 8.4 regarding dose delays.]  
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic (preferably) or brand name, indication, dose, 
route and dates of administration.  All non-drug therapies must be recorded in the respective 
sections of the case report form. 


 
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6 Study Drug Preparation and Administration 
6.1 Pegylated Liposomal Doxorubicin (PLD) 
Pegylated liposomal doxorubicin (PLD) is commercially available and will be ordered by the 
pharmacy at the investigative site. 
Please refer to the package insert for PLD for the most current formulation, preparation and 
administration.  The dose to be administered is 40 mg/m2, which is consistent with current 
clinical practice.   
Maximum body surface area for PLD dose calculations will be 2.0 m2.  Dose recalculation for each 
cycle will be needed if there is a weight change > 10%.  NOTE: The maximum body surface area 
and recalculations are recommendations; standard procedures for maximum body surface and 
recalculations at each site may be used.  
6.2 Motolimod 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
Motolimod is supplied by the Sponsor.  Prior to administration, motolimod must be reconstituted 
using sterile water for injection.  Please see to section 6.2.2 for preparation and administrative 
instructions. 
6.2.1 Motolimod Study Drug Information 
Manufacturer 
VentiRx 
Expiration/Retest Date 
Expiration/retest dates are documented on the Certificate of 
Analysis and/or stability certification. 
Container Description 
Type: 
Single use vial  
Material: 
clear-glass 
Size: 
3-mL 
Formulation 
Motolimod is supplied as an off-white, lyophilized cake and is 
comprised of an active pharmaceutical ingredient (VTX-378) 
formulated with a solubilizing agent at neutral pH. 
Active Ingredient Content 
Mass/Weight: 
8.4mg 
Volume: 
n/a  
Concentration: 
10mg/mL when 
reconstituted with 
0.7mL sterile water 
Storage Conditions 
2°C–8°C (26°F–46°F) 
Stability after 
reconstitution 
24 hours at 2-8°C or 8 hours at ambient 
Labeling 
Product name, lot number, route of administration, and 
storage conditions 
6.2.2  Motolimod Preparation  
Prior to administration, motolimod must be reconstituted using sterile water for injection, USP.  
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refrigerated at 2–8°C.  Motolimod should be prepared and transferred using aseptic technique in 
a biological safety cabinet.  Vials of motolimod are intended for single use only.  
1. Determine the appropriate dose based on the subject’s BSA.   
a. Calculate the total dose to be administered: 
BSA (__.__ __m2) x dose level (__. __ mg/m2) = total dose (__.__) mg) of motolimod. 
b. Calculate the dose volume: 
Total dose ( __. __ ) mg.) ÷ 10 mg/mL = dose volume (__. __ __ mL) of motolimod. 
2. Reconstitute 1 vial of motolimod with 0.7 mL Sterile Water for Injection 
3. Sterile Water for Injection, as described below, to yield 0.84 mL of solution with a 
concentration of 10 mg/mL. 
a. Add the sterile water for injection while directing the stream at the lyophilized cake. 
b. Swirl the vial to disperse the water throughout the cake 
c. Invert the vial repeatedly for approximately 2–3 minutes until the contents are fully 
dissolved.  The reconstituted solution should be clear, and will range in color from 
colorless to yellow. 
4. Using a syringe appropriate for subcutaneous dosing to draw up __. __ __ mL (dose volume; 
step 1b) from the vial of 10 mg/mL motolimod. 
6.2.3 Motolimod Administration 
On days with concurrent motolimod and MEDI4736 dosing, motolimod administration will occur 
30-60 minutes after the end of the MEDI4736 infusion.  Motolimod is administered as a 
subcutaneous injection.  Within 30 minutes prior to each dose of motolimod, subjects will be 
administered 650–1000 mg acetaminophen by mouth to help mitigate potential adverse events 
commonly associated with the administration of motolimod (e.g., fever, myalgia).  Subjects will 
be given or instructed to take an additional dose of 650–1000 mg acetaminophen by mouth 
approximately 4–6 hours after administration of motolimod, and as needed thereafter for 
symptoms of fever and/or body aches.  Acetaminophen is the preferred over-the-counter 
analgesic and antipyretic; due to their potentially immunosuppressive effects, administration of 
NSAIDS within 24 hours of dosing should be avoided if clinically feasible. 
To potentially reduce the effects of injection site reaction that may be associated with the 
administration of motolimod, an ice pack may be applied to the injection site for approximately 
30 minutes prior to injection, immediately following injection, and throughout the day of 
injection.  Additionally, at the discretion of the Investigator, single doses of motolimod may be 
divided and administered at two different anatomical locations. 
The dose of motolimod should be administered with a syringe suitable for subcutaneous 
injection.  To administer the injection, 1–2 inches of fatty tissue should be pinched up to avoid 
injection into the muscle layer.  The needle can be inserted at either 45 or 90 degrees; a 45 
degree angle is recommended when less than 2 inches of tissue can be pinched.  Appropriate 
anatomic areas for subcutaneous injection include the fatty tissue over the abdomen, triceps, 
thighs, or lower back.  The injection site should be rotated among anatomically appropriate 
locations to help avoid injection site reaction. 
Standard medications to treat possible hypersensitivity reactions and/or symptoms of cytokine 
release syndrome (CRS) should be readily available at the time of treatment, including 


 
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epinephrine, H1 antihistamines (e.g., diphenhydramine), H2 antihistamines (e.g., ranitidine), 
narcotics, IV fluids for volume expansion and supplemental oxygen. 
Due to their immunosuppressive effect, administration of systemic corticosteroids (e.g., 
dexamethasone) should be avoided in this setting if other means of treatment are available 
and appropriate.  If systemic corticosteroid use is clinically necessary, motolimod should not be 
administered within 24 hours.  Doses of motolimod should be delayed or skipped as 
appropriate. 
6.3 MEDI4736 
MEDI4736 is supplied by the Sponsor.  Commercially available 0.9% (w/v) saline or 5% (w/v) 
dextrose will be supplied by each site.  Please see Section 7.2.8, for additional details. 
6.3.1 MEDI4736 Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented in the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container 
Description 
Type: 
Single use vial  
Material: 
glass 
Size: 
10 mL 
Formulation 
Liquid solution containing 500 mg MEDI4736 per vial.  
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: 
500 mg 
Volume: 
10 mL 
Concentration: 
50 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 
6.3.2 MEDI4736 Investigational Product Inspection 
Each vial of MEDI4736 selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.3.3 MEDI4736 Preparation 
Preparation of MEDI4736 and preparation of the intravenous bag are to be performed aseptically 
by the IP manager or designated personnel.  No incompatibilities between MEDI4736 and 
polyvinylchloride or polyolefin copolymers have been observed. 


 
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6.3.3.1 MEDI4736 Preparation for Cohort at Dose Level 0a 
Dose Calculation: 
The volume of MEDI4736 (in mL) 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) 
The corresponding volume of MEDI4736 should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle are only needed for a greater than 10% change in weight.  
Dose Preparation: 
MEDI4736 will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose.  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 x 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. 
Per Amendment 3, fixed dosing will be used for the optional study treatment extension as 
described in Section 3.1.12 and Section 8.9.  See Section 6.3.3.2. 
6.3.3.2 MEDI4736 Preparation for all Subjects except Cohort at Dose Level 0a and for 
Treatment Extension 
Per Amendment 3, fixed dosing will be used for all subjects who proceed with the optional 
study treatment extension as described in Section 3.1.12 and Section 8.9. 
Dose Calculation: 
Subjects will receive a fixed dose of MEDI4736: 1500 mg Q4W for subjects > 30 kg.  If a subject’s 
body weight drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing 
equivalent to 20 mg/kg Q4W for MEDI4736 as long as the body weight remains ≤ 30 kg (e.g., a 
30 kg subject would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.). 
When the weight improves to >30 kg, the subject may return to fixed dosing of MEDI4736 
1500 mg.   
The volume of MEDI4736 (in mL) to add to the IV bag is calculated as follows: 
Volume of 
MEDI4736 (mL)  
= 
Dose (mg) 
÷ 
MEDI4736 Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
MEDI4736 will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose.  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 


 
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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 1500 mg dose (for subjects > 30 kg in weight), 30 mL of MEDI4736 is to be diluted 
in a 250 mL IV bag.  First, 30 mL of diluent is removed from the IV bag, and then 30 mL of 
MEDI4736 is added to the bag.  The bag is mixed by gentle inversion to ensure homogeneity of 
the dose in the bag. 
MEDI4736 does not contain preservatives, and any unused portion must be discarded. 
6.3.4 MEDI4736 Administration 
Following preparation of the dose, MEDI4736 will be administered according to the following 
guidelines: 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 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. 
• 
MEDI4736 must be administered at room temperature by controlled infusion 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. 
• 
MEDI4736 solution should not be infused with other solutions or medications. 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational products. Fully functional 
resuscitation facilities should be available.  
• 
MEDI4736 must not be administered via IV push or bolus but as an IV infusion.  
• 
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 6.3.5. 
• 
See Section 8.4.2.2 for management guidelines for infusion-related reactions. 
• 
The total time between needle puncture of the MEDI4736 vial to start of administration 
should not exceed 4 hours at room temperature, or 24 hours at 2°C to 8°C (36°F to 46°F).  
Standard infusion time is 60 ± 5 minutes.  However, if there are interruptions during 
infusion, the total allowed infusion time should not exceed 8 hours.  In the event that 
either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials.   
MEDI4736 does not contain preservatives, and any unused portion must be discarded. 


 
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6.3.5 Monitoring of MEDI4736 Dose Administration 
Subjects will be monitored during and after infusion with assessment of vital signs according to 
the table below: 
Vital Signs Assessment on 
study drug administration 
days 
Pre 
dose 
During Infusion 
End of 
Infusion (± 
5 minutes) 
Post 
infusion + 
30 (± 5) 
minutes 
Post 
Infusion + 
60 (± 5) 
minutes) 
MEDI4736 Vital Signs 
X 
every 15 (± 5) 
minutes 
X 
X 
x 
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) 
Pre 
dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
Post infusion + 15 
(± 5) minutes 
MEDI4736 Vital Signs 
X 
every 30 (± 5) 
minutes 
X 
X 
 


 
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6.4 Estimated Study Drug Requirements for Motolimod and MEDI4736 
Drug 
Calculation 
Required 
Quantity 
Motolimod 
53 subjects X 12 cycles  
53 subjects Cycles 1 - 3: 3 vials per cycle = 477 vials 
6 subjects (Dose Level 0a): 2 vials per Cycles 4-12: 108 vials  
47 subjects (all others): 1 vial per Cycles 4-12: 423 vials  
Total = 1,008 vials 
Total + 20% overage: 1,210 vials 
PER Amendment 2, motolimod dosing will be discontinued 
for all subjects. 
1,210 Vials 
MEDI4736 
53 subjects X 12 cycles: 
6 subjects (Dose Level 0a): 4 vials per cycle: 288 vials 
6 subjects (Dose Level -1): 1 vial per cycle: 72 vials 
41 subjects (all others): 3 vials per cycle: 1476 vials 
Total = 1836 vials 
Total + 20% overage:  2,203 
2,203 Vials 
MEDI4736 
Additional MEDI4736 for optional study treatment 
extension per Section 3.1.12 
Assumptions: 15% of subjects will continue for 12 cycles 
beyond Core Study 
343 vials 
6.5 Drug Overdose Management 
Any overdose with PLD should be managed according to the package insert/ prescribing 
information. 
Any overdoses with motolimod and MEDI4736 should be managed symptomatically.  There are 
no known antidotes available for these drugs.  An overdose is defined as a subject receiving any 
dose in excess of that specified in this protocol by >10%.  All such overdoses must be reported, 
with or without associated AEs/SAEs, according to Section 7.1.2.2. 


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


 
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7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (See Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.5) 
3. Hepatic function abnormality (as defined in Section 7.1.8). 
7.1.2.1 Pregnancy 
7.1.2.1.1 Maternal Exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of study drug (see Section 5.2, #17). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see section 7.1.6).  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the Sponsor (see Section 7.1.6 for Sponsor contact information) within 1 day, i.e., 
immediately, but no later than 24 hours of becoming aware of the event.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available. 
7.1.2.2 Overdose 
Any overdose (as defined in Section 6.5) of a study subject, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the Sponsor (see 
Section 7.1.6 for Sponsor contact information). If the overdose results in an AE, the AE must also 
be recorded as an AE according to Section 7.1.5. Overdose does not automatically make an AE 
serious, but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE according to 
Section 7.1.6. There is currently no specific treatment in the event of an overdose of MEDI4736 
or motolimod. The Investigator will use clinical judgment to treat any overdose. See Section 6.5 
for additional details. 


 
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7.1.2.3 Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed (see Section 7.1.6 for Sponsor contact information). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the Investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and MedImmune/AstraZeneca. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in Section 1 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 


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


 
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Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@licr.org 
Primary Sponsor Contact: 
Mary Macri 
Director, Clinical Project Management 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
666 3rd Ave, 28th Floor 
New York, New York 10017 
Tel: 
+1 212 450 1546 
Fax: 
+1 212 450 1535 
mmacri@licr.org  
 
Serious adverse events must also be reported by the Principal Investigator to the respective 
Institutional Review Board after being assigned a serious adverse event tracking number by the 
Sponsor.  Institutional Review Boards may have specific rules on which Adverse Events need to 
be reported expeditiously, as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory authorities and 
other investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered.  In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug(s) cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available, using the “SAE 
Follow-up Report form”, provided by the Sponsor or, if Medidata RAVE data capture is utilized, 
using the respective Adverse Event and Safety Case Summary eCRFs. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor.  An AESI may be serious or non-serious.  The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of the investigational products.   
AESIs for MEDI4736 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 


 
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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 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 version of the MEDI4736 Investigator Brochure.  Guidelines for the management of 
subjects experiencing toxicities for MEDI4736 can be found in Section 8.4 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).” 
• 
Colitis/Gastrointestinal Disorders 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs following 
dosing with MEDI4736.  In rare cases colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome, if not properly managed. 
• 
Pneumonitis/Interstitial lung disease (ILD)  
Pneumonitis has been reported with use of anti-PD-1 mAbs.(51) Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry.  Typically, 
pulmonary consultation is highly recommended. 
• 
Hepatic Function Abnormality (Hepatotoxicty, Hepatitis) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies.(52)  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated 
with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of 
ipilimumab-treated subjects included general weakness, fatigue, nausea and/or mild fever 
and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total 
bilirubin.  Hepatic function abnormality is defined as any increase in ALT or AST to > 3 × ULN 
and concurrent increase in total bilirubin to > 2 × ULN.  Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each 
other. Follow-up investigations and inquiries will be initiated promptly by the investigational 
site to determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a concurrent or pre-existing disease (e.g., 
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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• 
Neurotoxicity (Neuropathy/Neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypophysitis/hypopituitarism, adrenal 
insufficiency, and hyper- and hypothyroidism, diabetes insipidus, and Type 1 diabetes 
mellitus. 
Type 1 diabetes mellitus: For subjects with suspected diabetes mellitus, Investigators should 
obtain an endocrinology consult and institute appropriate management which may include 
the administration of insulin.  
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines.  
• 
Nephritis and increases in serum creatinine 
Consult with Nephrologist should be done as well as monitoring for signs and symptoms that 
may be related to changes in renal function (e.g., routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine output, 
proteinuria, etc.). Subjects should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, etc.). Steroids should be considered in the 
absence of clear alternative etiology even for low grade events (Grade 2), in order to prevent 
potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis: increased serum lipase, increased serum amylase)   
• 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-
PD-L1 and anti-PD-1 therapy.(52)  As with the administration of any foreign protein and/or 
other biologic agents, reactions following the infusion of monoclonal antibodies (MAbs) can 
be caused by various mechanisms, including acute anaphylactic (IgE-mediated) and 
anaphylactoid reactions against the MAb, and serum sickness.  Acute allergic reactions may 
occur, may be severe, and may result in death.  Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
• 
Other inflammatory responses that are rare with a potential immune-mediated aetiology 
include, but are not limited to, myocarditis, pericarditis, and uveitis.  
7.1.8.1  Additional AESIs for this Study  
Guidelines for the management of subjects experiencing toxicities for PLD and motolimod can be 
found in Sections 8.2 and 8.3, respectively. 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 


 
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7.1.8.1.1 Cytokine Release Syndrome (CRS) ≥Grade 3 
CRS is a symptom complex and is characterized by systemic symptoms which may include fever, 
nausea, chills, tachycardia, hypotension, dyspnea, asthenia, headache, and rash.  Motolimod 
directly targets TLR8, which is expressed on immune cells.  CRS may result from the release of 
cytokines from the activated immune cells, or from ‘downstream’ events that can be associated 
with cytokine production.  Symptoms of CRS may be acute or delayed by several hours after 
dosing with motolimod.  
7.1.8.1.2 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.  In addition, 
preclinical toxicology studies of motolimod, but not clinical studies, identified inflammatory 
uveitis as a drug-related toxicity; however, these observations occurred at dose levels higher 
than those currently administered in any clinical trial of motolimod and no specific requirement 
for ophthalmologic surveillance is required in this study.  Physicians should initiate 
ophthalmologic evaluation should symptoms develop. 
7.2 Administrative Sponsor Requirements 
7.2.1 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(“Study Master File”) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
7.2.2 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data entry, 
query management and sign-off.  Systems used for electronic data capture will be compliant with 
FDA regulations 21 CFR Part 11 and within the constraints of the applicable local regulatory 
agency guidelines (whichever provides the greatest protection to the integrity of the data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigators electronic signature indicates a thorough inspection of the data in the CRF and 
will certify its content. 
7.2.3 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 


 
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material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.4 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
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, 
regulatory inspection and sponsor audits.  Direct access is defined as permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the evaluation of 
the study.  All reasonable precautions within the constraints of the applicable regulatory 
requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary 
information will be exercised. 
It is the Clinical Monitor’s responsibility to inspect the case report forms at regular intervals 
throughout the trial to verify adherence to the protocol, the completeness, accuracy and 
consistency of the data, and adherence to Good Clinical Practice guidelines.  The Clinical Monitor 
should have access to subject charts, laboratory reports and other subject records needed to 
verify the entries on the case report forms (“source data verification”). 
7.2.5 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Institutional Review Board and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals.  However, in this case, approval must be obtained as soon as possible after 
implementation. Implementation of administrative amendments that do not affect the safety of 
the subjects do usually not require prior Institutional Review Board approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor if circumstances permit, to discuss the planned 
course of action.  Any departures from the protocol must be fully documented in the source 
documentation. 
7.2.6 Premature Subject Withdrawal 
A subject may withdraw 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 the study.  Specific subject withdrawal reasons 
are listed in Section 3.1.10.  Should a subject (or a subject’s legally authorized representative) 
decide to withdraw, 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, and an 
attempt should be made to perform a follow-up evaluation. 


