Clinical trial NCT02805660
Conditions: Advanced Cancer
Keywords: MGCD0103 MEDI4736 Mocetinostat Durvalumab HDAC Inhibitor PD-L1 Inhibitor Phase 1 Phase 2 Metastatic Solid Tumor Non-small cell lung cancer immunotherapy checkpoint inhibitor
Sponsor: Mirati Therapeutics Inc.
Start date: 2016-06-01; Completion date: 2019-12-20
Enrollment: 83 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Mocetinostat (MGCD0103) is an orally administered HDAC inhibitor. Durvalumab (MEDI4736) is a human monoclonal antibody that is an inhibitor of the Programmed Cell Death Ligand (or PD-L1). Durvalumab is also known as a checkpoint inhibitor.

This study is evaluating the combination regimen of mocetinostat and durvalumab in participants with Advanced or Metastatic Solid Tumors and Non-Small Cell Lung Cancer.

Detailed description:

Arms: arm 1: The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase. arm 2: The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase. arm 3: The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase. arm 4: Participants with non-small cell lung cancer (NSCLC) who were naïve to treatment with immunotherapy, and had a tumor with no/low programmed cell death ligand 1 (PD-L1) expression were included in this cohort. arm 5: Participants with non-small cell lung cancer (NSCLC) who were naïve to treatment with immunotherapy, and had a tumor with high programmed cell death ligand 1 (PD-L1) expression were included in this cohort. arm 6: Participants with non-small cell lung cancer (NSCLC) who have been previously treated with an anti-programmed cell death ligand 1 (PD-L1) or anti-programmed cell death 1 (PD-1) agent with clinical benefit response followed by progression of disease were included in this cohort. arm 7: Participants with non-small cell lung cancer (NSCLC) who have been previously treated with an anti-programmed cell death ligand 1 (PD-L1) or anti-programmed cell death 1 (PD-1) agent who had progression of disease ≤ 16 weeks after initiation of treatment were included in this cohort.
Interventions: intervention 1: Mocetinostat - 50 mg intervention 2: Mocetinostat - 70 mg intervention 3: Mocetinostat - 90 mg intervention 4: Mocetinostat - Recommended Phase 2 Dose (70 mg) intervention 5: Durvalumab - 1500 mg
Intervention descriptions: intervention 1: Participants received mocetinostat three times weekly as an oral capsule. intervention 2: Participants received mocetinostat three times weekly as an oral capsule. intervention 3: Participants received mocetinostat three times weekly as an oral capsule. intervention 4: Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg). intervention 5: Participants received durvalumab as an intravenous infusion every 4 weeks.

Protocol documents:
Prot_000.pdf: 
Protocol Number:  0103-020 
 
Official Title:     A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, 
in Combination With PD-L1 Inhibitor, Durvalumab, 
in Advanced or Metastatic Solid Tumors and 
Non-Small Cell Lung Cancer 
 
NCT Number:  NCT02805660 
 
Document Date:  10 May 2017 


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CLINICAL RESEARCH PROTOCOL 
 
DRUG: 
Mocetinostat (MGCD0103) and Durvalumab 
(MEDI4736) 
STUDY NUMBER(S): 
0103-020 
PROTOCOL(S) TITLE: 
A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, 
in Combination With PD-L1 Inhibitor, Durvalumab, 
in Advanced or Metastatic Solid Tumors and 
Non-Small Cell Lung Cancer 
IND NUMBER: 
128250 
SPONSOR: 
Mirati Therapeutics, Inc. 
9393 Towne Centre Drive, Suite 200 
San Diego, California, 92121, USA 
ORIGINAL PROTOCOL 
DATE: 
15 January 2016 
VERSION NUMBER: 
V3.0 
VERSION DATE: 
10 May 2017 
 
 
 
CONFIDENTIALITY STATEMENT 
This is a Mirati Therapeutics, Inc. document that contains confidential information.  It is intended solely for 
the use of the clinical Investigator(s) and other individuals involved in the study of mocetinostat and 
durvalumab.  This document is not to be reproduced, abstracted, or quoted without written authorization 
from Mirati Therapeutics. 
 


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DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol 
Version 1.0 
15 JAN 2016 
NA 
Amendment #1 
Version 2.0 
26 FEB 2016 
At the request of FDA during IND review –  
Following added to ECG evaluations during study: 
• Table 1 – Added single ECG to Day 1 of Cycle 3 and higher 
and at End of Treatment 
• Table 1 – Added X indicators for triplicate ECGs described 
in Table 2 for Day 1 of Lead-in Period, Cycle 1 and Cycle 2 
• Table 1 and Table 2 – Footnotes updated to indicate manual 
calculation of QTc intervals using Fridericia’s formula for all 
ECGs 
• Section 7.3.5 – Clarified calculation of QTc intervals 
manually using Fridericia’s formula  
Decision making during Phase 1 dose escalation using the 
modified toxicity probability interval (mTPI ) method was made 
more conservative by using the MTD definition of 0.25 
probability of toxicity rather than the original 0.3 probability.  
The definition of MTD in Section 3.1.3 was updated 
accordingly.  
In addition, a few word omissions or typographical errors were 
corrected. 
Amendment #2 
Version 3.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 MAY 2017 
• 
Study Summary: 
o 
Added language for Phase 2 clinical activity evaluable 
populations and included Predictive Probability Design 
(similar to Simon design, but allowing for more 
flexibility in the number of evaluable patients to take a 
decision on continuing or stopping additional patient 
enrollment).  
• 
Schedule of Assessments (Table 1): 
o 
Added optional tumor biopsy for biomarker studies at 
C2D1 
o 
Deleted liver enzyme panel as a separate assessment 
item as these tests are included in the serum chemistry 
panel 
o 
Clarified language in footnote 7 to allow for collection 
of safety labs one day prior to the start of Lead-in 
Day 1 and C1D1 (per Protocol Administrative letter 
dated 27Jul16) 
o 
Added language to footnote 10 noting that tumor 
biopsy samples will not be collected on subjects in the 
Phase 1 50 mg cohort (per Protocol Administrative 
letter dated 28Apr16) 
o 
Clarified language in footnote 12 for timing of single 
lead ECGs versus triplicate ECGs 
o 
Updated footnote 13 to allow for use of PET scans for 
assessment of bone lesions if per standard of care 


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Document 
Version Date 
Summary of Changes 
Amendment #2 
Version 3.0 (cont’d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Introduction and Rationale: 
o 
Updated mocetinostat clinical data section for 
consistency with most recent version of mocetinostat 
Investigator’s Brochure (v9.0) 
o 
Updated durvalumab clinical data section and adverse 
events of special interest for consistency with most 
recent version of durvalumab Investigator’s Brochure 
(v10.0) 
• 
Study Design: 
o 
Added language for Phase 2 clinical activity evaluable 
population and included Predictive Probability Design 
(similar to Simon design, but allowing for more 
flexibility in the number of evaluable patients to take a 
decision on continuing or stopping additional patient 
enrollment) (page 52) 
• 
Inclusion Criteria: 
o 
Inclusion criteria #2 updated to include patients that 
have received either a platinum-based chemotherapy or 
an immunotherapy regimen based on changing standard 
of care for first line therapy 
o 
Inclusion criteria #2.b.ii deleted to exclude patients 
with tumors that test positive for EGFR mutation or 
ALK fusion 
• 
Exclusion Criteria: 
o 
Added Exclusion for Patients with any history of 
tumors that test positive for EGFR, ROS1, ALK 
mutations or ALK fusions or any other mutations for 
which there are tyrosine kinase inhibitors available or 
under development 
o 
Revised Exclusion #12 to include patients with a 
history of chronic hepatitis C that is no longer present 
Revised Exclusion #17.c to allow for assessment from 
one ECG reading, as per Schedule of Assessments 
o 
Revised Exclusion #19 to note that subjects with active 
brain metastases are exclusionary. Subjects are eligible 
if brain metastases are adequately treated and subjects 
are neurologically stable (except for residual signs or 
symptoms related to the CNS treatment) for at least 
2 weeks prior to enrollment without the use of 
corticosteroids, or on a stable or decreasing dose of 
≤ 10 mg daily prednisone (or equivalent) 
• 
Study Treatment: 
o 
Updated Section 5.1.1 to add capsule strengths of 
10 mg and 25 mg for mocetinostat study drug treatment 
(per Protocol Administrative Letter dated 05Jul16) 
o 
Updated Section 5.1.6 to provide further direction 
around mocetinostat administration and vomiting, as 
well as mocetinostat administration around PK 
sampling 


 
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Document 
Version Date 
Summary of Changes 
Amendment #2 
Version 3.0 (cont’d) 
• 
Study Treatment (cont’d): 
o 
Updated Section 7.2 to allow for use of positron 
emission tomography (PET) scans for assessment of 
bone lesions if per standard of care 
o 
Added Section 9.3.2 to define the Phase 2 Clinical 
Activity Evaluable Population 
o 
Revised Section 5.1.8, Table 9, Table 10, Table 11 and 
Appendix 4 to include updated toxicity management 
guidelines for durvalumab (per Protocol Administrative 
letter dated 07Sep16) 
o 
In Table 13 clarified that Gamma glutamyltransferase is 
collected at Screening, C1D1, and as clinically 
indicated 
o 
Addressed clerical errors and made minor clarifications 
of language 
 
 


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STUDY SUMMARY 
Title:  
Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination 
With PD-L1 Inhibitor, Durvalumab, in Advanced or Metastatic Solid 
Tumors and Non-Small Cell Lung Cancer 
Rationale:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advanced tumors evade host immune responses by down regulation 
of major histocompatibility complex (MHC) molecules and tumor 
antigens and by creating an immune suppressive microenvironment 
around the tumor.  Histone deacetylases (HDACs) have been 
implicated in the epigenetic regulation of innate and adaptive 
immunity.  Increasing evidence supports the proposal that spectrum-
selective inhibitors of class I HDACs can reverse immune evasion and 
elicit antitumor host response through immunostimulatory 
mechanisms.  The immunomodulatory properties of class I HDAC 
inhibitors are reported to be mediated through multiple mechanisms 
including: 1) induction of programmed cell death ligand 1 (PD-L1) 
expression on the tumor cell surface, 2) induction of tumor associated 
antigens (TAAs) and MHC Class I and Class II molecules on tumor 
cells, 3) induction of immunogenic cell death via activation and 
cross-presentation of tumor antigens by antigen presenting cells 
(APCs), 4) enhanced function of T effector cells, and 5) decreased 
function of immunosuppressive cell subsets including T regulatory 
(Treg) cells and myeloid-derived suppressor cells (MDSCs).  In 
addition, HDAC inhibitors are associated with anticancer effects 
through inhibiting cell cycle progression and inducing apoptosis in 
tumor.  The combination of a class I HDAC inhibitor with an 
anticancer immunotherapy has the potential to enhance activity over 
that observed with either agent alone. 
Mocetinostat is a spectrum-selective Class I/IV HDAC inhibitor 
specifically targeting HDACs 1, 2, 3 and 11.  Class I and IV HDACs 
are of particular interest from an immunostimulatory and immune 
priming perspective.   
Durvalumab is a human monoclonal antibody (MAb) that inhibits 
binding of PD-L1 to programmed cell death 1 (PD-1) and CD80 
expressed on host immune effector cells, preventing immune 
suppression signaling.  Durvalumab is being developed as a potential 
anticancer therapy for patients with advanced solid tumors or 
hematological malignancies.   
 


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Rationale 
(cont’d): 
 
In this study, the treatment regimen will begin with a 7-Day Lead-in 
Period of mocetinostat followed by start of the combination regimen 
of mocetinostat and durvalumab.  The Recommended Phase 2 Dose 
(RP2D) of mocetinostat will be established in the Phase 1 dose 
escalation segment, followed by evaluation of the clinical activity of 
the combination regimen in patients having NSCLC.  
Target 
Population: 
Phase 1:  Patients with advanced solid tumors.  
Phase 2:  Patients with advanced or metastatic NSCLC, who have 
received prior treatment with at least one platinum-containing doublet 
chemotherapy regimen for advanced/metastatic disease.  
Number in 
Trial:  
Phase 1:  Approximately 24 patients. 
Phase 2:  As many as 261 patients.  
Primary 
Objectives:  
• To determine the Recommended Phase 2 Dose (RP2D) of 
mocetinostat administered in combination with full dose 
durvalumab. 
• To evaluate the clinical activity of mocetinostat in combination 
with durvalumab in cohorts of patients with NSCLC having 
differing tumor expression of PD-L1 or prior tumor 
responsiveness to treatment with checkpoint inhibitors.  
Secondary 
Objectives: 
 
• To evaluate the safety and tolerability of mocetinostat in 
combination with durvalumab in the selected population. 
• To evaluate secondary efficacy endpoints with mocetinostat in 
combination with durvalumab treatment in the selected 
population. 
• To evaluate mocetinostat and durvalumab pharmacokinetics (PK). 
• To evaluate the incidence of anti-drug antibodies (ADA) to 
durvalumab. 
• To evaluate the effect of mocetinostat during the Lead-in Period 
on tumor cell PD-L1 expression.   


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Primary 
Endpoints: 
• Incidence of Dose Limiting Toxicities (DLTs) occurring during 
the first 28-day cycle of combination treatment.  
• Objective Response Rate (ORR) as defined by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Secondary 
Endpoints: 
• Safety characterized by type, incidence, severity, timing, 
seriousness and relationship to study treatment of adverse events 
and laboratory abnormalities. 
• Secondary efficacy endpoints: 
o Duration of Response (DR); 
o Clinical Benefit Rate (CBR); 
o Progression-Free Survival (PFS); 
o 1-Year Survival Rate; and 
o Overall Survival (OS). 
• Blood plasma MGCD0103 and MEDI4736 concentrations. 
• Anti-drug antibody (ADA) detected in blood. 
• Tumor PD-L1 expression. 
 
 
 
 
 
 
 
 
 


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Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 0103-020 is an open-label Phase 1/2 evaluation of mocetinostat 
in combination with durvalumab.  The Phase 1 segment will define 
the RP2D of mocetinostat to be used in combination with the full dose 
regimen of durvalumab; eligible patients will have an advanced solid 
tumor disease that is not amendable to curative treatment.  The Phase 
2 segment will evaluate the clinical activity of mocetinostat in 
combination with durvalumab, as assessed by ORR in accordance 
with RECIST 1.1., in patients with locally advanced, unresectable or 
metastatic NSCLC who have previously received at least one 
platinum-containing doublet chemotherapy regimen for advanced 
disease.  Patients who have previously received treatment with 
checkpoint inhibitors may be in enrolled in the Phase 1 assessment 
and will be enrolled into dedicated cohorts in the Phase 2 assessment.  
Secondary objectives include secondary efficacy endpoints, PK, 
incidence of ADA and change in tumor PD-L1 expression.  
 
 The Schedule of Assessments to be 
performed in the study is presented in Table 1.  Triplicate ECG 
assessments, PK, and ADA collection time points are presented in 
Table 2. 
The treatment regimen to be evaluated in this study includes a 7-Day 
Lead-in Period of mocetinostat single agent administered three times 
weekly (TIW, e.g., Monday, Wednesday and Friday) followed by 
administration of the combination regimen with durvalumab.  The 
RP2D dose of mocetinostat will be established in successive dose 
escalation cohorts in the Phase 1 study and utilized in the Phase 2 
study.  The dose and regimen of durvalumab to be used throughout the 
study is 1500 mg on Day 1 of each 28-day cycle (i.e., Q4W).  
Guidelines for adverse event management and associated treatment 
modifications of each agent are provided in Section 5. 
The dose escalation phase of the study will employ the modified 
toxicity probability interval (mTPI [Ji-2013]) method.  The 
mocetinostat dose levels planned for evaluation include 50, 70, and 
90 mg TIW, depending on safety observations.  In addition, if 
necessary, dose de-escalation of mocetinostat to 40 mg TIW may be 
undertaken.   
 


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Study Design 
(cont’d): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Phase 2 study will enroll patients with NSCLC into one of the 
following 4 population cohorts: 
Cohort 1 – Patients naïve to treatment with immunotherapy, 
having tumor with no/low PD-L1 expression. 
Cohort 2 – Patients naïve to treatment with immunotherapy, 
having tumor with high PD-L1 expression. 
Cohort 3 – Patients previously treated with an anti-PD-L1 or 
anti-PD-1 agent with clinical benefit response followed by 
progression of disease. 
Cohort 4 – Patients previously treated with an anti-PD-L1 or 
anti-PD-1 agent with progression of disease ≤ 16 weeks after 
initiation of treatment. 
Tumor PD-L1 expression will be determined by the PD-L1 (SP263) 
CDx assay.  No/low PD-L1 expression is defined as positivity < 25% 
of tumor cells; high PD-L1 expression is defined as positivity ≥25% 
of tumor cells.  Tumor samples used to establish PD-L1 expression for 
eligibility must have been collected after the most recent systemic 
therapy. 
The sample sizes for the populations to be enrolled in the Phase 2 
portion of the study are based on Predictive Probability Design, which 
allows for flexibility in the number of patients to be included at first 
stage in order to ensure that sufficient number of evaluable patients 
are available for decision to continue or to stop enrollment of 
additional patients.   
• Cohorts 1, 3 and 4:  Stage 1 of enrollment will include a 
minimum of 9 evaluable patients.  With exactly 9 evaluable 
patients at Stage 1, if at least 1 patient has an Objective 
Response, 8 additional evaluable patients will be enrolled, for 
a total sample size of 17 evaluable patients.  If at least 
3 Objective Responses are observed, further investigation may 
be warranted.     
• Cohort 2:  Stage 1 of enrollment will include approximately 
17 evaluable patients. With exactly 17 evaluable patients at 
Stage 1, if at least 5 patients have Objective Responses, 
27 additional evaluable patients will be enrolled, for a total 
sample size of 44 evaluable patients.  If at least 18 Objective 
Responses are observed, further investigation may be 
warranted.   


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Study Design 
(cont’d): 
 
The exact stopping rules for all cohorts will be calculated based on the 
Predictive Probability Design, once the exact number of patients 
evaluable at Stage 1 is known. The aim is to get a minimum of 
9 evaluable patients at Stage 1 for cohorts 1, 3 and 4 and about 
17 evaluable patients at Stage 1 for cohort 2. 
The populations included in Cohorts 3 and 4, who have had 
progression of disease during or following treatment with a 
checkpoint inhibitor, represent a potential unmet medical need.  For 
this reason, if results in Stage 2 of enrollment are of high interest, 
enrollment may be expanded to as many as 100 patients total in each 
cohort to narrow the 95% Confidence Interval (CI) around the ORR 
point estimate and more fully characterize the secondary endpoints in 
the population of interest. 
In order to be part of the clinical activity evaluable population, the 
patient must have at least one on-study disease assessment or 
discontinue from treatment for PD prior to this assessment.  Patients 
who discontinue treatment prior to the first on-study disease 
assessment for an AE, toxicity, or withdraw consent are considered 
non-evaluable for disease assessment.  These patients will not be part 
of the clinical activity evaluable population. 
Disease response and progression as documented by the investigator 
in the Case Report Form (CRF) will be the basis for patient 
management and study expansion decision making.  Unconfirmed 
objective responses recorded in the CRF may be used as the initial 
basis for expansion of study enrollment; however, follow-up 
evaluations on patients with unconfirmed responses must continue to 
support the decision to continue to the full number of patients to be 
included in the next stage.  Central radiology review for disease 
response and progression may be added to the study during Stage 2.  
If this occurs, central review of all radiologic assessments performed 
in the study will be expected (including retrospective review of 
patients enrolled in Stage 1), and central radiology review for disease 
response will be the basis for the primary statistical analyses to 
estimate the objective response rate and its confidence interval, as 
well as the duration of response and PFS.   


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Table 1: 
Schedule of Assessments 
The Schedule of Assessments provides an overview of the protocol visits and procedures.  Refer to Section 7 for detailed information 
on each assessment.  Additional, unplanned assessments should be performed as clinically indicated, including for the purpose of fully 
evaluating adverse events. 
Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before study 
specific 
assessments 
 
 
 
 
 
 
 
 
Tumor PD-L1 Expression 
Testing2 
X 
 
X 
 
 
 
 
X 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
 
X 
 
Abbreviated Physical 
Exam3 
 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test5 
X 
As clinically indicated 
 
Hematology6,7 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 1: 
Schedule of Assessments – During Study (Continued) 
Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Coagulation6,7 
X 
As clinically indicated 
 
Urinalysis6,7 
X 
 
X 
 
X 
 
X 
 
 
Serum Chemistry6,7 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Test6,7 
X 
 
X 
 
X 
 
X 
 
 
Blood for 
Pharmcokinetics8 
 
See Table 2 
90 Days 
Blood for Anti-Drug 
Antibody9 
 
See Table 2 
90 Days 
Biopsy of tumor for 
Biomarker Studies10 
X 
 
X 
 
X10 
 
 
X 
 
Blood Samples for 
Biomarker Studies11 
X 
X 
X 
X11 
11 
 
 
 
 
Single 12-Lead ECG12 
X 
 
 
 
Cycle 3 
 
X 
X 
 
Triplicate 12-Lead ECG12 
 
X, See Table 2 
X 
 
Cycle 2 
 
 
 
 
Echocardiogram 
X 
 
 
X 
X 
 
X 
X 
 
 
 
 


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Table 1: 
Schedule of Assessments – During Study (Continued) 
Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Disease Evaluation13 
X 
 
Q 8 weeks Starting from Cycle 1, Day 1 until Week 49 (~1 year)  
and then Q 12 weeks 
 
Mocetinostat Dispensing 
and/or Reconciliation 
 
X 
X 
 
X 
 
X 
 
 
Durvalumab 
Administration 
 
 
X 
 
X 
 
X 
 
 
Adverse Events14 and 
Concomitant Medications 
SAEs only 
Throughout 
SAEs only 
for 90 Days 
Long Term Follow-up16 
 
 
 
 
 
 
 
 
X 
1 
Study Participation Informed Consent: May be performed prior to 28 days before first dose of study treatment and must be completed prior to study 
specific assessments. 
2 
Tumor Testing for PD-L1 Expression: Required test for patients enrolling in Cohorts 1 and 2; encouraged for patients enrolling in Phase 1 or Phase 2 
Cohorts 3 and 4.  Biopsy may precede informed consent if performed as Standard of Care (SOC) or to assess eligibility for a different clinical trial.  In 
Cohorts 1 and 2, the sample tested must have been collected following completion of the most recent systemic treatment regimen. 
3 
Physical Examinations: A complete physical examination required at Screening and End of Treatment only.  Height will be recorded at screening only.  
All other evaluations will be symptom-directed, abbreviated evaluations. 
4 
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated.  In addition, blood pressure and pulse rate 
will be assessed every 30 minutes (± 5 minutes) between the start and end of durvalumab infusions and, for the first infusion, for 1 hour post infusion.  If 
the Durvalumab infusion period lasts 60 minutes, the first BP and pulse assessment should be made 30 minutes into the infusion and 30 minutes later at 
the end.  If the infusion period lasts longer than 60 minutes, BP and pulse assessment should continue to be made at 30-minute (± 5 minutes) intervals. 


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5 
Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at 
screening will be required.  The informed consent process must include discussion of the risks associated with pregnancy and adequate contraception 
methods.  Additional pregnancy testing may be necessary if required by local practices or regulations, or if potential pregnancy is suspected. 
6 
Selected Lead-In, Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.   
7 
Safety Laboratory Assessments: Hematology, coagulation, chemistry and thyroid function evaluations (see Section 7.3.4) will be performed by local 
laboratories. For scheduling convenience, these assessments may be performed one day prior to the visit at the start of the 7-day Lead-in Period and 
Cycle 1 Day 1. 
8 
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Table 2.  In addition, in the 
event of a Serious Adverse Event (SAE), unscheduled PK blood samples should be drawn for each study treatment as soon as possible.  
9 
Anti-Drug Antibody Samples: Blood samples to be collected as scheduled in Table 2.   
10 
Tumor Biopsy for Biomarker Studies:  Consent for serial sampling of tumor tissue (preferably the same lesion) is requested but is not mandatory for 
study entry.  The tumor biopsy used to determine eligibility may be used for the baseline assessment.  Four collection timepoints are scheduled: 
baseline, C1D1, C2D1, and EOT. Markers of interest in tumor tissue include PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs), natural 
killer cells (NK-cells), T regulatory cells (Tregs), and myeloid derived suppressor cells (MDSCs). Tumor biopsy tissue samples will not be collected on 
subjects in the Phase 1 50 mg cohort, and are optional for subjects in all other cohorts. 
11 
Blood Samples for Biomarker Studies:  Blood samples for biomarker studies will not be collected on subjects in the Phase 1 50 mg cohort, but will be 
required for subjects in all other cohorts. At the beginning of the study, sampling will be scheduled on Cycle 1 Day 15.  During the study, emerging data 
may indicate that quality of information gained from the assessment should improve with increased duration of combination treatment  If so, the sample 
may be moved to Cycle 2 Day 1 and communicated to Investigators by Administrative Letter.  Markers of interest in circulation include circulating 
PD-L1, Tregs, MDSCs, NK-cells, flow cytometry for T- and B-cell including CD4, CD8 and Ki67, and selected cytokines including CD8A, GZMB, 
IFNγ, CXCL9, CXCL10, CXCL11, and TBX21. 
12 
ECGs: Single 12-lead ECGs are to be performed at screening and at points not accompanied by PK sampling, with the exception of C3D1, C4D1 and 
C7D1.  On days when PK samples are being collected, the single ECG should be performed prior to the blood draw.  Triplicate ECGs are to be 
performed to as noted in Table 2.  Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and QTc intervals 
(Fridericia’s formula).  Respiration rate should be recorded during each ECG assessment. 
13 
Disease Evaluations: To be performed at screening (28 day window allowed) and every 8 weeks ( ± 10 days window) from C1D1 for all other 
assessments except screening until Week 49 (~1 year) and then every 12 weeks.  At screening/baseline, assessments are to include CT with contrast of 
the chest, abdomen and pelvis, as well as brain Magnetic Resonance Imaging (MRI) with and without gadolinium or Computed Tomography Scan (CT) 
with contrast, a whole body bone scan and evaluation of any superficial lesions.  Subsequent disease assessments should include all sites of disease 
identified at baseline or suspected to have developed; bone scans may be performed at one-half the frequency of other radiology evaluations and should 
be performed during assessment for confirmation of disease response.  For those sites that routinely use PET scans for assessment of bone lesions in lieu 
of skeletal scintigraphy, PET scans may be used on-study, with the same modality planned throughout the study for any given patient.  More detailed 
guidance on exceptional circumstances is provided in the protocol.   


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14 
Adverse Events: SAEs will be reported from the time of informed consent until 90 days after the last administration of mocetinostat or durvalumab.  
Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution or 
stabilization of acute AEs and/or ongoing SAEs.  After the 90-day SAE observation period, post-treatment follow-up may be performed by remote 
contact (e.g., telephone call).   
15 
End of Treatment: Assessments that have been completed in the previous 4 weeks do not need to be repeated (8 or 12 weeks for tumor assessments in 
accordance with schedule).   
16 
Long Term Follow-up: Blood samples for MEDI4736 PK and ADA will be collected approximately 90 days after the last infusion of durvalumab.  
Survival status and subsequent therapies will be collected during long term follow-up every 2 months (±14 days) from the date the subject was 
discontinued from study treatment until death or lost to follow-up.  Follow-up beyond 90 days after last treatment may be performed by telephone 
contact.


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Table 2: 
Schedule of Triplicate ECG, PK and ADA Assessments 
Nominal Cycle Day 
Mocetinostat 1 
Durvalumab 1,2 
Triplicate ECG 3  
PK Sample 5,6,7 
PK Sample 5,6 
ADA Sample 6 
Lead-In Day 1 
Pre-4 and post-dose  
(1 hour only)  
Phase 1: Pre- and post-dose (1, 3 and 7 hour) 
Phase 2: Pre- and post-dose (1 hour) 
 
 
Cycle 1 Day 1 (Day 1, Week 1) 
Pre- and post-dose  
(1 hour only)  
Phase 1: Pre- and post-dose (1, 3 and 7 hour) 
Phase 2: Pre- and post-dose (1 hour) 
Pre-dose and end-of-infusion  
Pre-dose 
Cycle 1 Day 15 (Day 15, Week 3) 
 
Pre- and post-dose (1 hour) 
Pre-mocetinostat dose 
  
Cycle 2 Day 1 (Day 29, Week 5) 
Pre- and post-dose  
(1 hour)  
Pre- and post-dose (1 hour) 
Pre-dose 
Pre-dose 
Cycle 3 Day 1 (Day 57,Week 8) 
 
Pre- and post-dose (1 hour)  
Pre-dose 
  
Cycle 4 Day 1 (Day 85, Week 13) 
 
 
Pre-dose and end-of-infusion  
Pre-dose 
Cycle 7 Day 1 (Day 169, Week 25) 
 
Pre-dose 
Pre-dose 
Pre-dose 
Long Term Follow-up 
 
 
90-days after last dose 
90-days after last dose 
1. 
On days mocetinostat and durvalumab are both administered and scheduled for PK assessment, mocetinostat dosing and sampling should precede 
durvalumab dosing.  The 1 hour post-dose mocetinostat PK sample and the pre-dose durvalumab PK sample can be drawn at the same time, but separate 
samples for each must be collected as outlined in the Covance Lab Manual. 
2. 
The typical durvalumab infusion duration is 1-hour.  End-of-infusion samples are to be collected within 5 minutes from the contralateral arm.   
3. 
ECGs should be taken in triplicate, with readings at least 2 minutes apart.  QTc should be manually calculated using Fridericia’s formula. 
4. 
On Lead-In Day 1, two sets of triplicate ECGs should be done within 1 hour prior to dosing (e.g., at 20-30 minute intervals) to firmly establish the 
baseline.  In general, ECGs should be performed prior (within -30 to -5 minutes) to the respective PK blood collection. 
5. 
Scheduled vital signs and triplicate ECGs precede PK sample collection in all cases. 
6. 
Pre-dose sample allowable window up to 30 minutes prior to dose in all cases.   
7. 
Allowable windows for mocetinostat post-dose samples are plus or minus 30 minutes for 1 hour post-dose and plus or minus1 hour for 3 and 7 hour 
samples. 
 


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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
STUDY SUMMARY ..........................................................................................................5 
TABLE OF CONTENTS ................................................................................................17 
TABLE OF TABLES .......................................................................................................21 
TABLE OF FIGURES .....................................................................................................21 
LIST OF APPENDICES .................................................................................................21 
LIST OF ABBREVIATIONS .........................................................................................22 
1 
INTRODUCTION AND RATIONALE .................................................................25 
1.1 
Disease and Therapeutic Strategy ...............................................................25 
1.1.1 
Non-Small Cell Lung Cancer .....................................................25 
1.1.2 
HDAC Inhibition as a Therapeutic Strategy in Cancer ..........26 
1.1.3 
Programmed Cell Death Ligand 1 ............................................29 
1.2 
Mocetinostat ..................................................................................................30 
1.2.1 
Mocetinostat Drug Substance ....................................................30 
1.2.2 
Mocetinostat Non-Clinical Data ................................................30 
1.2.3 
Mocetinostat Clinical Data .........................................................34 
1.2.4 
Mocetinostat Human Pharmacokinetics and Product 
Metabolism ..................................................................................36 
1.3 
Durvalumab...................................................................................................37 
1.3.1 
Durvalumab Drug Substance ....................................................37 
1.3.2 
Durvalumab Non-Clinical Data.................................................37 
1.3.3 
Durvalumab Clinical Data .........................................................39 
1.3.4 
Durvalumab Human Pharmacokinetics ...................................42 
1.3.5 
Durvalumab Monotherapy Clinical Activity in Solid 
Tumor Diseases ...........................................................................43 
1.4 
Expectations for Combination of Mocetinostat and Durvalumab ...........43 
1.5 
Study Rationale .............................................................................................45 
2 
STUDY OBJECTIVES ............................................................................................47 
2.1 
Objectives ......................................................................................................47 
2.1.1 
Primary Objectives .....................................................................47 
2.1.2 
Secondary Objectives .................................................................47 
 
 
2.2 
Endpoints .......................................................................................................47 
2.2.1 
Primary Endpoints .....................................................................47 
2.2.2 
Secondary Endpoints ..................................................................48 
 
 
3 
STUDY DESIGN ......................................................................................................49 
3.1 
Phase 1 Study ................................................................................................49 
3.1.1 
Definition of Dose Limiting Toxicity .........................................49 
3.1.2 
Dose Escalation Plan...................................................................51 
3.1.3 
Definition of Maximum Tolerated Dose ...................................51 


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3.1.4 
Definition of Recommended Phase 2 Dose ...............................51 
3.2 
Phase 2 ...........................................................................................................52 
4 
SUBJECT SELECTION AND ENROLLMENT ..................................................54 
4.1 
Inclusion Criteria ..........................................................................................54 
4.2 
Exclusion Criteria .........................................................................................56 
4.3 
Life Style Guidelines .....................................................................................58 
4.4 
Enrollment into Study ..................................................................................59 
5 
STUDY TREATMENT ............................................................................................60 
5.1 
Mocetinostat Study Drug Management ......................................................60 
5.1.1 
Formulation and Packaging .......................................................60 
5.1.2 
Drug Storage and Accountability ..............................................60 
5.1.3 
Preparation and Dispensing .......................................................60 
5.1.4 
Medication Compliance ..............................................................61 
5.1.5 
Destruction ..................................................................................61 
5.1.6 
Administration ............................................................................61 
5.1.7 
Dose Modification and Discontinuation....................................62 
5.1.8 
Mocetinostat Adverse Event Management Guidelines ...........62 
5.1.8.1 
Management of Mocetinostat in Response 
to Immune-Related Adverse Event ........................62 
5.1.8.2 
Management of Mocetinostat in Event of 
Non-Hematological Toxicities .................................63 
5.1.8.3 
Management of Mocetinostat in Event of 
Hematological Toxicities .........................................63 
5.1.8.4 
Management of Mocetinostat Associated 
Cystitis ......................................................................64 
5.1.8.5 
Management of Mocetinostat in Event of 
Pericardial Toxicity .................................................64 
5.2 
Durvalumab Study Drug Management ......................................................66 
5.2.1 
Formulation and Packaging .......................................................66 
5.2.2 
Drug Storage and Accountability ..............................................66 
5.2.3 
Preparation and Dispensing .......................................................66 
5.2.4 
Medication Compliance ..............................................................67 
5.2.5 
Destruction ..................................................................................67 
5.2.6 
Administration ............................................................................67 
5.2.7 
Infusion Modification and Discontinuation..............................68 
5.2.8 
Durvalumab Adverse Event Management Guidelines ............68 
5.3 
Medication Error ..........................................................................................74 
5.4 
Concomitant Therapies ................................................................................74 
5.4.1 
Concomitant Medication(s) ........................................................74 
5.4.1.1 
Permitted Concomitant Medications .....................74 
5.4.1.2 
Cautioned Concomitant Medications and 
Substances ................................................................74 
5.4.1.3 
Concomitant Medications and Substances 
to be Avoided On-Study ..........................................75 
5.4.2 
Concomitant Surgery or Radiation Therapy ...........................76 


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5.4.3 
Other Anticancer or Experimental Therapy ...........................76 
6 
STUDY ASSESSMENTS .........................................................................................76 
6.1 
Screening .......................................................................................................76 
6.2 
Study Period ..................................................................................................76 
6.3 
End of Treatment Assessment .....................................................................76 
6.4 
Long-Term Follow-up and End of Study Assessment ...............................76 
6.5 
Patient Discontinuation/Withdrawal ..........................................................77 
7 
PROCEDURES .........................................................................................................78 
7.1 
Sample Collection for PD-L1 Expression ...................................................78 
7.2 
Efficacy ..........................................................................................................79 
7.3 
Safety Assessments ........................................................................................80 
7.3.1 
Adverse Events ............................................................................80 
7.3.2 
Documentation and Reporting of Pericardial Events .............80 
7.3.3 
Physical Examination and Vital Signs ......................................81 
7.3.4 
Laboratory Safety Assessments .................................................82 
7.3.5 
Electrocardiogram (ECG) ..........................................................83 
7.3.6 
Echocardiogram (ECHO) ..........................................................83 
7.4 
Laboratory Studies .......................................................................................83 
7.4.1 
Pharmacokinetic Evaluation......................................................83 
7.4.2 
Anti-Drug Antibody Evaluation ................................................84 
7.4.3 
Pharmacodynamic Evaluation in Tumor Tissue .....................84 
 
