Clinical trial NCT02489448
Conditions: Breast Neoplasms
Keywords: Breast Cancer
Sponsor: Yale University
Start date: 2015-11-01; Completion date: 2021-08-02
Enrollment: 68 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to address the following hypotheses: (i) Anti-PD-L1 therapy with MEDI4736 administered concomitantly with weekly nab-paclitaxel followed by MEDI4736 concomitant with ddAC neoadjuvant chemotherapy will induce higher pathologic complete response (pCR) rate (\>55%) in triple negative breast cancer than historical pCR rates (30-40%) observed with chemotherapy alone. (ii) MEDI4736 can be safely co-administered at full dose with sequential with nab-paclitaxel (100mg/m2) and ddAC (60 mg/m2 and 600 mg/m2 respectively).

Detailed description:
The primary objective of the Phase I portion of the trial is to assess the safety of MEDI4736 combined with chemotherapy and determine if full dose of MEDI4736 can be administered concomitantly with full dose weekly nab-paclitaxel followed by dose-dense AC chemotherapies, respectively.

The primary objective of the Phase II portion of the study is to estimate the pCR rate with MEDI4736 in combination with weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 treatments for estrogen receptor (ER), progesterone receptor (PR) and HER2 negative (triple negative, TNBC), clinical stage I-III breast cancer. Pathologic complete response is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e. ypT0/Tis ypN0).

Secondary objectives include: to assess the safety and toxicity of adding anti-PD-L1 antibody, MEDI4736 to standard of care neoadjuvant chemotherapy in the Phase II portion of the trial. The study will also monitor for events of special clinical interest with a suspected auto-immunologic etiology including grade ≥3 colitis, hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash and anti-drug-antibody (ADA) immune complex disease (manifested by symptoms of arthralgias, abdominal pain, back pain, and vasculitis).

Exploratory objectives include: to assess correlation between response to therapy and immune parameters of the tumor at baseline and post-treatment in patients who have residual cancer after therapy.

Arms: arm 1: The investigational product is MEDI4736 which will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 mg/mL for intravenous (IV) administration.

Routine, standard of care chemotherapy will be given together with the investigational product and will include weekly nab-paclitaxel x12 treatments followed by every two-week doxorubicin, cyclophosphamide (ddAC) x 4 treatments.
Interventions: intervention 1: MEDI4736
Intervention descriptions: intervention 1: The investigational product is MEDI4736 which will be supplied in glass vials containing 500 mg of liquid solution at a concentration of 50 mg/mL for intravenous (IV) administration.

Routine, standard of care chemotherapy will be given together with the investigational product and will include weekly nab-paclitaxel x12 treatments followed by every two-week doxorubicin, cyclophosphamide (ddAC) x 4 treatments.

Protocol documents:
Prot_000.pdf: 
NCT02489448 Neoadjuvant MEDI4736 Concomitant With Weekly Nab-paclitaxel and Dose-dense AC 
for Stage I-III Triple Negative Breast Cancer 
Protocol 
Date: 2/26/2021 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 1 of 117 
 
 
Investigational Drug 
Substance(s) 
MEDI4736 
Study Number 
ESR-14-10265 / Yale HIC 1409014537 
Version Number 
15 
Date 
05-Jun-2020  
Single arm neoadjuvant Phase I/II study of MEDI4736 (anti-PD-L1 antibody) 
concomitant with weekly nab-paclitaxel and dose dense doxorubicin/cyclophosphamide 
(AC) chemotherapy for clinical stage I-III triple negative breast cancer 
Principal Investigator:   
Lajos Pusztai, MD, D.Phil. 
Chief of Breast Medical Oncology 
Co-Director of the Yale Cancer Center Genetics and Genomics Program 
Yale School of Medicine 
300 George Street, Suite 120, Room 133, New Haven, CT  06511 
Tel: 203-737-8309, Fax: 203-785-5792 
Assistant:  Laurene Goode-Gade (59T59T59TLaurene.goode-gade@yale.edu59T59T59T) 
Sponsor:  Yale Cancer Center 
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APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 2 of 117 
 