 
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7.2.7 Early Trial Termination 
“End of study” is defined as the last visit of the last subject.  Sponsor and Investigator have the 
right to terminate the study early.  Specific study stopping rules are listed in Section 3.1.14.  In 
such case, one party must notify the other in advance in writing about the intent of and the 
reasons for the termination.  The investigator must also notify the appropriate Institutional 
Review Board accordingly. 
7.2.8 Study Drug Shipments & Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The Investigator 
is responsible for the accounting of all used and unused trial supplies.  At the end of the study, 
the Clinical Monitor will also collect the original study drug dispensing records. 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 Regulatory, Legal & 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-specific 
procedures are performed.  The subject should be given a copy of the informed consent 
documentation.  The original signed and dated informed consent form must be retained in the 


 
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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 subject letter code, date of birth and subject number on the case report forms 
or other documents submitted to the Sponsor.  The subject letter code does not necessarily have 
to correlate to the subject’s name. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent form) should be 
kept in a strictly confidential section of the study file by the Investigator. 
The investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As part 
of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 


 
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8 Appendices 
8.1 Protocol Version History 
Version 000 (Original Issue) 
Issue Date: 30-MAR-2015 
Summary of Changes: n/a 
 
Amendment 001 
Issue Date: 09-DEC-2015 
Summary of Changes: 
1. Administrative changes:  
o Updated footer and synopsis page with new protocol format and logo. Formatted 
headings to be aligned with current protocol templates 
o Changed “patient” to “subject” where appropriate 
o Changed format of Section 8.1 to allow for more space to record protocol changes 
o General spelling, capitalization, and formatting changes, as needed. 
o US Study Chair, Bradley J. Monk MD, was added 
2. Synopsis and Section 3.1.7:  
o The starting dose level cohort was renamed as dose level 0a, and dose level 0b was 
added to Phase 1 (dosing is detailed in the table below). Depending on the timing of 
Amendment 1, dose level 0b cohort could be running concurrently with the cohort at 
dose level 0a, -1, or +1. The dosing for the cohort in dose level 0a will continue per the 
protocol prior to Amendment 1 (i.e., MEDI4736 at 3 mg/kg Q2W); however, escalation 
or de-escalation dosing will be conducted according to Amendment 1. 
o A fixed dosing schedule for MEDI4736 was added for all subjects except those in the 
cohort that had already been started prior to Amendment 1 (i.e., dose level 0a). See 
table below for details. 
o Treatment schedule for cohort at dose level 0a will continue as it was prior to 
Amendment 1 
o Treatment schedule for all subjects except those at dose level 0a will be as follows: 
Day 
Cycles 1 – 3 
Cycles 4 – 12 
1 
PLD (IV) 
PLD (IV) 
3 
MEDI4736 (IV) + Motolimod (SC) 
MEDI4736 (IV) + Motolimod (SC) 
10 
Motolimod (SC) 
n/a 
17 
Motolimod (SC) 
n/a 
 
table was updated to indicate MEDI4736 will be administered only on Day 3 of 
each cycle (Q4W instead of Q2W) 
 
for Cycles 4-12, motolimod will be administered on Day 3 only instead of Days 3 
and 17 


 
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o Dose level table was updated as follows: 
Dose Level 
PLD 
[mg/m2 IV] 
MEDI4736 
[IV] 
Motolimod 
[mg/m2 SC] 
-1 
40 
450 mg Q4W  
2.0 
0a (Starting Level) 
40 
3 mg/kg Q2W 
(equivalent to 450 mg Q4W) 
2.5 
0b 
40 
1500 mg Q4W 
2.0 
+1 
40 
1500 mg Q4W 
2.5 
Q2W = every 2 weeks; Q4W = every 4 weeks 
 
Dose level -2 was deleted 
 
Dose level -1 and +1 were changed to fixed dosing for MEDI4736 Q4W 
 
Dose level 0b was added 
3. Sections 1.3 and 1.4.1 were updated with current information. 
4. Section 2.1: Rationale for implementing the changes in Synopsis and Section 3.1.7 was 
provided. 
5. Section 3.1.2:  
o The first sentence in paragraph 2 was modified (changes in bold): “For each cohort in 
Phase 1, the start of the Cycle 1 Day 3 study drug administration (MEDI4736 + 
motolimod)….” 
o The following paragraph was added: “Per Amendment 1, the cohort at dose level 0b will 
be added to Phase 1.  Depending on the timing of Amendment 1, dose level 0b cohort 
could be running concurrently with the cohort at dose level 0a, -1, or +1.  Thus, subject 
enrollment will occur as follows: 
a) when only 1 cohort is open: sequential enrollment; 
b) when 2 parallel cohorts are open: preferential sequential enrollment into the cohort 
with the higher motolimod dose level or into the cohort with the higher MEDI4736 
dose level if both cohorts have the same motolimod dose level. 
Subject enrollment will be centrally administered.” 
6. Section 3.1.9: 
o DLT Observation period was changed from 2 cycles to one cycle, i.e., “DLTs will be 
observed over a period of the first cycle including the pre-dose assessment for Cycle 2, 
defined as the DLT Evaluation Period.” 
o Neurological event and uveitis were added to #1, #2, and bullet for #2  
o For #3, bullet 3: “Grade 3 asymptomatic endocrinopathy” was changed to “Grade 3 
endocrinopathy that becomes asymptomatic …” 
7. Section 3.1.10:  
o Section was clarified to indicate reasons for withdrawal from treatment vs. withdrawal 
from study. Additional detail was added to conform to current standard protocol 
language. 
8. 
Section 3.1.15: duration of Post Study Follow-up was added. 
9. 
Section 3.1.16:  
o Clarification was provided for On Study Follow-up versus Post Study Follow-up. 
o Clarification was provided to indicate that If the determination is made to remove a 
subject from treatment at a visit that coincides with the first visit of the On Study 
Follow-up Period (which is 14 days after the last dose of study treatment), any 
assessments required in the 14 day 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 


 
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in at the earliest opportunity.  Any assessments or correlative samples required by both 
the protocol visit and 14 day post-last treatment visit should not be repeated. 
o Post Study Follow-up was clarified to indicate that frequency will be “Every 3 months for 
3 years from initiation of treatment.” This was also clarified in Section 3.1.7. 
10. Section 3.2, Study Flowchart: 
o Changed Day 0 to Day -1 to agree with standard conventions and eCRF 
o Moved visit windows from “Cumulative Visit Day” line to “Visit Day per Cycle.”  
“Cumulative Visit Day” to remain, but without windows. This will allow for better data 
management control if cycles are delayed to manage toxicity.  
o Cycle 2 cumulative visit days were corrected; there was computation error in the 
original issue. 
o On Study Follow-up:  Last Study Drug Administration +12, +45, and +90 days was 
changed to +14, +42, and +91 days, respectively, to be consistent with standard 
protocol format. 
o Free T3, Free T4, and TSH were separated from the rest of the chemistry panel, and 
assessment on Day 3 of each cycle was removed. Due to multiple visits during Week 1 
of each cycle, assessment on Day 1 was considered to be sufficient.  
o Footnote was added regarding the monitoring of vital signs during MEDI4736 
administration. 
o Serum collection was removed from PBMC sampling; plasma will be collected. 
o Footnote was added to indicate that “Screening/Baseline specimens for correlative 
assessments may be collected up to Cycle 1/Day1 prior to the PLD dose.” 
o “US sites only” was removed from Serametrix in the analysis of MDSC 
o For MEDI4736 PK, Cycle 1 Day 1 and Cycle 7 Day 1 post-infusion sample collection was 
added to Cycle 1 Day 3 and Cycle 7 Day 3 respectively in order to align with end of 
MEDI4736 IV dosing. Cycle 1 Day 1 and Cycle 7 Day 1 remained for the collection of pre-
dose samples. Footnote for post-infusion sample was updated 
o For tumor biopsy, ImmunoSeq was changed to TCR Sequencing. 
o The following note was added to the footnote for tumor biopsy: “Archival tissue will be 
requested for all subjects, preferably from primary tumor site prior to cancer 
treatment; however, archival tissue is not a requirement for study entry.” 
o Footnote was added to indicate that pregnancy tests are not required for subjects who 
are not of child-bearing potential as defined in Section 5.2, # 17. 
o Footnote regarding cumulative dose >550 mg / m2 – increasing Echo / MUGA frequency 
was removed because the maximum PLD exposure is 480 mg / m2 per protocol. 
o Clarification was provided to indicate that the second list of specimens in the flowchart 
are those for “Correlative Assessments.” 
o Footnote regarding pre-dose collections was clarified and/or added where applicable  
o Post Study Follow-up was clarified to indicate that frequency will be “Every 3 months 
for 3 years from initiation of treatment.” 
o Blood volume requirements were removed from the flowchart. These are included in 
the Informed Consent Form. 
o Administrative changes were made as needed for uniformity of layout and appearance 
o Two separate flowcharts were created to align with dosing schedule changes for all 
subjects except those in dose level 0a. The 2 flowcharts are labeled as follows:  


 
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1. Flowchart for subjects in dose level 0a cohort only – dosing schedule remained 
the same as prior to Amendment 1. 
2. Flowchart for all subjects except dose level 0a cohort: 
 
Deleted Day 17 dose of MEDI4736 for each cycle; dosing was changed 
from Q2W to Q4W 
 
Deleted Day 17 dose of motolimod from Cycles 4-12 
 
Deleted Day 17 study visit from Cycles 4-12 
 
Moved echocardiogram or MUGA assessment from Day 157 to 143; Day 
241 to 227; and Day 325 to 311. This was done to align with new dosing 
and visit schedules. 
11. Section 5.1: 
o #1, bullet 2: The following sentence was modified (changes in bold): “biologic therapy 
(e.g., bevacizumab) as part of their primary treatment regimen or as part of their 
treatment for management of recurrent or persistent disease.” 
o #4: The following note was added: Archival tissue will be requested for all subjects, 
preferably from primary tumor site prior to cancer treatment; however, archival tissue 
is not a requirement for study entry. 
o #6: inclusion criteria for AST/ALT was changed from ≤ 3.0 x ULN to ≤ 2.5 x ULN 
12. Section 5.2: 
o #5: Changed “Uncontrolled Hypertension, defined as systolic >150 mm Hg or diastolic 
>90 mm Hg” to “Resistant hypertension.” This was based on input from Investigators.  
o #7: deleted irritable bowel syndrome, as this is not an autoimmune disease. 
o #7: added “active” to Hashimoto’s thyroiditis. 
o #13: Changed “Participation” to “Prior treatment” in any other interventional clinical 
trial within 4 weeks prior to Day 1 of the study.”  
o #16: Note was added to indicate that Pregnancy tests are not required for subjects who 
are not of child-bearing potential as defined in Section 5.2, # 17 
o #17: Language for highly effective methods of contraception was updated based on 
current standards from MedImmune/AstraZeneca.  Definition of post-menopausal was 
updated. 
13. Section 5.3.1:  
o #2: added “or 5 half-lives (whichever is shorter)” to the wash-out period of 4 weeks. 
o Added #3, Live attenuated vaccines 1 month prior to Day 1 and for at least 6 months 
after the last dose of treatment. This statement was omitted in the original issue.  
14. Section 6.1:  The following note was added: “NOTE: The maximum body surface area and 
recalculations are recommendations; standard procedures for maximum body surface and 
recalculations at each site may be used.  Rationale: Sites have their own PLD dosing 
procedures, which would be difficult to modify for study purposes. 
15. Section 6.3.3:  
o Section 6.3.3.1 was identified as MEDI4736 dose preparation for dose level 0a. 
o Section 6.3.3.2 was added for MEDI4736 fixed dose preparation. 
16. Section 6.3.4:  
o Reference to Section 6.3.5 was added for monitoring MEDI4736 administration 
o Timing for the IV infusion was changed from 60 (± 10) to 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. 
(additions in bold; based on recommendations from MedImmune/AstraZeneca)   


 
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17. Section 6.3.5:  Monitoring of MEDI4736 Dose Administration was added to align vital sign 
safety measurements with other protocols using MEDI4736. 
18. Section 6.4: study drug requirements were updated based on study changes. 
19. Section 7.1.2: was updated according to current recommendations from 
MedImmune/AstraZeneca: 
o Defined additional expedited reporting requirements for study, specifically pregnancy, 
overdose, and hepatic function abnormality 
20. Section 7.1.5: Clarification was provided for recording of AEs during the On Study Follow-up 
based on clarifications provided in Sections 3.1.10 and 3.1.16.  
21. Section 7.1.6:   
o Additional detail and clarification were added regarding reporting of SAEs to the 
Sponsor within 24 hours. 
o Sponsor Contact information for reporting SAEs was added. 
22. Section 7.1.8:   
o Clarification was added regarding recording of AESIs. Expedited reporting by the 
Investigator to the Sponsor within 24 hours is not required. 
o Updated language in the entire section according to current recommendations from 
MedImmune/AstraZeneca. 
23. Section 7.3.4: The Subject’s “initials” was changed to “subject letter code.” The following 
was added: “The subject letter code does not necessarily have to correlate to the subject’s 
name.”  This change was required because a subject’s initials and date of birth are not 
allowed to appear together per Swiss Ethics Committee.  
24. Section 8.2.4: For PLD dose modifications for subjects with impaired hepatic function, the 
phrase “give 25% normal dose.” Was replaced with “give 25% normal dose, or proceed 
according to institutional standards.”   
25. Section 8.4.2: MEDI4736 Dose Modifications due to toxicity were updated according to 
current recommendations from MedImmune/AstraZeneca (Dated 02-OCT-2015). 
26. Section 8.4.3: MEDI4736 Dose Modifications not due to toxicities were added. 
27. Section 8.6.4: Two occurrences of irRC were corrected to irRECIST. 
28. Section 8.7.1: In the sentence: “T cell subsets will be assessed for activation/exhaustion by 
expression of PD-1…,” the first occurrence of PD-1 was changed to PD-L1. 
29. Section 8.7.6: Specific references to ImmunoSeq and Adaptive Biotechnologies were 
removed. 
30. Section 8.7.7: The following paragraph was removed: “Additionally, select pre- and post-
treatment plasma samples of interest will also be tested by a seromics approach for the 
autoantibodies directed against a panel of >9000 purified human proteins coated onto 
microarray slides (Invitrogen ProtoArrays).” Assay is no longer planned. 
31. Section 8.7.14 (mRNA and miRNA profiling) was added to coincide with the PaxRNA testing 
in the flowchart. 
32. Section 8.8 “ECOG PS Criteria” table was added. 
33. Section 8.9 “Abbreviations” table was added. 
 