 
7.5 
Post-treatment Follow-up ............................................................................84 
8 
ADVERSE EVENT REPORTING .........................................................................85 
8.1 
Sponsor Medical Monitor Personnel ..........................................................85 
8.2 
Adverse Events ..............................................................................................85 
8.2.1 
Laboratory Abnormalities .........................................................86 
8.2.2 
Severity Assessment ....................................................................86 
8.2.3 
Causality ......................................................................................86 
8.3 
Serious Adverse Events ................................................................................87 
8.3.1 
Definition of a Serious Adverse Events .....................................87 
8.3.2 
Exposure During Pregnancy ......................................................88 
8.3.3 
Adverse Events of Special Interest ............................................89 
8.3.3.1 
Durvalumab Adverse Events of Special 
Interest ......................................................................89 
8.3.3.2 
Mocetinostat Adverse Event of Special 
Interest ......................................................................90 
8.4 
Reporting of SAEs and AEs .........................................................................90 
8.4.1 
Reporting Period .........................................................................90 
8.4.2 
Reporting Requirements ............................................................91 
9 
STATISTICS .............................................................................................................91 
9.1 
Hypothesis and Sample Size ........................................................................91 
9.1.1 
Phase 1 .........................................................................................91 
9.1.2 
Phase 2 .........................................................................................92 
9.2 
Data Handling ...............................................................................................93 


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9.3 
Analysis Populations .....................................................................................93 
9.3.1 
Modified Intent-to-Treat Population ........................................93 
9.3.2 
Clinical Activity Evaluable Population .....................................93 
9.3.3 
Safety Population ........................................................................94 
9.3.4 
DLT Evaluable Population ........................................................94 
9.3.5 
Molecular Marker Evaluable Population .................................94 
9.3.6 
Pharmacokinetic Evaluable Population ...................................94 
9.3.7 
Pharmacodynamic Evaluable Population ................................94 
9.3.8 
Anti-Drug Antibody Evaluable Population ..............................94 
9.4 
Efficacy Endpoint Definitions and Analyses ..............................................94 
9.4.1 
Objective Response Rate ............................................................94 
9.4.2 
Clinical Benefit Rate ...................................................................95 
9.4.3 
Duration of Response .................................................................95 
9.4.4 
Progression Free Survival ..........................................................95 
9.4.5 
Overall Survival ..........................................................................96 
9.5 
Safety Data Presentations and Summaries .................................................96 
9.5.1 
Adverse Events ............................................................................96 
9.5.2 
Prior and Concomitant Medications .........................................96 
9.5.3 
Clinical and Laboratory Assessments .......................................96 
9.5.4 
Patient Demographics, Baseline Characteristics and 
Disposition ...................................................................................97 
9.5.5 
Analysis of Study Treatment Dosing.........................................97 
9.6 
Other Study Endpoints.................................................................................97 
9.6.1 
Pharmacokinetic Analysis ..........................................................97 
9.6.2 
Pharmacodynamic Analysis .......................................................97 
9.6.3 
Anti-Drug Antibodies .................................................................98 
9.7 
Interim Analysis ............................................................................................98 
9.8 
Data Monitoring Committee ........................................................................98 
10 ETHICS AND RESPONSIBILITIES .....................................................................98 
10.1 
Ethical Conduct of the Study .......................................................................98 
10.2 
Obligations of Investigators .........................................................................98 
10.3 
Institutional Review Board/Ethics Committee/Research Ethics 
Board (IRB/EC) ............................................................................................99 
10.4 
Informed Consent Form ...............................................................................99 
10.5 
CONFIDENTIALITY ................................................................................100 
10.6 
Reporting of Serious Breaches of the Protocol or ICH GCP ..................100 
11 RECORDS MANAGEMENT................................................................................100 
11.1 
Source Documentation ...............................................................................100 
11.2 
Study Files and Records Retention ...........................................................100 
12 QUALITY CONTROL AND QUALITY ASSURANCE ....................................101 
12.1 
Monitoring Procedures ..............................................................................101 
12.2 
Auditing and Inspection Procedures .........................................................101 
13 CHANGES IN STUDY CONDUCT .....................................................................102 
13.1 
Protocol Amendments ................................................................................102 
13.2 
Protocol Deviations .....................................................................................102 


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14 END OF TRIAL ......................................................................................................103 
14.1 
End of Trial in a European Union Member State ...................................103 
14.2 
End of Trial in all other Participating Countries ....................................103 
14.3 
Premature Termination .............................................................................103 
15 STUDY REPORT AND PUBLICATION POLICY ............................................103 
16 REFERENCES .......................................................................................................104 
 
TABLE OF TABLES 
Table 1: 
Schedule of Assessments ..........................................................................11 
Table 2: 
Schedule of Triplicate ECG, PK and ADA Assessments .....................16 
Table 3: 
Biochemical Inhibition of HDAC Activity by Mocetinostat ................31 
Table 4: 
In Vitro Anti-proliferative Activity Against Various Human 
Lymphoma Cancer Cell Lines ................................................................31 
Table 5: 
Dose Modifications for Mocetinostat .....................................................62 
Table 6: 
Mocetinostat Dose Modifications – Non-Hematological 
Drug-Related Toxicities1 .........................................................................63 
Table 7: 
Mocetinostat Dose Modifications – Hematological 
Drug-Related Toxicities ...........................................................................63 
Table 8: 
Pericardial Effusion and Patient Management Guidelines ..................65 
Table 9: 
Immune-Related Adverse Events, Overall Management .....................70 
Table 10: 
Durvalumab Infusion-Related Reactions ..............................................72 
Table 11: 
Non-immune Mediated Reactions ..........................................................73 
Table 12: 
Definitions of Pericardial Events ............................................................81 
Table 13: 
Laboratory Safety Parameters ...............................................................82 
Table 14: 
Estimates of 95% CI Using Clopper-Pearson in After 
Enrollment of 100 Patients ......................................................................93 
 
TABLE OF FIGURES 
Figure 1: 
Mocetinostat Modulates Expression of PD-L1 and Antigen 
Presentation Regulatory Genes in NCSLC Cell Lines .........................33 
Figure 2: 
Mocetinostat Modulates Key Immune Cell Populations In Vivo ........34 
 
LIST OF APPENDICES 
Appendix 1. ECOG Performance Status ...................................................................109 
Appendix 2. Dose-Finding Spreadsheet of the Modified Toxicity Probability 
Interval (MTPI) Method .......................................................................110 
Appendix 3. Medications or Substances Prohibited or to be used with 
Caution During Study Treatment with Mocetinostat.........................111 
Appendix 4. Management of Specific Immune-Related Adverse Events ...............113 
Appendix 5. Abbreviated Presentation of RECIST Version 1.1 Guidelines ..........123 
 


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LIST OF ABBREVIATIONS 
ADA 
Anti-drug Antibodies 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APC 
Antigen Presenting Cells 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CBR 
Clinical Benefit Rate 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography Scan 
CTA 
Clinical Trial Application 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EIU 
Exposure In-Utero 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HDAC 
Histone Deacetylases 
HDACi 
Histone Deacetylase Inhibitor 
HDPE 
High-Density Polyethlyene 
HLA 
Human Leukocyte Antigen 
IB 
Investigator’s Brochure 


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ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
INR 
International Normalized Ration 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IV 
Intravenous 
MAb 
Monoclonal Antibody 
MDSC 
Myeloid-derived Suppressor Cell 
MDSCs 
Myeloid-Derived Suppressor Cells   
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MHC 
Major Histocompatibility Complex 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTPI 
Modified Toxicity Probability Interval  
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NK 
Natural Killer 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Objective Progression of Disease 
PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PTT 
Partial Thromboplastin Time 


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QTc 
Corrected QT Interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
Standard of Care  
TAA 
Tumor Associated Antigens 
TIW 
Three Times Weekly 
Treg 
T Regulatory Cells 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 


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1 INTRODUCTION AND RATIONALE 
1.1 
Disease and Therapeutic Strategy 
1.1.1 
Non-Small Cell Lung Cancer 
Lung cancer remains the leading cause of cancer-related death in the United States (US).  
Approximately 221,200 new cases of lung cancer are expected to be diagnosed in the US 
in 2015, and approximately 158,040 deaths will be attributed to lung cancer 
(Cancer Facts and Figures-2015).  Non-small cell lung cancer (NSCLC) accounts for 
approximately 83% of lung cancer cases (Cancer Facts and Figures-2015), of which 
approximately half are classified as adenocarcinoma of the lung; squamous cell 
carcinoma accounts for approximately one-third of NSCLC cases and large cell 
carcinoma is less frequently diagnosed. 
In 1995, the use of cisplatin-based chemotherapy was reported to lead to modest 
improvement in survival in patients with advanced NSCLC as compared to best 
supportive care, with a 27% reduction in death as reported in a meta-analysis of 11 trials 
(NSCLC Collaborative Group-1995).  Subsequently, other chemotherapeutic agents have 
been reported to be active in NSCLC, leading to a comparison of 4 platinum-based 
doublets in the first-line treatment setting, all of which demonstrated similar activity 
(Schiller-2002).  The importance of histology in the selection of first-line treatment for 
NSCLC was later described in the development of bevacizumab and pemetrexed.  In a 
Phase 3 clinical trial, treatment with bevacizumab, a monoclonal antibody directed 
against vascular endothelial growth factor (VEGF), demonstrated an improvement in 
survival when added to doublet chemotherapy, specifically in patients with 
non-squamous NSCLC (Sandler-2006).  Similarly, treatment with pemetrexed, an 
antifolate chemotherapeutic agent, resulted in an improvement in survival when used as 
part of a chemotherapy doublet in patients non-squamous NSCLC, but with a probable 
decrease in survival among patients with squamous cell NSCLC (Scagliotti-2008).  Based 
on the results of these and other trials, platinum-based chemotherapy doublets, with or 
without bevacizumab in selected patients, remain a standard of care for most patients 
with advanced NSCLC in the first-line treatment setting. 
Effective options are limited however for patients with advanced NSCLC whose disease 
progresses after first-line treatment.  Over the past few years there has been increasing 
interest in treating cancer with immunotherapy, in particular manipulating the anticancer 
host immune response with human monoclonal antibodies (MAbs). 
Nivolumab, a fully human IgG4, PD-1 receptor antagonist, was evaluated in a Phase 3 
clinical trial of patients with squamous cell carcinoma of the lung with disease 
progression during or after first-line chemotherapy.  This study demonstrated a 
significant improvement in survival compared with docetaxel, with a hazard ratio (HR) of 
0.59 (95% CI: 0.44, 0.79, p<0.001) (Brahmer-2015).  A similar Phase 3 trial of patients 


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with non-squamous NSCLC that had progressed during or after platinum-based doublet 
chemotherapy demonstrated an improvement in survival with nivolumab over docetaxel 
(HR 0.73, 96% [sic] CI 0.59, 0.89, p=0.002) (Borghaei-2015).  Opdivo® (nivolumab) 
was approved by the FDA in for the treatment of patients with metastatic NSCLC with 
progression on or after platinum-based chemotherapy.  Nivolumab was approved in the 
US in March 2015 for squamous NSCLC and October 2015 for non-squamous NSCLC. 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  In a large international Phase 1 clinical trial, 
pembrolizumab was given to 495 patients with advanced NSCLC to evaluate safety, 
side-effect profile, and antitumor activity (Garon-2015).  Patients (some of whom had 
received previous therapy and some of who had not) were treated with various doses and 
regimens of pembrolizumab.  Pembrolizumab had an acceptable side-effect profile and 
showed anti-tumor activity.  Among all patients, the objective response rate was 19.4%, 
and the median duration of response was 12.5 months.  The median duration of 
progression-free survival was 3.7 months, and the median duration of overall survival 
was 12.0 months.  Keytruda® (pembrolizumab) was approved by the FDA in 
October 2015 for the treatment of patients with metastatic squamous or non-squamous 
NSCLC with progression on or after platinum-based chemotherapy. 
Significant activity has been observed with durvalumab in NSCLC.  In Study 
CD-ON-durvalumab-1108, 456 of 694 subjects were treated with durvalumab 10 mg/kg 
Q2W and evaluable for response (defined as having ≥ 24 weeks follow-up, measurable 
disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or 
death without any follow-up scan).  Among the 86 patients with PD-L1-positive NSCLC, 
the ORR was 26.7% and the disease control rate (DCR)-24w was 36.0% (durvalumab 
Investigator’s Brochure [IB Version 8.0], Rizvi-2015).  Among the 95 patients with 
PD-L1-negative NSCLC, the ORR was 6.3% and the DCR-24w was 25.3%. 
1.1.2 
HDAC Inhibition as a Therapeutic Strategy in Cancer 
Histone deacetylases (HDACs) are a family of enzymes that, together with histone 
acetyltransferases (HATs), exert epigenetic control over the acetylation state of 
chromatin.  In eukaryotic cells, transcriptionally active genes are associated with 
hyperacetylated chromatin, whereas transcriptionally silent genes are associated with 
hypoacetylated chromatin (Moradei-2005).  HATs, acting as transcription co-activators, 
catalyze the addition of acetyl groups onto the ε-amino group of lysine residues in the 
N-terminal tails of core histones, which weakens the histone-DNA interaction, thereby 
increasing the accessibility of a variety of transcription factors to DNA (Moradei-2005).  
Conversely, HDACs, acting as transcription corepressors, remove the acetyl groups from 
the acetylated lysines in histones, which condenses the structure of chromatin and 
restricts the access of transcription factors (Moradei-2005). 


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Three HDAC classes (Classes I, II and IV) and 11 NAD+-independent HDAC isotypes 
have been identified in humans (Moradei-2005, De Ruijter-2003).  Class I enzymes 
(HDACs 1, 2, 3, and 8) are ubiquitously expressed, predominantly nuclear, and mainly 
function as transcriptional co-repressors.  Class II enzymes (HDACs 4, 5, 6, 7, 9 and 10) 
are tissue specific, and have been theorized to have distinct functions in cellular 
differentiation and developmental processes (Bertos-2001).  HDAC 11 comprises Class 
IV HDACs (Gao-2002). 
As HDACs are involved in many cellular processes, such as cell cycle progression and 
differentiation, deregulation of HDAC activity is associated cancer progression resulting 
in the silencing of tumor suppressor genes and uncontrolled tumor growth in certain 
malignancies including lymphomas, bladder, and lung cancers.  Numerous studies using 
tumor cell lines and tumor cell extracts have observed increased HDAC activity in 
malignancy, beginning with the observations that histone acetylation and deacetylation 
rates were increased in hepatoma cells compared with normal cells (Horiuchi-1981), and 
continuing with observations associating HDAC activity with cell transformation 
(Brehm-1999) and linking HDAC with other nuclear proteins that are important in 
regulating gene expression in multiple cancer cell lines including leukemia cell lines 
(Brehm-1999), prostate cancer lines, (Patra-2001) and breast cancer lines (Babic-2004).  
HDAC inhibition has been implicated in the inhibition of angiogenesis, induction of 
cellular differentiation, growth arrest, and apoptosis in a broad spectrum of tumor cells, 
all effects contributing to tumor regression without affecting normal cells 
(Moradei-2005).  Inhibition of HDAC activity results in accumulation of acetylated 
proteins including histones, transcription factors, and heat shock proteins, leading to 
global cellular changes in transcription, mitosis, and protein stability.  These changes 
interfere with tumor cell proliferation, survival, and cellular homeostasis, contributing to 
an anti-tumor effect.  As cancer cells adapt to this insult, several mechanism of resistance 
may develop, including increased drug efflux, HDAC over-expression or desensitization, 
alterations of stress response mechanisms and increased anti-apoptotic signaling 
(Fantin-2007). 
HDACs have been implicated in the epigenetic regulation of innate and adaptive 
immunity.  Accumulating evidence indicates that tumors evade immune responses by 
down regulation of MHC molecules and tumor antigens or active suppression of 
anti-tumor immune responses at the site of the tumor by creating an immune suppressive 
tumor microenvironment.  In addition to a clearly defined anticancer mechanism of 
action of HDACi in inhibiting cell cycle progression and inducing apoptosis of a wide 
variety of tumor types, increasing evidence supports the proposal that spectrum-selective 
inhibitors of class I HDACs can reverse immune evasion and elicit antitumor efficacy 
through an immunostimulatory mechanism of action (Kroesen-2014, Leggatt-2012, 
West-2012).  The cellular effects of HDACis are mediated by accumulation of acetylated 
histone proteins and subsequent altered gene transcription.  Both the direct antitumor 
effects and the immunomodulatory activity of HDACis are reported to be mediated 
through both the modification of gene expression through histone lysine acetylation as 
well as and the post-translational modification of selected proteins and subsequent 


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protein function (Kroesen-2014, West-2012).  The immunomodulatory properties of class 
I HDACis are reported to be mediated through several distinct routes including: 
1) induction of PD-L1 expression, 2) enhancement of tumor antigenicity via induction of 
tumor associated antigens (TAAs) and MHC Class I and Class II molecules by tumor 
cells, 3) induction of immunogenic cell death via activation and cross-presentation of 
tumor antigens by antigen presenting cells (APCs), 4) enhanced function of T effector 
cells, and 5) decreased function of immunosuppressive cell subsets including 
T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSCs) (Kroesen-2014; 
Leggatt-2012; West-2014).  Additional support for the combination of HDAC inhibitors 
and immunomodulators is provided by nonclinical combination studies in 
immunocompetent models.  Because of the ability of HDAC inhibitors to modify disease 
biology and induce tumor antigens, induce PD-L1 ligand expression, or modulate tumor 
infiltrating lymphocyte effector and regulatory populations, the combination with 
immunotherapy has the potential to enhance activity over that observed with either agent 
alone (Christiansen-2011, Kim-2014, Shen-2012, West-2012). 
It should be noted that distinct and sometimes contrasting immunomodulatory properties 
of HDAC inhibitors have been reported for different structural classes and HDAC target 
spectra.  Multiple HDAC inhibitors were demonstrated to increase PD-L1 expression and 
select MHC molecules and TAAs.  However, contrasting effects on T effector cell 
populations and immunosuppressive cell subsets have been observed with different 
iHDACi classes.  The Class I HDAC inhibitor entinostat demonstrated the ability to 
deplete Tregs and MDSCs and enhance CD8 positive T cells in the tumor 
microenvironment whereas structurally distinct and broader spectrum HDACs including 
SAHA, vorinostat, and romidepsin enhanced Treg immunosuppressive activity and 
reduced T effector cell activity.  The class II HDACs including HDACs 6, 7, and 9 have 
been implicated in the inhibition of Treg immunosuppressive function. 
Consistent with this class I HDAC target profile, nonclinical studies with mocetinostat 
have demonstrated increased PD-L1 and MHC class I molecules, enhanced T effector 
populations, and reduced Treg and MDSC populations in both systemic and tumor 
compartments in syngeneic mouse tumor models.  In contrast, the dual 
immunosuppressive and immunostimulatory effects associated with Class II HDACs 
(HDAC 4-7/HDAC8-10) and pan-HDAC inhibition indicate that the target profile of 
HDAC inhibitors is of a critical consideration in defining immunomodulatory properties 
of this class of molecules.  In this regard, it should be noted that pan-HDAC inhibitors 
have been used to limit cytokine production and immune damage in autoimmune diseases 
including rheumatoid arthritis and following allogenic transplant.  The seemingly 
contrasting role for HDAC_is in distinct disease settings should be evaluated in the 
context of both disease indications and the difference in HDACi target profiles. 


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HDAC inhibition induces large scale epigenetic changes affecting multiple cancer 
signaling networks (Dokmanovic-2007, Marks-2000, Thiagalingam-2003).  The 
anticancer properties of HDAC inhibitors may be due to the accumulation of acetylated 
histones that leads to the activation (and/or repression) of specific genes, and thereby 
inhibits tumor cell growth (Moradei-2005).  Small molecule HDAC inhibitors identified 
to date include vorinostat (suberoylanilide hydroxamic acid, SAHA) (Richon-1998), 
romidepsin (FR901228) (Nakjima-1998), sodium butyrate (Hassig-1997), trichostatin A 
(TSA) (Yoshida-1995) and oxamflatin (Kim-1999).  Although structurally diverse, each 
of these HDAC inhibitors, particularly the hydroxamic acids (which include vorinostat, 
TSA and oxamflatin) are pan-inhibitors of all Class I and II HDAC enzymes.  
Mocetinostat (MGCD0103) is an oral second generation benzamide HDAC inhibitor that 
selectively inhibits Class I (HDAC 1, 2, 3) and IV (HDAC 11) enzymes (Fournel-2008, 
Zhou-2008). 
1.1.3 
Programmed Cell Death Ligand 1 
Immune responses directed against tumors are one of the body’s natural defenses against 
the growth and proliferation of cancer cells.  However, over time and under pressure from 
immune attack, cancers develop strategies to evade immune-mediated killing allowing 
them to develop unchecked.  One such mechanism involves upregulation of surface 
proteins that deliver inhibitory signals to cytotoxic T cells.  Programmed cell death ligand 
1 (PD-L1) is one such protein, and is upregulated in a broad range of cancers with a high 
frequency, with up to 88% expression in some tumor types.  In a number of these 
cancers, including lung (Mu-2011), renal (Thompson-2005; Thompson-2006; 
Krambeck-2007), pancreatic (Nomi-2007; Loos-2008; Wang-2010), ovarian cancer 
(Hamanishi-2007), and hematologic malignancies (Andorsky-2011; Brusa-2013) tumor 
cell expression of PD-L1 is associated with reduced survival and an unfavorable 
prognosis.  For example, in ovarian cancer, the 5-year survival rate in patients with low 
expression of PD-L1 was 80.2% compared to 52.6% in patients with high expression 
levels of PD-L1 (Hamanishi-2007).  In lung cancer, only 20% of patients with tumors 
expressing PD-L1 survived more than 3 years compared to 49% of patients with tumors 
lacking PD-L1 expression (Mu-2011).  These data suggest that an antibody targeting 
PD-L1 has the potential to affect multiple solid tumor types. 
PD-L1 is part of a complex system of receptors and ligands that are involved in 
controlling T-cell activation.  PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response.  In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to programmed cell death 1 (PD-1) or CD80 on activated 
T cells and delivers an inhibitory signal to the T cell (Keir-2008; Park-2010).  This results 
in reduced T-cell activation and fewer activated T cells in circulation.  In the tumor 
microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on 
activated T cells reaching the tumor.  This delivers an inhibitory signal to those T cells, 
preventing them from killing target cancer cells and protecting the tumor from immune 
elimination (Zhou-2008). 


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1.2 
Mocetinostat 
Mocetinostat (MGCD0103) is an oral, second generation benzamide inhibitor of HDAC 
1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo (Fournel-2008, 
Zhou-2008).  
1.2.1 
Mocetinostat Drug Substance 
Generic Name: 
Mocetinostat (free base) 
Other Name:  
MGCD0103 
Chemical Name:  
N-(2-amino-phenyl)-4-[(4-pyridin-3-yl-pyrimidin-2-ylamino)-
methyl]-benzamide  
Empiric Formula: 
C23H20N6O 
Molecular Weight:  
396.45 
1.2.2 
Mocetinostat Non-Clinical Data 
Mocetinostat has been investigated in non-clinical pharmacokinetic, metabolism and 
toxicology studies.  Detail on these studies can be found in the Investigator’s Brochure. 
Pharmacodynamics 
Mocetinostat was shown to be a selective, potent, and dose-dependent inhibitor of human 
Class I (isoforms 1, 2, and 3) and Class IV (isoform 11) HDACs (Table 3).  There was 
weak or no activity against Class II HDACs or HDAC 8.  A kinetic analysis using HDAC 
1 demonstrated that mocetinostat is a potent competitive inhibitor, with a Ki of 64 nM.  
Binding was reversible, with high affinity and slow kinetics.  In addition, mocetinostat 
induced acetylation of core histones H4 and H3 in human bladder carcinoma (T24) cells, 
with an EC50 of 0.4 μM and 0.2 μM, respectively.  Acetylation of histones was also 
observed in A549 human non-small cell lung carcinoma cells and A2780-S human 
ovarian carcinoma cells.  Core histone acetylation was dose-dependent and was 
correlated with HDAC inhibition. 
Mocetinostat induced cell cycle arrest of HCT116 human colon carcinoma cells in a 
dose-dependent manner.  G2/M and sub-G1 accumulation was also observed in HeLa 
human cervical cancer cells and A549 human non-small cell lung carcinoma cells.  These 
effects were shown to occur via a mechanism independent of tubulin polymerization.  
Exposure of HCT116 cells to mocetinostat at concentrations of 1 to 25 μM resulted in the 
dose-dependent induction of apoptosis.  Dose-dependent apoptosis also was observed in 
both A549 human lung carcinoma cells and HeLa human cervical carcinoma cells at 
concentrations of 1 μM (the lowest concentration tested).  Mocetinostat also induced 
significant apoptosis in several hematologic cancer cell lines, including Jurkat T-cell 


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leukemia cells, MV-4-11 acute myeloid leukemia cells, U266B1 multiple myeloma cells, 
and HL60 promyelocytic leukemia cells.  Induction of apoptosis in all four hematologic 
cancer cell lines was dose-dependent.  Expression of the cyclin-dependent kinase 
inhibitor p21waf1/Cip1 was upregulated both at the level of transcription and at the level 
of translation.  A concentration of 1 μM mocetinostat induced p21waf1/Cip1 expression 
at least 2-fold in HCT116 colon carcinoma cells.  This effect was independent of p53 
status: p21waf1/Cip1 induction was observed both in HeLa cervical cancer cells, which 
are p53-null, and in A549 lung carcinoma cells, which express wild type p53. 
Table 3: 
Biochemical Inhibition of HDAC Activity by Mocetinostat 
Parameter 
Class I HDAC Isoforms 
Class II HDAC Isoform 
Class IV 
HDAC 
Isoforms 
 
1 
2 
3 
8 
4 
5 
6 
7 
11 
Inhibition  
(+/-) 
+ 
+ 
+ 
- 
- 
- 
- 
- 
+ 
IC50 (µM) 
0.15 
0.29 
1.66 
>20 
15 
>20 
>20 
>20 
0.59 
 
Mocetinostat had anti-proliferative activity against A549 lung cancer cells and Du145 
prostate cancer cells (IC50 1.0 µM), but not against normal human mammary epithelial 
cells (IC50 > 20 µM).  Inhibition was independent of p53 status as A549 cells express 
p53, whereas Du145 cells are p53-null.  The anti-proliferative activity of mocetinostat 
was assessed against a variety of other human cancer cells with IC50 results in Table 4. 
Table 4: 
In Vitro Anti-proliferative Activity Against Various Human 
Lymphoma Cancer Cell Lines 
Cell Lines 
Subtype 
IC50 (µM) 
HMEC 
Normal mammary epithelium 
21.0 
T24 
Bladder Cancer 
0.71 
SKBR3 
Breast Cancer 
0.32 
HCT116 
Colon Cancer 
0.06 
MINO 
Mantle cell lymphoma 
0.48 
HDLM-2 
Hodgkin lymphoma 
0.25 
 


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Nonclinical Studies Supporting Mocetinostat and Durvalumab Combination 
A number of nonclinical studies were performed to evaluate the mechanism of action of 
mocetinostat, its immune stimulatory properties, and the optimal timing for 
administration in combination with immune checkpoint inhibitors such as PD-L1 
antagonists.  Initial studies were performed to assess the effect of mocetinostat on PD-L1, 
on major histocompatibility complex (MHC) class I and II molecules, and on immune 
co-stimulatory molecule gene and protein expression, across a panel of non-small cell 
lung cancer (NSCLC) cell lines in vitro.  Mocetinostat demonstrated a concentration-
dependent increase in PD-L1 gene expression ranging from 2- to 15-fold in all four 
NSCLC cell lines evaluated (H23, H1437, H1703, H1792) (Figure 1).  In addition, 
mocetinostat increased PD-L1 cell-surface protein expression in 5 NSCLC cell lines, 
demonstrated by flow-cytometric analysis utilizing a specific PD-L1 antibody 
(BL-MGCD0103-032).  The increased expression of PD-L1 on tumor cells by 
mocetinostat may signal a shift in dependence of tumor cells on evading tumor-immune 
response via a PD-1-dependent mechanism.  In addition, mocetinostat demonstrated a 
concentration-dependent increase in gene expression of several members of the human 
leukocyte antigen (HLA) gene complex, in all four NSCLC lines evaluated (Figure 1). 
HLA genes comprise the human MHC Class I and II molecules that regulate the 
presentation of tumor-associated antigens (TAAs) at the cell surface to enable recognition 
by cytotoxic T cells (CD8+) (BL-MGCD0103-032).  The induction of gene expression of 
MHC-class-I-related molecules, MIC-A and MIC-B, were also observed in all four 
NSCLC cell lines evaluated.  The effector cytolytic responses of T cells and NK cells 
against tumor cells are mediated by NKG2D receptor-dependent engagement of MIC-A 
and MIC-B on target tumor cells, indicating that immune stimulatory properties of 
mocetinostat involve both innate and adaptive immune responses.  Finally, mocetinostat 
induced the expression of the immune co-stimulatory molecule CD86, which is required 
for T-cell activation and antigen-dependent immune response against tumor cells 
expressing and presenting TAAs (BL-MGCD0103-032). 
 


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Figure 1: 
Mocetinostat Modulates Expression of PD-L1 and Antigen 
Presentation Regulatory Genes in NCSLC Cell Lines 
 
Gene modulation in NSCLC post mocetinostat treatment.  Cells were seeded in 10 cm dishes and incubated 
with various doses of mocetinostat or DMSO for 48 hours.  RNA was extracted with Qiagen RNEasy plus 
kit.  Relative gene expression, by quantitative polymerase chain reaction (PCR), was normalized to DMSO 
treatment.   
To determine effect on CD4- and CD8-positive effector T cells and immunosuppressive 
cellular subsets including T regulatory cells (Tregs) and myeloid-derived suppressor cells 
(MDSCs), mice bearing syngeneic subcutaneous CT26 colon tumors were treated with 
100 mg/kg mocetinostat by daily oral gavage.  In these studies, mocetinostat 
demonstrated an increase in splenic CD4-positive T effector cells and mature cytolytic 
CD8-positive T cells in tumors compared to vehicle controls by day six of administration 
(PH-MGCD0103-009) (Figure 2).  In addition, mocetinostat treatment decreased tumor 
FoxP3-positive immunosuppressive Tregs and CD11b/Gr1-positive MDSCs in tumors 
compared to vehicle controls by day nine of administration (PH-MGCD0103-009).   


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Figure 2: 
Mocetinostat Modulates Key Immune Cell Populations In Vivo 
 
Mocetinostat modulates immune cell populations.  Fresh tumor and spleen samples in cold PBS were 
delivered within 45 minutes.  Stained samples were loaded into Attune Autosampler for FACS analysis.  
Flow cytometry markers included percentages of: T-Cells (CD4+ and CD8+), Regulatory T-Cells (Tregs) 
Proliferation marker CD8+ cells that are Ki67+, MDSC (CD11b/Gr1+).  Error bars represent standard 
deviation. 
To determine the effects of mocetinostat and PD-L1 antibody combination therapy on 
tumor growth, CT26 tumor-bearing mice were treated with either agent alone or in 
combination over selected administration schedules.  On Day 23, a statistically 
significant decrease in relative tumor volume was observed in the mocetinostat plus 
PD-L1 antibody combination group with a three day mocetinostat lead-in period 
compared with either single agent alone (PH-MGCD0103-010). 
1.2.3 
Mocetinostat Clinical Data 
Mocetinostat monotherapy and mocetinostat in combination with other anticancer agents 
have been evaluated as part of the clinical development program.  As of November 2016 
Mocetinostat has been investigated in more than 489 clinical trial patients with the 
following malignancies: Hodgkin’s Lymphoma, Non-Hodgkin’s Lymphoma (including 
diffuse large B-cell DLBCL and follicular lymphoma), acute myeloid leukemia, 
myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphocytic leukemia, 
chronic myelogenous leukemia, urothelial carcinoma, non-small cell lung cancer, and 
advanced solid tumors including adenocarcinoma of the pancreas.  Detail on these studies 
can be found in the Investigator’s Brochure, as well as Siu-2008, and  
Garcia-Manero-2004.  When given daily as a single oral dose for 14 days followed by a 
7-day rest period, the Maximum Tolerated Dose (MTD) was 12.5 mg/m2.  The dose 
limiting toxicity at the next higher dose of 17 mg/m2 (20-30 mg) was fatigue.  The 
3 times weekly schedule appears to have improved tolerability compared with daily 
dosing as higher MTDs have been observed.  Studies with this schedule identified 


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60 mg/m2 (85-125 mg) as the MTD; however with additional testing, the recommended 
dose for Phase 2 studies is 70 mg or 90 mg, depending on the indication, as a fixed dose 
administered three times per week.  Dose-limiting toxicity at higher doses included 
fatigue, nausea, vomiting and diarrhea. 
In addition to Phase I studies, the safety profile of mocetinostat has been evaluated as a 
single agent in Phase 2 studies (Investigator’s Brochure, Younes-2011, Blum-2009).  
Four previous Phase 2 studies have evaluated mocetinostat as a monotherapy in the 
following populations: 1) Elderly, previously untreated patients with AML or MDS or 
adults with relapsed/refractory AML or high-risk MDS; 2) Patients with relapsed or 
refractory NHL; 3) Patients with refractory CLL; and 4) Patients with relapsed or 
refractory HL.  The safety profile of mocetinostat has also been investigated in 
combination with other anticancer agents in Phase 1/2 and Phase 2 studies.  Mocetinostat 
has been evaluated with Vidaza® (azacitidine) in patients with MDS, AML, HL, or NHL, 
with Gemzar® (gemcitabine) in patients with refractory solid tumors or pancreatic 
cancer, and with docetaxel in patients with solid malignancies.  The overall experience of 
patients receiving mocetinostat as a single agent or in combination with chemotherapy is 
summarized in the Investigator’s Brochure. 
Among 306 patients participating in clinical trials of mocetinostat single agent, treatment-
related AEs were reported in 90.5% of patients.  The most frequent AEs considered 
related to study drug (occurring in ≥10% of patients in a preferred term category) were 
reported for nausea (61.4%), fatigue (57.5%), diarrhea (46.7%), vomiting (37.3%), 
anorexia (26.8%), decreased weight (19.3%), anemia (15.4%), thrombocytopenia 
(13.1%), dyspepsia (11.8%) and abdominal pain (11.4%).  The most frequent Grade 3/4 
AEs considered related to study drug were the following fatigue (19.0%), 
thrombocytopenia (8.8%), neutropenia (6.5%), nausea (5.2%), anemia (5.6%), asthenia 
(4.6%), and anorexia (4.2%). 
Mocetinostat Adverse Events of Interest 
Fatigue 
Fatigue has been observed consistently throughout the mocetinostat clinical evaluation 
program and has been deemed a drug-related toxicity.  The etiology of fatigue is not yet 
understood. 
Cystitis 
Cystitis symptoms (e.g., dysuria, pollakiuria, hematuria, urgency, and bladder spasm) 
have been reported in some patients, most commonly after multiple cycles of treatment.  
Hemorrhagic cystitis has been described as a rare event. 
 