 
Protocol  
Date  
IRB 
IRB Approval 
Version 4 
25-Mar-15 
Initial Submission 
N/A – Pre-IRB 
Approval 
Version 5 
8-Jul-15 
Initial IRB Approval 
18-Aug-15 
Version 6 
16-Sep-15 
Amended in response to FDA clinical deficiencies 
N/A – Changes were 
included in version 8 & 
submitted to IRB 
Version 7 
17-Sep-15 
Amended in response to FDA clinical deficiencies 
N/A – Changes were 
included in version 8 & 
submitted to IRB 
Version 8 
17-Sep-15 
Protocol Amendment - FDA Revisions 
4-Nov-15 
Version 9 
12-Feb-16 
Protocol Amendment - Updated IB's 8 & 9 
6-Apr-16 
Version 
10 
6-Jun-16 
Protocol Amendment - Revised Treatment Plan 
22-Jul-16 
Version 11 
24-Jun-16 
Protocol Amendment - Accrual earlier cohort 
22-Jul-16 
Version 12  
19-Aug-16 
Protocol Amendment - Updated Toxicity Management 
7-Dec-16 
Version 13 
16-Jan-2018 
Protocol Amendment – Updated IB & Toxicity 
Management 
25-Apr-2018 
Version 
14 
06-Oct-
2018 
African American Extension Cohort 
26-Mar-2019 
Version 
15 
05-Jun-
2020 
Updated Toxicity Management 
 
 
PROTOCOL SYNOPSIS 
Clinical Protocol ESR-14-10265 
Study Title: Single arm neoadjuvant Phase I/II study of MEDI4736 (anti-PD-L1 antibody) 
concomitant with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide 
(ddAC) chemotherapy for clinical stage I-III triple negative breast cancer 
 
Protocol Number:  ESR-14-10265 
                                 Yale HIC # 1409014537 
 
Clinical Phase:  Single arm, Phase I-II 
 
Study Duration:  Accrual is estimated to take 24 to 38 months (2-3 patients/month) 
 
Investigational Product(s) and Reference Therapy: 
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APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 3 of 117 
 
 
The investigational product is MEDI4736 which will be supplied in glass vials containing 500 mg of 
liquid solution at a concentration of 50 mg/mL for intravenous (IV) administration. 
 
Routine, standard of care chemotherapy will be given together with the investigational product and will 
include weekly nab-paclitaxel x12 treatments followed by every two-week doxorubicin, 
cyclophosphamide (ddAC) x 4 treatments.  
   
Research Hypothesis: Our hypotheses are: (i) Anti-PD-L1 therapy with MEDI4736 administered 
concomitantly with weekly nab-paclitaxel followed by MEDI4736 concomitant with ddAC neoadjuvant 
chemotherapy will induce higher pathologic complete response (pCR) rate (>55%) in triple negative 
breast cancer than historical pCR rates (30-40%) observed with chemotherapy alone. (ii) We also 
hypothesize that MEDI4736 can be safely co-administered at full dose with sequential with nab-
paclitaxel (100mg/m2) and ddAC (60 mg/m2 and 600 mg/m2 respectively) 
Objectives: 
Primary Objectives:  
The primary objective of the Phase I portion of the trial is to assess the safety of MEDI4736 combined 
with chemotherapy and determine if full dose of MEDI4736 can be administered concomitantly with 
full dose weekly nab-paclitaxel followed by dose-dense AC chemotherapies, respectively.   
The primary objective of the Phase II portion of the study is to estimate the pCR rate with MEDI4736 
in combination with weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in combination 
with ddAC x 4 treatments for estrogen receptor (ER), progesterone receptor (PR) and HER2 negative 
(triple negative, TNBC), clinical stage I-III breast cancer. Pathologic complete response is defined as 
the absence of residual invasive cancer on hematoxylin and eosin evaluation of the resected breast 
specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e. ypT0/Tis ypN0).  
Secondary Objectives:  
To assess the safety and toxicity of adding anti-PD-L1 antibody, MEDI4736 to standard of care 
neoadjuvant chemotherapy in the Phase II portion of the trial. Safety will be assessed by using 
Common Terminology Criteria for Adverse Events, Version 4.3. We will also monitor for events of 
special clinical interest with a suspected auto-immunologic etiology including grade ≥3 colitis, 
hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash and anti-drug-antibody (ADA) 
immune complex disease (manifested by symptoms of arthralgias, abdominal pain, back pain, and 
vasculitis). For patients included in the Phase II portion of the trial, toxicity will be reported separately 
for acute toxicities observed on-therapy and for delayed toxicities observed during a 90-day follow up 
period after completion of therapy. Acute toxicities will also be reported separately for the combination 
with nab-paclitaxel and dose dense AC parts of the treatment. 
 