 
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Amendment 2 
Issue Date: 05-OCT-2016 
Summary of Changes: 
 
1. All sections, as appropriate (i.e., Synopsis, Sections 1.3, 2.1, 3.1.2, 3.1.6, 3.1.7, 3.1.8, 3.1.9, 
3.1.14, 4.1.2, 4.2.2, 4.3.1, 5.2, 5.3.2, 6.2, 6.4, 7.1.8.1, and 8.3):  Notations or changes were 
made to indicate that motolimod dosing was discontinued PER Amendment 2.  
2. Section 2.1: the following paragraph was added to rationale for fixed dosing of MEDI4736:  
“This dosing of MEDI4736 is recommended only for subjects with > 30 kg body weight due 
to endotoxin exposure.  Subjects with a body weight ≤ 30 kg are not eligible for enrollment 
in the current study. 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.”  The Note 
was also added to Sections 3.1.7 and 6.3.3.2).  
3. Synopsis and Section 3.1.7: PLD was changed to pegylated liposomal doxorubicin. This was 
based on request from DFCI to ensure clarity. 
4. Synopsis page: Added signature line for Local sponsor in Switzerland 
5. Section 3.1.8:  the following statement was added: “If a toxicity occurs that requires toxicity 
management in accordance with the toxicity management guidelines referenced above, and 
the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative 
guideline should be followed.” The statement was also added to Sections 8.2, 8.3, and 8.4. 
6. Section 3.1.10: for the list of reasons for a subject to be withdrawn from the study, reason 
#2 was changed as follows (changes in bold): “Initiation of alternative anti-cancer therapy 
including marketed or another investigational agent.”  
7. Added Section 3.1.0.1: Treatment beyond Progression 
8. Section 3.1.11: The following was changed FROM:  “Phase 1: Subjects are fully evaluable for 
DLT if 1) they experienced a DLT as per Section 3.1.9, or 2) in the absence of a DLT, they 
fulfill the criteria for the Per-Protocol Population as per Section 4.2.2.”  TO: “Phase 1: 
Subjects are fully evaluable for DLT if they fulfill the criteria for the Per-Protocol Population 
for DLT Assessment as defined in Section 4.2.2.” 
9. Section 3.1.13: Changed FROM: “No formal interim analyses will be performed, except for 
the cohort safety assessments for DLTs in Phase 1 (see Section 3.1.7)” TO: “Interim safety 
reviews will be performed to assess DLTs in Phase 1 (see Section 3.1.7).  Interim analyses 
may be performed to analyze the endpoints of progression free survival at 6 and 12 months 
and/or as specified in the statistical analysis plan. 
10. Section 3.1.15: Duration of On Study Follow-up was added. 
11. Section 3.1.16:  
o Paragraph 3 was changed FROM: “If the determination is made to remove a subject 
from treatment at a visit that coincides with the first visit of the On Study Follow-up 
Period (which is 14 days after the last dose of study treatment), any assessments 
required in the 14 day 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 14 day post-last treatment visit should not be repeated.”  TO: “If the 
determination is made to remove a subject from treatment at a visit that coincides with 


 
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the first visit of the On Study Follow-up Period, any assessments required in the first On 
Study Follow-up 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 last on-
treatment visit and the first On Study Follow-up visit should not be repeated.” 
o The following statement 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.” 
o Section 3.1.16.1, End of Study Visit, was added. 
12. Section 3.2, Flowchart: 
o Motolimod dosing was removed 
o Study visits that were specific only to motolimod were removed: (1) for Cohort 0a, Day 
10 for Cycles 1 to 3 were deleted; (2) for all other cohorts, Days 10 and 17 for Cycles 1 to 
3 were deleted.  PBMC collection on Cycle 1/Day 10 was also deleted. 
o HumanMAP® and TruCulture™ specimen collections were deleted, as these were 
specific for motolimod. 
o ECOG Perf Status was deleted as a single assessment at baseline and added to Physical 
Exam assessments 
o Deleted “and Pre-existing symptoms” from the Medical history line. 
o Added amylase and lipase assessments, as these are required for monitoring 
pancreatitis. 
o Deleted the following assessments: MEDI4736 PK, MEDI4736 ADA, sPD-L1, circulating 
soluble factors. Medimmune has determined that they have adequate data and samples 
are no longer needed. 
o Footnote a: added “Note: It is strongly recommended that hematology, chemistry and 
pregnancy test (when applicable) results are reviewed before dosing.” 
o Footnote b: added “before” to assessment of vital signs 
o Added Footnote h: “See Section 3.1.16 regarding assessments scheduled for both the 
last on treatment visit and the first post-last treatment visit.”  
o Echo/MUGA assessment: deleted assessment at Cycle 12/Day17 for Cohort 0A and 
Cycle 12/Day3 for all other subjects. Rationale: Only one echo/MUGA is needed after 
the last dose of PLD at cycle 12.  This will be covered at the on study follow-up visit. 
o Moved echo/MUGA assessment from Day 73 to Day 87 for all subjects except those in 
Cohort 0a. This was done to align with visit schedule after removal of motolimod. 
o Added Footnote i: “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 Footnote J: “See section 7.1.5 for details regarding collection of AEs for 90 days 
after last study drug administration.” 
o Footnote c was added to Pharmacogenomics and changed to: “An aliquot of the PBMC 
and or Tumor Biopsy/Archival Tissue will be used for pharmacogenomics – a separate 
sampling is not needed.” 
o Footnote d (which was related to motolimod) was deleted and Footnote J was re-
numbered as Footnote d  
o Changed Post Study Follow-up FROM: “Every 3 months for 3 years from initiation of 
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directed AE assessment for new onset or worsening of pre-existing autoimmune 
disease.”  TO: “Every 3 months for 3 years from initiation of treatment. Clinical 
outcomes data (dates of progression/relapse and survival) will be recorded (See Section 
3.1.16).  The new language is in agreement with Section 3.1.16 and other ongoing 
studies. 
o In the Study Flowchart for non-Cohort 0a Subjects, On Study Follow-up Intervals were 
changed from +14 to +28 days and from +42 to +56 days to align with the Q4W dosing 
intervals of the study. 
o MDSC: it was clarified that MDSC will be collected at US sites only (logistical reasons). 
o Disease assessment during On Study Follow-up was changed from a specific study visit 
to “'+84 ± 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. 
13. Section 4.1.1.1: the following sentence was added: “PFS rate at 6 months will be based on 
disease assessments at the scheduled visit at the start of Cycle 7.” 
14. Section 4.2.2: The following was changed FROM: “The Per-Protocol (PP) Population for 
safety and tolerability is defined as all subjects who received at least 75% of the scheduled 
doses of MEDI4736, motolimod, and PLD over the first 2 cycles, as well as respective safety 
assessments, without major protocol violations over the entire DLT Evaluation Period (as 
defined in Section 3.1.9).  The Intent-To-Treat (ITT) Population for safety and tolerability is 
defined as all subjects who receive at least one dose of PLD, motolimod or MEDI4736. In 
Phase 1, for the primary endpoint of determining DLTs and the MTD, the analysis of safety 
and tolerability will be based on the PP Population.  In both Phases 1 and 2, the overall 
analysis of safety and tolerability will be based on the ITT Population.” TO: “The Per-Protocol 
(PP) Population for DLT Assessment includes:  
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) 
• 
 All subjects with no DLT who receive at least 75% of the scheduled doses of MEDI4736, 
motolimod, and PLD as well as respective safety assessments, without major protocol 
violations, over the entire DLT Evaluation Period (as defined in Section 3.1.9).   
Refer to Section 3.1.11 for subject replacements. The Intent-To-Treat (ITT) Population for 
safety and tolerability is defined as all subjects who receive at least one dose of PLD, 
motolimod or MEDI4736. In Phase 1, for the primary endpoint of determining DLTs and the 
MTD, the analysis of safety and tolerability will be based on the PP Population for DLT 
Assessment. In both Phases 1 and 2, the overall analysis of safety and tolerability will be 
based on the ITT Population for safety and tolerability. 
15. Section 4.3: “Baseline Immune Responsiveness to TLR8 activation” was removed from the 
list of analyses. 
16. Section 5: the following statement 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.” 
17. Section 5.1:  
o Inclusion criterion 1, bullet 1 was changed as follows (changes in bold):  “one additional 
cytotoxic regimen and/or PARP inhibitor for management of recurrent or persistent 
disease.   
o Inclusion criterion #4: added “see Section 3.2 for biopsy time points” 


 
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o Added “Body weight > 30 kg” 
18. Section 5.2: 
o  #17: the definition of post-menopausal was expanded; updated language for highly 
effective methods of contraception 
o Added “History of allogenic organ transplant” 
o Added blood donor restriction 
19. Section 5.3.2: For the last sentence, the following change was made (change in bold): All 
non-drug therapies must be recorded in the respective sections of the case report form or 
as Adverse Events. 
20. Section 6.2.2: Added stability for motolimod (changes in bold): “Prior to administration, 
motolimod must be reconstituted using sterile water for injection, USP.  Reconstituted 
stock solutions are stable for 8 hours at room temperature and for 24 hours when 
refrigerated at 2–8°C.” 
21. Section 6.3: the option of using dextrose instead of saline as diluent for MEDI4736 was 
added. 
22. Section 6.3.3.2: for fixed dose of MEDI4736, the following statement replaced “regardless of 
weight”:  “Subjects will receive a fixed dose of MEDI4736: 1500 mg Q4W 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.” 
23. Section 7.1.2: Paragraph 1 was changed FROM: “For the purpose of this study, the following 
events are considered medically important conditions and must be reported in an expedited 
manner (See Section 7.1.6 for Sponsor contact information):” TO: “For the purpose of this 
study, the following events must be reported by phone or email to the Sponsor within 24 
hours of knowledge of the event (See Section 7.1.6 for Sponsor contact information) and 
may result in submission of an SAE based on certain criteria outlined below:” 
24. Section 7.1.2.1.1: the following statement was added: “Female subjects should avoid 
becoming pregnant and breastfeeding during the study and for 90 days after the last dose of 
study drug (see Section 5.2, #17).” 
25. Section 7.1.5: Text 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 
(see Section 3.1.16 for definition of On Study Follow-up) 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.   During the On Study Follow-up period, all AEs must be documented 
for 90 days after the last dose of study drug for subjects who complete the study as well as 
those subjects who discontinue study treatment prematurely (see Section 3.1.10 for 
subjects who begin other anti-cancer treatment).” 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 
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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).” 
26. Section 7.1.6: added the following statement: “Serious adverse event reporting to 
AstraZeneca/Medimmune is described in separate agreement.” 
27. Section 7.2.2: The following statement was added: “All subjects who sign an informed 
consent form, regardless of study procedures performed, will be assigned a screening 
number and have their data entered into the eCRF.” 
28. Section 8.4.1:  
o The statement, which referenced guidelines for ipilimumab, nivolumab, and 
pembrolizumab was deleted.  
o The title of the Medimmune Guideline for Toxicity Management for MEDI4736 was 
inserted. 
29. Section 8.4.2: MEDI4736 dose modifications were updated according to the 19Aug2016 
version of the AZ/Medimmune guidelines. Section 8.4.2.3 was changed as follows: 
o Grade 3 was separated from Grade 2 modifications 
o Grade 3 modifications were added:  "Hold MEDI4736. If AEs downgrade to ≤ Grade 2 
within 7 days or resolve to ≤ Grade 1 or baseline within 14 days, resume MEDI4736 
administration at next scheduled dose. Otherwise, discontinue MEDI4736 
permanently.” 
30. Section 8.4.3: 
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.”  
31. Section 8.7: the following Note was added to the following assessments: 
o Section 8.7.4: “NOTE: PER Amendment 2, samples will no longer be collected for 
analysis of TruCultureTM, as the analyses were related to motolimod dosing. The 
collection time points for these assays have been removed from the flowchart in 
Section 3.2.” 
o Section 8.7.7: “NOTE: PER Amendment 2, samples will no longer be collected for 
analysis of HumanMap®. The collection time points for these assays have been removed 
from the flowchart in Section 3.2.” 
o Section 8.7.10: “NOTE: PER Amendment 2, samples will no longer be collected for 
analysis of MEDI4736 PK and immunogenicity for 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.” 
o Section 8.7.11: “NOTE: PER Amendment 2, 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.” 
o Section 8.7.12: “NOTE: PER Amendment 2, 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.” 
32. Sections 8.7.1, 8.7.3, 8.7.4, and 8.7.7: clarification was provided to indicate that collection of 
samples will be done according to the flowchart in Section 3.2. 


 
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33. Section 8.7.6: the following clarification was added: “PBMCs will be assayed from 3 time 
points, which will be matched as closely as possible to the tumor biopsies (baseline, Cycle 2 
Day 1 and the PBMC collection closest to disease progression).” 
34. Section 8.7.8: The following statement was added: “An aliquot of the PBMC collection 
and/or tumor biopsy/archival tissue will be used for pharmacogenomics.” The sentence 
“DNA will be isolated from whole blood” was deleted.  
35. Sections 8.7.4, 8.7.5, 8.7.7, and 8.7.8: “shipped to” was changed to “analyzed by” 
36. Administrative:  
o Spelling, grammar and typographical errors were corrected.  
o Formatting/administrative changes were implemented, as applicable. 
o Monitor and Study Monitor were standardized as “Clinical Monitor”  
o Study Physician was changed to Medical Monitor in Section 7.1.8 
 
Amendment 3 
Issue Date: 05-DEC -2016 
Summary of Changes: 
1. Synopsis: The following statement was added: “Per Amendment 3, optional MEDI4736 
treatment extension beyond the initial 12-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 for up to 12 additional cycles upon 
agreement with subject, Sponsor and Investigator.  See Section 8.9 for details.” 
2. Section 3.1.12, Optional Study Treatment Extension: This section was changed FROM: 
”Treatment extension beyond 12 cycles is not planned” TO: “Optional MEDI4736 treatment 
extension beyond the initial 12-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 for up to 12 additional cycles upon agreement with subject, 
Sponsor and Investigator.  See Section 8.9 for details.” 
3. Section 3.1.15, Duration of Study:  For Duration of Treatment, the following statement was 
added: “See Section 3.1.12 for optional treatment extension.” 
4. Section 3.1.16, On Study and Post Study Follow-up: The following statement was added: 
”See Section 3.1.12 for optional study treatment extension.” 
5. Section 3.1.16.1, End of Study Visit: The last sentence of paragraph 1 was clarified (changes 
in bold): “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.” 
6. Section 3.2, Flowchart: 
a. For last On Study Follow-up visit, changed from 91 to 90 days to allow consistency with 
protocol text. 
b. Added Physical exam to On Study Follow-up visits 
c. Added Concomitant meds collection to On Study Follow-up visits 2 and 3. 
d. Added pregnancy test to last On Study Follow-up visit 
7. Section 6.3.3, MEDI4736 Prep: The following sentence was updated based on feedback from 
Medimmune (changes in bold): “No incompatibilities between MEDI4736 and polyethylene, 
polypropylene, polyvinylchloride, or polyolefin copolymers have been observed. 


 
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8. Section 6.3.3.1, MEDI4736 Prep for Cohort 0a: the following statement was added: “Per 
Amendment 3, fixed dosing will be used for the optional study treatment extension as 
described in Section 3.1.12 and Section 8.9.  See Section 6.3.3.2.” 
9. Section 6.3.3.2, MEDI4736 Prep for all other cohorts: The following statement was added: 
“Per Amendment 3, fixed dosing will be used for all subjects who proceed with the 
optional study treatment extension as described in Section 3.1.12 and Section 8.9. 
10. Section 6.3.4, MEDI4736 administration: The following changes were made based on 
feedback from Medimmune (changes in bold): 
a. “Investigational product(s) must be administered at room temperature by controlled 
infusion via an infusion pump into a peripheral vein or central line.” 
b. “Since the compatibility of MEDI4736 with other IV medications and solutions, other 
than normal saline (0.9% [w/v] Sodium Chloride for Injection) or dextrose, is not 
known, the MEDI4736 solution should not be infused with through an IV line in which 
other solutions or medications. are being administered.” 
c. “The total time between needle puncture of the MEDI4736 vial to start of 
administration should not exceed 4 hours at room temperature, or 24 hours at 2°C to 
8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes.  However, if there are 
interruptions during infusion (total infusion time not to exceed 4 hours), the total 
allowed time 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.  If MEDI4736 administration has to be delayed, temporally 
interrupted or the infusion rate decreased, or if administration time exceeds these 
limits, a new dose must be prepared from new vials.” 
d. Added “See Section 8.4.2.2 for management guidelines for infusion-related reactions.” 
11. Section 6.4, Drug Requirements: Additional MEDI4736 requirements for optional study 
treatment extension were added. 
12. Section 7.1.8, AESIs: additional details were added for AESIs to correspond with current 
Medimmune/AZ guidelines. 
13. Section 8.4.2.2, Infusion-related reactions: The following clarification was added to Grades 1 
and 2: “total infusion time not to exceed 4 hours” 
14. Section 8.4.3, MEDI4736 Dose Modifications not due to Toxicities: The rules were clarified 
by changing FROM:  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: 
1. The originally planned visit/treatment schedule should be maintained in general, 
i.e., dosing interruptions should not reset the original treatment schedule. 
Exceptions may be made only for individual dosing days, whereby the interval 
between any two doses shall be no less than 21 days (for subjects on Q2W 
dosing, the interval shall be no less than 10 days). All resulting protocol 
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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. 
15. Section 8.9 was added to provide additional details and flowchart for subjects who receive 
optional MEDI4736 treatment extension according to Section 3.1.12.   
16. Administrative:  Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 4 
Issue Date: 08-SEP-2017 
Summary of Changes: 
1. The duration of the treatment extension beyond the Core Study for MEDI4736 was changed 
from 12 cycles to “until confirmed disease progression.”   
a. This change was implemented in the Synopsis and in Sections 3.1.12 and 8.9. Language 
was changed as follows (changes in bold): “Optional MEDI4736 treatment extension 
beyond the initial 12-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 for up to 12 additional cycles upon agreement with subject, 
Sponsor and Investigator, and it may continue until confirmed disease progression, 
unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met. See Section 8.9 for details regarding treatment 
extension and collection/reporting of adverse events during this period”   
b. The header and footnote 2 for the flowchart in Section 8.9.1 were also modified to 
reflect this change. 
c. The following procedure point was added to Section 8.9:  “AE/SAE collection and 
reporting will be performed according to the protocol requirements (Section 7.1) and 
until disease progression is documented.  For AEs/SAEs that may be ongoing at the time 
of disease progression, follow-up will be performed until resolution or stabilization of 
the events or up to 90 days after the last dose of MEDI4736.” 
2. Per current Medimmune recommendations, the language was updated for MEDI4736 
dosing of subjects whose body weight drops to ≤ 30 kg while on the study; in these cases, 
MEDI4736 dose will be weight based.  Previously a fixed dose of 600 mg was recommended 
for ≤ 30 kg. This change was made in the Synopsis and in Sections 2.1, 3.1.7, 6.3.3.2, and 8.9. 
The following clarification was added in Sections 6.3.3.2 and 8.9: “If a subject’s body weight 
drops to ≤ 30 kg while on the study, the subject will receive weight-based dosing equivalent 
to 20 mg/kg of MEDI4736 as long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject 
would receive a 600 mg dose; a 25 kg subject would receive a 500 mg dose; etc.).  When the 
weight improves to >30 kg, the subject may return to fixed dosing of MEDI4736 1500 mg.” 
3. Section 5.2: the following change was made to exclusion criterion #17 (changes in bold): “ 
Female subjects of childbearing potential who are sexually active with a nonsterilized male 
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from screening, and must agree to continue using such precautions for 90 days after the 
final dose of investigational product (MEDI4736).”  
The following note was added: “NOTE: For the standard of care, pegylated liposomal 
doxorubicin (PLD, Doxil®, Caelyx®), the package insert advises females of reproductive 
potential to use effective contraception during and for 6 months after last treatment with 
the drug.  Therefore, all subjects of childbearing potential on this study should continue 
contraception use for 6 months after the last PLD administration.” 
4. Sections 6.3 (MEDI4736)- subsections for MEDI4736 information, preparation and 
administration were clarified and/or reorganized per current Medimmune 
recommendations and to maintain consistency with current protocols.  The following 
statement was updated (changes in bold):   
“The total time between needle puncture of the MEDI4736 vial to start of administration 
should not exceed 4 hours at room temperature, or 24 hours at 2°C to 8°C (36°F to 46°F).  
Standard infusion time is 60 ± 5 minutes.  However, if there are interruptions during infusion 
(total infusion time not to exceed 4 hours), the total allowed infusion time 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.” 
5. Section 7.1.8 (AESIs): section was updated per current Medimmune recommendations. 
Diabetes insipidus and Type 1 diabetes mellitus were added to endocrine disorders.  The 
following bullet was added:  
• 
Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis. 
6. Section 8.4.2 (MEDI4736 Dose Modifications due to toxicities) 
a. Added myocarditis to Pneumonitis/ILD bullet In Grades 1, 2, and 3 per current 
recommendations.  
b. For Infusion-related reactions Grades 1 and 2, the phrase “total infusion time not to 
exceed 4 hours.” was deleted per current Medimmune guidelines. 
7. Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
8. US Study Chair’s affiliation was changed from University of Arizona College of Medicine at St 
Joseph’s Hospital to Arizona Oncology. 
 