 


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Pericardial Events 
Pericardial AEs have been reported in clinical trials of mocetinostat.  The types of 
pericardial events included pericarditis, pericardial effusion, and cardiac tamponade.  Of 
the pericardial adverse events, pericardial effusion was the most common.  Findings of 
the analysis include a higher rate of pericardial SAEs among patients with Hodgkin 
lymphoma (9.5%) as compared to patients with leukemia or NHL (4.5% and 3.8%, 
respectively).  Most of the pericardial AEs occurred during the first cycle of treatment.  
The majority of pericardial findings, including SAEs, resolved completely without 
sequelae, and no pericardial event was considered fatal.  Screening assessments for 
pericardial events were not included in the mocetinostat program during most of the prior 
clinical trial experience.  The current study includes screening assessments and exclusion 
criteria to ensure that baseline status is known. 
Gastrointestinal Toxicities  
GI toxicities such as anorexia, nausea, vomiting, and diarrhea have been reported as 
related to mocetinostat.  Dehydration, electrolyte abnormalities (such as hypokalemia), 
hypotension, and syncope also have been observed in connection with GI toxicity. 
Cardiac Arrhythmias  
Grade 3 AEs of QTc prolongation (> 500 msec) were reported in 4 of 435 patients in 
clinical trials with mocetinostat; 3 of those 4 events were also reported as part of SAEs.  
Three of the 4 patients already had a prolonged QTc at baseline.  Three of the events of 
QTc prolongation occurred in a setting of GI disturbances associated with dehydration 
and/or hypotension.  In 2 cases, there was definite hypokalemia, with concomitant low 
magnesium in one patient, and in both cases, the QTc values decreased quickly to 
baseline levels after IV administration of potassium and magnesium.  Concomitant 
treatment with drugs identified as having the potential to cause QTc prolongation may 
have been a factor in 2 patients. 
Although therapy with mocetinostat does not appear to be an obvious risk factor for 
development of QTc prolongation, ECG monitoring may be warranted in the settings of 
GI disturbances associated with dehydration and/or electrolyte abnormalities. 
1.2.4 
Mocetinostat Human Pharmacokinetics and Product Metabolism 
The pharmacokinetic profile of mocetinostat has been evaluated in clinical trials, after 
single and repeated dose administration.  Plasma samples for pharmacokinetic analyses 
were collected over a 24-hour period following single and multiple doses.  Plasma drug 
concentrations were determined using a validated, sensitive, LC-MS/MS assay.  In 
general, mocetinostat was rapidly absorbed following administration with 200 mL of a 
low pH beverage, with maximum concentration (Cmax) occurring 0.5 to 1.5 hours after 
dosing.  The elimination half-life ranged from approximately 7 to 12 hours.  As 
determined from the Cmax and AUC values, exposure to mocetinostat following oral 


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dosing appears to increase with doses up to 110 mg.  Mocetinostat did not appear to 
accumulate following multiple dosing, and its elimination half-life was approximately 
10 hours. 
Mocetinostat is metabolized by CYP enzymes that include CYP 2E1 and CYP 3A4, and 
possibly also CYP 2C8 and CYP 2C19.  Caution should be used when mocetinostat is 
administered with concomitant medications that are inhibitors or inducers of CYP 2E1, or 
strong inhibitors or inducers of CYP 3A4. 
Mocetinostat does not appear to be a strong inducer of CYP enzymes but may be an 
inhibitor of CYP 2C9.  Caution should be used when mocetinostat is administered with 
concomitant medications that are substrates for CYP 2C9. 
In vitro studies indicate that mocetinostat has a low potential for P-gp inhibition at the 
levels observed in patients. 
1.3 
Durvalumab 
Durvalumab (also known as MEDI4736) is being developed as a potential anticancer 
therapy for patients with advanced solid tumors.  Durvalumab is a human monoclonal 
antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) subclass that inhibits binding 
of PD-L1 (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to PD-1 (CD279) 
and CD80 (B7-1).  Durvalumab is composed of 2 identical heavy chains and 2 identical 
light chains, with an overall molecular weight of approximately 149 kDa.  Durvalumab 
contains a triple mutation in the constant domain of the immunoglobulin (Ig) G1 heavy 
chain that reduces binding to complement protein C1q and the fragment crystallizable 
gamma (Fcγ) receptors involved in triggering effector function. 
1.3.1 
Durvalumab Drug Substance 
Generic Name: 
Durvalumab 
Other Name:  
MEDI4736 
Molecular Weight:  
149 kDa 
1.3.2 
Durvalumab Non-Clinical Data 
The non-clinical experience is fully described in the current version of the durvalumab 
Investigator’s Brochure (Investigator’s Brochure V10.0-Durvalumab).   
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its 
interaction with PD-1 and CD80.  In vitro studies demonstrate that durvalumab 
antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in their 
restored proliferation and release of interferon gamma (IFN-γ).  Additionally, 
durvalumab demonstrated a lack of antibody-dependent cell-mediated cytotoxicity 


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(ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional assays.  
In vivo studies show that durvalumab inhibits tumor growth in a xenograft model via a 
T lymphocyte (T-cell) dependent mechanism.  Moreover, an anti-mouse PD-L1 antibody 
demonstrated improved survival in a syngeneic tumor model when given as monotherapy 
and resulted in complete tumor regression in > 50% of treated mice when given in 
combination with chemotherapy.  Combination therapy (dual targeting of PD-L1 and 
cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression in a 
mouse model of colorectal cancer.   
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
PK/pharmacodynamics and potential toxicity of durvalumab.  Following intravenous (IV) 
administration, the PK of durvalumab in cynomolgus monkeys was nonlinear.  Systemic 
clearance (CL) decreased and concentration half-life (t1/2) increased with increasing 
doses, suggesting saturable target binding-mediated clearance of durvalumab.  No 
apparent gender differences in PK profiles were observed for durvalumab.   
In general, treatment of cynomolgus monkeys with durvalumab was not associated with 
any durvalumab-related adverse effects that were considered to be of relevance to 
humans.  Adverse findings in the non-Good Laboratory Practice (GLP) 
PK/pharmacodynamics and dose range-finding study, and a GLP 4-week repeat-dose 
toxicity study were consistent with antidrug antibody (ADA)-associated morbidity and 
mortality in individual animals.  The death of a single animal in the non-GLP, 
PK/pharmacodynamics, and dose range-finding study was consistent with an 
ADA-associated acute anaphylactic reaction.  The spectrum of findings, especially the 
clinical signs and microscopic pathology, in a single animal in the GLP, 4-week, 
repeat-dose study was also consistent with ADA immune complex deposition, and ADA: 
durvalumab immune complexes were identified in a subsequent non-GLP, investigative 
immunohistochemistry study.  Similar observations were reported in cynomolgus 
monkeys administered human mAbs unrelated to durvalumab.  Given that 
immunogenicity of human mAbs in nonclinical species is generally not predictive of 
responses in humans, the ADA-associated morbidity and mortality were not considered 
for the determination of the no-observed-adverse-effect level (NOAEL) of durvalumab.   
Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in 
cynomolgus monkeys showed that subchronic dosing of durvalumab was not associated 
with any adverse effects.  Therefore, the NOAEL of durvalumab in all the general 
toxicity studies was considered to be 100 mg/kg, the highest dose tested in these studies.  
In addition to the in vivo toxicology data, no unexpected membrane binding of 
durvalumab to human or cynomolgus monkey tissues was observed in GLP tissue 
cross-reactivity studies using normal human and cynomolgus monkey tissues. 


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1.3.3 
Durvalumab Clinical Data 
Clinical experience with durvalumab is fully described in the current version of the 
durvalumab Investigator’s Brochure (Investigator’s Brochure V10.0-Durvalumab). 
As of 12 Jul, 2016 across the entire clinical development program, an estimated 
5225 patients have been exposed to 1 or more doses of durvalumab in clinical studies, 
either as monotherapy or in combination, including 2878 patients in open label trials, and 
2347 patients as an estimate based on the random scheme in studies where the treatment 
arm is blinded. Of the 2878 patients in open label studies, 1,744 received durvalumab 
monotherapy, 808 received durvalumab in combination with tremelimumab, 140 patients 
received durvalumab in combination with other investigational products and 186 patients 
received durvalumab in combination with approved products. No studies have been 
completed or terminated prematurely due to toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer 
agents was consistent with the pharmacology of the target and other agents in the immune 
checkpoint inhibitor class.  No tumor types appeared to be associated with unique AEs.  
Immune-related AEs (irAEs), which are important risks of immune checkpoint inhibitors, 
have been observed with durvalumab and include colitis, pneumonitis, 
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, 
and nephritis.  In addition, pancreatitis is an important potential risk particularly with 
durvalumab and tremelimumab combination therapy.  These events are manageable by 
available/established treatment guidelines as described in the study protocols.  AEs 
reported with durvalumab monotherapy in key clinical studies are described below. 
Adverse Event Profile of Durvalumab Monotherapy 
The safety profile of durvalumab monotherapy in the 970 subjects with advanced solid 
tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab-1108 has been broadly 
consistent with that of the overall 1744 subjects who have received durvalumab 
monotherapy (not including subjects treated with blinded investigational product) across 
the clinical development program.  The majority of treatment-related AEs were 
manageable with dose delays, symptomatic treatment, and in the case of events suspected 
to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity.  As of 12Jul2016, among the 970 patients treated with 
10 mg/kg Q2W in Study CD-IN-durvalumab-1108, 947 patients (97.6%) had at least 
1 AE (regardless of causality). AEs (all grades) reported in decreasing order of frequency 
in ≥10% of patients were fatigue (37.6%), nausea (23.7%), decreased appetite (23.2%), 
dyspnoea (21.9%), constipation (20.2%), diarrhoea and cough (17.9% each), back pain 
(16.5%), vomiting (15.9%), anaemia (15.6%), abdominal pain (14.4%), pyrexia (13.9%), 
arthralgia (13.1%), oedemaperipheral (12.1%), pruritus (11.6%) and headache (11.2%). 
Across the tumor types, the overall incidence of AEs was generally similar. A majority of 
the treatment-related AEs were Grade 1 or Grade 2 in severity.  Grade 3 or higher events 
were reported in 295 subjects (30.4%) and were manageable by general treatment 
guidelines contained in each of the study protocols.  Events occurring in >2% of patients 


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were anaemia (6.2%), dyspnoea (6.0%), hyponatremia (5.4%), fatigue (3.9%), GGT 
increased (3.6%), abdominal pain (3.1%), AST increased (2.9%), back pain (2.9%) and 
dehydration (2.6%). A total of 554 patients (57.1%) reported AEs that were considered 
by the investigator to be related to investigational product. Treatment-related AEs 
(all grades) reported in >5% of patients were fatigue (18.7%); nausea (7.9%); diarrhoea 
(7.6%); pruritus (6.8%), decreased appetite (6.7%); hypothyroidism (6.3%) and rash 
(6.0%). The majority of the treatment-related AEs were Grade 1 or Grade 2 in severity 
with ≥Grade 3 events occurring in 88 patients (9.1%). Treatment-related ≥Grade 3 or 4 
events reported in ≥2 patients were fatigue (1.6%); AST increased (1.0%); ALT increased 
(0.8%); GGT increased (0.7%); hyponatremia, diarrhea (0.5% each); colitis (0.4%); 
decreased appetite and vomiting (0.3% each); and ALP increased, anaemia, arthralgia, 
autoimmune hepatitis, blood bilirubin increased, dyspnoea, hyperglycaemia, infusion 
related reaction, leukopenia, nausea, neutropenia, nervous system disorder, rash 
maculo-papular, thrombocytopenia, transaminases increased and weight decreased and 
(0.2% each). Four patients had a treatment-related Grade 5 event Treatment related SAEs 
that occurred in >1 patient each were colitis and pneumonitis (4 patients each); nervous 
system disorder (3 patients); and acute kidney injury, AST increased, and diarrhoea 
(2 patients each). The majority of the treatment-related SAEs were Grade 3 or higher in 
severity and recovered with or without sequelae. AEs that resulted in permanent 
discontinuation of durvalumab were considered as treatment related in 24 subjects 
(2.5%), with colitis being the most frequent treatment-related AE resulting in 
discontinuation (3 subjects).  A majority of the treatment-related AEs resulting in 
discontinuation of durvalumab were Grade 1 or 2 in severity and resolved with or without 
sequelae.  
The safety profile of durvalumab monotherapy in Study CD-ON-durvalumab-1108 is 
generally consistent with that of Study D4191C00003/ATLANTIC in subjects with 
locally advanced or metastatic non-small-cell lung cancer (NSCLC) treated with 
durvalumab 10 mg/kg Q2W.  As of 12Jul2016, 425 of 444 subjects (95.7%) reported any 
AE in Study D4191C00003/ATLANTIC.  Overall, events reported in ≥ 10% of subjects 
were fatigue (23.6%), decreased appetite (22.1%), cough (20.3%), pyrexia 
(17.3%),nausea (16.7%), asthenia (16.0%), dyspnoea (15.8%), constipation (15.1%), 
diarrhoea (13.3%), anaemia (13.1%), vomiting (11.0%), and pruritus (10.6%).  The 
majority of these AEs were Grade 1 or 2 in severity and manageable by general treatment 
guidelines as described in the current durvalumab study protocols.  The TEAEs of Grade 
3 or higher reported in more than 2% of patients in decreasing order of frequency were 
anaemia (4.7%), dyspnoea (4.3%), and GGT increased (2.7%); none of these events were 
Grade 5. A total of 40 patients (9.0%) experienced a treatment-related TEAE of Grade 3 
or higher. The events experienced by more than 1 patient were pneumonitis and GGT 
increased (4 patients each), diarrhoea and infusion-related reaction (3 patients each), AST 
increased, transaminases increased, vomiting and fatigue (2 patients each). All patients 
with treatment-related Grade 3 or higher pneumonitis, diarrhoea, infusion related 
reaction, transaminases increased and vomiting, recovered. Overall, the treatment-related 
Grade 3 or higher events were manageable by appropriate medical management, 
including in some cases the use of steroids or endocrine therapy, withholding durvalumab 


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dosing until the event resolved, or permanent discontinuation of durvalumab. SAEs were 
reported in 116 patients (26.1%); treatment-related SAEs were reported in 27 patients 
(6.1%). The SAEs with an incidence of ≥1.0% were dyspnoea (2.3%), pneumonia 
(2.0%), pleural effusion (1.6%), anaemia (1.1%), pneumonitis (1.1%) and pulmonary 
embolism (1.1%). Of these SAEs, only pneumonitis and anaemia were assessed by the 
Investigator as being treatment related (5 patients and 1 patient, respectively). All 
treatment-related SAEs of pneumonitis and anaemia resolved, except 1 pneumonitis 
event (ongoing at the time of death). A total of 11 patients (2.5%) have died due to an 
AE. The only TEAE with an outcome of death that was experienced by more than 
1 patient was pneumonia (2 patients). Other TEAEs with an outcome of death occurring 
in 1 patient each were, acute myocardial infarction, cardiac failure, cardio-respiratory 
arrest, gastric haemorrhage, gastrointestinal haemorrhage, pneumonitis, pulmonary 
embolism, pulmonary sepsis and sudden death. Four of the 11 deaths were due to both 
the TEAE and the underlying NSCLC. Ten of the 11 deaths were assessed as not 
treatment-related. One patient experienced a treatment-related fatal TEAE of pneumonitis 
after discontinuing durvalumab and starting a subsequent anticancer therapy (erlotinib). 
Twenty-nine of 444 subjects (6.5%) permanently discontinued durvalumab treatment due 
to AEs.  A total of 10 patients (2.3%) had a treatment-related event that led to 
discontinuation. 
Durvalumab Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) for durvalumab 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 durvalumab monotherapy and combination 
therapy.  An immune-related adverse event (irAE) is defined as an adverse event that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology.  Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis.  
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE.  
If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should promptly contact the Study Physician. 
AESIs based on observed safety events using durvalumab monotherapy and/or class 
effects for inhibitors of PD-L1 or PD-1 include: 
• Colitis 
• Pneumonitis 
• ALT/AST increases / hepatitis / hepatotoxicity  


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• Neuropathy / neuromuscular toxicity (i.e., events of encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e., events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Type 1 diabetes mellitus 
• Rash/ dermatitis  
• Nephritis  
• Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased 
serum amylase)   
Further information on these risks (e.g., presenting symptoms) can be found in the current 
version of the Investigator’s Brochure V10.0-Durvalumab.  
1.3.4 
Durvalumab Human Pharmacokinetics 
As of 09 Feb2015, PK data were available for 378 subjects in the dose-escalation and 
dose-expansion phases of Study CD-ON-durvalumab-1108 following treatment with 
durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W).  
The maximum observed concentration (Cmax) increased in an approximately 
dose-proportional manner over the dose range of 0.1 to 15 mg/kg.  The area under the 
concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than 
dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased 
dose-proportionally at ≥ 3 mg/kg.  These results suggest durvalumab exhibits nonlinear 
PK likely due to saturable target-mediated CL at doses < 3 mg/kg and approaches 
linearity at doses ≥ 3 mg/kg.  Near complete target saturation (soluble programmed cell 
death ligand 1 [sPD-L1] and membrane bound) is expected with durvalumab ≥ 3 mg/kg 
Q2W.  Exposures after multiple doses showed accumulation consistent with PK 
parameters estimated from the first dose.  In addition, PK simulations indicate that 
following durvalumab 10 mg/kg Q2W dosing, > 90% of subjects are expected to 
maintain PK exposure ≥ 40 µg/mL throughout the dosing interval. 
A population PK model was developed for durvalumab using monotherapy data from a 
Phase 1 study (Study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; 
solid tumors).  Population PK analysis indicated only minor impact of body weight (WT) 
on PK of durvalumab (coefficient of ≤ 0.5).  The impact of body WT-based (10 mg/kg 
Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing 
predicted steady state PK concentrations (5th, median and 95th percentiles) using the 
population PK model.  A fixed dose of 750 mg was selected to approximate 10 mg/kg 
(based on median body WT of ~75 kg).  A total of 1000 patients were simulated using 
body WT distribution of 40–120 kg.  Simulation results demonstrate that body WT-based 


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and fixed dosing regimens yield similar median steady state PK concentrations with 
slightly less overall between-subject variability with fixed dosing regimen.  Based on 
average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) is included in the current study.  
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis.  Only 8 of 
388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 
10 mg/kg cohort) were ADA positive with an impact on PK/pharmacodynamics in 
1 subject in the 3 mg/kg cohort. 
1.3.5 
Durvalumab Monotherapy Clinical Activity in Solid Tumor 
Diseases 
In Study CD-ON-durvalumab-1108, 456 of 694 subjects treated with durvalumab 
10 mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan).  In PD-L1 unselected patients, the 
objective response rate (ORR), based on investigator assessment per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma 
(n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate at 24 weeks 
(DCR-24w) ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 39.1% 
in advanced cutaneous melanoma (n = 23).  PD-L1 status was known for 383 of the 
456 response evaluable subjects.  Across the PD-L1-positive tumors, ORR was highest 
for bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma (HCC; 
n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the 
head and neck (SCCHN; n = 22, 18.2%).  In the PD-L1-positive subset, DCR-24w was 
highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 36.0%), HCC 
and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
1.4 
Expectations for Combination of Mocetinostat and Durvalumab 
Potential for Drug-Drug Interactions 
Treatment with mocetinostat in combination with durvalumab is unlikely to result in 
clinically relevant metabolism or elimination-based drug-drug interactions (DDI).  
Durvalumab is a mAb and is intravenously administered, whereas mocetinostat is a small 
molecule therapeutic administered orally; no absorption interaction is expected. 
The fractional binding of MGCD0103 to human plasma was measured via equilibrium 
dialysis.  At concentrations of 0.5, 1 and 10 μM, MGCD0103 showed binding of 95.1%, 
97.5%, and 95.2%, respectively.  MEDI4736 is a mAb and only binds specifically to 
IgG1κ, therefore, no risk of distribution interaction is expected. 


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Reaction phenotyping results indicated that MGCD0103 was metabolized by CYP2E1 
and CYP3A and possibly CYP2C8 and 2C19.  No studies on the metabolism of 
MEDI4736 have been performed in vitro or in humans.  Like most therapeutic proteins, 
MEDI4736 is not expected to be metabolized by liver cytochrome P450 (CYP) or other 
drug metabolizing enzymes and is unlikely to have an effect on CYPs or other 
metabolizing enzymes in terms of inhibition or induction.   
Evaluation of Potential for Increased Toxicities with Combination Use of 
Mocetinostat and Durvalumab 
PD-L1 is part of a complex system of receptors and ligands that are involved in 
controlling T-cell activation.  PD-L1 acts at multiple sites in the body to help regulate 
normal immune tolerance and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response.  Durvalumab (MEDI4736) is a 
mAb that inhibits binding of PD-L1 to PD-1 and CD80.   
Mocetinostat (MGCD0103) is a small molecule inhibitor of Class I and IV HDACs.  
HDACs are involved in cellular processes such as cell cycle progression and 
differentiation and have been implicated in the epigenetic regulation of innate and 
adaptive immunity.  Evidence supports the proposal that spectrum-selective inhibitors of 
Class I HDACs can reverse immune evasion and elicit antitumor efficacy through 
induction of PD-L1 expression; enhanced tumor antigenicity via induction of TAAs and 
MHC Class I and Class II molecules; activation and cross-presentation of tumor antigens 
by APCs; enhanced function of T effector cells; and decreased function of 
immunosuppressive cell subsets including Treg cells and MDSCs.   
When viewed together, the safety profiles of mocetinostat and durvalumab are largely 
non-overlapping.  Frequently observed AEs common to treatment with single agent 
durvalumab and mocetinostat are non-specific and typical of cancer treatment regimens, 
including fatigue, anorexia, nausea, vomiting, and diarrhea.  Potential exists for these 
AEs to be observed with increased severity or frequency during use of the combined 
agents.  Management of these effects in patients receiving cancer therapy is well 
precedented.   
More importantly, immune-related AEs of Special Interest based on observed safety 
events using durvalumab monotherapy and/or class effects for inhibitors of PD-L1 or 
PD-1 include colitis, pneumonitis, ALT/AST increases / hepatitis / hepatotoxicity, 
neuropathy / neuromuscular toxicity, endocrinopathy, dermatitis, nephritis and 
pancreatitis.  While Class I HDAC inhibitors may have immunostimulatory effects, 
autoimmune adverse effects have not been reported in mocetinostat clinical trials or as a 
class effect.  The potential for mocetinostat to exacerbate or promote these adverse events 
when administered in combination with durvalumab should be borne in mind.   


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One clinically relevant overlap in toxicity may arise between the immune-related colitis 
attributed to durvalumab and the non-specific, most often mild to moderate diarrhea 
observed with both durvalumab and mocetinostat.  Immune-related colitis has been 
reported in approximately 0.8% of patients treated with durvalumab, with a time to onset 
ranging from 43 to 138 days after the first dose.  Diarrhea of uncertain etiology has been 
reported in approximately half of patients treated with mocetinostat, most often with a 
time to onset within 30 days of first mocetinostat dose.  Low grade diarrhea is less 
common with durvalumab, occurring in fewer than 8% of patients treated at 10 mg/kg 
Q2W in Study CD-ON-durvalumab-1108.  The time to onset may be helpful in 
distinguishing diarrhea that may be attributed to autoimmune effects versus non-specific 
toxicity.   
Two AEs observed in previous clinical trials of mocetinostat for which causality and 
mechanism are unclear are cystitis and pericardial effusion.  The potential for an 
immune-based mechanism exists, therefore increased risk may be associated with the 
combination of mocetinostat with durvalumab. 
1.5 
Study Rationale 
Advanced tumors evade host immune responses by down regulation of major 
histocompatibility complex (MHC) molecules and tumor antigens and by creating an 
immune suppressive microenvironment around the tumor.  Histone deacetylases 
(HDACs) have been implicated in the epigenetic regulation of innate and adaptive 
immunity.  Increasing evidence supports the proposal that spectrum-selective inhibitors 
of class I HDACs can reverse immune evasion and elicit antitumor host response through 
immunostimulatory mechanisms.  The immunomodulatory properties of class I HDAC 
inhibitors are reported to be mediated through multiple mechanisms including: 
1) induction of programmed cell death ligand 1 (PD-L1) expression on the tumor cell 
surface, 2) induction of tumor associated antigens (TAAs) and MHC Class I and Class II 
molecules on tumor cells, 3) induction of immunogenic cell death via activation and 
cross-presentation of tumor antigens by antigen presenting cells (APCs), 4) enhanced 
function of T effector cells, and 5) decreased function of immunosuppressive cell subsets 
including T regulatory (Treg) cells and myeloid-derived suppressor cells (MDSCs).  In 
addition, HDAC inhibitors are associated with anticancer effects through inhibiting cell 
cycle progression and inducing apoptosis in tumor.  The combination of a class I HDAC 
inhibitor with an anticancer immunotherapy has the potential to enhance activity over that 
observed with either agent alone. 
Mocetinostat is a spectrum-selective Class I/IV HDAC inhibitor specifically targeting 
HDACs 1, 2, 3 and 11.  Class I and IV HDACs are of particular interest from an 
immunostimulatory and immune priming perspective.   


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Durvalumab is a human monoclonal antibody (MAb) that inhibits binding of PD-L1 to 
programmed cell death 1 (PD-1) and CD80 expressed on host immune effector cells, 
preventing immune suppression signaling.  Durvalumab is being developed as a potential 
anticancer therapy for patients with advanced solid tumors or hematological 
malignancies.   
The percent of tumor cells expressing PD-L1 is predictive for responsiveness to treatment 
with durvalumab (Rebelatto-2015).  The recommended threshold for positivity is ≥25% 
of tumor cells demonstrating membrane staining for PD-L1 at any intensity.  Among 
patients with NSCLC, the ORR for cases positive for PD-L1 was 27% (23 of 84; 95% 
Confidence Interval [CI] 18.2-38.2%) as compared to 5% (5 of 92; 95% CI 1.8-12.2%) 
for cases negative for PD-L1 expression (Rizvi-2015).  Subset analysis by histological 
classification shows the following disease response rates: 
Histology 
All Patients 
PD-L1 + 
PD-L1 - 
Squamous 
18/88 (21%) 
14/43 (33%) 
3/37 (8%) 
Non-squamous 
14/122 (13%) 
9/41 (22%) 
2/55 (4%) 
 
In this study, the treatment regimen will begin with a 7-Day Lead-In Period of 
mocetinostat followed by start of the combination regimen of mocetinostat and 
durvalumab.  The Recommended Phase 2 Dose (RP2D) of mocetinostat will be 
established in the Phase 1 dose escalation segment, followed by evaluation of the clinical 
activity of the combination regimen in patients having NSCLC. 
 
 


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2 STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objectives 
• To determine the RP2D of mocetinostat administered in combination with full dose 
durvalumab. 
• To evaluate the clinical activity of mocetinostat in combination with durvalumab in 
cohorts of patients with NSCLC having differing tumor expression of PD-L1 or prior 
tumor responsiveness to treatment with checkpoint inhibitors. 
2.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of mocetinostat in combination with 
durvalumab in the selected population. 
• To evaluate secondary efficacy endpoints with mocetinostat in combination with 
durvalumab treatment in the selected population. 
• To evaluate mocetinostat and durvalumab PK. 
• To evaluate the incidence of ADA to durvalumab. 
• To evaluate the effect of mocetinostat during the Lead-In Period on tumor cell PD-L1 
expression.   
 
 
 
 
 
 
 
 
 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
• Incidence of DLTs occurring during the first 28-day cycle of combination treatment.  
• ORR as defined by RECIST 1.1. 


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2.2.2 
Secondary Endpoints 
• Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of adverse events and laboratory abnormalities. 
• Secondary efficacy endpoints: 
o DR; 
o CBR; 
o PFS; 
o 1-Year Survival Rate; and 
o OS. 
• Blood plasma MGCD0103 and MEDI4736 concentrations. 
• ADA detected in blood. 
• Tumor PD-L1 expression. 
 
 
 
 
 
 
 
 
 
 
 


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3 STUDY DESIGN 
Study 0103-020 is an open-label Phase 1/2 evaluation of mocetinostat in combination 
with durvalumab.  The Phase 1 segment will define the RP2D of mocetinostat to be used 
in combination with the full dose regimen of durvalumab; eligible patients will have an 
advanced solid tumor disease that is not amendable to curative treatment.  The Phase 2 
segment will evaluate the clinical activity of mocetinostat in combination with 
durvalumab, as assessed by ORR in accordance with RECIST 1.1., in patients with 
locally advanced, unresectable or metastatic NSCLC who have previously received at 
least one platinum-containing doublet chemotherapy regimen for advanced disease.  
Patients who have previously received treatment with checkpoint inhibitors may be 
enrolled in the Phase 1 assessment and will be enrolled into dedicated cohorts in the 
Phase 2 assessment.  Secondary objectives include secondary efficacy endpoints, PK, 
incidence of ADA and change in tumor PD-L1 expression.  
 
he Schedule of 
Assessments to be performed in the study is presented in Table 1.  Triplicate ECG 
assessments, PK, and ADA collection time points are presented in Table 2. 
The treatment regimen to be evaluated in this study includes a 7-Day Lead-in Period of 
mocetinostat single agent administered TIW (e.g., Monday, Wednesday and Friday) 
followed by administration of the combination regimen with durvalumab.  The RP2D 
dose of mocetinostat will be established in successive dose escalation cohorts in the 
Phase 1 study and utilized in the Phase 2 study.  The dose and regimen of durvalumab to 
be used throughout the study is 1500 mg on Day 1 of each 28-day cycle (i.e., Q4W).  
Guidelines for adverse event management and associated treatment modifications of each 
agent are provided in Section 5. 
3.1 
Phase 1 Study 
The dose escalation phase of the study will employ the mTPI method will be employed in 
decision making concerning mocetinostat dose escalation (Appendix 2).   
The mocetinostat dose levels planned for evaluation include 50, 70, and 90 mg TIW, 
depending on safety observations.  In addition, if necessary, dose de-escalation of 
mocetinostat to 40 mg TIW may be undertaken.   
3.1.1 
Definition of Dose Limiting Toxicity 
The National Cancer Institute Common Toxicity Criteria for Adverse Events 
(NCI CTCAE) version 4.03 will be used throughout this study.  The definition of DLT 
includes any of the following events considered to be causally related to treatment with 
mocetinostat in combination with durvalumab: 
• Any Grade 4 immune-related Adverse Event (irAE is defined in Section 8.3.1) 
• Grade 3 or greater colitis  


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• Grade 3 or greater noninfectious pneumonitis irrespective of duration 
• Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation 
of maximal supportive care 
• Grade 3 irAE (excluding colitis or pneumonitis) that: 
o does not downgrade to Grade 2 within 3 days after onset of the event despite 
optimal medical management including systemic corticosteroids, or  
o does not downgrade to ≤ Grade 1 or baseline within 14 days 
• Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN 
• Grade 3 or greater non-irAE, except for the exclusions listed below: 
o Nausea, vomiting, anorexia, dehydration, or diarrhea that can be managed with 
typical medical interventions 
The definition of DLT excludes the following conditions:  
• Grade 3 fatigue lasting ≤ 7 days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the patient is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response  
(e.g., inflammatory reaction at sites of metastatic disease, lymph nodes, etc) 
• Concurrent vitiligo or alopecia of any grade 
• Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
• Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days.  Grade 3 or Grade 4 febrile neutropenia 
will be a DLT regardless of duration or reversibility 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least 1 grade within 3 days 


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• 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 
3.1.2 
Dose Escalation Plan 
The first cohort of patients to be enrolled will begin with the mocetinostat 7-Day Lead-in 
Period, receiving 50 mg on 3 days (e.g., Monday, Wednesday and Friday) and will 
continue into the combination regimen, with 50 mg mocetinostat administered TIW and 
1500 mg durvalumab administered Q4W.   
For a patient within a dose cohort to be considered evaluable for the dose-escalation 
decision, the patient must have either been on study for one full cycle and have received 
treatment with durvalumab and at least 9 of 12 scheduled mocetinostat doses (75%) in 
Cycle 1 or have experienced a DLT in Cycle 1.   
Decision making rules for cohort expansion and dose escalation or de-escalation based on 
the experience of patients treated at a dose level are presented in Appendix 2. 
To ensure sufficient patient experience at the dose selected as the RP2D, enrollment at 
any dose level under consideration may be expanded to include at least 6 patients.  
3.1.3 
Definition of Maximum Tolerated Dose 
The Maximum Tolerated Dose (MTD) is defined as the highest mocetinostat dose 
administered in the combination regimen associated with the decision to “stay with the 
current dose” as determined from the Dose-Finding Spreadsheet (Appendix 2) using the 
experience of at least 6 patients during the first 28-day treatment cycle.   
3.1.4 
Definition of Recommended Phase 2 Dose 
The RP2D will be the highest dose of mocetinostat evaluated that is associated with: 
• sufficient safety/tolerability to anticipate that patients will typically be able to receive 
treatment with at least 75% of the intended dose intensity of mocetinostat and 100% 
dose intensity of durvalumab; and 
• no observed ≥Grade 3 or serious irAEs causally related to the combination regimen. 
A dose level below the MTD may be selected as the RP2D. 


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3.2 
Phase 2 
The Phase 2 study will enroll patients with NSCLC into one of the following 
4 population cohorts: 
Cohort 1 – Patients naïve to treatment with immunotherapy, having tumor with 
no/low PD-L1 expression. 
Cohort 2 – Patients naïve to treatment with immunotherapy, having tumor with high 
PD-L1 expression. 
Cohort 3 – Patients previously treated with an anti-PD-L1 or anti-PD-1 agent with 
clinical benefit response followed by progression of disease. 
Cohort 4 – Patients previously treated with an anti-PD-L1 or anti-PD-1 agent with 
progression or disease ≤ 16 weeks after initiation of treatment. 
Tumor PD-L1 expression will be determined by the PD-L1 (SP263) CDx assay.  No/low 
PD-L1 expression is defined as positivity < 25% of tumor cells; high PD-L1 expression is 
defined as positivity ≥25% of tumor cells.  Tumor samples used to establish PD-L1 
expression for eligibility must have been collected after the most recent systemic therapy. 
The sample sizes for the populations to be enrolled in the Phase 2 portion of the study are 
based on Predictive Probability Design, which allows for flexibility in the number of 
patients to be included at each stage in order to ensure that sufficient number of evaluable 
patients are available for decision to continue or to stop enrollment of additional patients.  
•  Cohorts 1, 3 and 4:  Stage 1 of enrollment will include a minimum of 9 evaluable 
patients.  With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an 
Objective Response, 8 additional evaluable patients will be enrolled, for a total 
sample size of 17 evaluable patients.  If at least 3 objective responses are observed, 
further investigation may be warranted.   
• Cohort 2:  Stage 1 of enrollment will include approximately 17 evaluable patients. 
With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective 
Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 
44 evaluable patients.  If at least 18 Objective Responses are observed, further 
investigation may be warranted.   
The exact stopping rules for all cohorts will be calculated based on the Predictive 
Probability Design, once the exact number of patients evaluable at Stage 1 is known. The 
aim is to get a minimum of 9 evaluable patients at Stage 1 for cohorts 1, 3 and 4 and 
about 17 evaluable patients at Stage 1 for cohort 2. 


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The populations included in Cohorts 3 and 4, who have had progression of disease during 
treatment with a checkpoint inhibitor, represent a potential unmet medical need.  For this 
reason, if results in Stage 2 of enrollment are of high interest, enrollment may be 
expanded to as many as 100 patients total in each cohort to narrow the 95% Confidence 
Interval (CI) around the ORR point estimate and more fully characterize the secondary 
endpoints in the population of interest. 
In order to be part of the clinical activity evaluable population, the patient must have at 
least one on-study disease assessment or discontinue from treatment for PD prior to this 
assessment.  Patients who discontinue treatment prior to the first on-study disease 
assessment for an AE, toxicity, or withdraw consent are considered non-evaluable for 
disease assessment. These patients will not be part of the clinical activity evaluable 
population.  
Disease response and progression as documented by the investigator in the CRF will be 
the basis for patient management and study expansion decision making.  Unconfirmed 
objective responses recorded in the CRF may be used as the initial basis for expansion of 
study enrollment; however, follow-up evaluations on patients with unconfirmed 
responses must continue to support the decision to continue to the full number of patients 
to be included in the next stage.  Central radiology review for disease response and 
progression may be added to the study during Stage 2.  If this occurs, central review of all 
radiologic assessments performed in the study will be expected (including retrospective 
review of patients enrolled in Stage 1), and central radiology review for disease response 
will be the basis for the primary statistical analyses to estimate the objective response rate 
and its confidence interval, as well as the duration of response and PFS. 
Study treatment will continue until disease progression, unacceptable adverse events, 
patient refusal or death.  
 