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APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 4 of 117 
 
 
To assess the safety and toxicity of adding anti-PD-L1 antibody, MEDI4736 to standard of care 
neoadjuvant chemotherapy in the Phase II portion of the trial. Safety will be assessed by using 
Common Terminology Criteria for Adverse Events, Version 4.3. We will also monitor for events of 
special clinical interest with a suspected auto-immunologic etiology including grade ≥3 colitis, 
hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash and anti-drug-antibody (ADA) 
immune complex disease (manifested by symptoms of arthralgias, abdominal pain, back pain, and 
vasculitis). For patients included in the Phase II portion of the trial, toxicity will be reported separately 
for acute toxicities observed on-therapy and for delayed toxicities observed during a 90-day follow up 
period after completion of therapy. Acute toxicities will also be reported separately for the combination 
with nab-paclitaxel and dose dense AC parts of the treatment. 
 
Exploratory Objectives: 
To assess correlation between response to therapy and immune parameters of the tumor at baseline and 
post-treatment in patients who have residual cancer after therapy. Tissues and blood will also be stored 
for future studies.  
Study Design: 
The study will have an initial lead in safety portion that follows a 3+3 Phase I trial design. The 
subsequent efficacy assessment portion will follow a Simon’s two stage Phase II trial design. 
Number of Centers: single center (with option to extend if independent funding from Celgene, Inc 
becomes available to support the conduct and monitoring of a multicenter trial through CRITERIUM 
CRO.) 
Number of Subjects: Minimum 24 and maximum of 71 patients. 
Study Population: 
Stage I-III, triple negative breast cancer defined as ER and PR<1% positive and HER2 
negative (by FISH or IHC 1+ or 2+) for whom systemic chemotherapy is indicated.  
Inclusion Criteria:  
1. Newly diagnosed histologically confirmed stage I-III, ER, PR and HER2 negative invasive 
breast cancer as defined by the ASCO CAP guidelines for whom systemic chemotherapy 
would be indicated based on physician judgment following standard NCCN practice 
guidelines. 
2. Willing and able to provide written informed consent for voluntary participation in the trial. 
3. Willing to undergo a baseline tumor core needle biopsy and blood draws for correlative 
science studies. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 5 of 117 
 
 
4. Eighteen years of age or older on the day of signing informed consent.  
5. Female subjects must either be of non-reproductive potential or must have a negative urine 
or serum pregnancy test upon study entry. 
6. Patients should have adequate organ function to tolerate chemotherapy, as defined by: 
- 
peripheral granulocyte count of > 1,500/mm3  
- 
platelet count > 100,000/mm3 
- 
hemoglobin >9 g/dL 
- 
total bilirubin < 1.5 x upper limit of normal (ULN) 
- 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) each < 1.5 x 
ULN  
- 
serum creatinine < 1.5 x ULN or serum creatinine clearance > 50mL/min 
- 
INR/PT/PTT each < 1.5 x ULN 
-   TSH within normal limits 
 
Exclusion Criteria:  
Patients must not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Patients who underwent partial excisional biopsy or lumpectomy, segmental mastectomy 
or modified radical mastectomy or sentinel node. 
 
2. 
Patients for whom anthracycline, paclitaxel or antibody therapies are contraindicated 
 
3. 
Patients with active autoimmune disease or documented autoimmune disease within 2 
years. Patients with hypothyroidism that is clinically stable and have normal TSH levels 
with hormone replacement, or patients with vitiligo or psoriasis not requiring treatment 
remain eligible for the study. 
 
4. 
Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative 
colitis)  
 
5. 
Patients with known active hepatitis B or C or HIV infection or with history of 
tuberculosis.  
 
6. 
Patients with a syndrome that requires administration of chronic systemic steroids or 
immunosuppressive agents. Patients who only require intermittent use of bronchodilators 
or local steroid injections are eligible.   
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 6 of 117 
 
 
 
7. 
Attenuated vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, 
and typhoid vaccine. 
 
8. 
Female patients who are pregnant, breast-feeding or male or female patients of  
        reproductive potential who are not employing effective methods of birth control for  
        at least 6 months after completion of the last dose of MEDI4736 and AC chemotherapy.   
 
9. 
Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736.  
10. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Bazett’s Correction. 
11. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of MEDI4736, 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. 
12. History of primary immunodeficiency. 
13. History of allogeneic organ transplant.  
14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric 
illness/social situations that would limit compliance with study requirements or 
compromise the ability of the subject to give written informed consent 
15. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
 
 
Investigational Product(s), Dose and Mode of Administration: 
MEDI4736, either 3 mg/kg or 10 mg/kg, IV infusion every 2 weeks over the entire study treatment 
period (20 weeks). 
 