 


 
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8.2 Pegylated Liposomal Doxorubicin (PLD) Dose Delays and 
Adjustments 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.2, 8.3, or 8.4, 
and the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
Please refer to the package insert/product information for pegylated liposomal doxorubicin (PLD) 
for current instructions on dose delays and adjustments. 
Subjects should be carefully monitored for toxicity.  Adverse reactions, such as HFS, hematologic 
toxicities, and stomatitis may be managed by dose delays and adjustments.  Following the first 
appearance of a Grade 2 or higher adverse reactions, the dosing should be adjusted or delayed as 
described in the following tables.  Once the dose has been reduced, it should not be increased at 
a later time. 
In the event of a delay in PLD dosing due to drug-related toxicity, doses of MEDI4736 and 
motolimod should also be delayed, as per Section 3.1.8. 
As the standard of care agent, PLD is administered every 28 days.  Every effort should be made to 
adhere to this schedule.  Delays due to motolimod and/or MEDI4736 should not delay or shift the 
timing of PLD dosing. 
8.2.1 Hematological Toxicity 
Grade 
ANC 
Platelets 
Modification 
1 
1,500 – 1,900 
75,000 – 150,000 
Resume treatment with no dose reduction. 
2 
1,000 – <1,500 
50,000 – <75,000 
Wait until ANC ≥1,500 and platelets ≥75,000; 
redose with no dose reduction. 
3 
500 – 999 
25,000 – <50,000 
Wait until ANC ≥1,500 and platelets ≥75,000; 
redose with no dose reduction. 
4 
<500 
<25,000 
Wait until ANC ≥1,500 and platelets ≥75,000; 
redose at 25% dose reduction or continue full dose 
with cytokine support. 
 
8.2.2 Hand Foot Syndrome (HFS) 
HFS Toxicity Grade 
Dose Adjustment 
1 
(mild erythema, swelling, or 
desquamation not interfering with 
daily activities) 
Redose unless subject has experienced previous Grade 3 or 4 HFS. 
If so, delay up to 2 weeks and decrease dose by 25%.  Return to 
original dose interval. 
2 
(erythema, desquamation, or 
swelling interfering with, but not 
precluding normal physical 
activities; small blisters or 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
If resolved to Grade 0-1 within 2 weeks, and there are no prior 
Grade 3-4 HFS, continue treatment at previous dose and return to 
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ulcerations less than 2 cm in 
diameter) 
If subject experienced previous Grade 3-4 toxicity, continue 
treatment with a 25% dose reduction and return to original dose 
interval. 
3 
(blistering, ulceration, or swelling 
interfering with walking or normal 
daily activities; cannot wear 
regular clothing) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to original dose interval. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
4 
(diffuse or local process causing 
infectious complications, or a 
bedridden state or hospitalization) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to original dose interval. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
 
8.2.3 Stomatitis 
Stomatitis Toxicity Grade 
Dose Adjustment 
1 
(painless ulcers, erythema, or mild 
soreness) 
Redose unless subject experienced previous Grade 3 or 4 toxicity. 
If so, delay up to 2 weeks and decrease dose by 25%.  Return to 
original dose interval. 
2 
(painful erythema, edema, or 
ulcers, but can eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
If resolved to Grade 0-1 within 2 weeks and there was no prior 
Grade 3-4 stomatitis, continue treatment at previous dose and 
return to original dose interval. 
If subject experienced previous Grade 3-4 toxicity, continue 
treatment with a 25% dose reduction and return to original dose 
interval. 
3 
(painful erythema, edema, or 
ulcers, and cannot eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to original dose interval. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
4 
(requires parenteral or enteral 
support) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. 
Decrease dose by 25% and return to PLD original dose interval. 
If after 2 weeks there is no resolution, PLD should be discontinued. 
 
8.2.4 Subjects with Impaired Hepatic Function 
Limited clinical experience exists in treating subjects with hepatic impairment with PLD.  Based on 
experience with doxorubicin HCl, it is recommended that the PLD dosage be reduced if the bilirubin 
is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give 50% normal dose; serum bilirubin >3 
mg/dL - give 25% normal dose, or proceed according to institutional standards. 


 
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8.3 Motolimod Toxicity Management and Dose Adjustments 
PER Amendment 2, motolimod dosing will be discontinued for all subjects. 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.2, 8.3, or 8.4, 
and the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
8.3.1 Management of Injection Site Reactions  
Acute symptoms of injection site reactions typically resolve within 48 hours of injection, but more 
persistent reactions are not unexpected.  Grade 2 and 3 reactions may include a painful, raised, 
fluid-filled blister that mimics a sterile abscess.  Injection site reactions do not typically warrant 
antibiotic intervention as they have been found to be sterile.  A culture of the fluid can be 
obtained—using sterile technique—if infection is strongly suspected (i.e., associated with fever 
persisting more than 24 hours after injection). 
Ice and acetaminophen should be administered prophylactically.  Symptomatic treatment with 
ice, acetaminophen and narcotics is acceptable.  Due to their potentially suppressive effects, the 
use of NSAIDs within 24 hours of dosing with motolimod should be avoided, if clinically feasible. 
8.3.2 Management of Systemic Toxicities 
The most common systemic drug-related adverse events—Grade 1 or 2 chills, flu-like symptoms 
and fever—typically resolve in < 48 hours and do not require dose reductions or a delay in the 
dosing regimen.  Less commonly, dosing with motolimod may result in cytokine release 
syndrome (CRS), which is most likely to be grade 1 or 2, but more severe reactions have been 
reported. 
CRS is a symptom complex and is characterized by systemic symptoms which may include fever, 
nausea, chills, tachycardia, hypotension, dyspnea, asthenia, headache, and rash.  Motolimod 
directly targets TLR8, which is expressed on immune cells.  CRS may result from the release of 
cytokines from the activated immune cells, or from ‘downstream’ events that can be associated 
with cytokine production.  Symptoms of CRS may be acute or delayed by several hours after 
dosing with motolimod. 
Treatment of systemic drug-related events should be consistent with the severity of the reaction 
as well as institutional standards and may include: acetaminophen, H1- and H2-receptor 
antagonists, narcotics, IV fluids for volume expansion, and supplemental oxygen.  Due to their 
potentially immunosuppressive effect, administration of NSAIDs and systemic steroids (e.g., 
dexamethasone) should be avoided if other means of treatment are available and medically 
appropriate. 
In most cases the CRS will be Grade 1 or 2.  However, a severe, life-threatening reaction resulting 
from a substantial release of cytokines is possible.  Severe CRS is a medical emergency and urgent 
intervention must be taken to prevent life-threatening complications.  This may include 
administration of sympathomimetic amines for pressor support and/or hospitalization for acute 
monitoring and intervention. 


 
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8.3.3 Motolimod Dose Modifications due to Toxicities 
Motolimod will be dosed as defined in Section 3.1.7.  Any dose reductions that become necessary 
due to the toxicities outlined below, should be done in steps of 1 level of 0.5 mg/m2, down to a 
minimum dose of 1.5 mg/m2.  If 1.5 mg/m2 is not tolerated, motolimod should be discontinued.  
Delays in motolimod dosing should not delay or shift the timing of other treatment agents.  In the 
event of Grade 3 or 4 toxicities attributed to motolimod, subsequent doses should be delayed 
until recovery to ≤ Grade 1. 
8.3.3.1 Cytokine Release Syndrome 
Grade 1 
Dose reduction not required; consider prophylactic precautions—including volume 
expansion and treatment with oral or IV antihistamines—with next dose. 
Grade 2 
Reduce dose by 1 level at investigator’s discretion; consider prophylactic precautions—
including volume expansion and treatment with oral or IV antihistamines—with next dose. 
Grade 3-4 
Reduce dose by 1 level; use prophylactic precautions with next dose. 
 
8.3.3.2 Injection Site Reaction 
Grade 1 
Dose reduction not required; consider administering subsequent injections at distal 
anatomic site(s). 
Grade 2 
Delay dosing for up to 2 weeks if needed; administer subsequent injections at distal 
anatomic site(s) until resolved to ≤ grade 1. 
Reduce dose by 1 level if > 2 weeks delay or > 2 delays are required with consecutive 
injections. 
Grade 3-4 
Reduce dose by 1 level; delay dosing until resolved to ≤ grade 1. 
 
8.3.3.3 Non-Hematologic Drug-Related AEs 
Grade 1–2 Dose reduction not required; manage per institutional standards. 
Grade 3-4 
Reduce dose by 1 level. 
 
8.3.3.4 Hematologic Drug-Related AEs 
Grade 1–3 Dose reduction not required; manage per institutional standards. 
Grade 4 
Reduce dose by 1 level. 
 


 
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8.4 MEDI4736 Toxicity Management and Dose Adjustments 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.2, 8.3, or 8.4, 
and the toxicity causing drug can be clearly identified, then the respective guideline should be 
followed. If the toxicity causing drug cannot be identified, then the more conservative guideline 
should be followed. 
8.4.1 Management of MEDI4736-related Toxicities 
Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, 
Immune-related Adverse Events (irAE) may be observed during the conduct of this study.  IrAEs 
are defined as AEs of immune nature (i.e., inflammatory) in the absence of a clear alternative 
etiology.  Subjects should be monitored for signs and symptoms of irAEs. 
Potential irAEs with MEDI4736 are expected to be similar to those seen with other immune 
checkpoint inhibitors, and may include immune-mediated enterocolitis, pneumonitis, dermatitis, 
hepatotoxicity or hepatitis, endocrinopathy, neurotoxicity and uveitis. 
It is recommended that management of irAEs follow the Medimmune Guideline for Toxicity 
Management for MEDI4736 [“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)”] and the current MEDI4736 Investigator’s Brochure.  
In general, the following is recommended: 
1. Subjects should be evaluated to identify any alternative etiology. 
2. In the absence of clear alternative etiology, all events of an inflammatory nature 
should be considered to be immune-related. 
3. Symptomatic and topical therapy should be considered for low-grade events. 
4. Systemic corticosteroids should be considered for a persistent low-grade event or for 
a severe event. 
5. More potent immunosuppressive therapies should be considered for events not 
responding to systemic steroids (e.g., infliximab, mycophenolate, etc.). 
8.4.2 MEDI4736 Dose Modifications due to Toxicities 
MEDI4736 may have to be modified or discontinued due to toxicities.  Dose modifications will not 
be required for AEs that are clearly not attributed to MEDI4736 (such as an accident) or for 
laboratory abnormalities that are not deemed to be clinically significant.  Delays in MEDI4736 
dosing should not delay or shift the timing of other study drugs. 
Note: If MEDI4736 dosing is held temporarily until resolution of the event as per instructions 
below, treatment should resume at the next scheduled treatment date (and not at the date of 
resolution).   


 
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8.4.2.1 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 MEDI4736 depicted below, 
permanently discontinue MEDI4736 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 and myocarditis, consider holding MEDI4736 
dosing as clinically appropriate and during diagnostic work-up for other etiologies. 
Grade 2 
• 
In general, hold MEDI4736 until resolution to ≤ Grade 1 and after the end of any steroid 
taper, and discontinue MEDI4736 permanently if such resolution does not occur within 60 
days (30 days for neurotoxicities).  Criteria for temporary hold or permanent 
discontinuation of MEDI4736 may differ by event as detailed below. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate 
MEDI4736 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 MEDI4736 permanently if there 
are signs of respiratory insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism, follow general instructions 
above, but subjects may be retreated if the endocrinopathy is controlled and the subject 
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 MEDI4736 is at the discretion of the 
Investigator. 
• 
For elevated creatinine or rash, MEDI4736 should be held until resolution to ≤ Grade 1 or 
baseline. 
• 
For vitiligo, no dose modification required. 


 
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Grade 3 
• 
In general, hold MEDI4736 until resolution to ≤ Grade 1, and after the end of any steroid 
taper, and discontinue MEDI4736 permanently if such resolution does not occur within 60 
days (30 days for neurotoxicities and rash).  Criteria for permanent discontinuation of 
MEDI4736 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, myocarditis and elevated 
serum creatinine (e.g., nephritis or renal dysfunction), always discontinue MEDI4736 
permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold MEDI4736, and if complete 
work up shows no evidence of pancreatitis, MEDI4736 may be continued.  
• 
For hepatitis, discontinue MEDI4736 permanently for (1) transaminases or bilirubin not 
resolving to ≤ Grade 1 or baseline within 14 days, (2) transaminases > 8 × 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, MEDI4736 should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue MEDI4736 permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold MEDI4736, and if complete 
work up shows no evidence of pancreatitis, MEDI4736 may be continued. 
 
8.4.2.2 Infusion-related Reactions 
Grade 1 
• 
The infusion rate of MEDI4736 may be decreased 50% or temporarily interrupted until 
resolution of the event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at 
the discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion reactions 
Grade 2 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion 
rate. 
Grade 3-4 
• 
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). 
 


 
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8.4.2.3 All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2 
• 
Hold MEDI4736 until resolution to ≤ Grade 1 or baseline, and discontinue MEDI4736 
permanently if such resolution does not occur within 60 days. 
Grade 3 
• 
Hold MEDI4736. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or 
baseline within 14 days, resume MEDI4736 administration at next scheduled dose. 
Otherwise, discontinue MEDI4736permanently. 
Grade 4 
• 
In general, discontinue MEDI4736 permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment and in consultation with the 
Sponsor. 
8.4.3 MEDI4736 Dose Modifications Not Due to Toxicities 
MEDI4736 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 (after consultation with the Medical Monitor, if necessary): 
1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may be 
made only for individual dosing days, whereby the interval between any two doses 
shall be no less than 21 days (for subjects on Q2W dosing, the interval shall be no 
less than 10 days). All resulting protocol deviations should be documented. 
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned dose 
should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary. 
4. If the dosing interruption is greater than half the planned dosing interval, the dose should 
be skipped and the next dose(s) should be adjusted in accordance with #1, if necessary. 
 


 
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8.5 RECIST 1.1 Guidelines  
This section outlines the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) as published (53) and as summarized by NCI for CTEP-involved clinical trials.  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
8.5.1 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 


 
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Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.  
8.5.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   


 
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Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a subject to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published.(54-56)  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.(57) 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  


 
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However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
8.5.3 Response Criteria 
8.5.3.1 Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
8.5.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.   
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
8.5.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


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


 
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8.6 irRECIST Guidelines  
Determination of response via irRECIST should take into consideration all target and non-target 
lesions.  
A key distinction between standard RECIST 1.1 criteria and immune-related response criteria is 
that irRECIST requires early evidence of progressive disease (i.e., a determination of irPD ≤ 12 
weeks after starting study treatment) be confirmed by repeat, consecutive imaging ≥ 4 weeks 
after the initial documentation in the absence of rapid clinical deterioration.  During this interim 
≥ 4 week period, subjects should continue to be followed per protocol, including continued 
dosing of the study drug(s). 
8.6.1 Response in Measurable Lesions 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment (TA), the SumD 
of the target lesions and of new, measurable lesions (≥ 10 mm [lymph nodes ≥ 15 mm in shortest 
diameter]; up to 2 new lesions per organ, total 5 new lesions) are added together to provide the 
total measurable tumor burden (TMTB): 
TMTB = SumD target lesions + SumD new, measurable lesions. 
Percentage changes in TMTB per assessment time-point describe the size and growth kinetics of 
both old and new, measurable lesions as they appear.  At each TA, the response in target and 
new, measurable lesions is defined based on the change in TMTB (after ruling out irPD) as 
follows: 
Complete Response (irCR) 
Complete disappearance of all target and new, measurable 
lesions, with the exceptions of lymph nodes which must 
decrease to < 10 mm in short axis. 
Partial Response (irPR) 
Decrease in TMTB ≥ 30% relative to baseline. 
Stable Disease (irSD) 
Not meeting criteria for irCR or irPR, in absence of irPD. 
Progressive Disease (irPD) 
Increase in TMTB ≥ 20% relative to nadir. 
 