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4 SUBJECT SELECTION AND ENROLLMENT 
Patient eligibility must be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before patients are included in the study.  No 
exceptions to the patient eligibility requirements will be granted by the Sponsor. 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria as applicable for phase of the 
study to be eligible for enrollment into the study: 
1. Diagnosis and disease status: 
a. Phase 1 – Histologically or cytologically confirmed solid tumor 
malignancy with metastatic or unresectable, locally advanced disease 
b. Phase 2 – Histologically confirmed NSCLC (any histology) with 
metastatic or unresectable, locally advanced disease 
2. Prior treatments: 
a. Phase 1  
i. Not amenable to treatment with curative intent 
ii. May have received treatment with checkpoint inhibitors  
(e.g., anti-PD-1 or anti-PD-L1) 
b. Phase 2 
i. Receipt of at least one prior treatment in the advanced disease 
setting that included a platinum-based doublet or immunotherapy 
regimen.  If prior platinum-based therapy was received in the 
neoadjuvant or adjuvant setting, relapse must have occurred within 
1 year of end of treatment.   
ii. Cohorts 3 and 4 – Most recent treatment regimen must have 
included a checkpoint inhibitor, e.g., anti-PD-1 or anti-PD-L1 
treatment. 


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3. Molecular analysis for PD-L1 expression on tumor cells: 
a. Phase 1 – PD-L1 tumor expression testing is not required but is 
encouraged; any expression status is eligible 
b. Phase 2 
i. Cohorts 1 and 2 – Molecular analysis of tumor sample collected 
following most recent therapy, assessed using the PD-L1 (SP263) 
CDx assay.  Inclusion in the treatment arms will be based on 
documented no/low PD-L1 expression (positivity < 25% of tumor 
cells) or high PD-L1 expression (positivity ≥25% of tumor cells). 
ii. Cohorts 3 and 4 – PD-L1 tumor expression testing is not required 
but is encouraged; any expression status is eligible. 
4. Response to previous treatment with checkpoint inhibitor: 
a. Phase 1 – Any response is eligible, as applicable. 
b. Phase 2 
i. Cohort 3 – clinical benefit (i.e., RECIST defined partial or 
complete response or stable disease for at least 16 weeks [+2 week 
window permitted for radiograph scheduling]) followed by 
radiographic progression of disease 
ii. Cohort 4 – radiographic progression of disease ≤ 16 weeks after 
initiation of treatment (+2 week window permitted for radiograph 
scheduling)   
5. Measurable disease 
a. For Phase 1 – Measurable or evaluable, as per RECIST version 1.1 
b. For Phase 2 – Measurable disease, as per RECIST version 1.1.  Indicator 
lesions intended for repeat biopsy during the study should be excluded 
from selection as target lesions at baseline 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
7. Adequate bone marrow and organ function demonstrated by:  
a. Hemoglobin ≥ 9.0 g/dL  
b. Absolute neutrophil count ≥ 1,500/mm3 (≥ 1. 5 × 109/L) 


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c. Platelet count ≥ 100 × 109/L (> 100,000 per mm3) 
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × Upper Limit of Normal (ULN), or ≤ 5.0 × ULN for patients with 
documented liver metastases 
e. Serum bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for patients with Gilbert 
Syndrome or documented liver metastases   
f. Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula or by 
24-hour urine collection for determination of creatinine clearance 
8. ≥ 18 years of age 
9. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP 
agrees to use contraception while participating in this study, and for a period of 
6 months following termination of study treatment 
10. Completed informed consent process, including signing IRB/EC-approved 
informed consent form 
11. Willing to comply with clinical trial instructions and requirements 
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Prior therapies: 
a. All Cohorts 
i. HDAC inhibitor for the treatment of the malignancy under study 
ii. Immunotherapies not previously specified, including anti-CTLA-4, 
anti-OX40 and anti–CD137 
b. Phase 2 Cohorts 1 and 2 – prior treatment with anti-PD-1 or anti-PD-L1 
c. Phase 2 Cohorts 3 and 4 – receipt of systemic cancer treatments since 
progression of disease during or following administered checkpoint inhibitor 
2. Patients with any history of tumors that test positive for EGFR, ROS1, ALK mutations 
or ALK fusions or any other mutations for which there are tyrosine kinase inhibitors 
available or under development. 
3. Most recent prior therapeutic regimen discontinued ≤ 3 weeks before first study 
treatment dose date (i.e., mocetinostat Lead-in Period). 


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4. Lack of recovery from the adverse effects of prior therapy at the time of enrollment to 
≤ Grade 1 (excluding alopecia or neuropathy). 
5. Previous treatment-related, severe (≥ Grade 3) AE or any neurologic or ocular AE of 
any grade while receiving checkpoint inhibitors.  NOTE: Patients with a prior 
endocrine AE are permitted to enroll if they are stably maintained on appropriate 
replacement therapy and are asymptomatic. 
6. Active or prior documented autoimmune disease within the past 2 years. 
NOTE: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
7. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis). 
8. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid.   
9. Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving durvalumab. 
10. History of primary immunodeficiency. 
11. Known history of previous clinical diagnosis of tuberculosis. 
12. Known history of acute or chronic hepatitis B, human immunodeficiency virus (HIV), 
or acute hepatitis C. 
13. History of allogeneic organ transplant. 
14. History of hypersensitivity to durvalumab, mocetinostat or any drug product 
excipient.   
15. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis 
which required steroid treatment, or any evidence of clinically active interstitial lung 
disease. 
16. History of stroke or transient ischemic attack within the previous 6 months. 
17. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris, 
b. Congestive heart failure ≥ NYHA Class 3, 


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c. QTc ≥470 milliseconds on electrocardiogram (ECG) calculated using 
Frediricia’s Correction, or  
d. Current or history of a small, moderate or large pericardial effusion, and/or 
hemodynamic compromise due to pericardial effusion of any size.  Minimal or 
trivial pericardial effusion is not excluded. 
18. Concomitant medication known to cause prolonged QT which cannot be discontinued 
or changed to a different medication prior to enrollment. 
19. Active brain metastases. Subjects are eligible if brain metastases are adequately 
treated and subjects are neurologically stable (except for residual signs or symptoms 
related to the CNS treatment) for at least 2 weeks prior to enrollment without the use 
of corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone 
(or equivalent). 
20. Known or suspected presence of another malignancy that could be mistaken for the 
malignancy under study during disease assessments. 
21. Pregnancy.  WOCBP must have a negative serum or urine pregnancy test documented 
within the screening period prior start of study drug. 
22. Breast-feeding or planning to breast feed during the study or within 6 months after 
study treatment. 
23. Any psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the patient to give written informed 
consent. 
24. Any serious illness, uncontrolled inter-current illness, active or uncontrolled 
infection, or other medical history, including laboratory results, which, in the 
Investigator’s opinion, would be likely to interfere with the patient’s participation in 
the study, or with the interpretation of the results.   
4.3 
Life Style Guidelines 
Patients who are biologically capable of having children and sexually active must agree 
to use an acceptable method of contraception for the duration of the treatment period and 
for at least 6 months after the last dose of study treatment.  The investigator will counsel 
the patient on selection of contraception method and instruct the patient in its consistent 
and correct use.  Examples of acceptable forms of contraception include: 
1. Oral, inserted, injected or implanted hormonal methods of contraception, provided it 
has been used for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 


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3. Male condom or female condom used WITH a spermicide. 
4. Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy. 
The investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.   
Note: Women are considered post-menopausal and/or not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
6 months ago.  In case of any ambiguity, the reproductive status of the woman should be 
confirmed by hormone level assessment. 
4.4 
Enrollment into Study 
Evaluation of tumor PD-L1 expression for Phase 2 patients naïve to treatment with 
immunotherapy may have been performed historically or more recently for the purpose of 
determining enrollment into Cohort 1 or 2 of this study.  A 14-day turn-around time 
should be expected from the time of receipt of adequate samples at the central lab to test 
results returned to the study site.  Questions concerning adequacy of samples will cause 
delay beyond this timeframe.   
Following completion of the study-specific informed consent process and review of all 
screening procedures, patient eligibility will be confirmed by appropriately qualified staff 
at the investigational site.  Patients will be enrolled by entry into a patient registration log 
provided by the Sponsor and maintained by the study site, and completion of the patient 
registration procedure detailed in the Study Manual.  Each patient will be assigned a 
sequential number by the study site.  The patient number must be used on all 
documentation and correspondence with the Sponsor, Contract Research Organization 
(CRO) and laboratory vendors. 
 


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5 STUDY TREATMENT 
5.1 
Mocetinostat Study Drug Management 
5.1.1 
Formulation and Packaging 
Mocetinostat study drug contains the free-base form of mocetinostat (MGCD0103) and 
inert excipients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon 
dioxide, non-bovine magnesium stearate. 
Mocetinostat hard gelatin capsules will be supplied by the Sponsor.  Capsule strengths to 
be used in this study are 10 mg (white opaque capsule), 20 mg (white opaque capsule), 
25 mg (Swedish orange capsule), and 50 mg (Swedish orange capsule).  Refer to the 
Pharmacy Manual for details on number of capsules per bottle, and clinical trial material 
supply, distribution and control. 
Medication labels comply with the legal requirements of the United States and will be 
printed in the languages required in the countries in which the study is conducted. 
5.1.2 
Drug Storage and Accountability 
Mocetinostat capsules should be stored protected from light, at room temperature 
(suggested range is 15-30°C, 59-86°F) according to instructions on the label.  The storage 
area should be secure with limited access and monitored for temperature using a 
calibrated thermostat.  Shelf-life evaluation of the intact bottles is ongoing.  Available 
stability data support ≥ 12-months shelf-life when stored under the above conditions, 
depending on capsule strength.   
All study treatment supplies will be accounted for in the drug accountability inventory 
forms supplied by the Sponsor or using locally approved forms that include all required 
information.  The drug accountability inventory forms must identify the study drug, 
including batch or lot numbers and account for its disposition on a patient-by-patient 
basis, including specific dates and quantities.  The forms must be signed by the individual 
who dispensed the drug. 
5.1.3 
Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure 
to them and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents. 
Study site personnel should dispense to patients the appropriate number of capsules 
required to support one 28-day cycle (12 doses) plus one dose.  Mocetinostat capsules are 
to be dispensed in the Sponsor provided High-Density Polyethylene (HDPE) bottles 
along with a provided desiccant packet.   


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5.1.4 
Medication Compliance 
Study site personnel should provide each patient with written dosing information for 
mocetinostat capsules and review it with the patient during clinic visits.  Patients will be 
asked to record their daily mocetinostat dosing on Sponsor provided diary cards and 
report any missed doses or lost capsules at the next clinic visit.  Patients will also be told 
to bring study treatment capsule bottle(s) (empty or not) with them to the clinic visit for a 
compliance check and capsule count.  Study site personnel will record compliance 
information in the source document and on the CRF and retain the bottle(s) until a 
monitor has completed reconciliation.   
See the Study Manual for additional details regarding compliance and reconciliation. 
5.1.5 
Destruction 
At the end of the study, all unused mocetinostat drug supplies will  be destroyed in 
accordance with local Standard Operating Procedure provided to the Sponsor for the Trial 
Master File, or returned to the Sponsor or its appointed agent, as directed by the Sponsor. 
5.1.6 
Administration 
Mocetinostat capsules will be administered orally on a three times per week dosing 
schedule, in 28 day cycles.  The starting dose for mocetinostat in the Phase 1 dose 
escalation study is 50 mg orally TIW with potential to escalate to 70, and 90 mg TIW.  
The dose may be deescalated to 40 mg TIW depending on observed safety.  The RP2D 
will be established based on the Phase 1 results.   
The following guidelines should be followed for mocetinostat administration: 
• Patients should be instructed to take the dose of mocetinostat three days per week 
(e.g., Monday/Wednesday/Friday), in the morning, at approximately the same time 
each day. 
• Mocetinostat should be taken on an empty stomach (e,g,. after an overnight fast or at 
least 3 hours since the previous meal) and wait at least 2 hours before eating the next 
meal. 
• Capsules should be taken with at least 200 mL (7 oz.) of water. 
• Patients should swallow the capsules whole and not chew them. 
• If vomiting occurs after dosing, mocetinostat doses should not be replaced. If 
vomiting occurs on a day when PK collection is required, PK samples should 
continue to be collected. 
 


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• Mocetinostat doses should not be taken 2 days in a row and gaps longer than 3 days 
(~72 hours) should be avoided when possible. 
On days mocetinostat and durvalumab are both administered and scheduled for PK 
assessment, mocetinostat dosing and sampling should precede durvalumab. Mocetinostat 
dosing should occur in the clinic at each visit where Mocetinostat PK collection is 
scheduled, but there are no dosing time restrictions on non-PK days (e.g. C2D15, C4D1, 
C5D1). Cycle 1 Day 15 Mocetinostat dosing must occur at the clinic but all other Day 15 
Mocetinostat dosing can be done at home or at the clinic.   
5.1.7 
Dose Modification and Discontinuation 
Mocetinostat dose reductions will be performed as outlined in Table 5.  Once a dose has 
been reduced, re-escalation will not be permitted.  If the administration of mocetinostat is 
interrupted for reasons other than toxicity, then treatment with the study drug may be 
resumed at the same dose.   
If treatment with the study drug is withheld for ≥ 28 consecutive days, then study drug 
should be considered for permanent discontinuation. 
Table 5: 
Dose Modifications for Mocetinostat 
Mocetinostat Dose Levels to be Investigated and Sequential Dose Reductions* 
90 mg three times per week 
70 mg three times per week 
50 mg three times per week 
40 mg three times per week** 
* 
Dose reduction should be based on the worst preceding toxicity 
** 
Dose reduction below 40 mg 3×/week is not allowed.  If a dose reduction below 40 mg 3×/week is 
required, the patient should be permanently discontinued from mocetinostat. 
5.1.8 
Mocetinostat Adverse Event Management Guidelines 
5.1.8.1 
Management of Mocetinostat in Response to Immune-Related 
Adverse Event 
Administration of mocetinostat as a single agent or in combination with chemotherapy 
has not been associated with irAEs.  However, the potential exists for mocetinostat to 
contribute to irAEs associated with durvalumab treatment, which may include 
immune-mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies.  In the event 
of an irAE, administration of mocetinostat should be interrupted until the event stabilizes 
to Grade ≤1 and after completion of any steroid taper (similar to the guidance for 
resumption of durvalumab treatment as presented in Table 9, and Appendix 4).  At the 
time of resumption of mocetinostat dosing, a dose reduction may be implemented at the 
discretion of the Investigator.   


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5.1.8.2 
Management of Mocetinostat in Event of Non-Hematological 
Toxicities 
Non-hematological toxicities ≥ Grade 3 and considered to be treatment-related should be 
managed with mocetinostat treatment interruption until resolution of toxicity to ≤ Grade 1 
or to baseline value.  If the toxicity is adequately managed by routine supportive care 
(such as anti-emetics, anti-diarrheals, or electrolyte supplementation), treatment may be 
resumed at the same dose; if not, treatment may be resumed at a reduced dose (Table 6).  
Recurrence of the toxicity may be managed similarly.  If treatment is interrupted for 
≥ 28 days, permanent discontinuation from study treatment should be considered. 
Table 6: 
Mocetinostat Dose Modifications – Non-Hematological 
Drug-Related Toxicities1 
Toxicity 
Treatment Delay 
Dose Modification 
< Grade 3  
May be implemented based on Investigator and patient discretion 
Grade 3 or 4, manageable with 
routine supportive care 
Hold until ≤ Grade 1 or return to 
baseline 
Not required 
Grade 3 or 4, not manageable 
with routine supportive care 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at next lower dose level  
1 
For pericardial toxicity, see Section 5.1.8.5. 
5.1.8.3 
Management of Mocetinostat in Event of Hematological Toxicities 
Hematological toxicities ≥ Grade 3 and considered to be treatment-related should be 
managed with treatment interruption until resolution as described in Table 7.  Recurrence 
of the toxicity may be managed similarly.  If treatment is interrupted for ≥ 28 days, 
permanent discontinuation from study treatment should be considered. 
Table 7: 
Mocetinostat Dose Modifications – Hematological 
Drug-Related Toxicities 
Neutropenia 
Grade 1 (ANC < LLN – 1.5 × 109/L) 
Maintain dose level 
Grade 2 (ANC < 1.5-1.0 × 109/L) 
Grade 3 (ANC < 1.0 - 0.5 × 109/L) 
 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose 
level 
If resolved in > 7 days, then  by 1 dose 
level 
Grade 4 (ANC < 0.5 × 109/L) 
Febrile neutropenia  
(ANC < 1.0 × 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then  by 1 dose 
level 
 
 


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Table 7: 
Mocetinostat Dose Modifications – Hematological 
Drug-Related Toxicities (Continued) 
Thrombocytopenia 
Grade 1 (PLT < LLN – 75 × 109/L) 
 
Maintain dose level 
Grade 2 (PLT < 75 – 50 × 109/L) 
 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose 
level 
If resolved in > 7 days, then  by 1 dose 
level 
Grade 3 (PLT < 50-25 × 109/L) 
Omit dose until resolved to ≤ Grade 1, then  
by 1 dose level 
Grade 4 (PLT < 25 × 109/L) 
Treatment Delay ≥ 4 weeks 
Any hematologic or non-hematologic toxicity requiring 
interruption for ≥ 28 days 
Discontinue mocetinostat 
 
5.1.8.4 
Management of Mocetinostat Associated Cystitis 
In the event of symptoms of cystitis (e.g., dysuria, pollakiuria, hematuria, urgency, or 
bladder spasm) suspected to be attributable to mocetinostat treatment: 
• Perform diagnostic evaluation and manage per institutional standards; 
• If clinically significant symptoms persist despite a negative diagnostic assessments or 
treatment of an associated condition, interrupt study treatment until resolution of 
clinically significant symptoms; and  
• Resume dosing of mocetinostat when medically appropriate, at the same or a reduced 
dose level as per the Investigator’s judgment. 
5.1.8.5 
Management of Mocetinostat in Event of Pericardial Toxicity 
Patients will be assessed for evidence of pericardial toxicity during scheduled visits 
according to the Schedule of Assessments (Table 1). 
The following findings would heighten suspicion of pericardial effusion or pericarditis 
and prompt immediate evaluation by ECHO:  
• Symptoms: shortness of breath, orthopnea, chest pain, dizziness, rapid pulse 
• Clinical exam: hypotension, jugular venous distension, pulsus paradoxus, faint heart 
sounds, friction rub, and/or arrhythmia 


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• ECG: sinus tachycardia, atrial fibrillation, atrial flutter, low voltage with nonspecific 
ST-T wave changes and ST elevation or PR depressions, arrhythmia 
ECHOs will be used to assess and categorize pericardial fluid as minimal (or trivial), 
small, moderate or large and will assess for hemodynamic compromise. 
Pericardial effusions will be assessed and managed as follows (Table 8): 
Table 8: 
Pericardial Effusion and Patient Management Guidelines 
Category 
Definitions 
Patient Management 
Minimal  
(or trivial) 
A small echo-free space in the posterior 
atrioventricular groove that is visible only in 
systole when the heart has pulled away from 
the pericardium.  Typically represents a 
normal amount of pericardial fluid in a 
disease-free state. 
De novo (i.e., not present at baseline) 
pericardial effusion: 
• 
Study treatment may be continued 
at the discretion of the investigator. 
• 
Increased ECHO and ECG 
monitoring weekly until effusion is 
no longer present or has not 
progressed over a period of 
2 weeks. 
• 
Regular assessment schedule 
afterwards. 
Small  
< 1 cm of posterior echo-free space, with or 
without fluid accumulation elsewhere, 
present throughout the cardiac cycle, 
including diastole (and not only systole). 
• 
Study drug will not be discontinued 
in these Patients, at the discretion of 
the investigator, unless the effusion 
progresses. 
• 
Increased ECHO and ECG 
monitoring weekly for the first 
month after the new effusion first 
noted or until the effusion has 
regressed (if sooner).   
• 
Treatment for the effusion may be 
administered at the discretion of the 
Investigator.   
Moderate 
1 to 2 cm of echo-free space.  Moderate 
effusions tend to be seen along the length of 
the posterior wall but not anteriorly. 
• 
Remove immediately from study 
treatment. 
• 
Manage according to the standard 
of care at the discretion of the 
investigator. 
• 
Refer to cardiologist for follow-up 
as clinically indicated, until 
resolution of stabilization. 
Large  
> 2 cm of maximal separation.  Large 
effusions tend to be seen circumferentially. 
Hemodynamic 
Compromise 
RV compression, IVC dilation without 
respiratory variation, abnormal flow 
variation across the AV valves without 
respiratory variation, enlarged or collapsed 
ventricles.  RA diastolic collapse in 
isolation is too non-specific to signal 
hemodynamic compromise, but should be 
considered consistent with this diagnosis 
when accompanied by other findings 
• 
Remove immediately from study 
treatment. 
• 
Refer to cardiologist for follow up 
as clinically indicated, until 
resolution or stabilization.   
• 
Collect blood and test for anti-
nuclear antibody (ANA) and anti-
histone antibody. 


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In exceptional circumstances where ECHO is not considered a technically optimal 
assessment of pericardial space (e.g., overweight patient), other methods (e.g., MRI) 
should be used for pericardial assessments.  In such cases, the guidelines provided in 
Table 8 would not apply, and the evaluation should be performed in consultation with the 
Sponsor.  In the event that a pericardial effusion is first identified by a method other than 
ECHO, efforts should be made to obtain an ECHO for assessment of effusion size. 
5.2 
Durvalumab Study Drug Management 
5.2.1 
Formulation and Packaging 
Durvalumab study drug will be supplied as a 500-mg vial solution for infusion after 
dilution.  The solution contains 50 mg/mL durvalumab, 26 mM histidine/ 
histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0.  The nominal fill volume is 10 mL.  Refer to the 
Pharmacy Manual for details on durvalumab clinical trial material supply, distribution 
and control.  Medication labels comply with the legal requirements of the United States 
and will be printed in the languages required in the countries in which the study is 
conducted. 
5.2.2 
Drug Storage and Accountability 
Durvalumab investigational product vials should be stored at 2°C to 8°C (36°F to 46°F) 
and must not be frozen.  Durvalumab must be used within the individually assigned 
expiry date on the label.  The storage area should be secure with limited access and 
monitored for temperature using a calibrated thermostat.  
All study treatment supplies will be accounted for in the drug accountability inventory 
forms supplied by the Sponsor or using locally approved forms that include all required 
information.  The drug accountability inventory forms must identify the study drug, 
including batch or lot numbers and account for its disposition on a patient-by-patient 
basis, including specific dates and quantities.  The forms must be signed by the individual 
who dispensed the drug. 
5.2.3 
Preparation and Dispensing 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags 
have been observed.  Durvalumab for administration must be prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique.  Each dose of 
1500 mg durvalumab will be administered using an intravenous (IV) bag containing 
100 to 1000 mL 0.9% saline.  Remove a volume of solution from the IV bag equal to the 
calculated volume of durvalumab to be added (ie, 30.0 mL for 1500 mg of durvalumab).  
The final concentration should range from 1 to 20 mg/mL.  Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag.  Total time from needle puncture 
of the durvalumab vial to the start of administration should not exceed:  


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• 24 hours at 2°C to 8°C (36°F to 46°F), or 
• 4 hours at room temperature. 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials.  
Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration.   
5.2.4 
Medication Compliance 
Study site personnel should document durvalumab intravenous administration in the 
patient’s source document and CRF along with administration start/stop times. 
5.2.5 
Destruction 
At the end of the study, all unused durvalumab drug supplies will be destroyed in 
accordance with local Standard Operating Procedure provided to the Sponsor for the 
Trial Master File, or returned to the Sponsor or its appointed agent, as directed by the 
Sponsor. 
5.2.6 
Administration 
Durvalumab will be administered at room temperature (approximately 25°C) by 
controlled infusion via an infusion pump into a peripheral or central vein.  The entire 
contents of the IV bag should be administered over approximately 60 minutes 
(± 5 minutes), using a 0.2-, or 0.22-μm in-line filter.  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 solution (0.9% saline) equal to the priming volume of the 
infusion set used, or complete the infusion according to institutional policy to ensure the 
full dose is administered and document if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, 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 outlined above and in 
Section 5.2.3, a new dose must be prepared from new vials.  Durvalumab does not 
contain preservatives, and any unused portion must be discarded. 
On days mocetinostat and durvalumab are both administered and scheduled for PK 
assessment, mocetinostat dosing and sampling should precede durvalumab. 


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5.2.7 
Infusion Modification and Discontinuation 
Patients will be monitored before, during and after the infusion with assessment of vital 
signs, pulse rate and blood pressure every 30 minutes during the infusion period 
(including times where infusion rate is slowed or temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may 
be decreased by 50% or interrupted until resolution of the event (up to 4 hours) and 
re-initiated at 50% of the initial rate until completion of the infusion.  For patients with a 
≤Grade 2 infusion-related reaction, subsequent infusions may be administered at 50% of 
the initial rate.  Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or 
equivalent medications per institutional standard may be administered at the discretion of 
the investigator.  If the infusion-related reaction is Grade 3 or higher in severity, study 
drug will be discontinued.  The standard infusion time is 1 hour, however if there are 
interruptions during infusion, the total allowed time from infusion start to completion of 
infusion should not exceed 8 hours at room temperature.  The maximum total time from 
needle puncture to start of administration should not exceed 4 hours at room temperature 
(otherwise a new infusion preparation is required).   
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The 
study site must have immediate access to emergency resuscitation teams and equipment 
in addition to the ability to admit patients to an intensive care unit if necessary. 
5.2.8 
Durvalumab Adverse Event Management Guidelines 
For adverse events (AEs) that are considered at least partially due to administration of 
durvalumab, the following dose adjustment guidance may be applied: 
• Treat each AE with maximum supportive care (including holding the agent suspected 
of causing the toxicity where required). 
• If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing the same dose of durvalumab along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for 
durvalumab (see below). 
• All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued. 


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Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed.  Dose modification recommendations and toxicity 
management guidelines for immune-mediated reactions, for infusion-related reactions, 
and for non-immune-mediated reactions are detailed in Table 9, Appendix 4, Table 10 
and Table 11, respectively. 
Based on the mechanism of action of durvalumab, leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study.  
Potential irAEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies.   Patients should be monitored for signs and symptoms of irAEs.  In the 
absence of an alternate etiology (e.g., infection or progressive disease) signs or symptoms 
of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be 
immune-related.  Overall guidelines for management of durvalumab treatment in 
response to an irAE are detailed in Table 9 and in more detail by type of AE in  
Appendix 4.     


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Table 9: 
Immune-Related Adverse Events, Overall Management 
Durvalumab Treatment Modification 
Drug administration modifications made to manage potential immune-related AEs are based on severity of treatment-emergent toxicities graded per 
NCI CTCAE v4.03. 
In addition criteria for permanent discontinuation based on severity (Appendix 4), permanently discontinue for the following conditions:  
• 
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 
• 
Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of dosing. 
Grade 1 
No dose modification 
Grade 2 
Hold study drug dose until Grade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 3 or Grade 4 
 
Study drug/study treatment can be resumed once event stabilizes to Grade ≤1 and after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or continued steroid replacement can be retreated on the following conditions:  
1) the event stabilizes and is controlled,  
2) the patient is clinically stable as per Investigator or treating physician’s clinical judgment, and  
3) doses of prednisone are at less than or equal to 10mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may permanently discontinue.  Refer to guidelines below. 
Grade 4 
Permanently discontinue  
Note:  For Grade 3 and above asymptomatic amylase or lipase levels hold study drug/regimen and if complete work up shows no evidence of 
pancreatitis, may continue or resume study drug/regimen. 
 
 


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Table 9: 
Immune-Related Adverse Events, Overall Management (Continued) 
Toxicity Management  
• 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, concomitant medications, infections, etc.) 
• 
In the absence of a clear alternative etiology, all events should be considered potentially immune related 
• 
Symptomatic and topical therapy should be considered for low-grade (Grade 1 or 2, unless otherwise specified) events 
• 
For persistent (greater than 3 to 5 days) low-grade (Grade 2)  or severe (Grade ≥3) events  promptly start prednisone PO 1-2mg/kg/day or IV equivalent  
• 
If symptoms recur or worsen during corticosteroid tapering 28 days of taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2-4mg/kg/day or 
IV equivalent]) until stabilization or improvement of symptoms, then resume corticosteroid tapering at a slower rate (> 28 days of taper) 
• 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) – should be considered for events not responding to systemic steroids  
(also refer to the individual sections of the immune related adverse event for specific type of immunosuppressive)   
• 
Discontinuation of study drug is not mandated for Grade 3 / Grade 4 inflammatory reactions attributed to local tumour response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes etc.).  Continuation of study drug in this situation should be based on a benefit/risk analysis for that 
patient  
 
 
 


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Table 10: 
Durvalumab Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
• 
Management per institutional standard at the discretion of investigator 
• 
Monitor patients for signs and symptoms of infusion-related reactions  
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in heart 
rate and blood pressure, dyspnea or chest discomfort, skin rashes etc.) and 
anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension, 
tachycardia, etc.) 
Grade 1 
The infusion rate of durvalumab may be decreased by 
50% or temporarily interrupted until resolution of the 
event 
• 
For Grade 1 or Grade 2: 
• 
Acetaminophen and/or antihistamines may be administered per institutional 
standard at the discretion of the investigator  
• 
Consider premedication per institutional standard prior to subsequent doses 
• 
Steroids should not be used for routine premedication of ≤Grade 2 infusion 
reactions 
Grade 2 
 
The infusion rate of durvalumab be decreased 50% or 
temporarily interrupted until resolution of the event  
Subsequent infusions may be given at 50% of the initial 
infusion rate 
Grade 3/4 
Permanently discontinue 
• 
For Grade 3 or 4: 
• 
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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Table 11: 
Non-immune Mediated Reactions 
Severity 
Grade 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or for laboratory abnormalities not deemed to 
be clinically significant. 
Treat accordingly as per institutional 
standard  
1 
No dose adjustment  
Treat accordingly as per institutional 
standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 
14 days, resume study drug/study regimen administration.  Otherwise, discontinue study 
drug/study regimen 
Treat accordingly as per institutional 
standard 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with the sponsor)  
Treat accordingly as per institutional 
standard  
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase;  
AST = aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease;  
IM = intramuscular; irAE = immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; PO = by mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 


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5.3 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (e.g., a dose that is not planned in the study).  
Medication errors occurring during the conduct of this study will be documented as AEs 
(regardless of whether clinical signs or symptoms are observed) and if serious 
consequences are observed, will be reported on Serious Adverse Event (SAE) forms.  In 
all cases of medication error, the sponsor should be notified immediately. 
There is currently no specific treatment in the event of an overdose of mocetinostat or 
durvalumab.  The investigator will use clinical judgment to treat any overdose. 
5.4 
Concomitant Therapies 
5.4.1 
Concomitant Medication(s) 
Concomitant medications must be locally-approved and used at doses and regimens that 
are considered standard-of-care for the treated indication. 
Treatment for co-morbidities, disease signs and symptoms and treatment emergent 
adverse events should be provided as necessary in the judgment of the investigator.  
Antibiotics and analgesics should be used as needed.  Patients with neutropenic fever or 
infection should be treated promptly.  Therapeutic colony-stimulating factors should be 
used in accordance with ASCO guidelines.  Packed red blood cell and platelet 
transfusions may be administered as clinically indicated. 
5.4.1.1 
Permitted Concomitant Medications 
Supportive Care/Palliative Care:  Supportive and palliative care for disease related 
symptoms may be administered at the investigator’s discretion, including the use of 
analgesics.   
Anti-emetics: Patients may be premedicated for nausea and vomiting.  Recommended 
anti-emetic agents include granisetron 1 mg as premedication, and then granisetron 
and/or prochlorperazine as needed. 
Transfusions: Patients may receive transfusions as necessary. 
5.4.1.2 
Cautioned Concomitant Medications and Substances  
P450 Considerations: Caution should be used when mocetinostat is administered to 
patients taking medications metabolized by CYP2C9, or that inhibit or induce 
metabolism by CYP2E1 or CYA3A4.  See Appendix 3 for examples of medications of 
interest.  If a patient is taking a drug on one these lists, it is encouraged to substitute a 
different medication if possible. 


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Anti-Coagulation: At the discretion of the investigator and under medical supervision, 
patients may continue to receive prophylactic or therapeutic low molecular weight 
heparin (but not therapeutic treatment with warfarin, other coumarin derivatives) as 
clinically indicated.   
5.4.1.3 
Concomitant Medications and Substances to be Avoided On-Study 
Warfarin or Coumarin Derivatives: Therapeutic doses of warfarin or other coumarin 
derivative anticoagulants are not permitted.  Warfarin has a narrow therapeutic range and 
mocetinostat can have inhibitory effects on CYP2C9, the main metabolizing enzyme of 
warfarin.   
Drugs with QTc Prolonging Activity: As listed in Appendix 3.  This list is not exhaustive.   
Any questions should be discussed with the Sponsor. 
Herbal Medications/Preparations: Herbal medications and preparations are not allowed 
throughout the study, as a potential drug-drug interaction is always possible.  These 
herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe (yohimbine), saw 
palmetto, and ginseng.  Patients should stop using these herbal medications at least 7 days 
prior to first dose of study treatment. 
Gastric Acid Neutralizers: Medications that directly increase gastric pH such as 
short-acting antacids should be avoided 4 hours before and 2 hours after administration of 
mocetinostat.  Medications that affect gastric acid secretion, such as H2 antagonists or 
proton pump inhibitors should be avoided. 
Contraceptives: Hormonal contraceptives may be affected by cytochrome P450 
interactions, and are therefore not considered effective for this study, since induction of 
CYP3A4 may not be excluded in patients receiving mocetinostat. 
Immunosuppressive Medications:  Including, but not limited to systemic corticosteroids 
at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers.  Use of immunosuppressive medications for the 
management of investigational product-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled and intranasal corticosteroids is permitted.  A 
temporary period of steroids will be allowed for different indications, at the discretion of 
the principal investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, 
etc).   
Vaccines:  Live attenuated vaccines within 30 days of durvalumab dosing are to be 
avoided (i.e., 30 days prior to the first dose, during treatment with durvalumab and for 
30 days post discontinuation of durvalumab).  Inactivated vaccines, such as the injectable 
influenza vaccine, are permitted. 


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5.4.2 
Concomitant Surgery or Radiation Therapy 
The use of surgery to manage cancer lesions during study treatment is discouraged.  The 
impact of treatment with mocetinostat on wound healing has not yet been characterized.  
For patients with bone involvement, any foreseeable need for palliative radiotherapy 
should be addressed before study entry, if possible and clinically appropriate (e.g., bone 
lesions at risk for spontaneous micro-fractures or painful lesions).  However, these 
treatments may be used in cases where it is medically necessary.  
5.4.3 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the 
study treatment period, including chemotherapy, biological response modifiers, hormone 
therapies or immunotherapy.  No other investigational drug may be used during treatment 
on this protocol.  Concurrent participation in another therapeutic clinical trial is not 
allowed. 
 
6 STUDY ASSESSMENTS 
6.1 
Screening 
Voluntary, written, dated, and signed informed consent must be obtained before any 
study specific procedures are performed.  Patients who completed the informed consent 
process but did not enroll on the study will be considered as screen failures.  Limited 
information will be recorded in the CRF for these patients. 
6.2 
Study Period 
For details on procedures during the study period, see Schedule of Assessments as shown 
in Table 1 and Table 2. 
6.3 
End of Treatment Assessment 
All patients will be followed for AEs for at least 28 days and for SAEs for at least 
90 days following the last dose of Study Treatment.  See the Schedule of Assessments 
(Table 1) for evaluations to be performed at the End of Treatment visit. 
6.4 
Long-Term Follow-up and End of Study Assessment 
Blood samples for MEDI4736 PK and ADA will be collected approximately 90 days 
after the last infusion of durvalumab.  Survival status and subsequent therapies will be 
collected during long term follow-up as outlined in the Schedule of Assessments  
(Table 1) until death or lost to follow-up.  Beyond 90 days after last treatment, follow-up 


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may be performed by telephone contact.  Treatments received following participation in 
the study will be collected in the CRF. 
6.5 
Patient Discontinuation/Withdrawal 
Patients may discontinue from study treatment or from the study at any time at their own 
request, or they may be discontinued at any time at the discretion of the investigator or 
Sponsor for safety, behavioral reasons, or the inability of the patient to comply with the 
protocol required schedule of study visits or procedures at a given study site.   
Criteria that may be used to discontinue patients from receipt of study medication will 
include, but will not be limited to: 
• Objective disease progression according to RECIST 1.1 as determined by the 
investigator (patients who may derive clinical benefit may continue on treatment at 
the discretion of the investigator); 
• Global deterioration of health status requiring discontinuation; 
• Adverse event; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refusal for further treatment; 
• Study termination by Sponsor; 
• Death. 
Reasons for discontinuation from study follow-up may include: 
• Study terminated by Sponsor; 
• Lost to follow-up; 
• Refusal for further follow-up for survival; 
• Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient.  At least 2 attempts should be made to contact the patient, and each attempt 
should be recorded in the source documents.  In any circumstance, every effort should be 
made to document patient outcome, if possible.  The investigator should inquire about the 


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reason for withdrawal, request that the patient returns for a final visit, and if applicable, 
follow-up with the patient regarding any unresolved adverse events. 
If the patient withdraws from the study treatment and also withdraws consent for 
disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before such refusal for further follow-up. 
 