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 7 of 117 
 
 
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
Toxicities will be assessed every two weeks before each administration of MEDI4736 by complete 
physical examination and complete review of systems as well as laboratory assessment. Grading of 
toxicities will be according to the NCI CTCAE v5.0.  
During the Phase I portion of the study dose limiting toxicities (DLT) will be considered during the 
entire 20 weeks of therapy for determination of the Maximum Tolerated Dose/Recommended Phase 2 
Dose. The last safety assessment will be 90 days after completion of neoadjuvant therapy. For 
definitions of DLT see section 6.4 
Efficacy Assessments: 
The primary efficacy endpoint of pCR will be assessed in the surgically resected cancer and lymph 
nodes after completion of all chemotherapy by the local pathologist as part of routine care. Pathologic 
complete response is defined as no invasive cancer in the resected breast tissue and lymph nodes 
(ypT0/Tis, ypN0). This information will be extracted from the pathology report and patients will be 
assigned to one of two response categories, pCR or residual disease (RD) for the purpose of primary 
efficacy analysis.  
Pharmacodynamic / Pharmacokinetic Assessments (if applicable):  
61T61T61TPK studies will not be performed. 
Statistical Methods and Data Analysis: 
61T61T61TThe Phase I portion of the trial will follow the 3+3 design. 
61T61T61TThe Phase II portion will follow Simon’s two-stage design. 
 
Efficacy Analysis 
All patients who received at least 12 weeks of therapy (i.e. 6 courses) with MEDI4736 at the 
recommended Phase II dose will be included in the primary efficacy analysis. A secondary, intent to 
treat, efficacy analysis will also be performed and will include all patients who received at last one 
dose of MEDI4736 at the recommended Phase II dose.  
Safety Analysis and Toxicity Reporting 
All patients who received at least one dose of MEDI4736 will be included in toxicity analysis. 
Toxicities will be graded according to NCI CTCAE v5.0.  
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 8 of 117 
 
 
During the Phase I portion of the study dose limiting toxicities (DLT) will be considered during the 
entire 20 weeks of therapy for determination of the Maximum Tolerated Dose/Recommended Phase 2 
Dose (MTD/RP2D). Definition of DLT/RP2D  
During the Phase II portion of the trial, cumulative toxicity results over the entire duration of therapy 
will be reported. Toxicity will also be reported separately for acute (on-treatment) and delayed (within 
90 days after completion of treatment) toxicities and acute toxicities will be reported separately for the 
combination of MEDI4736 with nab-paclitaxel and the combination of MEDI4736 with dose-dense 
AC.  
Toxicities will be reported as frequency statistics with 95% confidence intervals. 
Statistical Plan of Exploratory Biomarker Analysis 
The following immune parameters, in order of priority in case of limited tissue availability, will be 
assessed using quantitative immunohistochemistry in base line core needle biopsies: PD1 (programmed 
death receptor 1) and PD-L1 and -L2 (programmed death receptor ligands 1 and 2), CD3+, CD4+, 
CD8+, CD137, FOXP3, OX40, CTLA4 and GITR. Tumor infiltrating lymphocyte (TIL) count will be 
estimated from an H&E section and quantified as the percent of stromal cells that are lymphocytes. 
Multivariate associations of these immune markers as continuous variables and pCR as dichotomous 
variable will be evaluated with logistic regression using backward feature elimination (LR test <0.05). 
Clinical tumor size, clinical nodal status and age will also be included in the model. 
RNA expression profiling will also be performed on all base line core needle biopsy samples to assess 
associations between pCR and published immune gene signatures. The 6 immune gene signatures are 
metagenes corresponding to the average expression of sets of highly co-expressed genes.  These 
metagenes represent semi-quantitative estimates of distinct cell types including plasma cells (IGG 
metagene), T-cells (CD8A metagene) and antigen-presenting cells (MHC2 metagene) and also capture 
important immune regulatory pathways such as MHC1 gene expression (MHC1 metagene), STAT1 
co-expressed genes (STAT1 metagene) and interferon-inducible genes (IF-I metagene including IFNg) 
and chemokine signaling through CXCL9 and CXCL1. These metagenes were selected because they 
have been repeatedly observed in gene expression data, can be assessed reliably and carry prognostic 
value. Multivariate associations of these immune metagenes as continuous variables and pCR as 
dichotomous variable will be evaluated with logistic regression using backward feature elimination 
(LR test <0.05). Clinical tumor size, clinical nodal status and age will also be included in the model. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 9 of 117 
 