8.6.2 Response in Non-measurable Lesions 
At each TA, the presence of any new, non-measurable lesions is assessed.  The presence of such 
lesions will rule out an overall response of irCR.  An increase in the size or number of new, non-
measurable lesions does not necessarily imply an overall response of irPD; if these lesions 


 
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become measurable (≥ 10 mm) at a subsequent TA, their measurement will at that point start to 
contribute to the TMTB.  In addition, the response in non-target lesions is defined as follows: 
Complete Response (irCR) 
Complete disappearance of all non-target lesions. 
Stable Disease (irSD) 
Non-target lesions are stable. 
Progressive Disease (irPD) 
Unequivocal increases in number or size of non-target lesions. 
To achieve unequivocal progression of non-target lesions, there 
must be an overall level of substantial worsening of non-target 
disease that is of a magnitude that the treating physician would 
feel it is important to change therapy.* 
*NOTE: Equivocal findings of progression of non-target lesions (e.g., small and uncertain new lesions; 
cystic changes or necrosis in existing lesions) should be considered irSD, and treatment may continue until 
the next scheduled assessment. 
8.6.3 Evaluation of Biomarkers 
Serum CA-125 must be within normal limits for a subject to be considered in complete clinical 
response. 
8.6.4 Overall Response 
The OR according to the irRECIST is derived from the responses in measurable lesions (based on 
TMTB) as well as the presence of any non-measurable lesions as follows: 
Complete Response (irCR) 
Complete disappearance of all lesions (whether measurable or 
not); lymph nodes must decrease to < 10 mm in shortest 
dimension.  Serum CA-125 within normal limits. 
Partial Response (irPR) 
Decrease in TMTB ≥ 30% relative to baseline. 
Stable Disease (irSD) 
Not meeting criteria for irCR or irPR, in absence of irPD. 
Progressive Disease (irPD) 
Increase in TMTB ≥ 20% relative to nadir. 
 
Target Lesions 
Baseline (Index) and 
New Measurable Lesions 
Non-Target Lesions* 
irRECIST Overall 
Response 
Total Measurable Tumor Burden 
(TMTB) 
Baseline 
Lesions 
Unequivocal 
New Lesions 
irCR 
irCR 
No 
irCR 
irCR 
irSD 
No 
irPR 
irPR 
irCR or irSD 
No 
irPR 
irSD 
irCR or irSD 
No 
irSD 
irPD 
Any 
Yes or No 
irPD 
Any 
Unequivocal 
Progression 
Yes or No 
irPD 
Any 
Any 
Yes 
irPD 
*Any increase in the size or number of non-measurable lesions does not necessarily imply an overall response of irPD.  
If new, non-measurable lesions become measurable (≥ 10 mm) at a subsequent TA, their measurement will at that 
point start to contribute to the TMTB.  To achieve unequivocal progression of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease that is of a magnitude that the treating physician would feel 
it is important to change therapy.  Equivocal findings of progression of non-target lesions (e.g., small and uncertain 


 
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new lesions; cystic changes or necrosis in existing lesions) should be considered irSD, and treatment may continue until 
the next scheduled assessment. 
8.6.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for irCR or irPR (whichever is first recorded) until the first date 
that progressive disease (irPD) is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded [nadir] since the treatment started).   
The duration of overall irCR is measured from the time measurement criteria are first met for 
irCR until the first date that irPD is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for irPD are met. 


 
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8.7 Exploratory Assessment of Correlative Immunologic Research 
Please refer to the lab manual for additional instructions and information on lab specimen 
handling and logistics. 
8.7.1 Phenotypic Analysis of PBMCs   
Samples for peripheral blood T-cells will be collected at the time points designated in the 
flowchart (Section 3.2).  Peripheral blood cell subsets will be quantitated through 
multiparametric flow cytometry for the following T-cell subsets: CD3, CD4, CD8, FoxP3.  T-cell 
subsets will be assessed for activation/exhaustion by expression of PD-L1, Ki-67, ICOS, PD-1, LAG-
3, TIM-3, CTLA-4.  PBMC may additionally be evaluated in a T-regulatory cell panel for the 
following: CD3, CD4, CD8, FoxP3, CD25, CD127, CD45A, CCR7, GITR, OX40, Ki-67, PD-1, CD56.  
8.7.2 Myeloid Derived Suppressor Cells (MDSC) 
MDSCs constitute a heterogeneous population of immature myeloid cells with various immune 
suppressive functions including suppression of T-cell proliferation, inducement of T-cell apoptosis 
and disruption of T-cell signaling pathways.  Levels of circulating MDSCs are increasingly 
recognized as important in determining clinical responses to novel drugs for cancer and 
autoimmune disease.  Samples will be collected for analyses at time points designated in the 
study flowchart (Section 3.2). 
MDSCs are defined as events that are:  
Lineageneg, CD14pos, HLA-‐DRlow/neg 
Each sample is analyzed using well-established flow cytometry techniques for the presence of 
MDSCs. For each sample a single data point will be delivered, being the mean of values for the 
percentage of Lineageneg, CD14pos events that are HLA-‐DRlow/neg to study the effects of treatment 
on levels of MDSCs. 
8.7.3 Quantification of Tumor-specific T-cell Responses 
PBMCs will be collected at the time points designated in the flowchart (Section 3.2). Peripheral 
blood T-cell responses against known tumor-associated antigens (TAAs) expressed in most 
ovarian cancers, including Her-2, p53, MUC-1, hTERT, survivin, mesothelin, folate binding protein, 
MAGE-A3, NY-ESO-1, SP-17, and WT1 will be assessed. Overlapping peptides (15-mers 
overlapping by 11 amino acids) that allow assaying T-cells independently of the haplotypes will 
be used. Functional assays will be performed both ex vivo and after in vitro T-cell expansion and 
readouts will include the analysis of biomarkers in the culture supernatant (e.g. using MSD to 
screen for up to 40 analytes as IFN-γ and granzyme-B, for instance), IFN-γ ELISpot and 
polychromatic intracellular cytokines staining. As controls, T-cell response to control non-tumor 
related peptides (e.g. the standard CEF peptide pool including immunodominant peptides from 
Cytomegalovirus, Epstein Barr Virus and Influenza or tetanus toxoid) will be tested.  
Whether therapy elicits T-cells specific against private mutated tumor antigens will be tested. 
Candidate antigens will be identified through exome sequencing of tumor tissue combined with 
gene expression profiling, and will be screened for candidate peptides for the subject’s 
haplotypes using appropriate bioinformatics algorithms, tested and validated in the Lausanne 


 
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Ludwig center. In silico-predicted candidate peptides will be tested for fitness and binding affinity 
to cognate class I HLAs using recombinant HLA in an in vitro screening algorithm developed by 
Immanuel Luescher at Ludwig Lausanne and provided by TC Metrics. Finally, best-in-class 
peptides will be validated using PBMCs as above. 
8.7.4 Baseline Immune Responsiveness to TLR8 activation 
TruCultureTM samples will be collected at the time points designated in the flowchart (Section 
3.2). Processed TruCultureTM tubes will be analyzed by Myriad/Rules Based Medicine (Austin, TX) 
to assess baseline immune responsiveness motolimod and MEDI4736.  
Considerable variability in immune reactivity can exist between individuals.  Despite the fact that 
motolimod activates a specific receptor (TLR8) on a restricted class of dendritic cells and 
monocytes, marked differences in responsiveness to treatment with this agent may relate to pre-
existing difference in immune activation at baseline.  It is hypothesized that measureable 
differences in response to motolimod at baseline (prior to dosing) may predict the 
pharmacodynamic response, and potentially clinical responses, to this agent. 
A validated assay (TruCultureTM) will be used to measure the baseline response to motolimod.  In 
preliminary studies using healthy volunteers and cancer patients and the TruCulture system, 
VentiRx has demonstrated variability between individuals following immune activation with 
lipopolysaccharide or motolimod, particularly with regards to IFN-γ and interleukin-12 
production.  Data from TruCulture at baseline will be correlated with TLR8 SNP data, immune 
responses after treatment, and clinical responses. 
NOTE: PER Amendment 2, samples will no longer be collected for analysis of TruCultureTM, as the 
analyses were related to motolimod dosing. The collection time points for these assays have 
been removed from the flowchart in Section 3.2. 
8.7.5 Immune Landscape: TILs and Tumor Microenvironment 
Immunohistochemisty (IHC): Unstained sections of tumor will be analyzed by The Center of 
Experimental Therapeutics in Lausanne, Switzerland, where an immune signature will be 
assessed using a multiplexed immunohistochemical approach followed by multispectral imaging 
and unmixing.  Multispectral imaging and linear unmixing offers the ability to analyze in a 
comprehensive, spatially oriented and quantitative fashion tumor slides, each stained with 
multiple antibodies, in either a brightfield (up to 3-4 antibodies + counterstain) or fluorescence 
(up to 6-8 antibodies + counterstain + autofluorescence removal) mode.  More specifically, 
lineage specific markers i.e. CD3, CD4, CD8 for T lymphocytes (and FoxP3 for Tregs), combined 
with markers of activation, or functional exhaustion, for example CD45RO, CD38, HLA-DR, TIA-1, 
granzyme-B, Ki67, PD-1, ICOS, LAG-3, Tim-3 and/or CTLA-4 will be used.  Furthermore, the spatial 
distribution of immune cell subsets with the level of expression on tumor cells of major 
components of the antigen presenting machinery i.e. HLA class I and II molecules, β2 
microglobulin, tapasin, and TAP1 and 2 will be evaluated.  Tumor cells and the whole 
microenvironment can also be interrogated for immunosuppressive factors such expression of 
PD-L1 and PD-L2, TGF-b, IL-10, COX1 and 2, IDO-1 etc.  Tumor cells can be interrogated for 
proliferation (Ki67), apoptosis (cleaved caspase-3), necrosis (HMGB1) or autophagy (beclin, LC3).  
Finally, innate cells can be characterized, for example by CD68 and CD163 for M1 and M2 


 
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macrophages, CD33 for MDSCs and NKp46 for NK cells.  Finally, the vasculature will be 
interrogated using several markers of activated and tumor endothelium and pericytes. 
As a complementary approach to the IHC, Nanostring platform will be used to assess the mRNA 
expression level of genes reflecting tumor microenvironment signatures, including genes of 
innate and adaptive immunity, inflammation, wound healing and angiogenesis. 
8.7.6 TCR sequencing 
In order to better understand the role of TCR in the control of tumor, next generation sequencing 
will be used to perform a large and comprehensive analysis of the repertoire in various tumors 
for whose clinical outcome is known.  DNA will be extracted from tumors and PBMCs to sequence 
the TCR beta chain of the infiltrating lymphocytes.  The data will reveal the nucleotide sequences 
of the TCR present and thus allow analysis of the diversity and the clonality of the repertoire. 
PBMCs will be assayed from 3 time points, which will be matched as closely as possible to the 
tumor biopsies (baseline, Cycle 2 Day 1 and the PBMC collection closest to disease progression). 
8.7.7 Immune biomarkers  
Cytokines and chemokines in peripheral blood will be assessed using the Rules Based Medicine 
platform (HumanMAP®).  HumanMAP® samples will be collected at the time points designated in 
the flowchart (Section 3.2).  Samples will be analyzed by Myriad/Rules Based Medicine (Austin, 
TX), and plasma will be used to assess specific analytes including chemokines, cytokines, and 
other inflammatory mediators by protein array technology.  
Plasma obtained from subjects pre- and post-treatment will be screened by ELISA for the 
presence of antibodies against a panel of cancer testis antigens and other tumor-associated 
antigens.   
NOTE: PER Amendment 2, samples will no longer be collected for analysis of HumanMap®. The 
collection time points for these assays have been removed from the flowchart in Section 3.2. 
8.7.8 Pharmacogenomics 
DNA will be analyzed by the University of Washington, Tumor Vaccine Group (Seattle, WA) and 
used to examine single nucleotide polymorphisms (SNPs) in the TLR8 gene by conventional 
methods. An aliquot of the PBMC collection and/or tumor biopsy/archival tissue will be used for 
pharmacogenomics.  
Genes encoding TLRs, particularly those encoding the intracellular TLR (TLR3, TLR7, TLR8 and 
TLR9) are evolutionarily conserved.  Still, various single nucleotide polymorphisms (SNPs) in the 
TLR8 gene have been identified from large scale sequencing efforts in multiple ethnic 
populations.  Recently, a common TLR8 SNP [denoted TLR8 A1G (rs3764880)] has been found to 
be associated with various infectious diseases, notably progression of HIV and TB.  This allele is 
present in all populations tested, and is found at a frequency of approximately 30% in most 
ethnic groups.  While one report suggests that the TLR8 A1G encodes a variant of TLR8 which 
decreases activity relative to the wild type allele, there are scant data, at present, to support this 
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Given the relatively high allele frequency of this common TLR8 genetic variant, the potential 
functional differences in this allele, and the human genetic association between this variant and 
several infectious diseases, it is reasonable to genotype individuals from clinical trials 
investigating motolimod.  Reliable methods to analyze DNA from blood or saliva to detect the TLR 
A1G SNP have been developed.  Genotyping of all subjects in the proposed trial for the A1G SNP 
will be conducted to assess the potential relevance of this allele to clinical responses (related to 
efficacy and safety) following treatment with motolimod. 
8.7.9 BRCA status of tumors 
The BRCA status of tumors by testing for mutations in the full BRCA1 and BRCA2 exons as well as 
additional genes involved in the homologous recombination repair pathway will be assessed.  
Expression of BRCA1 and BRCA2 proteins in tumors by immunohistochemistry will be tested; 
absence will indicate loss of expression, presumably through epigenetic regulation. 
8.7.10 MEDI4736 PK and Immunogenicity for Anti-drug Antibodies (ADA) 
A validated electrochemiluminescence assay (ECLA) using a Meso Scale Discovery (MSD) platform 
will be used for the quantitative determination of MEDI4736 concentrations in serum.  Anti-
MEDI4736 antibodies in human serum will be detected using a validated MSD electrochemi-
luminescence assay. 
NOTE: PER Amendment 2, samples will no longer be collected for analysis of MEDI4736 PK and 
immunogenicity for 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. 
8.7.11 sPD-L1 
The association of sPD-L1with response to treatment and clinical outcome will be evaluated. 
NOTE: PER Amendment 2, 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. 
8.7.12 Circulating soluble factors 
Analyses of circulating levels of soluble factors such as cytokines and chemokines may include but 
are not limited to VEGF, FGF, TGF, IL-1 IL-2, IL-4, IL-6, IL-8, IL-10, IFN, G-CSF, TNF. Their association 
with treatment and clinical outcome will be explored. 
NOTE: PER Amendment 2, 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. 
8.7.13 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.  Subjects 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 


 
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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. 
8.7.14 mRNA/miRNA Profiling 
Whole blood samples (pre- and during MEDI4736 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 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. 
 


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


 
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8.9 Details for Subjects Who Continue Optional MEDI4736 Treatment 
beyond the Core Study 
According to Section 3.1.12, optional MEDI4736 treatment extension 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 the subject, Sponsor and 
Investigator, and it may continue until confirmed disease progression, unless there is 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.   
Subjects who receive optional study treatment extension will receive the currently recommended 
fixed dose of 1500 mg MEDI4736 Q4W for subjects > 30 kg.  If a subject’s body weight drops to ≤ 
30 kg, the subject will receive weight-based dosing equivalent to 20 mg/kg Q4W for MEDI4736 as 
long as the body weight remains ≤ 30 kg (e.g., a 30 kg subject would receive a 600 mg dose; a 
25 kg subject would receive a 500 mg dose; etc.). When the weight improves to >30 kg, the 
subject may return to fixed dosing of MEDI4736 1500 mg. 
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 6.3.3.2.   
2. Administration of MEDI4736 will proceed according to Section 6.3.4.   
3. Subjects will be monitored by assessment of vital signs before, during and after each 
MEDI4736 dose administration according to Section 6.3.5. 
4. The 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 the first dose, MEDI4736 dosing will continue Q4W. 
6. The flowchart for optional treatment extension, which is provided in Section 8.9.1, will 
be followed. 
7. AE/SAE collection and reporting will be performed according to the protocol 
requirements (Section 7.1) and until disease progression is documented.  For AEs/SAEs 
that may be ongoing at the time of disease progression, follow-up will be performed 
until resolution or stabilization of the events or up to 90 days after the last dose of 
MEDI4736. 
 