7 PROCEDURES 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that there may be circumstances 
outside of the control of the investigator that may make it unfeasible to perform a 
protocol-specified assessment.  In these cases the investigator will take all steps 
necessary to ensure the safety and well-being of the patient.  When a protocol required 
test cannot be performed, the investigator will document in the source document and CRF 
the reason and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible.  The study team will be 
informed of these incidents in a timely fashion.   
7.1 
Sample Collection for PD-L1 Expression 
Tumor tissue testing for PD-L1 expression is required for patients enrolling in Phase 2 
Cohorts 1 and 2 and encouraged for patients enrolling in the Phase 1 study or Phase 2 
Cohorts 3 and 4.  In Cohorts 1 and 2, the sample tested must have been collected 
following completion of the most recent systemic treatment regimen.  In other patient 
cohorts, when the collection of a new sample is not clinically appropriate, archival 
samples may be utilized provided the specimen it is not older than 3 years of age.   
Samples should be collected via a core needle of 18 gauge or larger or be collected by an 
incisional or excisional tumor biopsy.  Where institutional practice uses a smaller gauge 
needle, samples should be evaluated for tumor cell quantity (i.e., > 100 tumor cells) to 
allow for adequate PD-L1 immunohistochemistry analyses.   
Samples submitted for PD-L1 testing should be formalin fixed and embedded in paraffin.  
Samples from fine needle aspirates (FNA) or decalcified bone are not appropriate for 
PD-L1 analysis.   
Further guidance on sample preparation and submission can be found in the Study 
Laboratory Manual. 


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7.2 
Efficacy 
All patients enrolled in the study are to be evaluated for disease activity as outlined in the 
Schedule of Assessments (Table 1).  Screening/baseline tumor assessments should 
include CT or MRI of the chest, abdomen, and pelvis, whole body bone scan, MRI of the 
brain and evaluation of any superficial lesions.  On-study assessments will include all 
known and suspected sites of disease and will be performed at 8 week intervals until 
approximately 1-year and then every 12 weeks.  The allowable windows for assessments 
are 4 weeks prior to first study treatment for screening/baseline assessments and ±10 days 
for on-study disease assessments.   
CT scans should be performed with contrast agents unless contraindicated for medical 
reasons.  If intravenous contrast is medically contraindicated, the imaging modality to be 
used (either CT without contrast or MRI) should be the modality which best evaluates the 
disease, and the choice should be determined by the investigator in conjunction with the 
local radiologist.  Depending on the adequacy for evaluation of disease, a combination of 
CT without contrast and MRI should most often be used.  CT without contrast is 
preferred for evaluation of lesions in lung parenchyma.  MRI is not adequate for 
evaluation of lung parenchyma but should also be performed to evaluate all other aspects 
of the chest.  MRI of the abdomen and pelvis should substitute for CT with contrast 
unless the method does not adequately depict the individual’s disease, in which case CT 
without contrast is preferred.  For those sites that routinely use PET scans for assessment 
of bone lesions in lieu of skeletal scintigraphy, PET scans may be used on-study, with the 
same modality planned throughout the study for any given patient.  
For patients having effusions or ascites, cytological proof of malignancy should be 
obtained prior to selection of the effusion as a non-target lesion.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be 
considered to be cancer lesions. 
Disease response will be assessed in accordance with RECIST 1.1 (Eisenhauer-2009).  
Appendix 5 provides guidance in using the response criteria and include a modification to 
RECIST 1.1 to address potential temporary treatment effects such as tumor lesion 
cavitation or flare response.  Assessments will be performed until objective disease 
progression is documented by the investigator, or subsequent anti-cancer therapy is 
begun.   
Patients experiencing tumor response (Partial Response [PR] or Complete Response 
[CR]) should undergo confirmatory assessment at least 4 weeks after initial 
documentation of response.  It is acceptable to perform confirmatory assessments at the 
next appointed evaluation per protocol.  Bone scan is required as an element of the 
confirmation of PR or CR if bone lesions were identified at the baseline assessment. 


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The investigator’s assessment of disease response and progression will be the basis for 
patient management and study expansion decision making.  Potential exists for individual 
tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time as 
the result of beneficial study treatment impact.  For example, tumor necrosis and 
cavitation may result in minor increase in overall individual lesion size or unclear tumor 
margins prior to recovery to a smaller lesion, development of scar tissue, or complete 
resolution.  For this reason, investigators may delay reaching the conclusion of disease 
progression until subsequent on-study disease assessments are performed.   
Central radiology review to assess RECIST outcome may be undertaken after Stage 1 of 
the study.  Materials to be forwarded for independent review will be all imaging studies 
performed at screening and on study, preferably in digital format, using an electronic 
transfer through a portal to the review vendor or transfer on compact disc or optical disc.  
All digital media must be in DICOM format.  Films may be forwarded for review if 
necessary; all films should be originals (second original films acceptable) rather than 
copies of films.   
7.3 
Safety Assessments 
7.3.1 
Adverse Events 
Assessment of adverse events will include type, incidence, severity (graded by the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE, Version 4.03]), timing, seriousness, and relatedness to study treatment. 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present at 
baseline will be recorded in the CRF as AEs beginning on Day 1 of study treatment and 
onward throughout the study.  The actual date of onset should be recorded in all cases.  
Ongoing AEs that change in attribution or severity should have the date of change 
entered as the “end date” and a new AE record should be opened with the changed 
details. 
7.3.2 
Documentation and Reporting of Pericardial Events 
Since pericardial abnormalities (e.g., pericarditis, pericardial effusion, and hemodynamic 
compromise) exist along a continuum with overlap between the clinical symptomatology 
and diagnoses, each pericardial AE (including grading of severity for each individual 
event) along the continuum should be captured separately (Table 12).   


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Table 12: 
Definitions of Pericardial Events 
Event Term 
Definition 
Characteristics/Diagnosis 
Pericarditis 
Inflammation of the 
pericardium 
The major clinical manifestations of acute pericarditis 
include: 1) chest pain, 2) pericardial friction rub, 3) ECG 
changes (with new, widespread ST elevation or PR 
depressions), and 4) pericardial effusion.  At least 2 of these 
features are usually considered necessary to make the 
diagnosis. 
Pericardial 
effusion 
Excess exudate, or fluid, 
in the pericardium 
Once a pericardial effusion is suspected, the diagnostic 
approach consists of 3 steps: 1) establish the presence of 
effusion, 2) assess the hemodynamic impact, and 
3) establish the cause.  Clinical evaluation and ECG 
findings may suggest the presence of a pericardial effusion, 
but imaging, usually ECHO, is required to establish a 
diagnosis. 
Hemodynamic 
Compromise 
Mechanical compression 
of the heart by large 
amounts of fluid or blood 
within the pericardial 
space that limits the 
normal range of motion 
and function of the heart 
The diagnosis of hemodynamic compromise is based upon 
clinical and imaging evidence.  The following physical 
findings 1) sinus tachycardia, 2) elevated jugular venous 
pressure, and 3) pulsus paradoxus are suggestive of frank 
tamponade.  Echocardiogram or other imaging of the 
pericardium is essential to the diagnosis of hemodynamic 
compromise. 
 
All pericardial findings, regardless of seriousness and relationship to study medication, 
should be reported to the Sponsor with the use of the “Pericardial Event Report Form” 
provided by the Sponsor, according to the procedures for SAE expedited reporting 
(see Section 8.4.2).  When reporting pericardial events, available ECHO results/reports 
(or other means of diagnosis if available) should also be provided, for review by the 
Medical Monitor. 
7.3.3 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and 
End of Treatment Visits only.  During study treatment, symptom directed physical 
examinations will be performed.   
Vital signs to be assessed include weight, body temperature, blood pressure, and pulse 
rate.  Height will be recorded at screening only.  In addition, blood pressure and pulse 
rate will be assessed every 30 minutes (± 5 minutes) between the start and end of 
durvalumab infusions (periods of infusion interruption included) and, for the first 
infusion, for 1 hour post infusion. 
Clinically significant findings noted during screening will be reflected on the medical 
history CRF, while those noted during study treatment will be collected on the AE CRFs.   


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7.3.4 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, coagulation, thyroid tests, urinalysis and chemistry parameters presented in 
Table 13. 
Laboratory tests will be drawn at the time points described in the Schedule of Assessment 
(Table 1) and analyzed at local laboratories.  Additional laboratory tests may be 
performed per standard of care, at the investigator's discretion for the purpose of planning 
treatment administration, dose modification, following adverse events, or as clinically 
indicated.   
Table 13: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (ALT) 
Platelet count 
Alanine aminotransferase (AST) 
White blood cell count (WBC) 
Alkaline phosphatase 
Neutrophil count 
Lactate dehydrogenase (LDH) 
Lymphocyte count 
Total bilirubin (if Total bilirubin is ≥2×ULN and 
no evidence of Gilbert’s syndrome, then fractionate 
into direct and indirect bilirubin) 
Basophil count 
Gamma glutamyltransferase Screening, C1D1, and 
as clinically indicated 
Monocyte count 
Lipase 
Eosinophil count 
Amylase 
Coagulation 
Creatinine 
International normalized ratio (INR) 
Blood urea nitrogen (BUN) or urea, depending on 
local practice 
Prothrombin time (PT) 
Uric acid 
Partial thromboplastin time (PTT) 
Total protein 
 
Glucose (non-fasted) 
Urinalysis (dip stick) 
Albumin 
Blood 
Calcium 
Glucose 
Sodium 
Protein 
Potassium 
 
Chloride 
Thyroid Function Test 
Magnesium 
Thyroid-stimulating hormone (TSH) 
Bicarbonate [CO2] 
Free-T3 (if TSH abnormal) 
 
Free-T4 (if TSH abnormal) 
 
 


 
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Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test 
will be performed at screening.  Pregnancy tests will also be done whenever pregnancy is 
suspected during the study.  Additional pregnancy testing may be necessary if required by 
local practices or regulations.   
7.3.5 
Electrocardiogram (ECG) 
Single and triplicate ECGs are to be performed as outlined in the Schedule of 
Assessments (Table 1).  It is preferable that the machine used has a capacity to calculate 
the standard intervals automatically.  In addition, QTc will be manually calculated using 
the Fridericia’s formula.  Assessments reported by automated read as prolongation of 
QTc should be over-read by a cardiologist to ensure accuracy of interpretation. 
7.3.6 
Echocardiogram (ECHO) 
Echocardiograms will be performed at screening, and thereafter as in the Schedule of 
Assessments (Table 1).  Additional assessments of LVEF and evaluation of pericardial 
effusions may be performed as clinically indicated at the investigator’s discretion if there 
are signs or symptoms of cardiotoxicity.  Where abnormalities indicating pericardial 
effusion exist, weekly assessments should be performed until normalization as described 
in Section 5.1.8.5.  In exceptional circumstances where ECHO is not considered a 
technically optimal assessment of pericardial space (e.g., overweight patient), other 
methods (e.g., MRI) should be used for pericardial assessments.   
7.4 
Laboratory Studies 
Laboratory studies for which blood will be collected include evaluation of PK, ADA, and 
PD.  The schedules for sample collection are outlined in Table 2.  Blood samples will be 
collected using an in-dwelling catheter or venipuncture into specified vacutainer tubes.  
Full details on sample collection, processing, storage and shipment are presented in the 
Study Laboratory Manual. 
7.4.1 
Pharmacokinetic Evaluation 
The PK of mocetinostat and durvalumab will be determined using plasma samples 
collected at specified time points prior to and following study treatment dosing.  Every 
effort will be made to collect these PK samples at the exact nominal times relative to 
dosing.  A variation window is allowed for each time point as outlined in Table 2.  The 
actual time of each sample collection will be recorded on the source document and CRF.   
All plasma samples will be stored frozen and shipped on dry ice according to instructions 
provided.  Analysis of plasma samples will be performed using specific validated 
bioanalytical methods.  Full details on sample collection, processing, storage and 
shipment will be provided in the Study Laboratory Manual. 


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7.4.2 
Anti-Drug Antibody Evaluation 
Blood samples for measurement of durvalumab ADA concentrations in serum will be 
collected in samples taken according to the schedules of study procedures presented in 
Table 2.  Details for collection, aliquoting, storage, and shipment of serum samples for 
ADA evaluations are presented in a separate Laboratory Manual.  Validated 
electrochemiluminescence assays using a Meso Scale Discovery platform will be used for 
the determination of ADAs to durvalumab in human serum.  
7.4.3 
Pharmacodynamic Evaluation in Tumor Tissue 
Pharmacodynamic parameters in tumor tissue that may be investigated in this study 
include but are not limited to PD-L1 expression, CD8+ TILs, NK-cells, Tregs, and 
MDSCs, prior to and during treatment.  Full details on sample collection, processing, 
storage and shipment will be provided in the Study Laboratory Manual. 
 
 
 
 
  
7.5 
Post-treatment Follow-up 
Blood samples for MEDI4736 PK and ADA will be collected approximately 90 days 
after the last infusion of durvalumab.  Survival status and subsequent therapies will be 
collected during long term follow-up as outlined in the Schedule of Assessments  
(Table 1) until death or lost to follow-up.  Beyond 90 days after last treatment, follow-up 
may be performed by telephone contact.  Treatments received following participation in 
the study will be collected in the CRF. 
 


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8 ADVERSE EVENT REPORTING 
8.1 
Sponsor Medical Monitor Personnel 
The contact information for the sponsor's Medical Monitor personnel for this trial is 
available in the study contact list located in the Study Manual. 
8.2 
Adverse Events 
An adverse event (AE) is any reaction, side effect or other undesirable medical event that 
occurs during participation in a clinical trial, regardless of treatment group or suspected 
causal relationship to study treatment.  A treatment emergent AE (TEAE) is an AE that 
occurs after the first dose of any study treatment or any preexisting condition that 
increases in severity after the first dose of study treatment. 
All observed or volunteered AEs will be recorded in source documents and reported in 
the CRF.  The best available medical terminology should be used to describe AEs in 
source documents and CRFs.  Terms describing the diagnosis are preferred over 
individual signs and symptoms of the diagnosis.  If determination of the diagnosis is 
delayed, record signs and symptoms and add the diagnosis as an AE when available; 
follow all recorded AEs to resolution.  Examples of AEs include but are not limited to:   
• Signs or symptoms of co-morbidity, illness, or toxicity of study treatment; 
• Signs or symptoms of worsening malignancy under study (disease progression 
assessed by measurement of malignant lesions should not be reported as an AE). 
• Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); 
• Hypersensitivity; 
• Drug abuse, dependency, overdose, withdrawal or misuse; 
• Signs or symptoms of drug interactions; 
• Extravasation; 
• Exposure during pregnancy or via breastfeeding; 
• Medication error; or 
• Occupational exposure. 


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8.2.1 
Laboratory Abnormalities 
An abnormal laboratory test results should be reported as an AE in the CRF only if it is 
associated with one or more of the following:  
• Clinical symptoms; 
• Requires additional tests (beyond repeats), treatment or intervention; 
• Results in change in study treatment dosing; 
• Requires discontinuation from study treatment; and/or 
• Considered by the investigator or Sponsor to be an AE. 
Hy’s Law 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN.  
Concurrent findings are those that derive from a single blood draw or from separate blood 
draws taken within 8 days of each other.  Follow-up investigations and inquiries will be 
initiated promptly by the investigational site to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by 
a disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an 
agent other than the investigational product. 
Cases where a patient shows an AST or ALT ≥ 3 × ULN and total bilirubin ≥ 2 × ULN 
may need to be reported as SAEs.  These cases should be reported as SAEs if 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.  Additionally, study drug should be permanently discontinued for a 
Hy’s Law case.   
8.2.2 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03).  
Documentation of AE grading in the source documents and CRF should be consistent 
with provided definitions. 
8.2.3 
Causality 
For each AE, the investigator should determine and document whether there exists a 
reasonable possibility that the study treatment caused or contributed to the AE.  The 
investigator’s assessment should be recorded in the source document.  The CRF will 
provide the options for attribution to study treatment as “related” and “not related.” If the 
investigator's causality assessment is "unknown but not related to investigational 


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product," this should be recorded in the CRF as “not related.” If the investigator does not 
know whether or not the study treatment is causally-related to the event, reporting for 
study purposes will be as “related” to study treatment.   
Collection of causal relationship for AEs associated with study procedures (e.g., tumor 
biopsy) is provided for separately in the CRF.   
8.3 
Serious Adverse Events 
8.3.1 
Definition of a Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/permanent damage (substantial 
disruption of the ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
• Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
Progression of the malignancy under study, including any signs or symptoms of 
progression that may require hospitalization, should not be reported as an SAE unless the 
outcome is fatal within the safety reporting period.   


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Definition of Terms 
Life threatening: An AE is life threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death.  For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. 
Hospitalization: In general, hospitalization signifies that the patient has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician's 
office or outpatient setting.  When in doubt as to whether 'hospitalization' occurred or was 
necessary, the AE should be considered serious.  Hospitalization for elective surgery or 
routine clinical procedures that are not the result of AE (e.g., elective surgery for a 
pre-existing condition that has not worsened) need not be considered AEs or SAEs.  If 
anything untoward is reported during the procedure, that occurrence must be reported as 
an AE, either 'serious' or 'non-serious' according to the usual criteria. 
Disability/permanent damage: An AE is disabling or caused permanent damage if it 
resulted in a substantial disruption of a person’s ability to conduct normal life functions, 
e.g., a significant, persistent or permanent change, impairment, damage or disruption in 
body function/structure, physical activities and/or quality of life.   
Adverse Event of Special Interest (AESI): AESIs are of scientific and medical interest 
specific to understanding of the Investigational Product and may require close monitoring 
and rapid communication by the investigator to the sponsor.  An AESI may be serious or 
non-serious.  The rapid reporting of AESIs allows ongoing surveillance of these events in 
order to characterize and understand them in association with the use of this 
investigational product. 
Immune-related Adverse Events (irAE):  An irAE is defined as an adverse event that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate aetiology.  Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis.  
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE. 
8.3.2 
Exposure During Pregnancy 
Exposure during pregnancy (i.e., exposure in-utero [EIU]) may occur in a female study 
participant, the female partner of a male study participant or study site personnel working 
with the investigational product (e.g., occupational exposure) if: 
• A female becomes or is found to be pregnant during treatment or within 6 months 
after discontinuing treatment or having been directly exposed to the investigational 
product;  


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• A male is exposed to the investigational product prior to or around the time of 
conception or during the pregnancy of his partner. 
If exposure in-utero occurs, the investigator must submit an SAE form and an EIU 
Supplemental Form within 24 hours of awareness of the exposure, regardless of whether 
an AE or SAE has occurred.   
In the event of pregnancy in a female study participant, if the pregnancy is continued, 
study treatment will be immediately discontinued. 
In the event of exposure of the pregnant partner of a male study participant, the study 
participant should be asked to deliver an EIU Pregnant Partner Release of Information 
Form to his partner.  The Investigator must document on the EIU Form that the patient 
was given this letter to provide to his partner. 
Follow-up to obtain pregnancy outcome information is to be conducted for all EIU 
reports.  In the case of a live birth, the health of the neonate should be assessed at the 
time of birth and for up to 3 months after birth.  Further follow-up of birth outcomes will 
be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify 
developmental delays).  In the event the pregnancy is terminated, the reason(s) for 
termination should be reported and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection. 
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), 
an SAE report should be submitted to the Sponsor. 
8.3.3 
Adverse Events of Special Interest 
8.3.3.1 
Durvalumab Adverse Events of Special Interest 
AESIs for durvalumab 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 durvalumab 
monotherapy and combination therapy.   
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, 
the Investigator should promptly contact the Study Sponsor. 
AESIs observed with durvalumab include: 
• Colitis 
• Pneumonitis 


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• ALT/AST increases / hepatitis / hepatotoxicity  
• Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• Dermatitis 
• Nephritis 
• Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased 
serum amylase)   
8.3.3.2 
Mocetinostat Adverse Event of Special Interest 
All pericardial findings, regardless of seriousness and relationship to study medication, 
should be reported to the Sponsor with the use of the “Pericardial Event Report Form” 
provided by the Sponsor, according to the procedures for SAE expedited reporting 
(see Section 8.4.2).  When reporting pericardial events, available ECHO results/reports 
(or other means of diagnosis if available) should also be provided, for review by the 
Medical Monitor. 
8.4 
Reporting of SAEs and AEs 
8.4.1 
Reporting Period 
The active reporting period for SAEs begins from the time that the patient provides 
informed consent (i.e., prior to undergoing any study-specific procedure or assessment) 
and continues until 90 days post last administration of either therapy.  All SAEs will be 
followed until the event has resolved or stabilized to a chronic condition, whichever is 
later.  Death must be reported if it occurs during the active reporting period for SAEs 
regardless of whether a subsequent anticancer therapy is administered.  Serious adverse 
events occurring to a patient after the active reporting period has ended should be 
reported to the Sponsor if the investigator becomes aware of them and if the investigator 
assesses at least a reasonable possibility of being related to study drug.   
The reporting period for non-serious AEs begins from the day of first dose of study 
treatment and continues until at least 28 days after last administration of study treatment 
and/or until recovery from all acute toxicities associated with the drug administration to a 
chronic condition, whichever is later.  If a patient begins a subsequent anticancer therapy, 
the AE reporting period ends at the time the new treatment is started.   


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8.4.2 
Reporting Requirements 
All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, 
irrespective of the extent of available AE information, by faxing the SAE report to the 
Sponsor’s pharmacovigilance representative designated in the Study Manual.  The 
24-hour timeframe also applies to additional new information (follow-up) on previously 
forwarded SAE reports and to the initial and follow-up reporting of exposure during 
pregnancy and exposure via breastfeeding.  The need for an expedited report to 
regulatory authorities will be determined by the Sponsor and necessary reporting will be 
performed by the Sponsor.  The Sponsor will notify study investigators of all Suspected, 
Unexpected (as judged against the Investigator Brochure) Serious Adverse Reaction 
(SUSAR) reports.  The investigator is responsible for reporting all SUSARs to the 
IRB/EC.   
All AE (including SAEs) must be documented in source documents and reported in the 
CRF.  Please note that the CRF and SAE report forms may collect information in 
somewhat different formats.  Where the requested data overlap in different formats, the 
information should be consistent between the two forms.   
 
9 STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained 
by the Sponsor.  The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
9.1 
Hypothesis and Sample Size 
9.1.1 
Phase 1 
Approximately 24 patients may be enrolled into the Phase 1 portion of the study and up 
to 261 patients will be enrolled into the Phase 2 portion.  Precise sample size cannot be 
defined, as it is dependent on the number of dose escalations based on the mTPI method, 
and the number of patients enrolled in the expansion cohorts.   
The mTPI method (Ji-2013) will be employed in decision making concerning dose 
escalation within each regimen investigated.  The assumptions to be applied in 
establishing the mTPI methodology are: 
• each specific regimen exploration will include up to 30 patients; 
• the MTD is defined to have 0.25 probability of toxicity; and 


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• the acceptable variance around the MTD is ± 0.05 (i.e., the region of the MTD is 20% 
to 30% incidence of dose limiting toxicity).   
9.1.2 
Phase 2 
The 4-cohort Phase 2 portion uses sample sizes based on Predictive Probability Design 
(Lee-2008).   ORR in accordance with RECIST 1.1 is the primary clinical benefit 
endpoint.  In creating the statistical designs, the Type 1 error (α) is constrained to <0.05 
and Power (1-β) is constrained to ≥0.90.   
Statistical Design Applied to Phase 2 Cohorts 1, 3 and 4 
The ORR using a PD-L1 inhibitor in the population with advanced NSCLC having no or 
low PD-L1 expression, or prior disease progression on a checkpoint inhibitor, is assumed 
to be 5% (p0); thus this rate is considered uninteresting.  The target ORR using 
mocetinostat in combination with durvalumab in this study is 30% (p1).  Stage 1 of 
enrollment will include a minimum of 9 evaluable patients.  With exactly 9 evaluable 
patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional evaluable 
patients will be enrolled, for a total sample size of 17 evaluable patients.  If at least 
3 Objective Responses are observed, further investigation may be warranted.  If the true 
ORR is 5% (null hypothesis), the probability of early termination during the study is 
0.63; the Type 1 error is equal to 0.0466 and the power is equal to 0.9045.   
Statistical Design Applied to Phase 2 Cohort 2 
The ORR using a PD-L1 inhibitor in the population with advanced NSCLC having high 
PD-L1 expression is assumed to be 27% (p0); thus this rate is considered uninteresting.  
The target ORR using mocetinostat in combination with durvalumab in this study is 
50% (p1). Stage 1 of enrollment will include approximately 17 evaluable patients. 
With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective 
Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 
44 evaluable patients.  If at least 18 Objective Responses are observed, further 
investigation may be warranted.  If the true ORR is 27% (null hypothesis), the probability 
of early termination during the study is 0.50; the Type 1 error is equal to 0.0303 and the 
power is equal to 0.9018.   
The exact stopping rules for all cohorts will be calculated based on the Predictive 
Probability Design, once the exact number of patients evaluable at Stage 1 is known. The 
aim is to get about 9 evaluable patients at Stage 1 for cohorts 1, 3 and 4 and about 
17 evaluable patients at Stage 1 for cohort 2. 
If Stage 2 results in Cohorts 3 and 4 are of high interest for efficacy, enrollment may be 
expanded to as many as 100 patients total in each cohort to narrow the 95% Confidence 
Interval (CI) around the ORR point estimate.  Table 14 presents estimates of the 95% CI 
around the observed ORR for several potential outcomes using the sample size of 
100 patients, and the Clopper-Pearson method. 


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Table 14: 
Estimates of 95% CI Using Clopper-Pearson in After 
Enrollment of 100 Patients 
Number of  
Observed Responses  
Among 100 Patients 
ORR 
95% CI 
25 
25% 
16.9-34.7% 
30 
30% 
21.2-40.0% 
35 
35% 
25.7-45.2% 
40 
40% 
30.3-50.3% 
50 
50% 
39.8-60.2% 
 
9.2 
Data Handling 
Listings of all patient data will be prepared.  Data summaries will be presented in tabular 
and/or graphical format and summarized descriptively, where appropriate.  Details of 
planned analyses will be described in the SAP. 
For all variables, only the observed data from patients will be used in the statistical 
analyses; there is no plan to estimate missing data.  Patients without a valid clinical 
response assessment will be assigned a best overall response of not evaluable (NE).  Data 
from patients who are lost to follow-up or have missing observations before reaching an 
endpoint in any of the time-to-event analyses will be treated as censored with specific 
rules defined in the SAP. 
9.3 
Analysis Populations 
9.3.1 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (mITT) population is defined as all patients who receive 
treatment with both mocetinostat and durvalumab on this study. 
The primary efficacy analyses of the primary and secondary efficacy endpoints will be 
performed in the mITT population.  In addition, the mITT population will be used in 
making decisions to expand the study to the next stage of enrollment (to up to 
100 patients). 
9.3.2 
Clinical Activity Evaluable Population 
In order to be considered eligible for the clinical activity evaluable population, the patient 
must have at least one on-study disease assessment or discontinue from treatment for PD.  
Patients who discontinue treatment prior to the first on-study disease assessment for an 
AE, toxicity, or withdraw consent are considered non-evaluable for disease assessment 
and will not be part of the clinical activity evaluable population. 


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This population will be used to present tumor responses as well as to make decision on 
the Predictive Probability design. 
9.3.3 
Safety Population 
The Safety population is defined as all patients who received at least 1 dose of either 
mocetinostat or durvalumab.  The Safety population will be used for all safety analyses. 
9.3.4 
DLT Evaluable Population 
For a patient to be considered evaluable for dose-escalation decisions, or 
“DLT-evaluable,” the patient must have either been on study for one full cycle and have 
received treatment with durvalumab and at least 9 of 12 scheduled mocetinostat doses 
(75%) in Cycle 1 or have experienced a DLT in Cycle 1.   
9.3.5 
Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at 
least one dose of either mocetinostat or durvalumab for whom PD-L1 expression results 
are available. 
9.3.6 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic evaluable population will consist of all patients who had sufficient 
concentration-time data to permit calculation of PK parameters for mocetinostat or 
durvalumab.  For patients who were noncompliant with respect to administration of 
mocetinostat, or for patients with incomplete data, a decision as to their inclusion in the 
analysis will be made on a case-by-case basis. 
9.3.7 
Pharmacodynamic Evaluable Population 
The Pharmacodynamic evaluable population will consist of all patients who receive at 
least one dose of either mocetinostat or durvalumab for whom PD results are available. 
9.3.8 
Anti-Drug Antibody Evaluable Population 
The ADA evaluable population will consist of all patients who receive at least one dose 
of durvalumab for whom ADA results are available. 
9.4 
Efficacy Endpoint Definitions and Analyses 
9.4.1 
Objective Response Rate 
Objective disease response will be categorized in accordance with RECIST v1.1 
(Appendix 5).  Objective Response Rate (ORR) is defined as the percent of patients 
documented to have a confirmed Complete Response (CR) or Partial Response (PR).  If 
central review of disease response is undertaken, ORR as reported by the central 


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radiology review laboratory will be used to calculate ORR and the exact 95% confidence 
intervals (CI).  ORR as reported by the investigator will be used in study expansion 
decision making (Predictive Probability design) and supportive analyses. 
Descriptive statistics (frequency and percentage) for ORR, CR, and PR will be presented.  
The exact 95% CI of these response rates will be calculated.  An exact test for single 
proportion (two-sided α=5%) will be performed to test H0: ORR ≤ 5% against H1: 
ORR > 5% in cohorts 1, 3 and 4 and to test H0: ORR ≤ 27% against H1: ORR > 27% in 
cohorts 2.  Other details will be described in the SAP. 
9.4.2 
Clinical Benefit Rate 
Clinical Benefit Rate (CBR) is defined as the percent of patients documented to have a 
confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) 
documented during at least 2 on-study assessments and including at least 14 weeks on 
study (e.g., allowance for 2-week window around Week 17 assessment).   
9.4.3 
Duration of Response 
Duration of Response (DR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of Objective Progression 
of Disease (PD) or to death due to any cause in the absence of documented PD.  
Censoring for the DR endpoint will be assigned on the date of the last tumor assessment 
if no assessment of tumor progression is identified and the patient does not die while on 
study.  DR will only be calculated for the subgroup of patients with an objective 
response.  The Kaplan-Meier method will be used to obtain the estimate of median DR.   
9.4.4 
Progression Free Survival 
Progression-free survival (PFS) is defined as the time from date of first study treatment to 
first PD or death due to any cause in the absence of documented PD.  Censoring for the 
PFS endpoint will be assigned on the date of the last tumor assessment if no assessment 
of tumor progression is identified and the patient does not die while on study.  For 
patients in whom two or more sequential assessments are missed, followed by the finding 
of tumor progression, the PFS endpoint will be censored on the date of the last tumor 
assessment before the gap.  Patients lacking an evaluation of disease after first study 
treatment will have their PFS time censored on the date of first dose with duration of 
1 day.  Patients who start a new anti-cancer therapy prior to documented PD will have the 
endpoint censored at the date of the last tumor assessment prior to the start of the new 
therapy.  The Kaplan-Meier method will be used to obtain the estimate of median 
progression-free survival time.   


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9.4.5 
Overall Survival 
Time to death is defined as the time from date of first study treatment to death due to any 
cause.  Censoring for the survival endpoint will be assigned on the date of the last 
on-study follow-up that the patient is reported to be alive.  The Kaplan-Meier method 
will be used to estimate the median OS and 1-year Survival Rate; the 95% confidence 
interval of the 1-year survival rate will also be reported.   
9.5 
Safety Data Presentations and Summaries 
9.5.1 
Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  Listings will include the verbatim term, preferred term, 
and system organ class (SOC).  The number of patients with treatment emergent AEs and 
the incidence of TEAEs by SOC and preferred term will be summarized.  TEAEs will be 
summarized by maximum intensity and relationship to study therapy.  Separate 
summaries will be provided for TEAEs, TESAEs, treatment-related AEs, 
treatment-related SAEs, and other significant AEs (e.g., AEs leading to study 
discontinuation).   
9.5.2 
Prior and Concomitant Medications 
Collected prior and concomitant medications will be coded by WHO medical dictionary; 
patients who received these medications will be listed and summarized.   
9.5.3 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, 
coagulation, urinalysis, thyroid function tests and chemistry), vital signs, ECHO and 
12-lead ECGs.   
Clinical laboratory results will be listed by patient and, as appropriate, summarized 
descriptively, which will include a display of change from baseline.  Selected parameters 
will be presented in shift tables of baseline against worst grade test result.  Laboratory 
values outside of the normal ranges will be identified.  Laboratory values that meet Grade 
3 or 4 criteria according to NCI CTCAE v.4.03 will be listed and summarized. 
ECG assessments will be evaluated for change of QTc from baseline as an exposure: 
response analysis.  The investigator’s interpretation of QTc will be used in the clinical 
management of patients.  The study analysis will use the Fridericia formula applied 
programmatically to the ECG data collected in CRFs.   
Vital signs, ECHO and ECG measurements will be listed for each patient at each visit.  
Descriptive statistics of observed values and changes from baseline will be summarized 
by treatment group. 


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9.5.4 
Patient Demographics, Baseline Characteristics and Disposition 
Presentations of patient characteristics will include a summary of the following for all 
patients enrolling in the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 
• Prior therapies/surgeries 
A summary of patient enrollment and disposition will include reasons for study 
discontinuation. 
9.5.5 
Analysis of Study Treatment Dosing 
Study treatment administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered for each agent separately and for 
the combination, dose intensity, and reasons for the deviations from planned therapy. 
9.6 
Other Study Endpoints 
9.6.1 
Pharmacokinetic Analysis 
The PK exposure data from this study may be used in the development of population PK 
and PK/PD models for mocetinostat and durvalumab.  Additional PK parameters may be 
defined and described in the Pharmacokinetic Analysis Plan.  Plasma concentrations will 
be listed by patient for the PK Population.  Summary statistics of MGCD0103 and 
MEDI4736 concentrations will be reported by dose level, Day and Cycle.  Only samples 
with acceptable PK (as defined in the Pharmacokinetic Analysis Plan) will be included in 
the summary statistics and a listing of individual data points or patients excluded from the 
analysis will be presented.   
9.6.2 
Pharmacodynamic Analysis 
No formal statistical analysis of PD endpoints will be performed.  PD data from each 
assay will be listed by dose level and Phase 2 cohort.  Possible relationships between PD 
variables, PK parameters, safety, and clinical activity may be examined if appropriate.   


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9.6.3 
Anti-Drug Antibodies 
The immunogenic potential of durvalumab following combination therapy with 
mocetinostat will be assessed by summarizing the number and percentage of patients who 
develop detectable ADAs.  The titer for the confirmed positive ADA samples will be 
reported.  Additionally, the impact of ADAs on PK, clinical response and safety will be 
assessed if data allow.   
9.7 
Interim Analysis 
No interim statistical analysis is planned during this study.   
9.8 
Data Monitoring Committee 
No Data Monitoring Committee is planned during this study. 
 
10 ETHICS AND RESPONSIBILITIES 
10.1 Ethical Conduct of the Study 
This study will be conducted in accordance with International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations 
of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International 
Conference on Harmonization [ICH] 1996), ICH E6 (R2), and concepts that have their 
origin in the Declaration of Helsinki (World Medical Association 1996, 2008 & 2013).  
Specifically, this study is based on adequately performed laboratory and animal 
experimentation; the study will be conducted under a protocol reviewed and approved by 
an IRB/EC; the study will be conducted by scientifically and medically qualified persons; 
the benefits of the study are in proportion to the risks; the rights and welfare of the 
patients will be respected; the physicians conducting the study do not find the hazards to 
outweigh the potential benefits; and each patient will give his or her written informed 
consent before any protocol-driven tests or evaluations are performed.  
10.2 Obligations of Investigators 
The Investigator is responsible for complying with the protocol and all applicable 
regulations and guidelines governing clinical research.  Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
All Investigators must provide the sponsor with a current curriculum vitae.  Only 
Investigators and designated Sub-Investigators are permitted to sign CRFs and 
examination findings (e.g., laboratory results or ECGs). 