 
Whole exome DNA sequencing will also be performed to identify somatic mutations and other 
alterations that could be potential novel predictive markers of response. These will represent 
exploratory analysis. Sequencing will be performed at the Yale Center for Genome analysis with 
average depths of UUU> UUU150x. We will use the Fisher Exact test, which evaluates the significance for over-
representation of a specific genomic alteration in the pCR versus no-pCR groups, to assess potential 
association between functional variants in immune genes and response. Due to the sparsely of data at 
individual variant level, we will aggregate high functional impact variants at gene level and also at 
pathway level. 
 
Selected immune parameters will also be assessed in residual cancer specimens in cases with less than 
pCR to assess changes in the immune microenvironment in response to therapy using pair-wise t-test 
and Bonferroni adjustment of p-values for multiple testing. Correlation coefficients will also be 
calculated for immune parameters between baseline and residual disease samples.    
 
Sample Size Determination: Total sample size is a minimum of 24 and maximum of 71 patients 
including both Phase I and phase II portions and allowing for replacement of non-evaluable patients for 
efficacy at a 10 % loss rate. 
Phase I safety portion of the trial  
Two dose levels will be assessed including 3mg/kg and 10mg/kg MEDI4736 in combination with 
weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 
treatments.  
UUU3 mg/kg MEDI4736 dose level 
The first 3 patients will be enrolled at dose level of 3 mg/kg MEDI4736 concomitant with 
chemotherapy. Further accrual will be halted after the first 3 patients are enrolled until the DLT 
assessment is complete for a given treatment part of the two-part (weekly nab-paclitaxel x 12 + AC x 
4) chemotherapy regimen . If no patients experience a DLT during the weekly nab-paclitaxel treatment 
period (12 weeks), the next 3 patients will start weekly nab-paclitaxel at the next dose level, 10 mg/kg, 
while the previous cohort is still receiving AC chemotherapy (with MEDI4736 at 3 mg/kg). If 1 patient 
experiences DLT during either the nab-paclitaxel or AC parts of the therapy, 3 additional patients will 
be enrolled at the 3 mg/kg dose-level in combination with the chemotherapy part of interest. If none of 
these 3 additional patients experience DLT (i.e. the final observed DLT rate is 1 of 6), the dose is 
escalated to 10 mg/kg for the given chemotherapy part. If 2 or more patients experience DLT among 
the first 6 patients treated at the 3 mg/kg dose level, the study will be halted and dose de-escalation will 
be considered as an amendment to the trial after consultation with the sponsor. If 2 or more patients 
experience DLT among the first 3 patients treated at 3 mg/kg dose level, the study will also be halted 
and dose de-escalation will be considered as an amendment to the trial.  
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APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 10 of 117 
 
 
Using the above design, the probabilities of halting dose escalation, in each treatment part, for true 
rates of DLT ranging from 5% to 70% are as follows: 
True rate of DLT: 
 