 


 
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8.9.1 Study Flowchart for Subjects Who Continue Optional MEDI4736 Treatment 
beyond the Core Study 
 
Post Study 
Follow-Up
Study Drug
MEDI4736 (IV)
Tumor & Disease Assessments
Disease Assessment  by RECIST and irRECIST 
(including appropriate imaging)
Study Procedures & Examinations
Physical Exam (incl. weight and ECOG Perf Status)
X
X
X
Vital Signs (T, HR, BP, RR) 4
X
X
X
12-Lead ECG3
X
Echocardiogram or MUGA
X
Concomitant Medication / Procedure (name, 
indication, dose, route, start & end dates)
X
X
X
Adverse Events (starting or worsening after IC)5
X
X
X
Specimens for Laboratory Procedures
Blood Hematology (complete blood count, 
differential, platelets)3
X
X
Chemistry (gluc., BUN, crea., Na, K, Ca, Cl, CO2, PO4, 
Mg, prot., alb., Tbili., AST, ALT,  ALP,LDH)3
X
X
Chemistry cont. (Amylase and lipase)3
X
X
Chemistry cont. (Free  T3, Free T4, TSH)3
X
X
Serum pregnancy test3
X
X
CA-1253 
Specimens for Correlative Assessments
PBMC/Plasma Collection & Banking 3
X
X
MDSC (Serametrix)3 (US sites only)
X
Tumor Biopsy (Tumor microenvironment, PD-L1 
expression, TCR sequencing)
optional at 
disease 
progression
Pharmacogenomics (including BRCA1 and BRCA2 
tumor status)6
PAX RNA3
optional at 
disease 
progression
1 - First MEDI4736 dose during optional treatment extension will be administered according to the following schedule: 
   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
3 - Collected pre-dose. Note: It is strongly recommended that results for hematology, chemistry and pregnancy test (when applicable) 
    are reviewed before dosing. Pregnancy tests are not required for subjects who are not of child-bearing potential as defined in Section 5.2, # 17
4 - See Section 6.3.5 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.
Study Flowchart for Subjects 
who Continue Optional 
MEDI4736 Treatment after 
Core Study 
SOC
6 -An aliquot of the PBMC and/or Tumor Biopsy tissue will be used for pharmacogenomics – a separate sampling is not needed
On Study Follow-up
Last Study Drug 
Administration 
+28 +3 days
At first optional treatment visit,
 then Q12W
At first optional treatment visit,
 then Q12W
X
X
At first optional treatment visit,
 then Q12W
At first optional treatment visit,
 then Q12W
X
X
At first optional treatment visit,
 then Q12W
2 - After first dose, MEDI4736 dosing will continue Q4W according to Section 8.9; assessments will continue Q4W unless otherwise noted.
Every 3 months for 3 years from initiation of treatment. 
Clinical outcomes data (dates of progression/relapse and survival) will be recorded (See Section 3.1.16).
Optional Study Treatment1,2
(Q4W following first optional 
study treatment dose)
+84 ± 7 days from last disease assessment
Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; SOC = Standard of Care
Last Study Drug 
Administration 
+56 +7 days
 Last Study Drug 
Administration 
+ 90 +7 days      
End of  Study
1500 mg
SOC
At first optional treatment visit only  
At first optional treatment visit,
 then Q12W
At first optional treatment visit only  
At first optional treatment visit,
 then Q12W
+84 ± 7 days from last disease assessment


 
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8.10 Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CD 
Cluster of differentiation 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4  
DC 
Dendritic cell 
DLT 
dose-limiting toxicity 
ECLA 
Electrochemiluminescence assay 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HLA 
Human Leukocyte Antigen 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IGSF 
Immunoglobulin superfamily 
IHC 
Immunohistochemistry 
IL 
interleukin 
IND 
Investigational new drug 
IP 
Investigational Product 
irAE 
Immune-related adverse event 
irRC 
immune-related response criteria 
irRECIST 
Immune-related Response Evaluation Criteria In Solid Tumors 
IV 
intravenous 
IRB 
Institutional Review Board 
LICR 
Ludwig Institute for Cancer Research 
mAb 
Monoclonal antibody 
mDC 
Myeloid dendritic cell 
MDSC 
myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSD 
Meso Scale Discovery 
MTD 
maximum tolerated dose 


 
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NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NK 
Natural killer 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD-1 
Programmed death-1  
PD-L1 
Programmed death ligand 1 
PEG 
polyethylene-glycol  
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PLD 
Pegylated Liposomal Doxorubicin 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCHN 
squamous cell carcinoma of the head and neck  
SD 
Standard Deviation 
SOC 
Standard of care 
TME 
Tumor microenvironment 
TIL 
tumor-infiltrating lymphocyte 
ULN 
Upper limit of normal 
 
 


 
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9 References 
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Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a 
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Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell 
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Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. PD-L2 expression extends beyond 
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Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, et al. Program death-1 
engagement upon TCR activation has distinct effects on costimulation and cytokine-driven 
proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. 
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Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD-1:PD-L inhibitory pathway 
affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. EurJImmunol. 2002;32(3):634-43. 
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Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the 
CTLA-4 and PD-1 pathways. ImmunolRev. 2008;224:166-82. 
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Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, et al. T-cell tolerance 
or function is determined by combinatorial costimulatory signals. EMBO J. 2006;25(11):2623-33. 
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Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML. PD-L2:PD-1 involvement in T cell 
proliferation, cytokine production, and integrin-mediated adhesion. EurJImmunol. 
2005;35(12):3561-9. 


 
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Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell 
stimulation, but only receptor ligation prevents T cell activation. JImmunol. 2004;173(2):945-54. 
35. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. ProcNatlAcadSciUSA. 2001;98(24):13866-71. 
36. 
Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on tumor 
cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL 
dysfunction. Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2013;19(6):1363-74. 
37. 
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-
infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human 
ovarian cancer. ProcNatlAcadSciUSA. 2010;107(17):7875-80. 
38. 
Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 
combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer 
research. 2013;73(12):3591-603. 
39. 
Oganesyan V, Gao C, Shirinian L, Wu H, Dall'Acqua WF. Structural characterization of a 
human Fc fragment engineered for lack of effector functions. Acta crystallographica Section D, 
Biological crystallography. 2008;64(Pt 6):700-4. 
40. 
Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-
infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable 
prognosis in ovarian cancer. Proceedings of the National Academy of Sciences of the United 
States of America. 2005;102(51):18538-43. 
41. 
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of 
regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. 
Nat Med. 2004;10(9):942-9. 
42. 
Pinheiro SP, Hankinson SE, Tworoger SS, Rosner BA, McKolanis JR, Finn OJ, et al. Anti-
MUC1 antibodies and ovarian cancer risk: prospective data from the Nurses' Health Studies. 
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for 
Cancer Research, cosponsored by the American Society of Preventive Oncology. 2010;19(6):1595-
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2013;39(1):1-10. 
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Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 
2013;39(1):61-73. 
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Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, et al. Cancer immunotherapy 
strategies based on overcoming barriers within the tumor microenvironment. Current opinion in 
immunology. 2013;25(2):268-76. 
46. 
Lee M, Park CS, Lee YR, Im SA, Song S, Lee CK. Resiquimod, a TLR7/8 agonist, promotes 
differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells. Archives 
of pharmacal research. 2014;37(9):1234-40. 
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Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski M, et al. 
Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated 
liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial 
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Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, et al. Phase III trial of 
gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian 
cancer. J Clin Oncol. 2008;26(6):890-6. 


 
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49. 
Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, et al. 
Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in 
patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25(19):2811-8. 
50. 
Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial 
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus 
topotecan. J Clin Oncol. 2001;19(14):3312-22. 
51. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of 
medicine. 2012;366(26):2443-54. 
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Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
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Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. Re: New 
guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). Journal of the 
National Cancer Institute. 2004;96(6):487-8. 
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Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility and 
response guidelines for phase II clinical trials in androgen-independent prostate cancer: 
recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 
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Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end 
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Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, et al. 
Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. 
Gynecologic Cancer Intergroup. Journal of the National Cancer Institute. 2000;92(18):1534-5. 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
Ludwig Institute for Cancer Research 
(LICR) 
 
STATISTICAL ANALYSIS PLAN 
 
Phase 1/2 Study of Chemo-immunotherapy with  
Toll-like Receptor 8 Agonist Motolimod (VTX-2337) and anti-PD-
L1 Antibody MEDI4736 in Subjects with Recurrent, Platinum-
Resistant Ovarian Cancer for Whom Pegylated Liposomal 
Doxorubicin (PLD) is Indicated 
 
Clinical Trial Protocol LUD2014-001 
NCT02431559 
 
 
 
SAP Version: 
Date of Statistical Analysis Plan: 
Version 1.0 
 
 
17April 2018 
Version 2.0                             08 January 2019 
 
 
 
 
 
 


 
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LUD2014-001  
 
 
Version 2.0: 08JAN2019 
 
 
 
 
 
 
Page 2 of 34 
 
 
SIGNATURE PAGE 
 
 
 
 
Date 
 
Prepared by:  
Suzanne Granger, MS 
Project Biostatistician 
PROMETRIKA, LLC 
 
 
 
Date 
 
Reviewed by: 
Nicole LaVallee, PhD 
Director, Biostatistics 
PROMETRIKA, LLC 
 
 
 
Date 
 
Reviewed by:  
Miganush Stepanians, PhD 
President and CEO 
PROMETRIKA, LLC 
 
 
 
 
 
Date 
 
Reviewed and Approved by:  
Lisa Shohara 
Clinical Project Manager 
Ludwig Institute for Cancer Research 
 
 
 
Date 
 
Reviewed and Approved by:  
Paul Schwarzenberger, MD 
Medical Monitor 
Ludwig Institute for Cancer Research 
 
 


 
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LUD2014-001  
 
 
Version 2.0: 08JAN2019 
 
 
 
 
 
 
Page 3 of 34 
 
Table of Contents 
1 
INTRODUCTION 
9 
2 
STUDY SUMMARY 
9 
2.1 
STUDY OBJECTIVES 
9 
2.2 
STUDY DESIGN 
10 
2.2.1 
Number of Subjects............................................................................... 12 
2.2.2 
Randomization and Blinding Procedures.............................................. 12 
2.2.3 
Efficacy Assessments............................................................................ 12 
2.2.4 
Safety Assessments ............................................................................... 13 
2.2.5 
Biological Activity ................................................................................ 13 
3 
STATISTICAL METHODS 
18 
3.1 
General Methods 
18 
3.1.1 
Computing Environment ....................................................................... 18 
3.1.2 
Reporting of Numerical Values ............................................................ 18 
3.1.3 
Baseline Value and Change from Baseline ........................................... 18 
3.1.4 
Handling of Missing/Incomplete Values .............................................. 18 
3.1.5 
Handing of Repeated Assessments ....................................................... 18 
3.2 
Analysis Populations 
19 
3.2.1 
Intent-To-Treat Population ................................................................... 19 
3.2.2 
Per-Protocol Population ........................................................................ 19 
3.3 
Analysis Variables 
19 
3.3.1 
Clinical Efficacy ................................................................................... 19 


 
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3.3.2 
Safety Variables .................................................................................... 21 
3.3.3 
Immunological Response ...................................................................... 22 
3.4 
Subjects Disposition and Evaluability 
22 
3.4.1 
Subject Disposition ............................................................................... 22 
3.4.2 
Protocol Deviations ............................................................................... 22 
3.5 
Demographics and Baseline Characteristics 
23 
3.5.1 
Demographics ....................................................................................... 23 
3.5.2 
Medical History .................................................................................... 23 
3.5.3 
Oncological Treatment History............................................................. 23 
3.6 
Prior and Concomitant Medications/Procedures 
23 
3.7 
Treatment Exposure 
24 
3.8 
Efficacy Analysis 
24 
3.8.1 
Progression-free Survival...................................................................... 24 
3.8.2 
Tumor Response ................................................................................... 25 
3.8.3 
Overall Survival .................................................................................... 26 
3.9 
Safety Analysis 
26 
3.9.1 
Adverse Events ..................................................................................... 26 
3.9.2 
Clinical Laboratory Evaluation ............................................................. 29 
3.9.3 
Vital Signs ............................................................................................. 29 
3.9.4 
ECOG Performance Status ................................................................... 29 
3.9.5 
12-Lead ECG ........................................................................................ 29 
3.9.6 
ECHO or MUGA .................................................................................. 29 


 
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3.9.7 
Physical Examination............................................................................ 30 
4 
LIST OF TABLES 
31 
5 
LIST OF LISTINGS 
33 
6 
LIST OF FIGURES 
34 
 


 
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Page 6 of 34 
 
DOCUMENT HISTORY 
Version 
Author 
Description 
1.0 
Suzanne Granger 
New Document 
2.0 
Suzanne Granger 
• (Section 2.2.4 and 3.9.2) Removed 
reference to CTCAE grades for 
laboratory data. 
• (3.1.5) Added detail regarding 
handling of repeated assessments 
on scheduled time points post-
treatment. 
• (3.3.2) Added definition of TEAE 
and TRAE. 
• (3.3.1) Updated list of 
demographic data included. 
• (3.9) Updated with additional 
detail regarding adverse event 
reporting. 
• (3.9.3) Added detail regarding pre-
dose and end of infusion records to 
include in analysis of change in 
vital signs. 
• (3.9.5 and 3.9.6) Updated 
derivation of percentages to be 
based on subjects with non-
missing data for both baseline and 
corresponding post-treatment time 
point. 


 
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Page 7 of 34 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Class 
BRCA 
Breast Cancer susceptibility gene 
CA-125 
Cancer Antigen 125 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
ITT 
Intent to Treat 
irPD 
Immune Response Progressive Disease 
MDSC 
Myeloid Derived Suppressor Cell 
MedDRA 
Medical Dictionary of Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ODCR 
Overall Disease Control Rate 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 


 
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Abbreviation 
Full Term 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PLD 
Pegylated Liposomal Doxorubicin 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Preferred Term 
Q4W 
every 4 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TRAE 
Treatment Related Adverse Event 
WHO 
World Health Organization 
 
 
 


 
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LUD2014-001 
 
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          Page 9 of 34 
 
1 INTRODUCTION 
LUD2014-001 is an open-label, non-randomized, multicenter Phase 1/2 study of 
motolimod and MEDI4736 in subjects with recurrent, platinum-resistant ovarian 
cancer, scheduled to receive pegylated liposomal doxorubicin (PLD). The clinical 
efficacy and safety of the study drugs in combination will be evaluated during this 
clinical trial. 
 
Per Amendment 2, motolimod dosing was discontinued for all subjects as of 18 Aug 
2016. At the time of Amendment 2, Phase 1 was completed, and Phase 2 was initiated 
at the +1 dose level (PLD 40 mg/m2, MEDI4736 1500 mg Q4W). Subjects who 
initiated treatment prior to August 18, 2016 continued the trial at their respective dose 
levels for PLD and MEDI4736; however, motolimod was discontinued. 
 
This statistical analysis plan (SAP) contains a detailed description of the data 
presentations and statistical analyses that will be included in the clinical study report 
for Protocol LUD2014-001. The statistical methods and analyses described here are 
based on those presented in the study protocol (Amendment 4 dated 08SEP2017).   
2 STUDY SUMMARY 
2.1 STUDY OBJECTIVES 
 
For the Phase 1 study period, the primary objective is to determine the maximum 
tolerated dose (MTD) and the safety profile of the combination.  
 
For the Phase 2 study period, the primary objective is the evaluation of clinical 
efficacy as measured by the Progression-free Survival (PFS) rate using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria at 6 months.   
 
For all Phase 1 and 2 cohorts, the secondary objectives are the evaluation of clinical 
efficacy as measured by overall response rate (ORR), PFS rate at 12 months (and 6 
months in Phase 1), overall survival (OS), and biological activity defined as 
immunological responses.  
 
Safety will be assessed by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. Clinical efficacy will be assessed using RECIST v1.1 and irRECIST 
criteria.  


 
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          Page 10 of 34 
 
2.2 STUDY DESIGN 
This is an open-label, non-randomized, multicenter Phase 1/2 study of motolimod and 
MEDI4736 in subjects with recurrent, platinum-resistant ovarian cancer, scheduled to 
receive pegylated liposomal doxorubicin (PLD). The estimated study duration is 39 
months (duration of treatment: 12 months, study follow-up: 3 months, post study 
follow-up: 3 years from initiation of treatment). 
Per Amendment 2 (05-OCT-2016), motolimod dosing was discontinued for all 
subjects as of August 18, 2016. At the time of Amendment 2, Phase 1 was completed, 
and Phase 2 was initiated at the +1 dose level (PLD 40 mg/m2, MEDI4736 1500 mg 
Q4W). Subjects who initiated treatment prior to August 18, 2016 continued the trial 
at their respective doses levels for PLD and MEDI4736; however, motolimod was 
discontinued. Prior to Amendment 2, all subjects were treated with PLD 
intravenously, MEDI4736 intravenously and motolimod subcutaneously during each 
28-day cycle. On days with concurrent motolimod and MEDI4736 dosing, motolimod 
administration was given 30-60 minutes after the end of the MEDI4736 infusion. 
Phase 1 dose escalations and de-escalations for the determination of the MTD (or 
highest tolerable dose tested) were performed based on the available dose levels and 
the respective rules for a standard 3 + 3 study design, as per Dose Level Table and 
Schema below: 
Dose Level Table  
Dose Level  
Pegylated liposomal 
doxorubicin [mg/m2 IV] 
day 1 
MEDI4736 [ IV]  
Motolimod [mg/m2 SC]  
 
-1  
40  
450 mg Q4W Day 3 
2.0  
Days 3, 10 and 17 Cycles 1-
3 and day 3 Cycles 4-12 
0a (Starting Level)  
40  
3 mg/kg Q2W Days 3 and 
17 
(equivalent to 450 mg 
Q4W)  
2.5 
Days 3, 10 and 17 Cycles 1-
3 and days 3 and 17 Cycles 
4-12 
0b (Started with Level 0a) 
40  
1500 mg Q4W Day 3 
2.0  
Days 3, 10 and 17 Cycles 1-
3 and day 3 Cycles 4-12 
+1  
40  
1500 mg Q4W Day 3 
2.5 
Days 3, 10 and 17 Cycles 1-
3 and day 3 Cycles 4-12 
Q2W = every 2 weeks; Q4W = every 4 weeks  
Note for fixed dose of 1500 mg MEDI4736: If a subject’s body weight drops to ≤ 30 kg while on the study, the MEDI4736 
dose will be 600 mg Q4W as long as the subject’s body weight remains ≤ 30 kg.  
  
Phase 2 subjects are treated at the MTD level determined in Phase 1. Subjects are 
followed on study for 90 days after the last drug administration and off-study every 3 
months thereafter for 3 years from initiation of treatment. 
 