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The Investigator or designee is responsible for informing the patient of all available 
information relevant to his/her safety and obtaining signed, written consent from all 
participating patients.  Additionally, the Investigator is responsible for monitoring patient 
safety and providing periodic and requested reports to the IRB/EC. 
The Investigator is responsible for the accuracy and completeness of all study records 
including CRFs, source documents, and the Site Trial Master File.  The Investigator will 
allow the study monitor, Sponsor, auditor, regulatory agencies, and IRB/EC full access to 
the study and source documents. 
10.3 Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC) 
Prior to the shipment of clinical supplies or initiation of the study, the clinical trial 
protocol along with the informed consent form (ICF), Investigator’s Brochure, and any 
other written information or instructions for the patient must be submitted to the IRB/EC 
for written approval.  The Investigator will provide the Sponsor with a copy of the 
IRB/EC’s written approval, as well as the membership list or a compliance statement 
from the IRB/EC.  The Investigator is responsible for notifying the IRB/EC of any 
Sponsor-approved amendments to the protocol or ICF, SAEs occurring in patients treated 
at the study site in accordance with local IRB/EC practice, and all expedited safety 
reports from SAEs occurring at other study sites participating in the drug development 
program. 
10.4 Informed Consent Form 
The ICF must contain all elements required by the Food and Drug Administration (FDA) 
under 21 Code of Federal Regulations (CFR) Part 50 and the ICH GCP guidelines (ICH 
E6) in addition to any other elements required by applicable national, state, provincial, 
and local regulations, or institutional policies. 
All patients who choose to participate in the study must provide written consent after 
having had adequate time to consider whether they will participate in the study.  The 
written consent must be obtained prior to any protocol-related procedures that are not part 
of the patient’s normal medical care.  The patient must be advised of his/her right to 
withdraw from the study at any time.   
Written documentation of consent must be recorded in the patient’s source documents, 
study records and CRF indicating the date the consent was signed.  The patient should 
receive a signed copy of the consent form according to GCP guidelines. 


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10.5 CONFIDENTIALITY 
All information generated in this study is considered confidential, is subject to applicable 
privacy rules and regulations, and must not be disclosed to any person or entity not 
directly involved with the study unless prior written consent is gained from the Sponsor 
and otherwise except in accordance with applicable law or regulations.  However, 
authorized regulatory officials, IRB/EC personnel, the Sponsor and its authorized 
representatives (as and to the extent authorized in the patient’s ICF) are allowed access to 
the records. 
Identification of patients in CRFs shall be by study assigned patient numbers only.  If 
required, the patient's full name may be made known to an authorized regulatory agency 
or other authorized official. 
10.6 Reporting of Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction (i.e., clinical hold) imposed by an applicable 
Regulatory Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the 
Sponsor must be informed immediately.  In addition, the investigator will inform the 
Sponsor immediately of any serious breaches of this protocol or of ICH GCP of which 
the investigator becomes aware. 
 
11 RECORDS MANAGEMENT 
11.1 Source Documentation 
Source documents include hospital or clinical patient charts, pertinent historical medical 
records, laboratory test reports, ECG tracings and reports, pathology reports, radiographs, 
etc.  All source documents must be legible.  Data reported in CRFs and evidence of 
patient’s informed consent must be documented in source documents.   
11.2 Study Files and Records Retention 
A CRF must be completed for each patient for whom informed consent for the study is 
obtained.  The CRFs must be maintained by properly trained and delegated site 
representatives.  The Principal Investigator has responsibility for ensuring the 
authenticity, accuracy, completeness and timeliness of all data collected in the CRF.  
CRFs must be signed by the Principal Investigator or by an authorized Sub-Investigator 
to attest that the information included is true.   
The study site will maintain a Site Trial Master File in accordance with GCPs. 


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The Investigator shall retain all records for the longest of the following periods: 
(i) 15 years; (ii) the period of time that conforms to ICH GCP guidelines; (iii) the period 
of time required by applicable law or regulations, or (iv) the period of time specified in 
the Clinical Research Agreement. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring Procedures 
Sponsor appointed Site Monitor(s) must be allowed access to all study records, original 
source documents, and investigational products throughout the duration of the study.  
These personnel are responsible to assess compliance with the protocol, appropriate 
health authority regulations, ICH GCP guidelines, and Sponsor requirements. 
The study monitor is responsible for complying with the monitoring guidelines 
established by the Sponsor for the study, assessing the site’s needs, and liaising with the 
assigned Sponsor staff. 
Source documents are defined as all medical records, medical notes, pathology or 
radiology reports, laboratory results, ECG tracings, and any additional documents that 
have original patient information contained within it.   
If the Investigator withdraws from the study and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the Sponsor in writing so 
arrangements can be made to properly store the study materials. 
12.2 Auditing and Inspection Procedures 
The Sponsor’s Quality Assurance representatives, IRB/EC reviewers, or inspectors from 
regulatory agencies may perform an audit or inspection at any time during or after 
completion of the clinical study.  All study-related documentation must be made 
available to the designated auditor.  In addition, representatives of applicable regulatory 
health authorities may choose to inspect a study.  A Sponsor representative will be 
available to assist in the preparation for such an inspection.   
 


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13 CHANGES IN STUDY CONDUCT 
13.1 Protocol Amendments 
Changes to the study protocol, except those intended to reduce immediate risk to study 
patients, may be made only by the Sponsor.  A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/EC is notified within 5 days.  Any urgent safety measures taken by the investigator 
to protect the study patients against any immediately life threatening hazard must be 
reported immediately to the Sponsor. 
Any permanent change to the protocol must be handled as a protocol amendment.  The 
change and the justification will be documented in writing by the Sponsor, as an 
Administrative Letter or amended protocol.  Protocol amendments will be provided with 
a separate document describing each change and rationale.  The written Administrative 
Letter or amendment must be submitted to the IRB/EC and the investigator must await 
approval before implementing the changes.  The Sponsor will be responsible for 
submitting protocol amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/EC, the investigator, and/or the Sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written informed consent form will require similar modification.  In 
such cases, informed consents (revised as appropriate to address protocol amendments) 
will be obtained for patients enrolled in the study before continued participation. 
13.2 Protocol Deviations 
Prospective permission to deviate from the eligibility criteria for this protocol will not be 
provided by the Sponsor.  Study specified assessments should not be omitted and the 
study treatment regimen should not deviate from protocol specifications.  Minor, 
occasional adjustments in the clinic visit schedule may be necessary for logistical reasons 
(e.g., due to weather conditions) but must not become routine or systematically alter the 
study schedule.  The IRB/EC should be informed of any deviations that may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, which 
must receive prior written approval by the IRB/EC.   
 


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14 END OF TRIAL 
14.1 End of Trial in a European Union Member State  
End of Trial in a Member State of the European Union is defined as the time at which it 
is deemed that sufficient patients have been recruited and completed the study as stated in 
the regulatory application (i.e., Clinical Trial Application (CTA)) and ethics application 
in the Member State. 
14.2 End of Trial in all other Participating Countries 
End of Trial in all other participating countries is defined as the time at which all patients 
enrolled in the study have completed the last study visit and data from those visits have 
been reviewed by the investigator or designee. 
14.3 Premature Termination 
Premature termination of this study may occur at any time because of a regulatory 
authority decision, change in opinion of the IRB/EC, drug safety concerns, or at the 
discretion of the Sponsor.  In addition, the Sponsor retains the right to discontinue 
development of mocetinostat and durvalumab at any time.  If termination becomes 
necessary, the Sponsor will inform the appropriate regulatory authorities of the 
termination and the reason.  The Principal Investigator will inform the IRB/EC of the 
same.  In terminating the study, the Sponsor and the Principal Investigator will assure that 
adequate consideration is given to the protection of the patients’ interests. 
 
15 STUDY REPORT AND PUBLICATION POLICY 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication of study results will be governed by the applicable Clinical Research 
Agreement between the Sponsor and the Study Site and Investigator (as applicable).   
 
 
 


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Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
Cancer. 2005;104(10):2084-91. 
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Appendix 1. ECOG Performance Status 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or chair 
5 
Dead 
 


 
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Appendix 2. Dose-Finding Spreadsheet of the Modified Toxicity Probability Interval (MTPI) Method 
 
Number of Patients Treated at Current Dose 
Number of Dose Limiting Toxicities 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
U 
D 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
4 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
5 
U 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
6 
U 
U 
U 
U 
U 
U 
U 
U 
D 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
7 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
8 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
9 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U  
U  
U  
S 
S 
S 
S 
S 
S 
S 
S 
10 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
S 
S 
S 
11 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
S 
S 
12 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
13 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
14 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
15 
E = Escalate to the next higher dose 
S = Stay at the current dose 
D = De-escalate to the next lower dose 
U = The current dose is unacceptably toxic 
MTD = 0.25 
Sample Size = 30 
ɛ1 = 0.05 
ɛ2 = 0.05 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
16 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
17 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
18 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
19 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
20 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
21 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
22 
U 
U 
U 
U 
U 
U 
U 
U 
U 
23 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
U 
U 
24 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
U 
25 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
U 
26 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
U 
27 
 
 
 
 
 
 
 
 
U 
U 
U 
U 
28 
 
 
 
 
 
 
 
 
U 
U 
U 
29 
U 
U 
30 
U 


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Appendix 3. Medications or Substances Prohibited or to be used with 
Caution During Study Treatment with Mocetinostat 
Bold font indicates medications or substances that might be relatively commonly used. 
Italic font indicates medications for indications that are exclusionary for the current study 
or would likely result in discontinuation from study treatment with mocetinostat for 
management of a concurrent illness. 
 
DRUGS THAT MAY PROLONG QT INTERVAL 
Drugs Prohibited During Treatment with Mocetinostat 
Drugs with a 
Known Risk of 
Torsades de 
Pointes 
Amiodarone, anagrelide, arsenic trioxide, astemizole (off US 
market), azithromycin, bepridil (off US market), chloroquine, 
chlorpromazine, cisapride (off US market), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone 
(not on US market), dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, halofantrine, haloperidol, ibutilide, 
levomethadyl (off US market), mesoridazine (off US market), 
methadone, moxifloxacin, ondansetron, pentamidine, pimozide, 
probucol (off US market), procainamide, quinidine, sevoflurane, 
sotalol, sparfloxacin (off US market), sulpiride (not on US market), 
terfenadine (off US market), thioridazine, vandetanib. 
 
Drugs To Be Used with Caution During Treatment with Mocetinostat 
Drugs with a 
Conditional Risk 
of Torsades de 
Pointes 
Amantadine, amisulpride, amitriptyline, amoxapine, chloral 
hydrate, ciprofloxacin, clomipramine, desipramine, 
diphenhydramine, doxepin, fluconazole, fluoxetine, furosemide, 
galantamine, hydrochlorothiazide, imipramine (melipramine), 
indapamide, itraconazole, ivabradine, ketoconazole, 
metronidazole, nelfinavir, nortriptyline, paroxetine, posaconazole, 
protriptyline, quinine sulfate, ritonavir, sertraline, solifenacin, 
telaprevir, trazodone, trimethoprim-sulfa, trimipramine, 
voriconazole. 
 
 
 


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CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS AND 
SUBSTANCES 
Enzyme 
 
Inhibitor of 
CYP 2E1 
Disulfiram   
Inducers of 
CYP 2E1 
Ethanol, isoniazid, tobacco 
Strong Inhibitors 
of CYP 3A4 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil 
(withdrawn from US market), nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, voriconazole 
Strong Inducers 
of CYP 3A4 
Carbamazepine, phenytoin, rifampin 
Substrates of 
CYP 2C9 
Celecoxib, diclofenac, fluvastatin, glipizide, ibuprofen, irbesartan, 
losartan, naproxen, phenytoin, piroxicam, rosiglitazone, 
sulfamethoxazole, tamoxifen, tolbutamide, torsemide 
 
 


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Appendix 4. Management of Specific Immune-Related Adverse Events 
Pneumonitis/ILD 
Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or worsening shortness of breath or cough).  Patients should be evaluated with imaging and pulmonary 
function tests including other diagnostic procedures as described below. 
Initial work-up may include clinical evaluation, monitoring of oxygenation via pulse oximetry (resting and exertion), laboratory work-up and high-resolution CT scan. 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1  
(Asymptomatic, clinical or 
diagnostic observations 
only, intervention not 
indicated) 
• 
None required.  
• 
Consider holding as clinically 
appropriate and during 
diagnostic work-up for other 
etiologies 
• 
Monitor, follow up in 2-4 days for clinical symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated 
• 
Consider pulmonary and infectious disease consult 
Grade 2  
(Symptomatic, medical 
intervention indicated, 
limiting instrumental ADL)  
• 
Hold until ≤ Grade 1 
• 
If worsens, treat as Grade 3 or 
Grade 4  
• 
If improves to ≤ Grade 1, 
decision to reinitiate study 
drug/regimen based on clinical 
judgment and after completion 
of steroid taper. 
 
• 
Monitor daily and consider hospitalization 
• 
Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day or IV equivalent) 
• 
Reimage as clinically indicated 
• 
If no improvement within 3-5 days, consider additional workup and prompt treatment with IV 
methylprednisolone 2-4 mg/kg/day started  
• 
If still no improvement within 3-5 days despite IV methylprednisone, promptly start immunosuppressive 
therapy such as TNF inhibitor (e.g. infliximab at 5 mg/kg every 2 weeks). Caution: Important to rule out 
sepsis and refer to infliximab label for general guidance before using infliximab  
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungal or anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections (Category 2B recommendation, ASCO Educational Book 2015. Michael Postow MD. 
“Managing Immune Checkpoint Blocking Antibody Side Effects”) 
• 
Consider pulmonary and infectious disease consult 
• 
Consider as necessary discussing with study physician 
Grade 3 or 4  
(Grade 3: Severe 
symptoms; limiting  
self-care ADL; oxygen 
indicated;  
 
Grade 4: life threatening 
respiratory compromise, 
urgent intervention 
indicated  
[e.g. tracheostomy or 
intubation])  
• 
Permanently discontinue  
• 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent  
• 
Obtain pulmonary and infectious disease consult 
• 
Hospitalize the patient 
• 
Supportive Care (oxygen, etc.) 
• 
If no improvement within 3-5 days, additional workup should be considered and prompt treatment with 
additional immunosuppressive therapy such as TNF inhibitors  
(e.g. infliximab at 5mg/kg every 2 weeks dose) started. Caution: rule out sepsis and refer to infliximab 
label for general guidance before using infliximab  
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and in particular, anti PCP treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections (Category 2B recommendation) 
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Diarrhea/ Enterocolitis 
• 
Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal pain, cramping, or changes in bowel habits such as increased frequency over baseline or blood 
in stool) or related to bowel perforation (such as sepsis, peritoneal signs and ileus) 
• 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, other medications, infections including testing for clostridium difficile 
toxin, etc.) 
• 
Steroids should be considered in the absence of clear alternative etiology, even for low grade events, in order to prevent potential progression to higher grade event 
• 
Use analgesics carefully; they can mask symptoms of perforation and peritonitis 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1 diarrhea (stool 
frequency of < 4 over 
baseline per day)  
• 
None required 
• 
Monitor for worsening symptoms 
• 
Consider symptomatic treatment including hydration, electrolyte replacement, dietary changes  
(e.g., American Dietetic Association colitis diet), and loperamide. Use of probiotics per clinical 
judgment. 
Grade 2 diarrhea (stool 
frequency of 4-6 over 
baseline per day)  
• 
Hold until resolution to ≤ 
Grade 1 
• 
If  worsens treat as Grade 3 or 
Grade 4 
• 
If improves to ≤ Grade 1, 
study drug/study regimen can 
be resumed after completion 
of steroid taper.    
• 
Consider symptomatic treatment including hydration, electrolyte replacement, dietary changes  
(e.g., American Dietetic Association colitis diet), and loperamide and/or budesonide  
• 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent  
• 
If not responsive within 3-5 days or worsens despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further workup such as imaging and/or colonoscopy 
to confirm colitis and rule out perforation, and prompt treatment with IV methylprednisolone  
2-4mg/kg/day started. 
• 
If still no improvement within 3-5 days despite 2-4mg/kg IV methylprednisolone, promptly start 
immunosuppressives such as (infliximab at 5mg/kg once every 2 weeks). Caution: Important to rule out 
bowel perforation and refer to infliximab label for general guidance before using infliximab   
• 
Consult study physician if no resolution to ≤ Grade 1 in 3-4 days 
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]) 
Grade 3 or 4 diarrhea  
 
(Grade 3: stool frequency 
of ≥ 7 over baseline per 
day;  
 
Grade 4: life threatening 
consequences) 
• 
Permanently discontinue 
• 
Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day or equivalent  
• 
Monitor stool frequency and volume and maintain hydration   
• 
Urgent GI consult and imaging and/or colonoscopy as appropriate 
• 
If still no improvement within 3-5 days of IV methylprednisolone 2-4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g. infliximab at 5 mg/kg once every 2 weeks).   
• 
Caution: Ensure GI consult to rule out bowel perforation and refer to infliximab label for general 
guidance before using infliximab.  
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]) 
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Hepatitis (Elevated LFTs)  
• 
Infliximab should not be used for management of Immune Related Hepatitis 
• 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin  
• 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant medications) 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1  
(AST or ALT > ULN to  
3 times ULN and/or TB > 
1.5 times ULN) 
• 
None required 
• 
If it worsens, treat as Grade 2 
event 
• 
For Grade 1 AST or ALT and/or TB elevation 
• 
  Continue LFT monitoring per protocol   
Grade 2  
(AST or ALT > 3-5 times 
ULN and/or TB > 
1.5-3.0 times ULN) 
• 
Hold dose until Grade 2 
resolution to ≤ Grade 1 
• 
If worsens then treat as Grade 
3 or Grade 4 
• 
If improves to ≤ Grade 1 or 
baseline resume study 
drug/study regimen after 
completion of steroid taper.    
• 
For Grade 2 AST or ALT and or TB elevation - Frequent checking of LFTs (e.g. every 1-2 days) until 
elevations improving or resolved.   
• 
If no resolution in 1-2 days, discuss with study physician. 
• 
If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1-2 mg/kg/day PO or IV 
equivalent.  
• 
If still no improvement within 3-5 days despite 1-2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and prompt treatment with IV methylprednisolone 2-4 mg/kg/day started. 
• 
If still no improvement within 3-5 days despite 2-4mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil).  Discuss with study physician if mycophenolate mofetil 
is not available.  Infliximab should NOT be used. 
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]) 
Grade 3 
(AST or ALT > 5-20 times 
ULN and/or TB >  
3.0-10 times ULN 
• 
For elevations in 
transaminases ≤ 8 × ULN, or 
elevations in bilirubin  
≤ 5 × ULN  
• 
Hold dose until resolution to ≤ 
Grade 1 or baseline   
• 
Resume if elevations 
downgrade ≤ Grade 1 or 
baseline within 14 days, and 
after completion of steroid 
taper 
• 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
• 
Promptly initiate empiric IV methylprednisolone at 1-4 mg/kg/day or equivalent  
• 
If still no improvement within 3-5 days despite 1-4 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive therapy (mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available.  Infliximab should NOT be used. 
• 
Hepatology consult, abdominal workup, and imaging as appropriate. 
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]) 
 
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Hepatitis (Elevated LFTs)  
• 
Infliximab should not be used for management of Immune Related Hepatitis 
• 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin  
• 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, concomitant medications) 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 3 
(AST or ALT > 5-20 times 
ULN and/or TB >  
3.0-10 times ULN (cont’d) 
• 
Permanently discontinue if the 
elevations do not downgrade 
to ≤ Grade 1 or baseline 
within 14 days  
• 
For elevations in 
transaminases > 8 × ULN or 
elevations in bilirubin > 5 × 
ULN, discontinue  
• 
Permanently discontinue for 
any case meeting Hy’s law 
criteria (AST and/or ALT > 3 
× ULN + bilirubin > 2 × ULN 
without initial findings of 
cholestasis (i.e. elevated 
alkaline P04) and in the 
absence of any alternative 
cause 
• 
(FDA Liver Guidance 
Document 2009 Guidance for 
Industry: Drug Induced Liver 
Injury – Premarketing Clinical 
Evaluation NCI CTCAE 
version 4.03) 
See above. 
Grade 4  
(AST or ALT > 20 times 
ULN and/or TB >  
10 times ULN)  
• 
Permanently discontinue  
 
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Nephritis or Renal Dysfunction (Elevated Serum Creatinine) 
Consult with Nephrologist 
Monitor 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.)  
Patients 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 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1 (Serum Creatinine 
> 1-1.5 × baseline; >  
ULN to 1.5 × ULN)  
• 
No dose modification 
• 
Monitor serum creatinine weekly and any accompanying symptom 
• 
If creatinine returns to baseline, resume its regular monitoring per study protocol. 
• 
If it worsens, depending on the severity, treat as Grade 2 or Grade 3 or 4  
• 
Consider symptomatic treatment including hydration, electrolyte replacement, diuretics, etc. 
Grade 2 (Serum 
Creatinine>1.5-3.0 × 
baseline; >1.5 ×-3.0 × 
ULN) 
 
• 
Hold until resolution to  
≤ Grade 1 or baseline 
• 
If toxicity worsens then treat 
as Grade 3 or Grade 4 
• 
If toxicity improves to 
≤ Grade 1 or baseline resume 
study drug/study regimen after 
completion of steroid taper.    
• 
Consider symptomatic treatment including hydration, electrolyte replacement, diuretics, etc. 
• 
Carefully monitor serum creatinine every 2-3 days and as clinically warranted 
• 
Consult Nephrologist and consider renal biopsy if clinically indicated 
• 
If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1-2 mg/kg/day PO or IV 
equivalent  
• 
If event is not responsive within 3-5 days or worsens despite prednisone at 1-2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and prompt treatment with IV methylprednisolone 
at 2-4mg/kg/day started.   
• 
Once improving gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).   
• 
When event returns to baseline, resume and routine serum creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 3.0 × baseline; 
> 3.0-6.0 × ULN 
 
Grade 4: Serum Creatinine 
> 6.0 × ULN)  
• 
Permanently discontinue 
• 
Carefully monitor serum creatinine on daily basis 
• 
Consult Nephrologist and consider renal biopsy if clinically indicated 
• 
Promptly start prednisone 1-2 mg/kg/day PO or IV equivalent  
• 
If event is not responsive within 3-5 days or worsens despite prednisone at 1-2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and prompt treatment with IV methylprednisolone 
2-4 mg/kg/day started.   
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]  
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Rash (excluding Bullous skin formations)  
Refer to NCICTCAE for definition of severity/grade depending on type of skin rash 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY PHYSICIAN SHOULD BE CONTACTED AND STUDY DRUG DISCONTINUED** 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1  
• 
No dose modification 
• 
Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream) 
Grade 2 
• 
For persistent (> 1-2 weeks) 
Grade 2 events, hold until 
resolution to ≤ Grade 1 or 
baseline  
• 
If toxicity worsens then treat 
as Grade 3  
• 
If toxicity improves to 
≤ Grade 1 or baseline resume 
study drug/study regimen after 
completion of steroid taper.   
• 
Obtain dermatology consult  
• 
Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream) 
• 
Consider moderate-strength topical steroid  
• 
If no improvement within 3-5 days or is worsening despite symptomatic treatment and/or use of 
moderate strength topical steroid, discuss with study physician and promptly start systemic steroids 
prednisone 1-2 mg/kg/day PO or IV equivalent   
• 
Consider skin biopsy if persistent for > 1-2 weeks or recurs 
Grade 3 
• 
Hold until resolution to 
≤ Grade 1 or baseline 
• 
If holding does not provide 
improvement to ≤ Grade 1 or 
baseline within 30 days, then 
permanently discontinue   
• 
For Grade 3 or 4: 
• 
Consult dermatology  
• 
Promptly initiate empiric IV methylprednisolone 1-4 mg/kg/day or equivalent  
• 
Consider hospitalization 
• 
Monitor extent of rash [Rule of Nines] 
• 
Consider skin biopsy (preferably more than 1) as clinically feasible. 
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]) 
• 
Discuss with Study Physician 
Grade 4 
• 
Permanently discontinue   
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Endocrinopathy (e.g., hyperthyroidism, hypothyroidism, hypopituitarism, adrenal insufficiency, etc.) 
• 
Depending on the type of endocrinopathy, refer to NCI CTCAE version 4.03 for defining the CTC grade/severity 
• 
Consult Endocrinologist 
• 
Monitor patients for signs and symptoms of endocrinopathies.  Non-specific symptoms include headache, fatigue, behavior changes, changed mental status, vertigo, abdominal pain, unusual bowel 
habits, hypotension and weakness. 
• 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression including brain metastases, infections, etc.) 
• 
Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and other relevant endocrine labs depending on suspected endocrinopathy.   
• 
If a patient experiences an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the investigator should send a blood sample for 
appropriate autoimmune antibody testing 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1 
• 
No dose modification 
• 
For Grade 1: (including those with asymptomatic TSH elevation) 
• 
Monitor patient with appropriate endocrine function tests 
• 
If TSH < 0.5 × LLN, or TSH > 2 × ULN or consistently out of range in 2 subsequent measurements, include FT4 at 
subsequent cycles as clinically indicated and consider endocrinology consult. 
Grade 2  
• 
For Grade 2 endocrinopathy other 
than hypothyroidism, hold dose 
until patient is clinically stable 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4  
• 
Can resume once event stabilizes 
and after completion of steroid 
taper.  
• 
For Grade 2: (including those with symptomatic endocrinopathy) 
• 
Isolated hypothyroidism may be treated with replacement therapy without treatment interruption and without 
corticosteroids 
• 
Initiate hormone replacement as needed for management 
• 
Evaluate endocrine function, and as clinically indicated, consider pituitary scan 
• 
For patients with abnormal endocrine work up, except for those with isolated hypothyroidism, consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day methylprednisolone or IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. Levothyroxine, hydrocortisone, or sex hormones).   
• 
Once improving, gradually taper steroids over ≥ 28 days and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (refer to current NCCN guidelines for treatment of cancer-related infections [Category 2B 
recommendation]) 
• 
For patients with normal endocrine work up (lab or MRI scans), repeat labs/MRI as clinically indicated. 
 
Note: Patients with endocrinopathies who may require prolonged or continued steroid replacement can be retreated on the 
following conditions: 1) the event stabilizes and is controlled ,2) the patient is clinically stable as per Investigator or 
treating physician’s clinical judgement, and 3) doses of prednisone are at less than or equal to 10mg/day or equivalent. 
Grade 3 or 4 
(Depending on the type of 
endocrinopathy, refer to NCI 
CTCAE version 4.03 for 
defining the CTC 
grade/severity 3 or 4)  
• 
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism, hold 
dose until endocrinopathy 
symptom(s) are controlled 
• 
Can be resume at the next 
scheduled dose once event 
stabilizes to grade ≤ 1 and  
5-7 days have passed after 
completion of steroid taper  
• 
Consult endocrinologist 
• 
Isolated hypothyroidism may be treated with replacement therapy without treatment interruption and without 
corticosteroids 
• 
Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or equivalent 
• 
Administer hormone replacement therapy as necessary. 
• 
For adrenal crisis, severe dehydration, hypotension, or shock: immediately initiate intravenous corticosteroids with 
mineralocorticoid activity 
• 
Once improving, gradually taper immunosuppressive steroids over ≥ 28 days and consider prophylactic antibiotics, 
antifungals and anti PCP treatment (refer to current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
• 
Discuss with study physician 
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Immune mediated Neurotoxicity (to include but not limited to limbic encephalitis, autonomic neuropathy, excluding Myasthenia Gravis and Guillain-Barre)   
• 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, metabolic syndromes and medications, etc.)  
• 
Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, or weakness) 
• 
Consider appropriate diagnostic testing (e.g. electromyogram and nerve conduction investigations) 
• 
Symptomatic treatment with neurological consult as appropriate 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1 
• 
None required 
• 
See recommendations above. 
Grade 2 
• 
For acute motor neuropathies 
or neurotoxicity, hold dose 
until resolution to ≤ Grade 1 
• 
For sensory 
neuropathy/neuropathic pain, 
consider holding dose until 
resolution to ≤ Grade 1. 
• 
If toxicity worsens then treat 
as Grade 3 or Grade 4  
• 
Can resume once event 
improves to Grade ≤ 1 and 
after completion of steroid 
taper.  
• 
Discuss with the study physician  
• 
Obtain Neurology Consult  
• 
Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., gabapentin, 
duloxetine, etc.) 
• 
Promptly start systemic steroids prednisone 1-2mg/kg/day PO or IV equivalent  
• 
If no improvement within 3-5 days despite 1-2mg/kg/day prednisone PO or IV equivalent consider 
additional workup and promptly treat with additional immunosuppressive therapy (e.g. IVIG)  
Grade 3 
• 
Hold until resolution to  
≤ Grade 1 
• 
Permanently discontinue if 
Grade 3 irAE does not resolve 
to ≤ Grade 1 within 30 days. 
• 
For Grade 3 or 4: 
• 
Discuss with study physician 
• 
Obtain Neurology Consult 
• 
Consider hospitalization 
• 
Promptly initiate empiric IV methylprednisolone 1-2 mg/kg/day or equivalent  
• 
If no improvement within 3-5 days despite IV corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g. IVIG)  
• 
Once stable, gradually taper steroids over ≥ 28 days 
Grade 4 
 
• 
Permanently discontinue  
 
 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Immune-mediated peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis 
• 
Prompt diagnosis of immune-mediated peripheral neuromotor syndromes is important, since certain patients may unpredictably experience acute decompensations which can 
result in substantial morbidity or in the worst case, death.  Special care should be taken for certain sentinel symptoms which may predict a more severe outcome, such as 
prominent dysphagia, rapidly progressive weakness, and signs of respiratory insufficiency or autonomic instability 
• 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, metabolic syndromes and medications, etc.).  It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor syndromes can be particularly challenging in patients with underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis.  Given the importance of prompt and accurate diagnosis, it is essential to have a low threshold to obtain a 
neurological consult 
• 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction investigations, and “repetitive stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be best facilitated by means of a neurology consultation  
• 
Important to consider that the use of steroids as the primary treatment of Guillain-Barre is not typically considered effective.  Patients requiring treatment should be started 
with IVIG and followed by plasmapheresis if not responsive to IVIG 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 1 
• 
None required 
• 
Discuss with the study physician 
• 
Care should be taken to monitor patients for sentinel symptoms of a potential decompensation as 
described above 
• 
Obtain a neurology consult unless the symptoms are very minor and stable 
Grade 2 
• 
Hold until ≤ Grade 1 
• 
Permanently discontinue if 
does not resolve within 
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability 
• 
Discuss with the study physician  
• 
Care should be taken to monitor patients for sentinel symptoms of a potential decompensation as 
described above 
• 
Obtain a Neurology Consult  
• 
Sensory neuropathy/neuropathic pain may be managed by appropriate medications (e.g., gabapentin, 
duloxetine, etc.) 
• 
MYASTHENIA GRAVIS 
• 
Steroids may be successfully used to treat Myasthenia Gravis.  Important to consider that steroid therapy 
(especially with high doses) may result in transient worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of a consulting neurologist. 
• 
Patients unable to tolerate steroids may be candidates for treatment with plasmapheresis or IVIG.  Such 
decisions are best made in consultation with a neurologist, taking into account the unique needs of each 
patient. 
• 
If Myasthenia Gravis-like neurotoxicity present, consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids.  Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
• 
GUILLAIN-BARRE: Important to consider here that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective.  Patients requiring treatment should be started with 
IVIG and followed by plasmapheresis if not responsive to IVIG. 


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Appendix 4 Management of Specific Immune-Related Adverse Events (Continued) 
Immune-mediated peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis 
• 
Prompt diagnosis of immune-mediated peripheral neuromotor syndromes is important, since certain patients may unpredictably experience acute decompensations which can 
result in substantial morbidity or in the worst case, death.  Special care should be taken for certain sentinel symptoms which may predict a more severe outcome, such as 
prominent dysphagia, rapidly progressive weakness, and signs of respiratory insufficiency or autonomic instability 
• 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, metabolic syndromes and medications, etc.).  It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor syndromes can be particularly challenging in patients with underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the neuraxis.  Given the importance of prompt and accurate diagnosis, it is essential to have a low threshold to obtain a 
neurological consult 
• 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction investigations, and “repetitive stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be best facilitated by means of a neurology consultation  
• 
Important to consider that the use of steroids as the primary treatment of Guillain-Barre is not typically considered effective.  Patients requiring treatment should be started 
with IVIG and followed by plasmapheresis if not responsive to IVIG 
Grade of AE 
Dose Modifications 
Toxicity Management 
Grade 3 
• 
Hold dose until resolution to  
≤ Grade 1 
• 
Permanently discontinue if 
Grade 3 irAE does not resolve 
to  
≤ Grade 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability 
• 
For severe or life threatening (Grade 3 or 4) events 
• 
Discuss with study physician 
• 
Recommend hospitalization 
• 
Monitor symptoms and obtain neurological consult 
• 
MYASTHENIA GRAVIS 
• 
Steroids may be successfully used to treat Myasthenia Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting neurologist. 
• 
Patients unable to tolerate steroids may be candidates for treatment with plasmapheresis or IVIG. 
• 
If Myasthenia Gravis-like neurotoxicity present, consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids.  Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
• 
GUILLAIN-BARRE: Important to consider here that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective.  Patients requiring treatment should be started with 
IVIG and followed by plasmapheresis if not responsive to IVIG 
Grade 4 
• 
Permanently discontinue   
 
 
 


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Appendix 5. Abbreviated Presentation of RECIST Version 1.1 Guidelines 
A modification to RECIST 1.1 has been made to account for the possibility of temporary 
changes resulting from the potentially beneficial treatment responses of tumor necrosis, 
cavitation or flare response.   
Categorizing Lesions at Baseline 
Measurable Lesions 
• Accurately measured in at least one dimension. 
• When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice 
thickness 5-8 mm), measured in the axial plane.  If the slice thickness is greater than 
5 mm (including any inter-slice gap), the longest diameter must be at least twice the 
slice thickness. 
• Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed 
by CT or MRI. 
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other lesions.   
Non-Measurable Disease 
• Lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) or truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, and abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques. 
• Bone disease is non-measurable with the exception of soft tissue components that can 
be evaluated by CT or MRI and meet the definition of measurability at baseline.   
• Previously irradiated lesions (or those subjected to other local treatment) are 
non-measurable unless it they have progressed since completion of treatment. 


 
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Normal Lesions 
• Non-malignant simple cysts should not be recorded either as target or non-target 
disease.  Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above.   
• Lymph nodes with short axis <10 mm are considered normal and should not be 
followed as disease. 
Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  All required scans must be done within the window 
of time specified in the Schedule of Assessments (Table 1) prior to treatment.  If the 
baseline assessment is inadequate, subsequent statuses generally should be indeterminate.   
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial.  Once selected as a target lesion, a lesion 
remains target throughout the trial. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in 
the case of pathological lymph nodes for which the short axis should be recorded.  The 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions at baseline will be the basis for comparison to look for partial response at 
later assessments.   
• If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is 
used.  If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded. 
• When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 


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Non-Target Lesions 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
qualitative evaluations of status will be recorded.  Multiple non-target lesions in one 
organ may be recorded as a single item on the CRF (e.g., ‘multiple liver metastases’). 
Objective Response Status at Each Evaluation 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast.  If not, subsequent objective statuses may be indeterminate.   
Target Disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
< 10 mm).  All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed.   
• Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir, but enough that a previously documented 30% 
decrease no longer holds.   
• Progressive Disease (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy) with a minimum absolute increase of 5 mm.   
• Indeterminate: Progression has not been documented, and  
o one or more target lesions have not been assessed,  
o or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
o or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure), 
o or one or more target lesions were excised or irradiated and have not reappeared 
or increased.   