 
5%   10%    20%    30%   40%   50%   60%   70%  
Probability of halting dose escalation: 
0.03  0.09   0.29     0.51    0.69   0.83    0.92   0.97 
UUU10 mg/kg MEDI4736 dose level 
If dose escalation is feasible, the next cohort of patients will receive MEDI4736 at 10 mg/kg dose 
concomitant with chemotherapy. Accrual will be halted after the first 3 patients are enrolled at the 10 
mg/kg dose until DLT assessment is complete for nab-paclitaxel (i.e. all 3 patients have completed 12 
weeks of nab-paclitaxel chemotherapy). If  only 1 patient experiences DLT after the first 3 patients are 
treated at this dose level, the study will proceed to enroll 3 additional patients at the 10 mg/kg dose 
level in combination with nab-paclitaxel. If none or only 1 of these additional 3 patients show DLT 
(final observed DLT 1 of 6), this dose level will be moved forward to the Phase II portion for efficacy 
assessment and accrual will start on the nab-paclitaxel part of treatment while patients are completing 
the AC part of their therapy. If 2 or more patients experience DLT among the first 6 patients treated at 
the 10 mg/kg dose level, the dose will be de-escalated to 3 mg/kg and this dose is designated as the 
RP2D for the subsequent Phase II portion of the trial. If 2 or more patients out of the first 3 experience 
DLT, the dose will be de-escalated to 3 mg/kg dose and this dose will be moved forward to the Phase 
II portion for efficacy assessment. DLT will be assessed similarly and the same expansion rules will be 
followed during the AC part of the treatment. 
Two-stage Phase II portion of the trial  
The interim efficacy and toxicity analyses will be performed after the first 22 patients evaluable for 
primary efficacy analysis. Patients will be considered evaluable for efficacy assessment if they 
received at least 12 weeks of MEDI4736 at the Recommended Phase 2 dose concomitant with 
chemotherapy.  Patients who received lower than the Recommended Phase 2 dose during the Phase I 
portion of the trial will not be included in the efficacy analysis. Patients who did not receive at least 12 
weeks (i.e. 6 courses) of MEDI4736 are also not eligible for efficacy analysis but will be included in 
the toxicity assessment. Trial accrual will continue while efficacy and toxicity data is accumulating for 
the 22 patients. 
The trial will terminate for lack of efficacy if < 7 patients out of the first 22 experience pCR (Alpha = 
beta = 10%, probability of early termination if the response rate is 30%=0.67). If > 7 patients 
experience pCR, accrual will continue until a maximum of 50 patients are accrued. 
Safety analysis: If > 2/22 patients experience DLT or a serious treatment related adverse event (SAE), 
the MEDI4736 dose schedule will be re-evaluated. If futility criteria is not met (i.e. >7/22 patients have 
pCR), the trial may reopen after the MEDI4736 dose and schedule is amended to improve safety.  With 
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 11 of 117 
 
 
22 patients in the first stage, there is > 90% chance of observing at least 1 DLT event, if the true 
underlying rate of the adverse event is > 10%.  
If the study proceeds to full accrual after the first interim analysis, the final efficacy analysis will be as 
follows: 
If >20 of 50 evaluable patients have pCR (i.e. at least 40% observed pCR rate) then the treatment will 
be considered successful and recommended for further study in a randomized trial. With 50 patients 
included in the efficacy analysis of the study, for the targeted pCR rate of 50% the corresponding 95% 
confidence interval ranges from 38% to 69%.  
African American extension cohort 
We will perform one additional efficacy analysis which includes assessing pCR rates in African 
America (AA) and non-AA patients separately in the Phase II portion of the trial. In order to make this 
exploratory analysis, we need at least N=20 AA patients accrued to the study. An AA only extension 
cohort will remain open until N=20 AA patients are accrued, this may extend the maximum sample 
size to a total of 71 (as of October 8, 2018; 10 AA patients have been accrued and the total accrual 
number is 50). Assuming that the baseline pCR=35% for AA patients with TNBC, a cohort of 20 AA 
patients will have a 76% power to detect an improvement in pCR from 35% to 65% based on the exact 
binomial test. This is a similar magnitude of improvement, a near doubling of pCR rate, as was 
observed when trastuzumab was added to paclitaxel/AC neoadjuvant chemotherapy in HER2 positive 
breast cancers. The comparison of pCR rates between the two racial cohorts will be performed as 
exploratory analysis. 
 
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Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 12 of 117 
 
 
SCHEDULE OF STUDY ASSESSMENTS 
Screening, Treatment Period and Post-treatment follow-up 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of a patient. 
Screening 
Treatment Period (Assessments to be performed pre-infusion unless stated otherwise) 
Baseline 
Every week 
Every 2 weeks 
Every 4 weeks Follow-up after completion of all 
neoadjuvant therapy 
Day 
-42 to -1  Day 1  
Day 1 of the week 
Week 
-6 to 1 
1 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12  1, 3, 5, 7, 9, 11, 13, 15, 
17, 19 
5, 9, 13, 17 
22, 26, 33 
 
 
Written informed 
consent/assignment of  
subject identification 
number 
X 
 
 
 
 
 
Preliminary eligibility 
assessment (investigator’s 
opinion) 
X 
 
 
 
 
 
Demographic information  
X 
 
 
 
 
 
Tumour biopsy and blood 
draw for research 
X* 
 
 
 
 
Research blood draw is repeated 
after week 20 but before surgery 
Formal verification of 
eligibility criteria 
X 
 
 
 
 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 13 of 117 
 
 
Screening, Treatment Period and Post-treatment follow-up 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of a patient. 
Screening 
Treatment Period (Assessments to be performed pre-infusion unless stated otherwise) 
Baseline 
Every week 
Every 2 weeks 
Every 4 weeks Follow-up after completion of all 
neoadjuvant therapy 
Day 
-42 to -1  Day 1  
Day 1 of the week 
Week 
-6 to 1 
1 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12  1, 3, 5, 7, 9, 11, 13, 15, 
17, 19 
5, 9, 13, 17 
22, 26, 33 
 