Subjects are enrolled in a non-randomized, competitive multicenter, sequential 
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of the combination regimen are reviewed on an ongoing basis by an internal data 
safety monitoring panel. 
For each cohort in Phase 1, the start of the Cycle 1 Day 3 study drug administration 
(MEDI4736 + motolimod) for the first and second subject was separated by at least 
24 hours. All subjects’ safety data is reviewed for DLTs, before proceeding with a 
cohort expansion or to a dose-escalated/de-escalated cohort.  
Per Amendment 1 (09-DEC-2015), the cohort at dose level 0b was added to Phase 1. 
Depending on the timing of Amendment 1, dose level 0b cohort could be running 
concurrently with the cohort at dose level 0a, -1, or +1. Thus, subject enrollment will 
occur as follows:  
a) When only 1 cohort is open: sequential enrollment;  
b) When 2 parallel cohorts are open: preferential sequential enrollment into 
the cohort with the higher motolimod dose level or into the cohort with the 
higher MEDI4736 dose level if both cohorts have the same motolimod dose 
level.  
Subject enrollment is centrally administered.  
Enrollment in Phase 2 was initiated after the MTD was established in Phase 1. One 
patient was enrolled in Phase 2 when motolimod dosing was discontinued for all 
subjects. The Phase 2 dosing schedule is as follows: 
 
Phase 2 Dosing Schedule  
DAY  
CYCLES 1 – 12  
1  
Pegylated liposomal doxorubicin (IV) 40 mg/m2 
3  
MEDI4736 (IV)  1500mg  
Per Amendment 3 (05-DEC -2016), an optional MEDI4736 treatment extension 
beyond the initial 12-cycle treatment period (Core Study) was added for subjects who 
complete the Core Study with Stable Disease or better. The optional treatment 
extension was permitted for up to 12 additional cycles upon agreement with subject, 
Sponsor and Investigator, and continued until confirmed disease progression, unless 
there was unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion was met. Under Amendment 4 (08-SEP-2017), the duration of the optional 
MEDI4736 treatment extension was changed from 12 cycles to “until confirmed 
disease progression.” 
Subjects who receive optional study treatment extension receive the currently 
recommended fixed dose of 1500 mg MEDI4736 Q4W for subjects > 30 kg. If a 
subject’s body weight drops to ≤ 30 kg, the subject will receive weight-based dosing 
equivalent to 20 mg/kg Q4W for MEDI4736 as long as the body weight remains ≤ 30 
kg (e.g., a 30 kg subject would receive a 600 mg dose; a 25 kg subject would receive 
a 500 mg dose; etc.). When the weight improves to >30 kg, the subject may return to 
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2.2.1 Number of Subjects 
 
Approximately 6 to 9 sites; and 6 to 53 evaluable subjects were anticipated per the 
protocol for this study:  
Phase 1: 6-18 evaluable subjects to identify the MTD.    
Phase 2: 41 evaluable subjects, including the 6 subjects treated in Phase 1 at the 
MTD.   
2.2.2 Randomization and Blinding Procedures 
This is an open-label study; therefore, no randomization or blinding procedures are 
used. 
2.2.3 Efficacy Assessments 
The assessment of clinical efficacy is the primary objective of Phase 2 and the 
secondary objective of Phase 1 and is evaluated using RECIST v1.1 and irRECIST 
criteria.  
2.2.3.1 Progression-free Survival Rate 
The Phase 2 primary endpoint is the proportion of subjects who survive and do not 
progress, PFS rate, within the first 6 months of treatment. This endpoint will be based 
on RECIST v1.1 criteria.  The PFS status at 6 months will be based on disease 
assessments at the scheduled visit at the start of Cycle 7. 
The Phase 2 secondary endpoints include PFS rate at 6 months based on irRECIST 
and PFS rate at 12 months based on RECIST v1.1 and irRECIST. 
For Phase 1, the PFS rate at 6 and 12 months based on RECIST v1.1 and irRECIST 
are secondary endpoints. 
2.2.3.2 Progression-free Survival Time 
Median PFS time evaluated using RECIST v1.1 and irRECIST criteria is a Phase 1 
and Phase 2 secondary endpoint. 
PFS time will be defined as the number of days from the date of first dose to the date 
of earliest disease progression based on radiological or clinical assessment or to the 
date of death, if disease progression does not occur. Every effort will be made to 
follow subjects for PFS if they complete or discontinue the study prior to progression. 


 
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2.2.3.3 Overall Response Rate 
The Phase 1 and Phase 2 secondary endpoints also include ORR based on RECIST 
v1.1 and irRECIST. ORR is defined as the percentage of subjects meeting criteria of 
complete response (CR) or partial response (PR) over a period of at least 4 weeks. 
2.2.3.4 Overall Disease Control Rate 
Overall Disease Control Rate (ODCR) is defined as stable disease (SD), PR, or CR 
over a period of at least 4 weeks.  
2.2.3.5 Overall Survival Time  
OS time is a secondary endpoint for Phase 1 and Phase 2 and is defined as the interval 
of time initiating at the date of study day 1 up to the recorded date of death or last 
follow-up. Subjects lost to follow-up will be censored on the date when they were last 
known to be alive. Every effort will be made to follow subjects for OS after they 
complete or discontinue the study.   
2.2.4 Safety Assessments 
Laboratory tests, vital sign measurements, physical exams and subject interviews are 
performed to detect new abnormalities and deteriorations of any pre-existing 
conditions. The investigator evaluates any laboratory abnormalities for clinical 
significance, and clinically significant abnormalities are recorded as adverse events. 
All clinically significant abnormalities and deteriorations from time of signing of 
informed consent to the end of study visit should be recorded in the Case Report 
Form(CRF) as adverse events and graded according to the National Cancer Institute  
CTCAE version 4.03. 
2.2.5 Biological Activity 
Samples for exploratory assessment of correlative immunologic research are collected 
according to the Study Flowchart in Section 3.2 of the protocol. Assessments include, 
but are not limited to: Phenotypic analysis of peripheral blood mononuclear cells 
(PBMCs), Characterization of Myeloid Derived Suppressor Cells (MDSCs), 
Quantification of tumor-specific T-cell responses, Immune Landscape: Tumor 
Infiltrating Lymphocytes and Tumor Microenvironment, TCR sequencing, Immune 
Biomarkers, Pharmacogenomics, and BRCA status of tumors.  
A comprehensive list of variables to be analyzed for the exploratory assessment of 
correlative immunologic research is located in Section 8.7 of the protocol.  
The analyses of these data are being performed by another entity and are not included 
in the analysis section of this SAP.


 
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Table 1.  Schedule of Events 
 
 


 
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3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher for 
Windows. 
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in subject data listings.  All by-visit 
summarizations will be conducted using data from Cycle 1, Cycle 2, and/or the last 
cycle, as applicable.  All data presentations will be by the planned cohorts in the 
protocol, separately for Phase 1 and Phase 2.   
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) 
will be calculated by cohort for continuous variables.   
Frequencies and percentages will be presented by cohort for categorical and ordinal 
variables.  If there are missing values, the number missing will be presented, but 
without a percentage.   
Means and medians will be reported to one decimal place more than the data reported 
in the EDC.  Standard deviations will be reported to two decimal places more than the 
data reported.  Minimum and maximum will be reported to the same number of 
decimal places captured in the EDC.     
3.1.3 Baseline Value and Change from Baseline  
Baseline value is defined as the most recent non-missing value obtained immediately 
prior to administration of first dose.  Change from baseline will be calculated by 
subtracting the baseline value from the post-treatment assessment for each subject 
(i.e., post-treatment – baseline).   
3.1.4 Handling of Missing/Incomplete Values 
Unless otherwise explicitly specified, missing data will not be imputed.   
3.1.5 Handing of Repeated Assessments 
If multiple results are available for a test at the same scheduled time point post-
baseline then the following rules will be used: 


 
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• If multiple pre-dose assessments are available at the same scheduled time 
point and all results are considered normal, then the first (earliest) result will 
be used in all summarizations. 
• If multiple pre-dose assessments are available at the same scheduled time 
point and at least one result is considered abnormal, then the worst (most 
abnormal) result will be used in the summarization.   
3.2 Analysis Populations  
3.2.1 Intent-To-Treat Population 
The Intent-To-Treat (ITT) Population and the Safety Population are the same for this 
study and are defined as all subjects who receive at least one dose of PLD, motolimod 
(pre Amendment 2), or MEDI4736.  All tables, listings, and figures will identify this 
group of subjects as the Intent-to-Treat Population.  
3.2.2 Per-Protocol Population 
The Per-Protocol (PP) Population is defined as all subjects enrolled in Phase 2 of the 
study, including the 6 subjects treated in Phase 1 at the MTD, who received at least 
75% of the scheduled doses of MEDI4736 and PLD over the first 2 cycles, as well as 
respective disease assessments, without major protocol violations.   
Phase 2: The Per-Protocol (PP) Population for Phase 2 is defined as all subjects 
enrolled in Phase 2 of the study who received at least 75% of the scheduled doses of 
MEDI4736 and PLD over the first 2 cycles, as well as respective disease assessments, 
without major protocol violations.   
3.3 Analysis Variables 
3.3.1 Clinical Efficacy 
Tumor response will be assessed using RECIST v1.1 and irRECIST criteria. When a 
radiological assessment is unavailable to determine RECIST (irRECIST), a clinical 
assessment of progressive disease and/or death may be used in lieu of the RECIST 
(irRECIST) to determine disease response.   This combined clinical efficacy endpoint 
will be used in the primary efficacy analysis.  RECIST and irRECIST criteria are 
described in detail in the protocol, and an abbreviated description is provided below. 
 


 
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RECIST evaluation of target lesions are as follows: 
Response 
Criteria for Response 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions 
taking as reference the baseline sum diameters 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD 
Progressive Disease (PD) 
At least 20% increase in the sum of the diameters of target lesions taking 
as reference the baseline sum diameters or new lesion identification 
 
irRECIST evaluation of target and new lesions are as follows: 
Complete Response (irCR) 
Complete disappearance of all target and new, measurable lesions, with 
the exceptions of lymph nodes which must decrease to < 10 mm in 
short axis. 
Partial Response (irPR) 
Decrease in TMTB* ≥ 30% relative to baseline. 
Stable Disease (irSD) 
Not meeting criteria for irCR or irPR, in absence of irPD. 
Progressive Disease (irPD) 
Increase in TMTB ≥ 20% relative to nadir. 
*TMTB = SumD target lesions + SumD new, measurable lesions. 
For both RECIST and irRECIST, if CA125 levels are initially above the upper normal 
limit, they must normalize for a subject to be considered in complete clinical 
response. 
Efficacy variables include: 
• Progression-free Survival 
o Proportion of subjects surviving without progression at 6 months 
(based on RECIST v1.1 and/or clinical progression/death) – Phase 2 
primary endpoint 
o Proportion of subjects surviving without progression at 6 months 
(based on irRECIST and/or clinical progression/death) – Phase 2 
secondary endpoint 
o Proportion of subjects surviving without progression at 12 months 
(based on RECIST v1.1 and irRECIST and/or clinical 
progression/death) – Phase 2 secondary endpoints 
o Proportion of subjects surviving without progression at 6 and 12 
months (based on RECIST v1.1 and irRECIST and/or clinical 
progression/death) – Phase 1 secondary endpoints 
o Progression-free survival time (based on RECIST v1.1 and  irRECIST 
and/or clinical progression/death) – Phase 1 and 2 secondary endpoints 


 
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• Tumor Response 
o Overall Response Rate (ORR) based on RECIST v1.1 and irRECIST 
and/or clinical progression/death – Phase 1 and 2 secondary endpoints 
o Overall Disease Control Rate – stable disease (SD), PR, or CR over a 
period of at least 4 weeks based on RECIST v1.1 and irRECIST- 
Phase 1 and 2 secondary endpoints 
• Overall Survival  
o Median overall survival time – Phase 1 and 2 secondary endpoint 
3.3.2 Safety Variables 
Safety variables include: 
• Incidence of treatment emergent adverse events (TEAEs), defined as an 
adverse event (AE) that is first identified, or is identified to worsen in 
intensity, at a time point occurring after the first dose of study drug 
o All TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
o All TEAEs by PT 
o TEAEs by maximum severity (according to CTCAE version 4.03) 
o Treatment related TEAEs (TRAE) defined as events with a 
relationship to any study drug of ‘Definitely Related’, ‘Probably 
Related’ or Possibly Related’ 
o Treatment related TEAEs by maximum severity (according to CTCAE 
version 4.03) 
o TEAEs leading to study drug withdrawal 
o Serious TEAEs 
• Change in clinical laboratory parameters (hematology, chemistry, amylase, 
lipase, thyroid) from baseline to each selected post-treatment assessment time 
point and shifts in clinical laboratory parameters from baseline to each 
selected post-treatment assessment time point 
• Change in vital signs (systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature) from pre-dose to end of infusion at 
selected post-treatment assessment time points 
• Change in ECOG performance status from baseline to last assessment 
• Shifts in ECG from baseline to each selected post-treatment assessment time 
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• Shifts in ECHO or MUGA from baseline to each selected post-treatment 
assessment time point 
3.3.3 Immunological Response 
The following immunological response variables are being analyzed by another entity 
and are not included in the analysis sections below: 
Assessments include, but are not limited to: Phenotypic analysis of PBMCs, 
Characterization of MDSCs, Quantification of tumor-specific T cell responses, 
Immune Landscape: Tumor Infiltrating Lymphocytes and Tumor Microenvironment, 
TCR sequencing, Immune Biomarkers, Pharmacogenomics, and BRCA status of 
tumors.  
A comprehensive list of variables to be analyzed for the exploratory assessment of 
correlative immunologic research is located in Section 8.7 of the protocol. 
3.4 Subjects Disposition and Evaluability 
3.4.1 Subject Disposition 
Subject disposition will be presented by cohort and overall.  The number of subjects 
enrolled and in the ITT and PP populations will be presented. 
The following will be summarized: 
• number and percentage of ITT subjects experiencing a DLT 
• number and percentage of ITT subjects discontinuing study treatment and the 
reasons for treatment discontinuation 
• number and percentage of ITT subjects completing and not completing the 
study (through 90 day on Study Follow-up period), and the reasons for study 
discontinuation 
• number and percentage of ITT subjects entering and discontinuing from the 
Follow-up Extension, and the reasons for discontinuation  
Descriptive statistics will also be presented for duration of time in study for subjects 
(start of therapy to last visit of follow-up). 
3.4.2 Protocol Deviations 
Protocol violations and deviations are recorded in a written log.  Any major protocol 
deviations will be described in the study report.   


 
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3.5 Demographics and Baseline Characteristics 
3.5.1 Demographics 
Subject demographics, height and weight will be summarized for the ITT and PP 
populations.  
Descriptive statistics will be provided for age (years), height (cm), and weight (kg).  
Frequencies and percentages will be tabulated for sex, race, ethnicity, disease staging 
at initial diagnosis and study entry, and for prior anti-cancer treatment use and the 
corresponding indications. 
3.5.2 Medical History 
The number and percentage of subjects having a non-oncological medical condition 
in each body system will be summarized for the ITT Population.  Non-oncological 
medical history will be presented in a subject listing. 
3.5.3 Oncological Treatment History  
. Prior oncological treatment, radiation and surgical history will be presented in subject 
listings. 
3.6 Prior and Concomitant Medications/Procedures 
Prior and concomitant medications will be coded using the World Health 
Organization (WHO) Drug dictionary (Version Dec 2014).   
A concomitant medication is defined as any drug or substance administered between 
the time of the first dose of study treatment and the time of the last study visit.  This 
includes medications that were started prior to screening, if their use continued during 
or after dosing.  In order to define whether a medication with missing start or stop 
dates is a concomitant medication, refer to the following additional criteria. 
• if both the start and stop dates of a particular medication are missing, that 
medication will be considered concomitant; 
• if the start date of a medication is missing and the stop date of that medication 
falls on or after the first dose date, that medication will be considered 
concomitant; 
• if the start date of a medication is missing and the stop date of the medication 
is prior to the first dose date, that medication is considered not concomitant; 
• If the start date of a medication is prior to the first dose date and the stop date 
of the medication is missing, that medication is considered concomitant. 


 
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Concomitant medication use will be classified by Anatomical Therapeutic Class 
(ATC) level 4 and PT for the ITT population.  For the presentation of concomitant 
medications, the ATC level 4 terms will be sorted alphabetically, and within ATC 
level 4 term, the PT will be used and presented by decreasing total frequency overall. 
Frequencies and percentages of subjects using each concomitant medication will be 
presented for the ITT population. Prior and concomitant medications and concomitant 
procedures/surgeries will be presented in subject listings. 
3.7 Treatment Exposure 
For each subject, treatment duration and the total number of cycles treated will be 
calculated based on the expected treatments for that subject in accordance with their 
assigned cohort.  Treatment duration (weeks) will be calculated for each subject as: 
([date of last dose of any study drug received – date of first dose of any study drug 
received +1]/7).  
Descriptive statistics for treatment duration and the total number of treatment cycles 
will be displayed. The number of doses and cumulative dose received will be 
summarized for PLD, MEDI4736, and Motolimod. Study drug administration will be 
presented in a subject listing. 
3.8 Efficacy Analysis 
3.8.1 Progression-free Survival 
The primary endpoint in Phase 2 of this study is the PFS rate at 6 months defined as 
the visit at the start of Cycle 7, where progression is assessed for subjects based on a 
combination of RECIST v1.1 and/or the clinician’s assessment of clinical progression 
or death. The primary efficacy analysis will be based on the Per Protocol population.  
A sensitivity analysis will be conducted on the ITT population.  A secondary efficacy 
analysis will be conducted on the Phase 2 Per Protocol population. 
The primary efficacy analysis entails testing the null hypothesis that PFS at 6 months 
is less than or equal to 25% against the alternative hypothesis that PFS at 6 months is 
higher for those treated with PLD and MEDI4736 combination.  This hypothesis will 
be tested at α=0.05 using the 90% two-sided confidence interval for the PFS rate at 6 
months based on Kaplan-Meier product limit estimates.  The null hypothesis will be 
rejected in favor of the alternative if the lower bound of that confidence interval is 
greater than 25%. The null hypothesis will also be tested using a one-sided binomial 
test as a sensitivity analysis.  In this analysis, if a subject has no tumor response 
assessment, or discontinued treatment or withdrew from the study for other reasons, 
he or she will be considered as “progressed.” The null hypothesis will be rejected in 
favor of the alternative if the lower bound of a two-sided 90% binominal confidence 
interval is greater than 25%.    