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Non-Target Disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.   
• PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.   
• Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the 
etiology.  If repeat assessments confirm the lesion, then progression should be recorded 
on the date of the initial assessment.  A lesion identified in an area not previously 
scanned will be considered a new lesion. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flare 
response to treatment or become otherwise difficult to evaluate for a period of time as the 
result of beneficial study treatment impact.  For example, tumor necrosis, cavitation or 
flare may result in increase in overall size of individual lesions or unclear tumor margins 
prior to recovery to smaller lesions, development of scar tissue, or complete resolution.  
The true tumor measurements of lesions should be recorded but the conclusion of 
progressive disease may be suspended until continued assessment clarifies the nature of 
the tumor change.  If repeat assessments indicate progression of disease, then PD should 
be recorded on the date of the first assessment giving the impression of progression.  If 
repeat assessments indicate that the change was a process of transition, then NE (not 
evaluable) should be recorded during the period of transition, and PR or CR may be 
recorded for subsequent evaluations.  The CRF will collect information on the 
observations during the period of transition to support the assessment conclusions.   
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 


Protocol 0103-020 v3.0 – Phase 1/2 Mocetinostat and Durvalumab Combination 
Confidential
Mocetinostat and Durvalumab 
Page 127 of 127
 
 
 
Mirati Therapeutics Inc. 
 
 
 
 
 
 
 
 
Best Objective Response 
Target Lesions Non-Target Lesions 
New Lesion 
Point in Time 
Response 
Best Response 
CR 
CR 
No 
CR 
CR and PR require 
confirmation at least 
4 weeks after first 
observation 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
SD requires an on-study 
assessment after at least 
6weeks on treatment. 
Unconfirmed PR or CR are 
reported as SD. 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Subjective Progression 
Patients requiring discontinuation of treatment due to worsening health status attributable 
to advancement of the malignancy under study but without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of 
Health Status.   

SAP_001.pdf: 
Protocol Number:  0103-020 
 
Official Title:    A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, 
in Combination With PD-L1 Inhibitor, Durvalumab, 
in Advanced or Metastatic Solid Tumors and 
Non-Small Cell Lung Cancer    
 
NCT Number:  NCT02805660 
 
Document Date:  30-Oct-2017 


Statistical Analysis Plan 
Version Date: 30-Oct-2017  
 
Sponsor: Mirati Therapeutics, Inc. 
Protocol no: 0103-020 
PRS 005 T 17 F 
Page 1 of 38 
Statistical Analysis Plan 
Sponsor: 
Mirati Therapeutics, Inc. 
Protocol No: 
0103-020 
PRA Project Id: 
MRT10302-103020 
Version Date: 
10-May-2017 
Version No. 
3.0 
 
Title: 
A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination With PD-L1 
Inhibitor, Durvalumab in Advanced or Metastatic Solid Tumors and Non-Small 
Cell Lung Cancer 
CRF Version 
No./Date: 
2.0 / 23-Jun-2016 
SAP No. / Date 
1.0 / 30-Oct-2017 
 
1.0 Approvals 
Sponsor 
Sponsor Name: 
Mirati Therapeutics, Inc. 
 
 
Signature /Date: 
 
 
 
Signature /Date: 
 
 
 
 
Signature /Date: 
 
 
 
Signature /Date: 
 


Statistical Analysis Plan 
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Protocol no: 0103-020 
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Page 2 of 38 
 
Table of Contents 
1.0 Approvals ............................................................................................................................................................................ 1 
Table of Contents ..................................................................................................................................................................... 2 
2.0 Purpose ................................................................................................................................................................................ 5 
3.0 Scope ..................................................................................................................................................................................... 5 
4.0 Introduction ....................................................................................................................................................................... 5 
5.0 Study Objectives and Endpoints ................................................................................................................................ 5 
5.1 Objectives ....................................................................................................................................................................... 5 
5.1.1 Primary Objectives ............................................................................................................................................. 5 
5.1.2 Secondary Objectives ........................................................................................................................................ 5 
 
5.2 Endpoints ........................................................................................................................................................................ 6 
5.2.1 Primary Endpoints ............................................................................................................................................. 6 
5.2.2 Secondary Endpoints......................................................................................................................................... 6 
 
6.0 Study Design ....................................................................................................................................................................... 7 
6.1 Phase 1 Portion of the Study ................................................................................................................................. 14 
6.1.1 Definition of Dose Limiting Toxicity ......................................................................................................... 14 
6.1.2 Dose Escalation Plan ........................................................................................................................................ 15 
6.1.3 Definition of Maximum Tolerated Dose .................................................................................................. 15 
6.1.4 Definition of Recommended Phase 2 Dose ............................................................................................ 15 
6.2 Phase 2 Portion of the Study ................................................................................................................................. 16 
6.3 Sample Size Considerations .................................................................................................................................. 17 
6.3.1 Phase 1 .................................................................................................................................................................. 17 
6.3.2 Phase 2 .................................................................................................................................................................. 17 
6.3.3 Statistical Design Applied to Phase 2 Cohorts 1, 3 and 4 ................................................................. 17 
6.3.4 Statistical Design Applied to Phase 2 Cohort 2 ..................................................................................... 18 
6.4 Randomization ........................................................................................................................................................... 18 
7.0 Analysis Populations ..................................................................................................................................................... 18 
7.1 Enrolled Population ................................................................................................................................................. 18 
7.2 Modified Intent-to-Treat Population................................................................................................................. 18 
7.3 Clinical Activity Evaluable Population .............................................................................................................. 18 
7.4 Safety Population ...................................................................................................................................................... 18 
7.5 DLT Evaluable Population ..................................................................................................................................... 19 
7.6 Molecular Marker Evaluable Population ......................................................................................................... 19 
7.7 Pharmacokinetic Evaluable Population ........................................................................................................... 19 
7.8 Pharmacodynamic Evaluable Population ....................................................................................................... 19 
7.9 Anti-Drug Antibody Evaluable Population ..................................................................................................... 19 
8.0 Endpoint Definitions ..................................................................................................................................................... 19 
8.1 Efficacy Variables ...................................................................................................................................................... 19 
8.1.1 Objective Response Rate ORR) .................................................................................................................... 19 
8.1.2 Best Overall Response .................................................................................................................................... 20 
8.1.3 Clinical Benefit Rate (CBR) ........................................................................................................................... 20 
8.1.4 Duration of Response (DR) ........................................................................................................................... 20 
8.1.5 Overall Survival (OS) ....................................................................................................................................... 20 
8.1.6 Progression-Free Survival (PFS) ................................................................................................................ 20 


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8.2 Study Drug Exposure Variables ........................................................................................................................... 21 
8.3 Safety Variables .......................................................................................................................................................... 22 
8.3.1 Adverse Events .................................................................................................................................................. 22 
8.3.2  Vital Signs ............................................................................................................................................................ 22 
8.3.3 Clinical Laboratory Assessments ............................................................................................................... 23 
8.3.4 Electrocardiograms and echocardiograms ............................................................................................ 23 
8.3.5 Prior and Concomitant Medications ......................................................................................................... 23 
9.0 Data Handling .................................................................................................................................................................. 24 
9.1 Missing Dates .............................................................................................................................................................. 24 
9.2 Protocol Deviations .................................................................................................................................................. 25 
9.3 Study Day ...................................................................................................................................................................... 25 
10.0 Interim Analyses .......................................................................................................................................................... 25 
11.0 Data Review ................................................................................................................................................................... 25 
12.0 Statistical Methods ...................................................................................................................................................... 25 
12.1 Patient Disposition ................................................................................................................................................. 26 
12.2 Important Protocol Deviations ......................................................................................................................... 26 
12.3 Treatments ................................................................................................................................................................ 26 
12.3.1 Extent of Study Treatment Exposure ..................................................................................................... 26 
12.3.2 Concomitant Medications ........................................................................................................................... 26 
12.4 Demographic and Baseline Characteristics ................................................................................................. 27 
12.5 Efficacy Analyses ..................................................................................................................................................... 27 
12.5.1 ORR, Best Overall Response and CBR .................................................................................................... 27 
12.5.2 Time-to-event Variables .............................................................................................................................. 27 
12.5.3 ADA ...................................................................................................................................................................... 28 
12.5.4 PD-L1 ................................................................................................................................................................... 28 
 
12.6 Safety Analyses ........................................................................................................................................................ 28 
12.6.1 Adverse Events ................................................................................................................................................ 28 
12.6.2 Deaths and Serious Adverse Events ....................................................................................................... 29 
12.6.3 Laboratory Data .............................................................................................................................................. 29 
12.6.4 Hematology ....................................................................................................................................................... 30 
12.6.5 Chemistry .......................................................................................................................................................... 30 
12.6.6 Urinalysis ........................................................................................................................................................... 30 
12.6.7 Thyroid ............................................................................................................................................................... 30 
12.6.8 CTCAE Coding of Laboratory Data .......................................................................................................... 30 
12.6.9 Vital Signs .......................................................................................................................................................... 31 
12.6.10 Physical Examinations, ECGs, and Other Observations Related to Safety ........................... 31 
12.6.11 Physical Examination ................................................................................................................................. 31 
12.6.12 Electrocardiogram ...................................................................................................................................... 31 
12.6.13 Echocardiogram ........................................................................................................................................... 31 
12.6.14 Pregnancy Test ............................................................................................................................................. 31 
12.6.15 Long Term Follow-up ................................................................................................................................ 32 
13.0 Validation ........................................................................................................................................................................ 32 
14.0 References ...................................................................................................................................................................... 32 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 33 
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output Appendices .......................................... 35 
Appendix 3 Dose-Finding Spreadsheet of the Modified Toxicity Probability Interval (mTPI) Method
 ....................................................................................................................................................................................................... 36 


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Appendix 4 Programming Specifications for Baseline Characteristics and Safety Variables ................ 38 
 


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2.0 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Mirati Therapeutics, Inc. Protocol 0103-020. 
3.0 Scope 
This plan is a living document that supplements the study protocol for statistical analyses related aspects.    
The SAP outlines the following: 
• 
Study objectives and endpoints 
• 
Study design 
• 
Analysis populations 
• 
Endpoint and variable definitions 
• 
Data handling 
• 
Data review 
• 
Statistical methods 
 
Deviations from the statistical analysis plan will be described in the Clinical Study Report (CSR). 
4.0 Introduction 
This SAP describes the statistical methods to be used during the analysis and reporting of data collected 
under Mirati Therapeutics, Inc. Protocol 0103-020.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol dated 10 May 2017 and CRF dated 06SEP2016. Any 
further changes to the protocol or CRF may necessitate updates to the SAP. 
The SAP is to be developed in two stages. An initial SAP, known as SAP1, is finalized based on the 
current protocol and CRF, so that programming may be created.  Changes following approval of SAP1 
will be tracked in the SAP Change Log.A final version of the SAP, known as SAP2, will be issued prior to 
database lock. 
Each version of the SAP requires approval by the project manager and the sponsor. 
5.0 Study Objectives and Endpoints 
5.1 Objectives 
5.1.1 Primary Objectives 
• 
To determine the recommended Phase 2 dose (RP2D) of mocetinostat administered in 
combination with full dose durvalumab, 
• 
To evaluate the clinical activity of mocetinostat in combination with durvalumab in cohorts of 
patients with non-small cell lung cancer (NSCLC) having differing tumor expression of 
programmed cell death ligand 1 (PD-L1) or prior tumor responsiveness to treatment with 
checkpoint inhibitors. 
5.1.2 Secondary Objectives 
• 
To evaluate the safety and tolerability of mocetinostat in combination with durvalumab in the 
selected population, 


Statistical Analysis Plan 
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• 
To evaluate secondary efficacy endpoints with mocetinostat in combination with durvalumab in 
the selected population, 
• 
To evaluate mocetinostat and durvalumab pharmacokinetics (PK) [PK analysis will be covered by 
a separate analysis plan], 
• 
To evaluate the incidence of anti-drug antibodies (ADA) to durvalumab, 
• 
To evaluate the effect of mocetinostat during the Lead-In Period on tumor cell PD-L1 expression. 
 
 
 
 
 
 
 
 
 
 
5.2 Endpoints 
5.2.1 Primary Endpoints 
• 
Incidence of dose limiting toxicities (DLTs) occurring during the first 28-day cycle of combination 
treatment. 
• 
Objective response rate (ORR) defined by RECIST 1.1. 
5.2.2 Secondary Endpoints 
• 
Safety characterized by type, incidence, severity, timing, seriousness and relationship to study 
treatment of adverse events and laboratory abnormalities. 
• 
Secondary efficacy endpoints: 
o 
Duration of response (DR) 
o 
Clinical benefit rate (CBR) 
o 
Progression free survival (PFS) 
o 
1-year survival rate; and 
o 
Overall survival (OS). 
• 
Blood plasma MGCD0103 and MED14736 concentrations. 
• 
ADA detected in blood. 
• 
Tumor PD-L1 expression. 
 
 
 
 
 
 
 
 
 


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6.0 Study Design 
This is an open-label Phase 1/2 evaluation of mocetinostat in combination with durvalumab. The Phase 1 
segment will define the RP2D of mocetinostat to be used in combination with full dose regimen of 
durvalumab; eligible patients will have an advanced solid tumor disease that is not amendable to curative 
treatment. The Phase 2 segment will evaluate the clinical activity of mocetinostat in combination with 
durvalumab, as assessed by ORR in accordance with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1, in patients with locally advanced, unresectable or metastatic NSCLC who have 
previously received at least one platinum-containing doublet chemotherapy regimen for advanced 
disease. Patients who have previously received treatment with checkpoint inhibitors may be enrolled in 
the Phase 1 assessment and will be enrolled into dedicated cohorts in the Phase 2 assessment. 
Secondary objectives include secondary efficacy endpoints, PK, incidences of ADA and change in tumor 
PD-L1 expression. 
 
The schedule of assessments to be performed in the study is presented in Table 1. Triplicate 
electrocardiogram (ECG) assessments, PK, and ADA collection time points are presented in Table 2. 
The treatment regimen to be evaluated in this study includes a 7-Day Lead-In Period of mocetinostat 
single agent administered three times weekly (TIW; e.g., Monday, Wednesday and Friday) followed by 
administration of the combination regimen with durvalumab. The RP2D dose of mocetinostat will be 
established in successive dose escalation cohorts in the Phase 1 portion of the study and utilized in the 
Phase 2 portion of the study. The dose and regimen of durvalumab to be used throughout the study is 
1500 mg on Day 1 of each 28-day cycle (i.e., Q4W). 


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Table 1: Schedule of Assessments 
The Schedule of Assessments provides an overview of the protocol visits and procedures.  Refer to Section Error! Reference source 
not found. for detailed information on each assessment.  Additional, unplanned assessments should be performed as clinically 
indicated, including for the purpose of fully evaluating adverse events. 
Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 
days) 
Day 1 
(± 2 
days) 
Day 15 
(± 2 
days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Study Participation 
Informed Consent1 
Before study 
specific 
assessments 
 
 
 
 
 
 
 
 
Tumor PD-L1 
Expression Testing2 
X 
 
X 
 
 
 
 
X 
 
Medical History, 
Disease History, 
Prior Therapy  
X 
 
 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
 
X 
 
Abbreviated 
Physical Exam3 
 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test5 
X 
As clinically indicated 
 
Hematology6,7 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Coagulation6,7 
X 
As clinically indicated 
 
Urinalysis6,7 
X 
 
X 
 
X 
 
X 
 
 
Serum Chemistry6,7 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Test6,7 
X 
 
X 
 
X 
 
X 
 
 
Blood for 
Pharmcokinetics8 
 
See Error! Reference source not found. 
90 Days 
Blood for Anti-Drug 
Antibody9 
 
See Error! Reference source not found. 
90 Days 
Biopsy of tumor for 
Biomarker Studies10 
X 
 
X 
 
X10 
 
 
X 
 
Blood Samples for 
Biomarker Studies11 
X 
X 
X 
X11 
11 
 
 
 
 
Single 12-Lead ECG12 
X 
 
 
 
Cycle 3 
 
X 
X 
 
Triplicate 12-Lead ECG12 
 
X, See Error! 
Reference 
source not 
found. 
X 
 
Cycle 2 
 
 
 
 
Echocardiogram 
X 
 
 
X 
X 
 
X 
X 
 


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Assessments 
Screen/ 
Baseline 
7-Day 
Mocetinostat 
Lead-In Period 
Mocetinistat + Durvalumab 
End of Treatment15 
 
Cycle 1 
Cycle 2 and 3 
≥Cycle 4 
Within  
28 days 
Day 1 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Disease Evaluation13 
X 
 
Q 8 weeks Starting from Cycle 1, Day 1 until Week 49 (~1 year)  
and then Q 12 weeks 
 
Mocetinostat Dispensing 
and/or Reconciliation 
 
X 
X 
 
X 
 
X 
 
 
Durvalumab 
Administration 
 
 
X 
 
X 
 
X 
 
 
Adverse Events14 and 
Concomitant Medications 
SAEs only 
Throughout 
SAEs only 
for 90 Days 
Long Term Follow-up16 
 
 
 
 
 
 
 
 
X 
1 
Study Participation Informed Consent: May be performed prior to 28 days before first dose of study treatment and must be completed prior to study 
specific assessments. 
2 
Tumor Testing for PD-L1 Expression: Required test for patients enrolling in Cohorts 1 and 2; encouraged for patients enrolling in Phase 1 or Phase 2 
Cohorts 3 and 4.  Biopsy may precede informed consent if performed as Standard of Care (SOC) or to assess eligibility for a different clinical trial.  In 
Cohorts 1 and 2, the sample tested must have been collected following completion of the most recent systemic treatment regimen. 
3 
Physical Examinations: A complete physical examination required at Screening and End of Treatment only.  Height will be recorded at screening only.  
All other evaluations will be symptom-directed, abbreviated evaluations. 
4 
Vital Signs: Weight, temperature, blood pressure, and pulse rate to be assessed prior to dosing as indicated.  In addition, blood pressure and pulse rate 
will be assessed every 30 minutes (± 5 minutes) between the start and end of durvalumab infusions and, for the first infusion, for 1 hour post infusion.  If 


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the Durvalumab infusion period lasts 60 minutes, the first BP and pulse assessment should be made 30 minutes into the infusion and 30 minutes later at 
the end.  If the infusion period lasts longer than 60 minutes, BP and pulse assessment should continue to be made at 30-minute (± 5 minutes) intervals. 
5 
Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at 
screening will be required.  The informed consent process must include discussion of the risks associated with pregnancy and adequate contraception 
methods.  Additional pregnancy testing may be necessary if required by local practices or regulations, or if potential pregnancy is suspected. 
6 
Selected Lead-In, Day 1 Assessments: Repeat assessment not required if screening assessment performed within 7 days before the first dose.   
7 
Safety Laboratory Assessments: Hematology, coagulation, chemistry and thyroid function evaluations (see Section Error! Reference source not 
found.) will be performed by local laboratories. For scheduling convenience, these assessments may be performed one day prior to the visit at the start 
of the 7-day Lead-in Period and Cycle 1 Day 1. 
8 
Pharmacokinetic Samples: Blood samples to be collected following ECGs and assessment of vital signs as scheduled in Error! Reference source not 
found..  In addition, in the event of a Serious Adverse Event (SAE), unscheduled PK blood samples should be drawn for each study treatment as soon as 
possible.  
9 
Anti-Drug Antibody Samples: Blood samples to be collected as scheduled in Error! Reference source not found..   
10 
Tumor Biopsy for Biomarker Studies:  Consent for serial sampling of tumor tissue (preferably the same lesion) is requested but is not mandatory for 
study entry.  The tumor biopsy used to determine eligibility may be used for the baseline assessment.  Four collection timepoints are scheduled: 
baseline, C1D1, C2D1, and EOT. Markers of interest in tumor tissue include PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs), natural 
killer cells (NK-cells), T regulatory cells (Tregs), and myeloid derived suppressor cells (MDSCs). Tumor biopsy tissue samples will not be collected on 
subjects in the Phase 1 50 mg cohort, and are optional for subjects in all other cohorts. 
11 
Blood Samples for Biomarker Studies:  Blood samples for biomarker studies will not be collected on subjects in the Phase 1 50 mg cohort, but will be 
required for subjects in all other cohorts. At the beginning of the study, sampling will be scheduled on Cycle 1 Day 15.  During the study, emerging data 
may indicate that quality of information gained from the assessment should improve with increased duration of combination treatment  If so, the sample 
may be moved to Cycle 2 Day 1 and communicated to Investigators by Administrative Letter.  Markers of interest in circulation include circulating 
PD-L1, Tregs, MDSCs, NK-cells, flow cytometry for T- and B-cell including CD4, CD8 and Ki67, and selected cytokines including CD8A, GZMB, 
IFNγ, CXCL9, CXCL10, CXCL11, and TBX21. 
12 
ECGs: Single 12-lead ECGs are to be performed at screening and at points not accompanied by PK sampling, with the exception of C3D1, C4D1 and 
C7D1.  On days when PK samples are being collected, the single ECG should be performed prior to the blood draw.  Triplicate ECGs are to be 
performed to as noted in Error! Reference source not found..  Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and 
QTc intervals (Fridericia’s formula).  Respiration rate should be recorded during each ECG assessment. 
13 
Disease Evaluations: To be performed at screening (28 day window allowed) and every 8 weeks ( ± 10 days window) from C1D1 for all other 
assessments except screening until Week 49 (~1 year) and then every 12 weeks.  At screening/baseline, assessments are to include CT with contrast of 
the chest, abdomen and pelvis, as well as brain Magnetic Resonance Imaging (MRI) with and without gadolinium or Computed Tomography Scan (CT) 
with contrast, a whole body bone scan and evaluation of any superficial lesions.  Subsequent disease assessments should include all sites of disease 
identified at baseline or suspected to have developed; bone scans may be performed at one-half the frequency of other radiology evaluations and should 
be performed during assessment for confirmation of disease response.  For those sites that routinely use PET scans for assessment of bone lesions in lieu 
of skeletal scintigraphy, PET scans may be used on-study, with the same modality planned throughout the study for any given patient.  More detailed 
guidance on exceptional circumstances is provided in the protocol.   


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14 
Adverse Events: SAEs will be reported from the time of informed consent until 90 days after the last administration of mocetinostat or durvalumab.  
Adverse events will be reported from the first day of study treatment until at least 28 days after last dose of study drug, and until resolution or 
stabilization of acute AEs and/or ongoing SAEs.  After the 90-day SAE observation period, post-treatment follow-up may be performed by remote 
contact (e.g., telephone call).   
15 
End of Treatment: Assessments that have been completed in the previous 4 weeks do not need to be repeated (8 or 12 weeks for tumor assessments in 
accordance with schedule).   
16 
Long Term Follow-up: Blood samples for MEDI4736 PK and ADA will be collected approximately 90 days after the last infusion of durvalumab.  
Survival status and subsequent therapies will be collected during long term follow-up every 2 months (±14 days) from the date the subject was 
discontinued from study treatment until death or lost to follow-up.  Follow-up beyond 90 days after last treatment may be performed by telephone 
contact. 
 


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Table 2: Schedule of Triplicate ECGs, PK and ADA Assessments 
 
 


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6.1 Phase 1 Portion of the Study 
The dose escalation phase of the study will employ the modified toxicity probability interval (mTPI) 
method in decision making concerning mocetinostat dose escalation (Appendix 3). 
The mocetinostat dose levels planned for evaluation include 50, 70, and 90 mg TIW, depending on safety 
observations. In addition, if necessary, dose de-escalation of mocetinostat to 40 mg TIW may be 
undertaken. 
  
6.1.1 Definition of Dose Limiting Toxicity 
The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.03 
will be used throughout this study. The definition of DLT includes any of the following events considered 
to be causally related to treatment with mocetinostat in combination with durvalumab: 
• 
Any grade 4 immune-related adverse event (irAE is defined in Section 8) 
• 
Grade 3 or greater colitis 
• 
Grade 3 or greater noninfectious pneumonitis irrespective of duration 
• 
Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of maximal 
supportive care 
• 
Grade 3 irAE (excluding colitis or pneumonitis) that: 
o 
Does not downgrade to Grade 2 within 3 days after onset of the event despite optimal 
medical management including systemic corticosteroids, or  
o 
Does not downgrade to ≤ Grade 1 or baseline within 14 days 
• 
Liver transaminase elevation > 8 × upper limit of normal (ULN) or total bilirubin > 5 × ULN 
• 
Grade 3 or greater non-irAE, except for the exclusions listed below: 


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o 
Nausea, vomiting, anorexia, dehydration, or diarrhea that can be managed with typical 
medical interventions. 
The definition of DLT excludes the following conditions: 
• 
Grade 3 fatigue lasting ≤ 7 days 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with 
or without systemic corticosteroid therapy and/or hormone replacement therapy and the patient is 
asymptomatic 
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc) 
• 
Concurrent vitiligo or alopecia of any grade 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that 
resolves within 6 hours with appropriate clinical management 
• 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that improves by 
at least 1 grade within 3 days.  Grade 3 or 4 febrile neutropenia will be a DLT regardless of 
duration or reversibility 
• 
Grade 3 or 4 lymphopenia  
• 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that requires 
medical intervention, and improves by at least 1 grade within 3 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. 
Note that the DLT evaluation period does not include the 7 day run in of mocetinostat. 
6.1.2 Dose Escalation Plan 
The first cohort of patients to be enrolled will begin with the mocetinostat 7-Day Lead-In Period, receiving 
50 mg on 3 days (e.g., Monday, Wednesday and Friday) and will continue into the combination regimen, 
with 50 mg mocetinostat administered TIW and 1500 mg durvalumab administered Q4W. 
For a patient within a dose cohort to be considered evaluable for the dose-escalation decision, the patient 
must have either been on study for 1 full cycle and have received treatment with durvalumab and at least 
9 of 12 scheduled mocetinostat doses (75%) in Cycle 1 or have experienced a DLT in Cycle 1. 
Decision making rules for cohort expansion and dose escalation or de-escalation based on the 
experience of patients treat at a dose level are presented in Appendix 3. 
To ensure sufficient patient experience at the dose selected as the RP2D, enrollment at any dose level 
under consideration may be expanded to include at least 6 patients. 
6.1.3 Definition of Maximum Tolerated Dose 
The maximum tolerated dose (MTD) is defined as the highest mocetinostat dose administered in the 
combination regimen associated with the decision to “stay with the current dose” as determined from the 
Dose-Finding Spreadsheet (Appendix 3) using the experience of at least 6 patients during the first 28-day 
treatment cycle. 
6.1.4 Definition of Recommended Phase 2 Dose 
The RP2D will be the highest dose of mocetinostat evaluated that is associated with: 


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• 
Sufficient safety/tolerability to anticipate that patients will typically be able to receive treatment 
with at least 75% of the intended dose intensity of mocetinostat and 100% dose intensity of 
durvalumab; and 
• 
No observed ≥ Grade 3 or serious irAEs causally related to the combination regimen. 
A dose level below the MTD may be selected as the RP2D. 
6.2 Phase 2 Portion of the Study 
The Phase 2 portion of the study will enroll patients with NSCLC into one of the following 4 population 
cohorts: 
• 
Cohort 1 – Patients naïve to treatment with immunotherapy, having tumor with no/low PD-L1 
expression 
• 
Cohort 2 – Patients naïve to treatment with immunotherapy, having tumor with high PD-L1 
expression 
• 
Cohort 3 – Patients previously treated with an anti-PD-L1 or anti-programmed cell death 1 (PD-1) 
agent with clinical benefit response followed by progression of disease 
• 
Cohort 4 – Patients previously treated with an anti-PD-L1 or anti-PD-1 agent with progression of 
disease ≤ 16 weeks after initiation of treatment. 
Tumor PD-L1 expression will be determined by the PD-L1 (SP263) CDx assay. No/low PD-L1 expression 
is defined as positivity <25% of tumor cells; high PD-L1 expression is defined as positivity ≥25% of tumor 
cells. Tumor samples used to establish PD-L1 expression for eligibility must have been collected after the 
most recent systemic therapy. 
The sample sizes for the populations to be enrolled in the Phase 2 portion of the study are based on 
Predictive Probability Design, which allows for flexibility in the number of patients to be included at each 
stage in order to ensure that sufficient number of evaluable patients are available for decision to continue 
or to stop enrollment of additional patients.  
• 
 Cohorts 1, 3 and 4:  Stage 1 of enrollment will include a minimum of 9 evaluable patients.  With 
exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional 
evaluable patients will be enrolled, for a total sample size of 17 evaluable patients.  If at least 3 
objective responses are observed, further investigation may be warranted.   
• 
Cohort 2:  Stage 1 of enrollment will include approximately 17 evaluable patients. With exactly 17 
evaluable patients at Stage 1, if at least 5 patients have Objective Responses, 27 additional 
evaluable patients will be enrolled, for a total sample size of 44 evaluable patients.  If at least 18 
Objective Responses are observed, further investigation may be warranted.   
The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, 
once the exact number of patients evaluable at Stage 1 is known. The aim is to get a minimum of 9 
evaluable patients at Stage 1 for cohorts 1, 3 and 4 and about 17 evaluable patients at Stage 1 for cohort 
2. 
The populations included in Cohorts 3 and 4, who have had disease progression during treatment with a 
checkpoint inhibitor, represent a potential unmet medical need. For this reason, if results in Stage 2 of 
enrollment are of high interest, enrollment may be expanded to as many as 100 patients total in each 
cohort to narrow the 95% confidence interval (CI) around the ORR point estimate and more fully 
characterize the secondary endpoints in the population of interest. 
In order to be part of the clinical activity evaluable population, the patient must have at least one on-study 
disease assessment or discontinue from treatment for PD prior to this assessment.  Patients who 


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discontinue treatment prior to the first on-study disease assessment for an AE, toxicity, or withdraw 
consent are considered non-evaluable for disease assessment. These patients will not be part of the 
clinical activity evaluable population.  
 
Disease response and progression as documented by the investigator in the CRF will be the basis for 
patient management and study expansion decision making. Unconfirmed objective responses recorded in 
the CRF may be used as an initial basis for expansion of study enrollment; however, follow-up 
evaluations on patients with unconfirmed responses must continue to support the decision to continue to 
the full number of patients to be included in the next stage. Central radiology review for disease response 
and progression may be added to the study during Stage 2.  If this occurs, central review of all radiologic 
assessments performed in the study will be expected (including retrospective review of patients enrolled 
in Stage 1), and central radiology review for disease response will be the basis for the primary statistical 
analyses to estimate the ORR and its confidence interval, as well as the DR and PFS. 
Study treatment will continue until disease progression, unacceptable AEs, patient refusal, or death. 
6.3 Sample Size Considerations 
6.3.1 Phase 1 
Approximately 24 patients may be enrolled into the Phase 1 portion of the study. A precise sample size 
cannot be defined, as it is dependent on the number of dose escalations based on the mTPI method. 
The mTPI method (Ji 2013) will be employed in decision making concerning dose escalation within each 
regimen investigated.  The assumptions to be applied in establishing the mTPI methodology are: 
• 
Each specific regimen exploration will include up to 30 patients 
• 
The MTD is defined to have 0.25 probability of toxicity; and 
• 
The acceptable variance around the MTD is ± 0.05 (i.e., the region of the MTD is 20% to 30% 
incidence of DLT). 
6.3.2 Phase 2 
Up to 261 patients may be enrolled into the Phase 2 portion of the study. 
The 4-cohort Phase 2 portion uses sample sizes based on Predictive Probability Design (Lee-2008).   
ORR in accordance with RECIST 1.1 is the primary clinical benefit endpoint.  In creating the statistical 
designs, the Type 1 error (α) is constrained to <0.05 and Power (1-β) is constrained to ≥0.90.   
6.3.3 Statistical Design Applied to Phase 2 Cohorts 1, 3 and 4 
The ORR using a PD-L1 inhibitor in the population with advanced NSCLC having no or low PD-L1 
expression, or prior disease progression on a checkpoint inhibitor, is assumed to be 5% (p0); thus this 
rate is considered uninteresting.  The target ORR using mocetinostat in combination with durvalumab in 
this study is 30% (p1).  Stage 1 of enrollment will include a minimum of 9 evaluable patients per cohort.  
With exactly 9 evaluable patients at Stage 1, if at least 1 patient has an Objective Response, 8 additional 
evaluable patients will be enrolled, for a total sample size of 17 evaluable patients.  If at least 3 Objective 
Responses are observed, further investigation may be warranted.    If the true ORR is 5% (null 
hypothesis), the probability of early termination during the study is 0.63; the Type 1 error is equal to 
0.0466 and the power is equal to 0.9045. 


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6.3.4 Statistical Design Applied to Phase 2 Cohort 2 
The ORR using a PD-L1 inhibitor in the population with advanced NSCLC having high PD-L1 expression 
is assumed to be 27% (p0); thus this rate is considered uninteresting.  The target ORR using mocetinostat 
in combination with durvalumab in this study is 50% (p1). Stage 1 of enrollment will include approximately 
17 evaluable patients. With exactly 17 evaluable patients at Stage 1, if at least 5 patients have Objective 
Responses, 27 additional evaluable patients will be enrolled, for a total sample size of 44 evaluable 
patients.  If at least 18 Objective Responses are observed, further investigation may be warranted.  If the 
true ORR is 27% (null hypothesis), the probability of early termination during the study is 0.50; the Type 1 
error is equal to 0.0303 and the power is equal to 0.9018.   
The exact stopping rules for all cohorts will be calculated based on the Predictive Probability Design, 
once the exact number of patients evaluable at Stage 1 is known. The aim is to get about 9 evaluable 
patients at Stage 1 for cohorts 1, 3 and 4 and about 17 evaluable patients at Stage 1 for cohort 2. 
If Stage 2 results in Cohorts 3 and 4 are of high interest for efficacy (as decided by the sponsor), 
enrollment may be expanded to as many as 100 patients total in each cohort to narrow the 95% 
Confidence Interval (CI) around the ORR point estimate.   
6.4 Randomization 
There is no randomization for the study. 
7.0 Analysis Populations 
7.1 Enrolled Population 
The enrolled population is defined as all patients who sign an informed consent for the study. Disposition 
summaries will be displayed using the enrolled population. 
7.2 Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (mITT) population is defined as all patients who receive treatment with both 
mocetinostat and durvalumab on this study. 
7.3 Clinical Activity Evaluable Population 
In order to be considered eligible for the clinical activity evaluable population, the patient must have at 
least one on-study disease assessment or discontinue from treatment for PD.  Patients who discontinue 
treatment prior to the first on-study disease assessment for an AE, toxicity, or withdraw consent are 
considered non-evaluable for disease assessment and will not be part of the clinical activity evaluable 
population. 
 
This population will be used to present tumor responses as well as to make decision on the Predictive 
Probability design. 
7.4 Safety Population 
The safety population is defined as all patients who received at least 1 dose of either mocetinostat or 
durvalumab. The safety population will be used for all safety analyses. 


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7.5 DLT Evaluable Population 
For a patient to be considered evaluable for dose-escalation decisions, or “DLT-evaluable,” the patient 
must have either been on study for 1 full cycle and have received treatment with durvalumab and at least 
9 of 12 scheduled mocetinostat doses (75%) in Cycle 1 or have experienced a DLT in Cycle 1. 
Note that the DLT evaluation period does not include the 7 day run in of mocetinostat. 
7.6 Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients who receive at least one dose of 
mocetinostat or durvalumab for whom PD-L1 expression results are available. 
7.7 Pharmacokinetic Evaluable Population 
The pharmacokinetic evaluable population will consist of all patients who had sufficient concentration-time 
data to permit calculation of PK parameters for mocetinostat or durvalumab. For patients who were 
noncompliant with respect to administration of mocetinostat, or for patients with incomplete data, a 
decision as to their inclusion in the analysis will be made on a case-by-case basis. 
The PK analyses will be described in a PK analysis plan separate from this document. 
7.8 Pharmacodynamic Evaluable Population 
The pharmacodynamic evaluable population will consist of all patients who receive at least one dose of 
either mocetinostat or durvalumab for whom pharmacodynamic results are available. 
7.9 Anti-Drug Antibody Evaluable Population 
The ADA evaluable population will consist of all patients who receive at least one dose of either 
mocetinostat or durvalumab for whom ADA results are available. 
 