 
Medical and surgical 
history, review of systems 
 
X 
 
 
 
X 
 
Hepatitis B and C; HIV if 
clinically indicated 
X 
 
 
 
 
 
 
Urine hCG or serum 
βhCGPPPa 
X 
 
 
 
MEDI4736 administration 
 
X 
 
XPPPc,d  
 
 
 
Nab-paclitaxel 
administration 
 
X 
X 
 
 
 
 
ddAC administration 
 
 
 
Weeks 13,15,17,19  only  
 
 
Physical examination 
 
X 
 
X 
 
X 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 14 of 117 
 
 
Screening, Treatment Period and Post-treatment follow-up 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of a patient. 
Screening 
Treatment Period (Assessments to be performed pre-infusion unless stated otherwise) 
Baseline 
Every week 
Every 2 weeks 
Every 4 weeks Follow-up after completion of all 
neoadjuvant therapy 
Day 
-42 to -1  Day 1  
Day 1 of the week 
Week 
-6 to 1 
1 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12  1, 3, 5, 7, 9, 11, 13, 15, 
17, 19 
5, 9, 13, 17 
22, 26, 33 
 
 
Vital signs (pre- during 
and post-infusion vital 
signs assessments)PPPb 
 
X 
X 
X 
 
X 
 
Weight 
 
X 
X 
X 
 
X 
 
Electrocardiogram 
X 
 
Week 6 
Week 17 
 
 
 
Adverse event/serious 
adverse event assessment 
 
X 
Weeks 3, 5, 7,8, 9 and 11 
X 
 
X 
 
Concomitant medications 
 
X 
Weeks 3, 5, 7,8, 9 and 11 
X 
 
X 
 
ECOG performance status 
 
X 
Weeks 3, 5, 7,8, 9 and 11 
X 
Serum AST, ALT, T Bili 
XPPP,e 
 
 
 
X 
X 
 
TSH (free T3 and T4 if 
TSH is elevated) 
XPPP,e 
 
 
 
X  
 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date:  05-Jun-2020  
 
Page 15 of 117 
 
 
Screening, Treatment Period and Post-treatment follow-up 
 
Assessments to be 
performed at the times 
stipulated in the table and 
as clinically required in the 
management of a patient. 
Screening 
Treatment Period (Assessments to be performed pre-infusion unless stated otherwise) 
Baseline 
Every week 
Every 2 weeks 
Every 4 weeks Follow-up after completion of all 
neoadjuvant therapy 
Day 
-42 to -1  Day 1  
Day 1 of the week 
Week 
-6 to 1 
1 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12  1, 3, 5, 7, 9, 11, 13, 15, 
17, 19 
5, 9, 13, 17 
22, 26, 33 
 
 
CBC/Diff 
XPPP,e 
 
X 
X 
 
X 
 
PT, PTT, INR 
XPPP,e 
 
 
 
 
 
Urinalysis 
XPPP,e 
 
 
 
X 
 
 
a  Pre-menopausal female subjects of childbearing potential only 
b Subjects will have their temperature, blood pressure, pulse, and respiratory rate measured before, during and after the infusion as per hospital standard operating procedure. 
  
c MEDI4736 will be administered on the same day as nab-paclitaxel in weeks 1-12.  Nab-paclitaxel will be administered first.  
d dose dense doxorubicin plus cyclophosphamide will be administered on day 1 of Weeks 13, 15, 17, and 19.  MEDI4736 will be administered on day 2 of weeks 13, 15, 17, and 
19, approximately 24 hours after the administration of doxorubicin + cyclophosphamide immediately after subcutaneous administration of pegfilgrastrim, as outlined in Section 
5.3.2.   
e Laboratory test results that are considered abnormal, but continue to meet the eligibility requirements, during the screening phase will be repeated at baseline (C1D1). 
 
*Research tissue and blood can be drawn any time after consenting and before receiving the first treatment; this includes Day 1 before administration of therapy.  