 
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Table displays will include PFS rate at 6 months and the corresponding 90% 
confidence interval along with the corresponding number of subjects at risk.  In 
addition, PFS will be presented graphically.   
Secondary efficacy analyses will use the secondary efficacy endpoints listed in 
section 3.3.1 of the SAP and will be based on the ITT population.  PFS rate and the 
corresponding 95% confidence interval will be calculated based on Kaplan-Meier 
product limit estimates and will be displayed by cohort and phase.   
Descriptive analyses of PFS will include the following: 
• Number and percentage of subjects that died or had a confirmed progression, 
• Number and percentage of subjects that survived without a confirmed 
progression,  
• Number and percentage of subjects lost to follow up (unknown survival 
and/or progression status), and  
• Number of subjects missing the tumor response assessment  
PFS time will be summarized for each cohort and phase and will include the 25th 
percentile, median, 75th percentile, corresponding 95% CIs, minimum and maximum, 
where PFS time will be calculated using the Kaplan-Meier method. In addition, PFS 
will be presented graphically. 
PFS time is defined as time from the start date of the treatment (Day 1) to the first 
occurrence of confirmed progression (clinical or radiological), or the date of death 
due to any cause, whichever occurs first. Subjects without documentation of 
progression at the time of the analysis will be censored at the date of the last tumor 
response assessment, date of start of alternate therapy, or last contact if in post study 
follow-up, whichever comes first. Subjects with no tumor response assessment will 
be censored at the start date of the treatment.  
3.8.2 Tumor Response  
Tumor response will be summarized and analyzed descriptively for the ITT 
population. 
The number and percentage of subjects meeting criteria of CR, PR, SD, and PD will 
be displayed.  The number and percentage of subjects meeting criteria of CR or PR 
over a period of at least 4 weeks (Overall Response Rate – ORR) based on RECIST 
v1.1 and irRECIST, as well as the number and percentage of subjects meeting criteria 
of SD, PR, or CR over a period of at least 4 weeks (Overall Disease Control Rate – 
ODCR) will be displayed along with the corresponding 95% binomial CIs.  In 
calculating ORR and ODCR, subjects who drop out prior to meeting the responder 
criteria will be considered as non-responders. Descriptive statistics will be presented 
for duration of response, defined as the time from the first response of PR or CR to 


 
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the date of disease progression or death. Tumor response and tumor marker CA-125 
will be presented in subject listings.  
3.8.3 Overall Survival 
Overall survival (OS) time will be based on data collected during study and Post 
Study Follow-up. OS time is defined as the time from the start date of the treatment 
(Day 1) to the date of death due to any cause and will be analyzed descriptively.   
The number and percentage of subjects who died, who were lost to follow up, and 
who survived will be summarized. Subjects who withdrew from the study or were lost 
to follow-up (survival status unknown) will be censored at the date of last contact/last 
data point collected in the CRF. 
OS Rate and the corresponding 95% confidence intervals at 6 months and 12 months 
will be calculated based on Kaplan-Meier product limit estimates and will be 
displayed along with the corresponding number of subjects at risk at each time point.  
OS time will be summarized descriptively. The 25th percentile, median, 75th 
percentile, corresponding 95% CIs as well as the minimum and maximum survival 
time will be calculated using the Kaplan-Meier method.  In addition, OS estimates 
will be presented graphically. 
3.9 Safety Analysis 
All safety analyses will be performed using the ITT population.  For clinical 
laboratory, data collected from all core study cycles and/or on-study follow-up 
assessments will be analyzed for each subject.  For vital signs, ECOG performance 
status, and ECG, only data collected from the first two cycles and/or on-study follow-
up assessments will be analyzed for each subject.  All subject data including those 
from the additional cycles will be presented in subject listings.   
3.9.1 Adverse Events 
All adverse events will be coded using the Medical Dictionary of Regulatory 
Activities (MedDRA) Version 19.0 and will be classified by MedDRA system organ 
class (SOC) and preferred term (PT).   
The following imputation rules will be used for missing or incomplete AE start dates:  
• Missing AE start day:  
o If the partial date contains a different month from the date of first study 
dose, then impute it as the first day of the month.  
o If it contains the same month as the date of first dose, then impute it as 
date of first dose.  
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o If the partial date contains a different year from the date of first dose, then 
impute the missing day and month as Dec 31.  
o If it contains the same year as the date of first dose, then impute the 
missing day and month as day and month of first dose.  
• Completely missing AE date:  
o Impute the missing date as the date of first dose.  
3.9.1.1   Overall Summary of Treatment Emergent Adverse Events 
An overall summary of TEAEs will be presented by cohort and for all subjects 
combined.  The number and percentage of subjects who experienced at least one AE, 
at least one TEAE, at least one TRAEs, at least one TEAE of Grade 3 or higher, at 
least one TRAE of Grade 3 or higher, at least one serious TEAE, at least one DLT, at 
least one serious TRAE, at least one TEAE leading to treatment discontinuation, at 
least one TRAE leading to treatment discontinuation, and number of subjects with an 
adverse event resulting in death will be displayed. 
3.9.1.2 Treatment Emergent Adverse Event Incidences 
The incidence of TEAEs will be presented by cohort and for all cohorts combined. 
The number and percentage of subjects who experienced at least one TEAE as well as 
the number and percentage of subjects who experienced at least one TEAE within 
each specific SOC and PT will be presented.  For this analysis, if a subject has more 
than one occurrence of the same PT, then the PT will be counted only once for that 
subject.  Similarly, if a subject has more than one PT within the same SOC, the 
subject will be counted only once in that SOC. 
A summary table of TEAEs by PT will also be presented by cohort and for all cohorts 
combined. 
For the presentation of AE incidences, the SOCs will be sorted alphabetically, and 
within SOC, the preferred term (PT) will be presented by decreasing total frequency. 
Adverse events leading to study withdrawal, leading to study drug interruption or 
discontinuation, treatment emergent adverse events, serious adverse events, dose-
limiting toxicities, and deaths will be displayed in subject listings.  
3.9.1.3   Adverse Events by Maximum CTCAE Grade 
TEAEs will be presented by maximum CTCAE grade for each PT by cohort and for 
all subjects combined.  For this analysis, if a subject has more than one occurrence of 
the same PT, then the PT will be counted only once for that subject under the 
maximum grade at which it was experienced.   


 
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3.9.1.4  Treatment Related Adverse Events 
Adverse events with a relationship to study drug of “possibly,” “probably” or 
“definitely” related will be classified as treatment related.   
The number and percentage of subjects who experienced at least one treatment related 
AE within each specific SOC and PT will be presented overall and by cohort.  For the 
presentation of AE incidences, the SOCs will be sorted alphabetically, and within 
SOC, the preferred term (PT) will be presented by decreasing total frequency. 
The incidences of adverse events related to MEDI4736, motolimod, and PLD will 
also be summarized by SOC and PT. 
Incidence of treatment related AEs will be presented by maximum CTCAE grade for 
each PT by cohort.  For this analysis, if a subject has more than one occurrence of the 
same PT, then the PT will be counted only once for that subject under the maximum 
grade at which it was experienced.   
The incidences of adverse events related to MEDI4736, motolimod, and PLD will 
also be presented by maximum CTCAE grade for each PT overall and by cohort. 
3.9.1.5  TEAEs Leading to Study Drug Withdrawal 
TEAEs leading to study drug withdrawal of MEDI4736, motolimod, or PLD will be 
presented by SOC and PT and will also be presented in a subject listing. 
3.9.1.6  DLTs  
DLTs will be presented in subject listings. 
3.9.1.7  Serious Adverse Events 
The incidences of serious adverse events will be summarized by SOC and PT overall 
and by cohort. SAEs will be presented in a subject listing. 


 
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3.9.2 Clinical Laboratory Evaluation 
For each continuous laboratory (hematology and chemistry) parameter, results will be 
categorized as low, normal, or high based on the laboratory normal ranges.  
Frequencies and percentages will be presented by cohort and overall for the shifts in 
these categories from baseline to selected post-treatment assessment time points (i.e., 
low to normal, low to high, high to low, etc.).  Percentages for the shift tables will be 
calculated based on the number of subjects who had results for both baseline and the 
corresponding post-treatment assessment time point. Additionally, for continuous 
hematology and chemistry parameters, descriptive statistics will be presented for the 
changes from baseline to each selected post-treatment assessment time point.   
Abnormal laboratory values with their clinical significance status will be presented in 
a subject listing.   
3.9.3 Vital Signs 
For vital signs, descriptive statistics will be presented for changes from pre-dose to 
end of infusion on MEDI4736 dosing days in the first two cycles and for On Study 
Follow-up assessments.  End of infusion time points and change from pre-dose to end 
of infusion for subjects who experienced an interruption in the study drug 
administration (administration was stopped and subsequently restarted) will not be 
included. 
3.9.4 ECOG Performance Status  
ECOG Performance Status will be summarized by cohort by presenting the number 
and percentage of subjects with ECOG score 0, 1, 2, 3, and 4 at baseline and ECOG 
score of 0, 1, 2, 3, 4, and 5 at the last on-treatment assessment time point (including 
optional treatment extension time points) and last on-study follow-up time point for 
which ECOG Performance Status was assessed. ECOG data will be provided in a 
subject listing.   
3.9.5 12-Lead ECG  
Shift of normality status (normal, abnormal with no clinical significance, abnormal 
with clinical significance) from baseline to each selected post-treatment assessment 
time point will be presented for the ECG data. Based on the number of subjects who 
had non-missing results for both baseline and corresponding post-treatment 
assessment time point, percentages for the shift tables will be calculated.  ECG results 
will be provided in a subject listing.   
3.9.6 ECHO or MUGA  
For the ECHO or MUGA data, shift of normality status (normal, abnormal with no 
clinical significance, abnormal with clinical significance) from baseline to each 
selected post-treatment assessment time point will be presented. Percentages for the 


 
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shift tables will be calculated based on the number of subjects who had non-missing 
results for both baseline and corresponding post-treatment assessment time point. 
ECHO and MUGA data will be provided in a subject listing.   
3.9.7 Physical Examination 
Physical examination assessments, if performed, will be shown in a subject listing.   
 


 
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4 LIST OF TABLES  
Table 14.1.1 
Subject Disposition, All Subjects 
Table 14.1.2 
Demographics and Baseline Characteristics, ITT Population 
Table 14.1.3 
Demographics and Baseline Characteristics, Per-Protocol Population 
Table 14.1.4 
Non-Oncological Medical History, ITT Population 
Table 14.1.5 
Concomitant Medication, ITT Population 
Table 14.1.6 
Treatment Exposure, ITT Population 
Table 14.2.1.1 Progression-free Survival (PFS) Based on RECIST v1.1, Per-Protocol 
Population 
Table 14.2.1.2 Progression-free Survival (PFS) Based on RECIST v1.1, ITT Population 
Table 14.2.2.1 Summary of Progression-free Survival (PFS) Based on RECIST v1.1, ITT 
Population 
Table 14.2.2.2 Summary of Progression-free Survival (PFS) Based on irRECIST, ITT 
Population 
Table 14.2.3.1 Summary of Tumor Response, Overall Response Rate and Overall Disease 
Control Rate Based on RECIST v1.1 Criteria, ITT Population 
Table 14.2.3.2 Summary of Tumor Response, Overall Response Rate and Overall Disease 
Control Rate Based on irRECIST Criteria, ITT Population  
Table 14.2.4 
Summary of Overall Survival (OS), ITT Population 
Table 14.3.1  
Summary of Adverse Events, ITT Population 
Table 14.3.2 
Incidence of Treatment Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term, ITT Population 
Table 14.3.3 
Incidence of Treatment Emergent Adverse Events by MedDRA Preferred 
Term, ITT Population 
Table 14.3.4 
Incidence of Treatment Emergent Adverse Events by Maximum CTCAE 
Grade, MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.5.1 Incidence of Treatment Related Adverse Events by MedDRA System Organ 
Class and Preferred Term, ITT Population 
Table 14.3.5.2 Incidence of MEDI4736 Related Adverse Events by MedDRA System Organ 


 
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Class and Preferred Term, ITT Population 
Table 14.3.5.3 Incidence of Motolimod Related Adverse Events by MedDRA System Organ 
Class and Preferred Term, ITT Population 
Table 14.3.5.4 Incidence of Pegylated Liposomal Doxorubicin (PLD) Related Adverse Events 
by MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.6.1 Incidence of Treatment Related Adverse Events By Maximum CTCAE Grade, 
MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.6.2 Incidence of MEDI4736 Related Adverse Events By Maximum CTCAE 
Grade, MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.6.3 Incidence of Motolimod Related Adverse Events By Maximum CTCAE 
Grade, MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.6.4 Incidence of Pegylated Liposomal Doxorubicin (PLD) Related Adverse Events 
By Maximum CTCAE Grade, MedDRA System Organ Class and Preferred 
Term, ITT Population 
Table 14.3.7.1 Incidence of Treatment Related Adverse Events Leading to MEDI4736 
Withdrawal by MedDRA System Organ Class and Preferred Term, ITT 
Population 
Table 14.3.7.2 Incidence of Treatment Related Adverse Events Leading to Motolimod 
Withdrawal by MedDRA System Organ Class and Preferred Term, ITT 
Population 
Table 14.3.7.3 Incidence of Treatment Related Adverse Events Leading to PLD Withdrawal 
by MedDRA System Organ Class and Preferred Term, ITT Population 
Table 14.3.8 
Incidence of Serious Adverse Events by MedDRA System Organ Class and 
Preferred Term, ITT Population 
Table 14.4.1 
Hematology Parameters – Change from Baseline, ITT Population 
Table 14.4.2 
Hematology Parameters – Shift from Baseline, ITT Population 
Table 14.4.3 
Chemistry Parameters – Change from Baseline, ITT Population 
Table 14.4.4 
Chemistry Parameters – Shift from Baseline, ITT Population 
Table 14.4.5 
Vital Signs – Change from Pre-dose to End of Infusion, ITT Population 


 
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Table 14.4.6 
ECOG Performance Status at Baseline and Last Assessment, ITT Population 
Table 14.4.7 
ECG-Shift from Baseline, ITT Population 
Table 14.4.8 
ECHO or MUGA-Shift from Baseline, ITT Population 
 
 
5 LIST OF LISTINGS 
Listing 16.2.1 
Inclusion or Exclusion Criteria Not Met  
Listing 16.2.2 
Protocol Deviations 
Listing 16.2.3 
Study Disposition 
Listing 16.2.4 
Demographic Characteristics 
Listing 16.2.5 
Baseline Disease Characteristics 
Listing 16.2.6 
Non-Oncological Medical History and Procedures 
Listing 16.2.7 
Prior Oncological Treatment History 
Listing 16.2.8 
Prior Oncological Radiation History 
Listing 16.2.9 
Prior Oncological Surgical History 
Listing 16.2.10 
Study Drug Administration 
Listing 16.2.11 
Tumor Response by Visit 
Listing 16.2.12 
CA-125 
Listing 16.2.13 
Progression-free Survival and Overall Survival 
Listing 16.2.14 
Prior/Concomitant Medications 
Listing 16.2.15 
Concomitant Procedures/Surgeries 
Listing 16.2.16 
Treatment Emergent Adverse Events 
Listing 16.2.17 
Serious Adverse Events 
Listing 16.2.18 
Adverse Events Leading to Study Drug Interruption 
or Discontinuation 
Listing 16.2.19 
Adverse Events Leading to Study Withdrawal 
Listing 16.2.20 
Dose-Limiting Toxicities 


 
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Listing 16.2.21 
Deaths 
Listing 16.2.22 
Hematology Laboratory Findings 
Listing 16.2.23 
Chemistry Laboratory Findings 
Listing 16.2.24 
Abnormal Laboratory Findings 
Listing 16.2.25 
Vital Signs  
Listing 16.2.26 
ECOG Performance Status 
Listing 16.2.27 
ECGs  
Listing 16.2.28 
ECHO and MUGA  
Listing 16.2.29 
Physical Examination and Weight 
 
6 LIST OF FIGURES 
Figure 1.1.1 
KM Estimate of Progression-free Survival based on RECIST v1.1, 
Phase 1 Cohort Dose Level +1 and Phase 2 Combined Per-Protocol 
Population 
Figure 1.1.2 
KM Estimate of Progression-free Survival based on RECIST v1.1, 
Phase 2 Per-Protocol Population 
 Figure 1.2 
KM Estimate of Progression-free Survival based on RECIST v1.1,  
Phase 1 Cohort Dose Level +1 and Phase 2 Combined Intent-to-
Treat Population 
Figure 2.1 
KM Estimate of Progression-free Survival based on RECIST v1.1 
by Cohort, Intent-to-Treat Population 
Figure 2.2 
KM Estimate of Progression-free Survival based on irRECIST by 
Cohort, Intent-to-Treat Population 
Figure 3 
KM Estimate of Overall Survival by Cohort, Intent-to-Treat 
Population