8.0 Endpoint Definitions 
8.1 Efficacy Variables 
Disease assessments involving radiographic evaluations may be performed over the course of a few 
days.  The date of response or progression (CR, PR, SD, PD or NE) will be recorded as the date of the 
last radiographic evaluation included in the series for that time point assessment.  For central review (if 
this is done), the date of response or progression will be determined using the Date of Assessment 
associated with the applicable Time Point Assessment provided by the central review vendor; for the 
investigator assessment, the date will be determined using the latest Date of Assessment recorded 
among the radiologic modalities included for the applicable Time Point Assessment. 
8.1.1 Objective Response Rate ORR) 
Objective disease response will be categorized in accordance with RECIST v1.1. ORR is defined as the 
proportion of patients documented to have a confirmed CR or PR. If central review of disease response is 
undertaken, ORR as reported by the central radiology review laboratory will be used to calculate ORR 
and the exact binomial 95% CIs.  ORR as reported by the investigator will be used in study expansion 
and decision making (PPD design).  
 


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8.1.2 Best Overall Response       
Best Overall Response is defined as the best response among all overall responses (in the order 
complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD] and not 
evaluable [NE]) recorded from the start of study treatment until disease progression/ recurrence or end of 
the treatment, whichever comes first. Per RECIST version 1.1, the status of best overall response of PR 
or CR must be confirmed by repeat tumor assessment within no less than 4 weeks. If the status of CR or 
PR cannot be confirmed by repeat tumor assessment, the best overall response of unconfirmed CR and 
PR will be recorded as SD and NE. The status of best overall response of SD requires an on-study 
assessment after at least 35 days on treatment. 
8.1.3 Clinical Benefit Rate (CBR)  
CBR response will be categorized in accordance with RECIST v1.1. CBR is defined as the proportion of 
patients documented to have a confirmed CR or PR or SD documented during at least 2 on-study 
assessments and including at least 14 weeks on study (e.g., allowance for 2-week window around Week 
17 assessment).  
8.1.4 Duration of Response (DR) 
DR is defined as the time in days from date of the first documentation of objective response (CR or PR) to 
the first documentation of objective progression of disease (PD) or to death due to any cause in the 
absence of documented PD (i.e., min [PD date, death date] – date of the first observation of response 
+1).  Duration of response will only be calculated for the subgroup of patient achieving a Best Overall 
Response of CR or PR and will be presented for responses assessed by both central review and 
investigator’s assessment. 
Censoring rules will be applied to DR: 
• 
Event time will be censored on the date of the last evaluable assessment documenting 
response for: 
• 
Patients on-study and progression-free at the time of an analysis; 
• 
Patients who have PD or death on study after ≥2 consecutive missed tumor 
assessments (i.e., >12 weeks + 14 days after the last on-study disease assessment);  
• 
Patients given alternative cancer treatment prior to PD or death on-study.   
• 
Patients who die on-study after ≥2 consecutive missed tumor assessments (i.e., >12 
weeks + 14 days after the last on-study disease assessment) will have their event time censored 
on the date of the last evaluable assessment documenting response. 
8.1.5 Overall Survival (OS) 
OS is defined as the time from first dose of study drug to the date of death due to any cause.  OS (in 
months) is calculated as (date of death − date of first dose of study drug +1)/30.4.  For patients who are 
continuing study at the time of an analysis, lost to follow-up or who withdraw consent, the OS endpoint 
will be censored on the last date that patients were known to be alive.  The date last known to be alive is 
derived from the CRF and may include the latest Visit date for patients on-going study or the latest Date 
of Contact on the Long-Term Follow-Up/Survival Status page, whichever occurs latest. For patients with 
no follow-up after first dose of study drug, OS will be censored at the date of first dose.   
8.1.6 Progression-Free Survival (PFS) 
PFS is defined as the time from the first dose of study drug to the date of PD or death due to any cause, 
whichever occurs first. PFS (in months) will be calculated as (first event date – first dose date +1)/30.4.  
Censoring rules will be applied to PFS:   


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• 
Patients lacking evaluation of disease after first study treatment will have their PFS time 
censored on the date of first dose with duration of 1 day unless they die within 2 tumor 
assessments of baseline, then they will be treated as an event with date of death as the event 
date.  
• 
Patients with baseline or post-baseline assessments inadequate to apply RECIST criteria 
will have their event time censored on the date of the first dose of study drug. 
• 
Event time will be censored on the date of the last evaluable assessment documenting 
absence of PD for: 
• 
Patients on-study and progression-free at the time of an analysis; 
• 
Patients who have PD or death on study after ≥2 consecutive missed tumor 
assessments (i.e., >12 weeks + 14 days after the last on-study disease assessment);  
• 
Patients given alternative cancer treatment prior to PD or death on-study.   
• 
Patients who die on-study after ≥2 consecutive missed tumor assessments (i.e., >12 
weeks + 14 days after the last on-study disease assessment) will have their event time censored 
on the date of the last evaluable assessment documenting absence of PD. 
8.2 Study Drug Exposure Variables   
Study Treatment Duration 
Study treatment duration (days) is defined as (the last dose date – the first dose date +1) for mocetinostat 
and as (the last dose date – the first dose date +29) for durvalumab. 
Days on Study Drug 
Days on study drug is defined as the total number of days patient received drug, after subtracting time for 
interruptions or drug missed, that is, the latest Stop Date - the earliest Start Date captured on the Study 
Drug Administration CRF page – number of days with 0 mg dose +1 for mocetinostat and the latest Stop 
Date - the earliest Start Date captured on the Study Drug Administration CRF page – number of days with 
0 mg dose +29 for durvalumab. 
Cumulative Dose Received 
For durvalumab, cumulative dose received (mg) is defined as the total amount of durvalumab a patient 
receives during the study, that is, the sum of dose administered as recorded on the Durvalumab 
Administration CRF form where dose administered equals 1500 when the planned dose was 
administered and is equal to the result of “If No, Dose Other Specify” question if the planned dose was 
not administered. 
For mocetinostat, cumulative dose received (mg) is defined as the total amount of mocetinostat a patient 
receives during the study, that is, Sum of [(Stop date – Start date + 1) * Dose administered * Number of 
doses during this period of time] as recorded on the Mocetinostat Administration CRF form. 
Cycles Started 
A patient is considered to have started a cycle if they received at least one dose in that cycle, per the 
Study Drug Administration CRF page. 
Dose Intensity  
Absolute Dose intensity (mg/day) is calculated as cumulative dose received (mg) / Treatment duration 
(days). 
Relative dose intensity is calculated as the cumulative dose received (mg) / initial planned cumulative 
dose (mg). Initial planned cumulative dose is calculated as the starting dose (day 1 cycle 1) multiplied by 
the study treatment duration. 


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Compliance is calculated as cumulative dose received (mg) / cumulative planned dose (mg, including 
dose decreased and interruptions as per physician’s decision).   
 
8.3 Safety Variables 
Adverse events and laboratory values will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.   
8.3.1 Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 15.1 or higher). 
 
Baseline Signs and Symptoms     
• 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present on Day 1 of 
study drug dosing are recorded in the CRF as non-treatment emergent AEs, with actual start 
date, which will most often predate first dose.  Baseline signs and symptoms will be reported 
separately from TEAEs. 
 
Treatment-Emergent AEs (TEAEs)     
• 
TEAEs are AEs that begin on Day 1 of study treatment or later during the on-study period.  
Baseline signs and symptoms that change attribution or severity during the on-study period are 
TEAEs. Any ongoing TEAEs that changes in attribution or severity is captured as a new AE.  
 
Adverse Events of Special Interest (AESI) 
AEs of special interest (AESI) for durvalumab based on observed safety event during durvalumab 
monotherapy and/or class effects for inhibitors of PD-L1 or PD-1 include: 
• 
Colitis 
• 
Pneumonitis 
• 
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increases / hepatitis / 
hepatotoxicity 
• 
Neuropathy / neuromuscular toxicity (i.e., events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e., events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• 
Dermatitis 
• 
Nephritis 
• 
Pancreatitis (or labs suggestive of pancreatitis – increased serum lipase, increased serum 
amylase). 
 
Immune-related Adverse Event (irAE) 
An irAE is defined as an AE that is associated with drug exposure and is consistent with an immune-
mediated mechanism of action and where there is no clear alternate aetiology.   
8.3.2  Vital Signs 
Vital signs: systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature, 
height and weight.    
 


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8.3.3 Clinical Laboratory Assessments 
Clinical laboratory parameters to be collected routinely on-study are listed in Table 3 below.   
 
                             Table 3: Laboratory Safety Parameters 
 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet count 
Aspartate aminotransferase (AST) 
White blood cell count (WBC) 
Alkaline phosphatase 
Neutrophil count 
Lactate dehydrogenase (LDH) 
Lymphocyte count 
Total bilirubin (if Total bilirubin is ≥2xULN and no 
evidence of Gilbert’s syndrome, then fractionate into 
direct and indirect bilirubin) 
Basophil count 
Gamma glutamyltransferase Screening, Day 1, and as 
clinically indicated 
Monocyte count 
Lipase 
Eosinophil count 
Amylase 
 
Creatinine 
Coagulation 
Blood urea nitrogen (BUN) or urea, depending on 
local practice 
International normalized ratio (INR) 
Uric acid 
Prothrombin time (PT) 
Total protein 
Partial thromboplastin time (PTT) 
Glucose (non-fasted) 
 
Albumin 
Urinalysis (dip stick) 
Calcium 
Blood 
Sodium 
Glucose 
Potassium 
Protein 
Chloride 
 
Magnesium 
Thyroid Function Test 
Bicarbonate [CO2] 
Thyroid-stimulating hormone (TSH) 
 
Free-T3 (if TSH abnormal) 
 
Free-T4 (if TSH abnormal) 
 
 
8.3.4 Electrocardiograms and echocardiograms 
12-Lead electrocardiogram (ECG): rhythm, heart rate, PR, QRS, QT, RR and QTcF, the QT 
interval corrected for heart rate by the Fridericia’s formula. Left ventricular ejection fraction (LVEF; 
%), pericardial effusion and hemodynamic compromise. 
8.3.5 Prior and Concomitant Medications 
Medications administered to study participants during the on-study period are captured on a log 
CRF page.  Prior medications are defined as any medications with start and stop dates prior to 
the date of first dose of study drug. Concomitant medications are defined as medications 
administered to study participants on or after the date of first dose of study drug.   
 
 


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9.0 Data Handling 
9.1 Missing Dates 
The following rules will be applied to impute missing start and stop dates in appropriate data 
types (e.g., adverse events or concomitant medications).  
Start Date 
 
If the start date is completely missing (i.e., the day, month, and year are all unknown) the start 
date will be set to the date of first dose of study medication. 
 
Missing Day Only  
• 
If the month and year of the incomplete date are the same as the month and year of the 
first dose date, then the day of the first dose date will be assigned to the missing day.  
• 
If either the year is before the year of the first dose date or if both years are the same 
but the month is before the month of the first dose date, then the last day of the month 
will be assigned to the missing day.  
• 
If either the year is after the year of the first dose date or if both years are the same but 
the month is after the month of the first dose date, then the first day of the month will be 
assigned to the missing day.  
 
Missing Month Only  
• 
The day will be treated as missing and both month and day will be replaced according to 
the below procedure.  
 
Missing Day and Month  
• 
If the year of the incomplete date is the same as the year of the first dose date, then the 
day and month of the first dose date will be assigned to the missing fields.  
• 
If the year of the incomplete date is before the year of the first dose date, then January 
1 will be assigned to the missing fields.  
• 
If the year of the incomplete date is after the year of the first dose date, then January 01 
will be assigned to the missing fields.  
 
If the stop date is complete and the imputed start date is after the stop date, then the start date 
will be imputed using the stop date.  
Stop Date 
 
Missing Day Only  
• 
If the month and year of the incomplete date are the same as the month and year of the 
last visit date, then the day of the last visit date will be assigned to the missing day.  
• 
If either the year is before the year of the last visit date or if both years are the same but 
the month is before the month of the last visit date, then the last day of the month will be 
assigned to the missing day.  
• 
If either the year is after the year of the last visit date or if both years are the same but 
the month is after the month of the last visit date, then the first day of the month will be 
assigned to the missing day.  
 
Missing Month Only  


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• 
The day will be treated as missing and both month and day will be replaced according to 
the below procedure.  
 
Missing Day and Month  
• 
If the year of the incomplete date is the same as the year of the last visit date, then the 
day and month of the last visit date will be assigned to the missing fields.  
• 
If the year of the incomplete date is before the year of the last visit date, then January 1 
will be assigned to the missing fields.  
• 
If the year of the incomplete date is after the year of the last visit date, then January 01 
will be assigned to the missing fields.  
9.2 Protocol Deviations 
 
Potential planned or unplanned protocol deviations noted during clinical monitoring will be documented by 
category (i.e., inclusion criteria, exclusion criteria, study drug, safety assessment, efficacy assessment, 
visit window, informed consent, prohibited medication, and other). All deviations will be reviewed, 
categorized, designated important or not important, and finalized prior to database lock. Important 
protocol deviations will be defined as those potentially impacting safety or efficacy assessments. 
Additional details of what will be considered important can be found in the Protocol Deviation Guidance 
document. 
9.3 Study Day 
Study day is defined relative to the date of the first dose of the study treatment. For assessments that 
occur after the first dose date, study day is calculated as (assessment date – the first dose date + 1). For 
assessments that occur prior to the first dose date, study day will be calculated as (assessment date – 
the first dose date); there is no Study Day 0. 
Study Treatment 
In this study, the study treatment refers to mocetinostat and/or durvalumab. 
10.0 Interim Analyses 
Tumor assessment is planned as per the Predictive Probability Design, after a first stage of enrollment, to 
decide whether or not a cohort should be stopped for lack of tumor response as detailed in Section 6.2. 
11.0 Data Review 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed data issues will 
be output into SAS logs identified by the word “Problem” and extracted from the logs by a SAS macro and 
sent to PRA Data Management. 
Review of a pre-freeze TFL run on clean patients and a post-freeze TFL run on the frozen database allow 
for further data screening prior to lock. The post-freeze TFLs will be discussed with the sponsor in a data 
review meeting to identify any final data issues and seek corrections prior to database lock. The PRA 
statistician and the sponsor must approve database lock. 
12.0 Statistical Methods 
All data collected during this study will be displayed in data listings, unless otherwise specified. Data 
listings will be sorted by dose level and patient identifier (regardless of phase) for safety listings and by 


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phase, dose level/cohort, and patient identifier for efficacy. Screen failures will be excluded from all tables 
and listings.  In addition, listings will include all relevant derived variables. 
Descriptive statistics (mean, median, standard deviations [STD], minimum and maximum values) for 
continuous variables will be presented. Mean and median will be presented to 1 decimal more than 
original data. STD will be presented to 2 decimals more than original data. Minimum and maximum will 
match the decimal points in the original data. For categorical variables, summary measures will include 
the frequency and percentage (with 1 decimal place) of patients in each category. 
The summary tables will be presented by dose level (both phases combined) for safety and by phase and 
dose level/cohort for efficacy. 
Unless otherwise noted, missing data will not be imputed or carried forward.  
All data summaries and tabulations will be prepared with SAS Version 9.4 or higher. 
12.1 Patient Disposition 
The number and percentage of patients enrolled and treated in the study will be presented, together with 
the number and percentage of patients who withdrew from the study prematurely and a breakdown of the 
corresponding reasons for withdrawal and the number and percentage of patients who discontinued 
mocetinostat and durvalumab with the corresponding reasons. will be reported by category for each 
phase and dose level/cohort, as well as overall within each phase. Additionally the number of patients in 
the mITT, Clinical activity evaluable, Safety, and DLT Evaluable populations will be presented. 
12.2 Important Protocol Deviations 
Important protocol deviations (see definition in Section 9.2) for patients in the Enrolled Population will be 
reported by category for each study arm. Important protocol deviations will be listed. 
12.3 Treatments 
12.3.1 Extent of Study Treatment Exposure 
Exposure to treatment will be summarized by dose level for the Safety population separately for 
mocetinostat and durvalumab.  Descriptive statistics will be provided for the duration of exposure (weeks), 
the total number of cycles started, number of doses received, cumulative dose received (mg) and dose 
intensity (mg/week). 
Number and percentage of patients with at least 1 dose reduced (only for mocetinostat), at least 1 dose 
interrupted and reasons for dose reduction and interruption will be presented separately for mocetinostat 
and durvalumab. 
Information regarding patients’ dosing regimens will be listed separately for mocetinostat and 
durvalumab.  
12.3.2 Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Enhanced (version: 
March 2016). 
Prior and concomitant medications will be tabulated separately for the Enrolled population by dose level 
Anatomical Therapeutic Chemical Classification and preferred drug name using counts and percentages. 
The number and percentage of patients using at least one medication within each dose level will also be 
displayed. See Section 8.3.5 for the definition of concomitant medications.  
Prior and concomitant medications will be included in a patient data listing. 


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12.4  Demographic and Baseline Characteristics 
Demographic and baseline data will be summarized descriptively by phase and by dose level/cohort and 
overall within each phase for the Safety population.  For continuous variables, descriptive statistics will 
include the mean, STD (or standard error), median, range, and interquartile range.  For categorical 
variables, descriptive statistics will include the number and percent.   
Demographic variables to be summarized include age (years), gender, reproductive status for female, 
ethnicity, race, weight (kg), height (m), smoking history and Eastern Cooperative Oncology Group 
(ECOG) status.  
Medical history will be tabulated by system organ class (SOC) and preferred term (PT) using counts and 
percentages for the Safety population.  
Primary Disease history will be tabulated for the Safety population and include the summary statistics 
(count and percentage) for Histology (Adenocarcinoma,  squamous Cell Carcinoma,  Large Cell 
Carcinoma and Other) and Current Stage (Locally Advanced, Metastatic). 
Prior Primary Disease Treatment (Systemic therapy, radiotherapy and surgery) will be tabulated for the 
Safety population and include the summary statistics (count and percentage) for the following: 
• 
Prior Systemic therapy - Platinum agent received (Cisplatin, Carboplatin, Other), Regimen 
(Neo-Adjuvant or Adjuvant, Advanced Disease Treatment Regimen, Other), Prior checkpoint 
inhibitor use (Nivolumab, Pembrolizumab, Durvalumab, Other) 
• 
Prior radiotherapy – Type (Adjuvant, Palliative)) 
• 
Prior surgery – Location (Lung, Liver, Lymph Node, Adrenal, Brain, Other)  
Demographic, medical history, primary disease history, and prior primary disease treatment data will be 
listed by patient. 
12.5  Efficacy Analyses 
12.5.1 ORR, Best Overall Response and CBR 
Descriptive statistics (frequency and percentage) for ORR, CBR and of best overall response (CR, PR, 
SD, PD) based on the Response Assessments by the Investigator and the exact 95% Clopper-Pearson 
confidence interval (SAS® PROC FREQ) of the response rate will be presented by phase and by dose 
level/cohort and overall within each phase. An exact test (SAS® PROC FREQ) for single proportion (two-
sided α=5%) will be performed to test H0: ORR ≤5% against H1: ORR >5% in cohorts 1, 3, and 4 and to 
test H0: ORR ≤27% against H1: ORR >27% in cohort 2, for phase 2 of the study. Patients who cannot be 
assessed for response will be counted as non-responders. Descriptive statistics (frequency and 
percentage) for CR and PR rate will be presented by phase, dose level/cohort, and overall within each 
phase. In addition, exact binomial 95% CIs for the percentage will be displayed for CR and PR rate, 
respectively. 
The primary analyses will be conducted in the clinical activity evaluable population. Supportive analyses 
will be presented in the mITT population. 
12.5.2 Time-to-event Variables 
Time-to-event variables, DR, PFS, and OS, will be summarized by phase and by dose level/cohort and 
overall within each phase, descriptively using the Kaplan-Meier estimate (SAS® PROC LIFETEST).  The 
median, 25th percentile, and 75th percentile of DR, PFS, and OS and their two sided 95% CIs using the 
complementary log-log transformation method (Collett, 1994) will be calculated where appropriate. In 
addition, minimum and maximum will also be displayed. Kaplan-Meier plots will be provided for DR, PFS, 
and OS.  


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DR, PFS, and CBR will be based on the Response Assessments by the Investigator.  DR will be 
conducted in both the clinical activity evaluable and mITT populations. PFS and OS will be conducted in 
the mITT population. 
12.5.3 ADA  
The proportion of patients with ADA detected in the blood at any point throughout the study as well as at 
each time point will be summarized using counts and percentages in the ADA Evaluable population by 
phase, dose level/cohort and overall within each phase. The titer for the confirmed positive ADA samples 
will also be reported. If enough observations in ADA positive and negative groups are observed, AEs and 
ORR ( per cohort and overall for phase 2 and overall for phase 1) will be evaluated per those subgroups. 
12.5.4 PD-L1  
For PD-L1 tumor expression, no/low PD-L1 expression is defined as positivity < 25% of tumor cells; high 
PD-L1 expression is defined as positivity ≥25% of tumor cells. The number of patients with no/low or high 
PD-L1 expression at baseline will be summarized using counts and percentages in the clinical activity 
evaluable and mITT populations by phase and dose level/cohort. ORR and OS (by phase) will be 
evaluated by those subgroups as well. 
 
 
 
12.6  Safety Analyses 
All safety analyses will be summarized by dose level, regardless of phase and all doses combined, by 
phase, in the Safety population. 
12.6.1 Adverse Events 
A summary of TEAEs, including the number and percentage of DLTs, number and percentage of patients 
reporting at least one TEAE, the number and percentage of patients reporting at least one CTCAE Grade 
3 or greater TEAE, the number and percentage of patients discontinuing due to a TEAE, the number and 
percentage of patients with at least one serious adverse event (SAE), number and percentage of patients 
with at least one SAE by CTCAE grade, number and percentage of patients with at least 1 mocetinostat 
related TEAE, number and percentage of patients with at least 1 durvalumab related TEAE, number and 
percentage of patients with at least 1 TEAE related to both durvalumab and mocetinostat, number and 
percentage of patients with at least 1 mocetinostat related SAE, number and percentage of patients with 
at least 1 durvalumab related SAE, number and percentage of patients with at least 1 SAE related to both 
durvalumab and mocetinostat, number and percentage of patients discontinuing mocetinostat due to a 
TEAE, number and percentage of patients discontinuing durvalumab due to a TEAE, number and 
percentage of patients discontinuing mocetinostat due to a TEAE related to mocetinostat, number and 
percentage of patients discontinuing durvalumab due to a TEAE related to durvalumab, and the number 
and percentage of deaths will be presented. TEAEs are those that first occur or increase in severity or 
relationship to study treatment after the first dose of study treatment and not more than 30 days after the 
last dose of study treatment. In reality, all adverse events that change in severity or relationship to study 
treatment are assigned a new start date and captured as a new record. All AEs will be coded according to 
the MedDRA Version 19.0 dictionary by SOC, PT, and severity grade using NCI CTCAE Version 4.03.   
A breakdown of the number and percentage of patients reporting each adverse event categorized by 
SOC and PT will be presented. Note that counting will be by patient not event and patients are only 
counted once within each SOC or PT. Similar summaries for CTCAE Grade ≥ 3 TEAEs, 
mocetinostat-related TEAEs, durvalumab-related TEAEs,  CTCAE Grade ≥ 3 mocetinostat-related 
TEAEs, and CTCAE Grade ≥ 3 durvalumab-related TEAEs will be presented. 


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A further summary of the number and percentage of patients reporting each adverse event in at least 
10% of patients will be categorized by PT in descending order of frequency. 
A summary of events reported categorized by maximum CTCAE grade will also be provided. Patients with 
multiple events within a particular SOC or PT will be counted under the category of their most severe 
event within that SOC or PT. Similar summaries for mocetinostat-related TEAEs and durvalumab-related 
TEAES will be presented. 
Separate summaries of adverse events leading to mocetinostat and durvalumab discontinuation will be 
provided, grouped by SOC and PT. Separate listings of patients who discontinue mocetinostat and 
durvalumab due to a TEAE will be presented. Further summaries of mocetinostat-related TEAEs leading 
to mocetinostat discontinuation and durvalumab-related TEAEs leading to durvalumab discontinuation will 
be provided. 
Pericardial adverse events will be categorized by PT in descending order of frequency. Patients with 
pericardial events will be listed. 
All AEs (including non-treatment-emergent events) recorded on the CRF will be listed. 
12.6.2 Deaths and Serious Adverse Events 
TEAEs that lead to death will be summarized by SOC and PT. A listing of patients who die will be 
presented. SAEs will be summarized by SOC and PT. A listing of patients who experience a SAE will also 
be presented. 
Separate summaries for SAEs related to mocetinostat and related to durvalumab grouped by SOC and 
PT will be presented. 
12.6.3 Laboratory Data 
All laboratory data will be summarized in International System (SI) units. The conversion factors from 
conventional to SI units will be documented in the Local Lab Conventions document for this study. In 
general, laboratory data will be presented by visit. Values at unscheduled visits will be included in the 
summary of maximum for all cycles and minimum for all cycles, which will present the largest and 
smallest values observed for each patient post-baseline for each test.  
Selected parameters will be presented in shift tables of baseline against worst grade test result. The shift 
from baseline to worst post baseline (including unscheduled visit) NCI CTCAE Version 4.03 grade will be 
presented by dosing group and overall for albumin (albumin increased), AST (AST increased), ALT (ALT 
increased), bilirubin (bilirubin increased), creatinine (creatinine increased), hemoglobin (anemia), 
neutrophils (neutrophil count decreased), platelets (platelet count decreased), sodium (hyponatremia and 
hypernatremia), potassium (hypokalemia and hyperkalemia), calcium (hypocalcemia and hypercalcemia), 
phosphate (hypophosphatemia), and uric acid (hyperuricemia). 
For sodium, potassium, and calcium, separate grading criteria exist depending whether the analyte is 
high or low.  For the purpose of shift tables, all low values will be included in the Grade 0 group in the shift 
tables for high values, and vice versa (all high values should be included in the Grade 0 group in the shift 
tables for low values. 
Subjects with at least 1 on-study measurement for each laboratory parameter will be included, regardless 
of whether or not a baseline assessment is present. 
Clinical laboratory results will be listed by subject. Laboratory values that meet Grade 3 or 4 criteria 
according to NCI CTCAE Version 4.03 will also be listed separately. 


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12.6.4 Hematology  
Hematology parameters include hemoglobin, platelet count, white blood cell (WBC) count, lymphocytes, 
monocytes, neutrophils, eosinophils, and basophils. The coagulation parameters include prothrombin 
time (PT), partial thromboplastin time (PTT) and international normalization ratio (INR).  
Descriptive statistics will be provided for each test result and for change from baseline by cycle. Multiple 
measurements taken during the visit for a patient will be represented by the most severe value for each 
hematology test. The most severe value will be determined first by the value closest to the upper or lower 
limit of the normal limits (dependent on which direction is considered severe) if the value is within the 
normal limits. If the value is outside the normal limits, the value furthest from the upper or lower limit will 
be selected (dependent on which direction is considered severe). In the event that this algorithm does not 
allow for determining the most severe (e.g., a tie, etc.) the first chronological value will be selected. Low 
values are considered the most severe for all hematology parameters. Shift tables tables (for hemoglobin 
(anemia), neutrophils (neutrophil count decreased), platelets (platelet count decreased)), summarizing the 
shift from baseline grade to each post-baseline visit, maximum post-baseline CTCAE grade including 
unscheduled visits, and last assessment on study will be presented. Patients who develop a ≥ Grade 3 
toxicity will be listed.  
12.6.5 Chemistry  
Serum chemistry parameters include ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), 
total bilirubin, direct bilirubin, indirect bilirubin, gamma glutamyl transferase (GGT), lipase, amylase, 
creatinine, uric acid, blood urea nitrogen (BUN), total protein, glucose (non-fasted), albumin, sodium, 
potassium, chloride, total calcium, magnesium, and bicarbonate.  
Descriptive statistics will be provided for each test result and for change from baseline by cycle. Multiple 
measurements taken during the visit for a patient will be represented by the most severe value as noted 
in Section 12.6.3. For all chemistry analytes, the most severe value is the highest value, with the 
exception of albumin, chloride, and bicarbonate. The most severe could be in either direction for glucose, 
potassium, sodium, and calcium. For these analytes, if within the normal limits, then the value closest to 
the normal limit (either direction) will be selected. If outside the normal limits, then the value most distant 
from the normal limit (either direction) will be used. Shift tables (for AST (AST increased), ALT (ALT 
increased), creatinine (creatinine increased), sodium (hyponatremia and hypernatremia), potassium 
(hypokalemia 
and 
hyperkalemia), 
calcium 
(hypocalcemia 
and 
hypercalcemia), 
phosphate 
(hypophosphatemia), and uric acid (hyperuricemia), summarizing the shift from baseline grade to each 
post-baseline visit, maximum post-baseline CTCAE grade including unscheduled visits, and last 
assessment on study will be presented. Patients who develop a ≥ Grade 3 toxicity will be listed.  
12.6.6 Urinalysis 
Urinalysis results for the parameters blood, protein, and glucose will be listed. 
12.6.7 Thyroid  
Results will be listed for thyroid-stimulating hormone (TSH), and if TSH is abnormal, then Free-T3 and 
Free-T4 will also be listed. 
12.6.8 CTCAE Coding of Laboratory Data 
Where laboratory values are categorized into NCI CTCAE v4.03 grades, the categories are defined 
according to the criteria available on the following website: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


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Note that grades are applied based only on the numeric SI value of the parameter assessed; clinical 
signs and symptoms are not considered. For example, Grade 4 hyperglycemia will be assigned based 
solely on the value of the glucose measurement, and acidosis will not be considered.  Where categories 
are only distinguished by clinical signs or symptoms, the lowest of the possible grades will be assigned. 
NCI CTCAE grades will be applied for the following lab parameters:  
• 
Hematology:  hemoglobin, white blood cell (WBC), lymphocyte, neutrophils, and platelets. 
• 
Chemistry:  ALT, albumin, Alkaline, phosphatase, AST, total bilirubin, calcium, creatinine, 
phosphate, magnesium, potassium, sodium, uric acid. 
Laboratory measurements that are within their institutional limits of normal and are not graded as 1-4, per 
the CTCAE, will be summarized as “Grade 0,” which is defined as normal.  
12.6.9 Vital Signs 
Clinically significant findings noted during screening will be reflected on the medical history CRF, while 
those noted during study treatment will be collected on the AE CRFs. The following vital signs will be 
summarized: pulse rate (beats/min), systolic blood pressure (SBP; mmHg), diastolic blood pressure 
(DBP; mmHg), body temperature (C), and weight (kg). Vital signs and change from baseline will be 
summarized in two ways. First, all vital signs and change from baseline through the last Cycle will be 
summarized. In these tables, baseline will generally be the Cycle 1 Day 1 measurement for all 
comparisons. This will include a summary of the maximum and minimum values observed while the 
patient was on treatment and change from baseline to that observed value 
All vital signs including baseline ECOG will be listed. 
12.6.10 Physical Examinations, ECGs, and Other Observations Related to Safety 
12.6.11 Physical Examination 
Complete physical examinations will be conducted during screening and at the End of Treatment visit. 
Abbreviated physical examinations will be performed on Day 1 of the 7-day Mocetinostat Lead-in Period, 
Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of the remaining cycles. Any new abnormal physical exam 
findings will be collected as AEs. Physical Examination data will be listed for the Safety population. 
12.6.12 Electrocardiogram 
A summary of ECG parameters including heart rate (beats/min), PR (msec), QRS (msec), QT interval 
(msec), QTcF (msec), and RR interval (msec) and change from baseline will be presented for each 
planned visit. A summary of change from baseline to worst grade for ICH E14 categories will also be 
presented. In addition, listings and summaries will be generated for patients with QTcF increased to value 
>480 and <500 msec, and value >500 msec, and patients with change-from-baseline QTcF increased by 
30 to <60 msec, and by >60 msec. 
A separate listing of the ECG results along with the overall interpretation will be presented. 
12.6.13 Echocardiogram  
A summary of the left ventricular ejection fraction (LVEF; %) and change from baseline will be presented 
for each planned visit. Additionally, the number of patients with pericardial effusion assessment along with 
the result of the assessment and the hemodynamic compromise will be summarized 
12.6.14 Pregnancy Test 
For patients of childbearing potential, a serum or urine pregnancy test will be performed at screening. 
Pregnancy tests will also be done whenever pregnancy is suspected during the study. Additional 
pregnancy testing may be necessary if required by local practices or regulations. Pregnancy testing data 
will be listed by dose level for the Safety population.  


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12.6.15 Long Term Follow-up 
Long term follow-up/survival data will be listed for the safety population. Additionally, all follow-up anti-
cancer therapy will be listed. 
13.0 Validation 
PRA seeks to ensure the quality of the results provided for the study in the form of TFLs, and the derived 
datasets used in their creation, through the following processes: 
The entire set of TFLs will be checked for completeness and consistency prior to its delivery to the client 
by the lead analysis programmer, the lead statistician, and a senior level statistician, or above, who is not 
a member of the project team. 
The PRA validation process will be repeated any time TFLs are redelivered using different data. 
Execution of this validation process will be documented through the study Table of Programs that will be 
provided to Mirati at study conclusion. 
14.0 References 
Collet, D. (1994), Modeling Survival Data in Medical Research, London: Chapman & Hall. 
Ji Y and Wang SJ. Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than 
the 3 + 3 Design For Practical Phase I Trials. J Clin Oncol, 31:1785-1791, 2013. 
 
 


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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GGT 
Gamma Glutamyl Transferase 
HDAC 
Histone Deacetylases 
irAE 
Immune-related Adverse Event 
INR 
Internal Normalization Ratio 
LDH 
Lactate Dehydrogenase 
LVEF 
Left Ventricular Ejection Fraction 
mITT 
Modified Intent-to-treat 
MTD 
Maximum Tolerated Dose 
mTPI 
Modified Toxicity Probability Interval 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 


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PD-1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death Ligand 1 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SLD 
Sum of Lonest Diameter 
SD 
Stable Disease 
SI 
International System 
SOC 
System Organ Class 
STD 
Standard Deviation 
TEAE 
Treatment-emergent Adverse Event 
TFL 
Tables, Figures, and Listings  
TSH 
Thyroid-stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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 Appendix 2 Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
The TFL shells for this study are provided in a separate document titled “Mirati 0103-020 SAP TLFs 
Shells Version 0.1.docm”. 


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Appendix 3 Dose-Finding Spreadsheet of the Modified Toxicity Probability Interval (mTPI) Method 
 


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Appendix 4 Programming Specifications for Baseline Characteristics 
and Safety Variables 
 
Patient Disposition 
• 
Enrolled Patients    
An enrolled patient is one with response to “Was the patient enrolled into the study?” on the 
Eligibility Criteria and Enrollment CRF page is Yes. 
• 
On Treatment  
A patient will be considered on treatment if he/she has had at least one dose of the study 
treatment and is not captured on either the End of Treatment Mocetinostat or the End of 
Treatment Durvalumab CRF pages.   
• 
Discontinued Treatment  
A patient will be considered to have discontinued mocetinostat or durvalumab if he/she is 
captured on the End of Treatment Mocetinostat or the End of Treatment Durvalumab CRF page, 
respectively.   
• 
In Long Term Follow Up 
A patient will be considered to be in long term follow up if the response to the question “Will the 
patient be followed for Follow-up?” on either the End of Treatment Mocetinostat or the End of 
Treatment Durvalumab CRF pages is “Yes.” 
• 
On Study   
A patient will be considered on study if the End of Study CRF page has NOT been completed 
indicating primary reason for ending study. 
• 
Discontinued Study 
A patient will be considered to have discontinued from the study when an End of Study CRF page 
is completed indicating primary reason for ending study. 
Age 
The following SAS® code will be used to calculate patient age (years): 
Age = floor ([intck{‘month’, birth date, Informed Consent Date} - {day(Informed Consent date) < day(birth 
date)}] / 12), where intck is a SAS® function counting integer days. If the day and month of a patient’s date 
of birth are not collected due to some countries’ Privacy Laws, age will be calculated using the year of 
informed consent/assent minus year of birth. 
Baseline, Change from Baseline 
Baseline is defined as the most recent measurement prior to the first dose of study treatment. 
Change from baseline is defined as (value at post baseline visit – value at baseline). 
Percent change from baseline is defined as [(value at post baseline visit – value at baseline) / value at 
baseline] * 100%. 
Postbaseline values for tabulations generally will exclude unscheduled visit values, but unscheduled visit 
values will be included in listings.  
QTcF 
QT corrected for heart rate by Fridericia's correction, i.e., QTcF = QT / RR1/3.