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Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
Page 16 of 117 
 
 
TABLE OF CONTENTS 
PAGE 
SYNOPSIS ......................................................................................................... 1-10 
SCHEDULE OF ASSESSMENTS .................................................................. 11-15 
TABLE OF CONTENTS ....................................................................................... 16 
ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 21 
1. 
INTRODUCTION ................................................................................................. 25 
1.1 
Background ............................................................................................................ 25 
1.2 
MEDI4736 Background ......................................................................................... 25 
1.2.1 
Summary of non-clinical experience ..................................................................... 26 
1.2.2 
Summary of clinical experience ............................................................................. 26 
1.3 
Research hypothesis ............................................................................................... 29 
1.4 
Rationale for conducting this study ....................................................................... 29 
1.5 
Benefit/risk and ethical assessment........................................................................ 30 
2. 
STUDY OBJECTIVES .......................................................................................... 31 
2.1 
Primary objective(s) ............................................................................................... 31 
2.2 
Secondary objective(s) ........................................................................................... 31 
2.3 
Exploratory objective(s) ......................................................................................... 32 
3. 
STUDY DESIGN ................................................................................................... 33 
3.1 
Overview of study design ...................................................................................... 33 
3.2 
Study schema ......................................................................................................... 33 
3.3 
Study Oversight for Safety Evaluation .................................................................. 34 
4. 
SUBJECT SELECTION ........................................................................................ 34 
4.1 
Inclusion criteria .................................................................................................... 34 
4.2 
Exclusion criteria ................................................................................................... 35 
4.3 
Withdrawal of Patients from Study Treatment and/or Study ................................. 37 
4.4 
Replacement of patients ......................................................................................... 39 
5. 
INVESTIGATIONAL PRODUCT(S) ................................................................... 39 
5.1 
MEDI4736 ............................................................................................................. 39 
5.1.1 
Formulation/packaging/storage .............................................................................. 39 
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Page 17 of 117 
 
 
5.1.2 
Doses and treatment regimens ............................................................................... 40 
5.1.3 
Study drug preparation ........................................................................................... 40 
5.1.4 
Dose administration ............................................................................................... 40 
5.1.5 
Monitoring of dose administration ......................................................................... 41 
5.1.6 
Accountability and dispensation ............................................................................ 41 
5.1.7 
Disposition of unused investigational study drug .................................................. 42 
5.2 
Nab-paclitaxel ........................................................................................................ 42 
5.2.1 
Formulation/packaging/storage .............................................................................. 42 
5.2.2 
Doses and treatment regimens ............................................................................... 42 
5.2.3 
Product preparation ................................................................................................ 42 
5.2.4 
Dose administration ............................................................................................... 42 
5.2.5 
Monitoring of dose administration ......................................................................... 42 
5.2.6 
Accountability and dispensation ............................................................................ 43 
5.2.7 
Disposition of unused drug .................................................................................... 43 
5.3 
Doxorubicin combined with Cyclophosphamide (AC) ......................................... 43 
5.3.1 
Formulation/packaging/storage .............................................................................. 43 
5.3.2 
Doses and treatment regimens ............................................................................... 43 
5.3.3 
Product preparation ................................................................................................ 44 
5.3.4 
Dose administration ............................................................................................... 44 
5.3.5 
Monitoring of dose administration ......................................................................... 44 
5.3.6 
Accountability and dispensation ............................................................................ 44 
5.3.7 
Disposition of unused drug .................................................................................... 44 
6. 
TREATMENT PLAN ............................................................................................ 44 
6.1 
Subject enrollment ................................................................................................. 44 
6.2 
Dosage and Administration .................................................................................... 45 
6.3 
Dose Escalation Decision Rules ............................................................................ 45 
6.4 
Definition of DLT .................................................................................................. 47 
6.5 
Dose Modification and Toxicity Management ...................................................... 48 
6.5.1 
MEDI4736 ............................................................................................................. 48 
6.5.2 
Nab-paclitaxel .................................................................................................... 8179 
6.5.3 
Dose dense doxorubicin/cyclophosphamide (ddAC) ......................................... 8179 
6.5.4 
Toxicity management guidelines for combination treatment regimen .............. 8179 
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) .............................................................................................. 8280 
7.1 
Restrictions during the study ............................................................................. 8280 
7.2 
Concomitant treatment(s) ................................................................................... 8381 
7.2.1 
Permitted concomitant medications ................................................................... 8381 
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Page 18 of 117 
 
 
7.2.2 
Excluded Concomitant Medications .................................................................. 8381 
8. 
STUDY PROCEDURES ................................................................................... 8381 
8.1 
Schedule of study procedures ............................................................................ 8381 
8.1.1 
Screening Phase ................................................................................................. 8482 
8.1.2 
Treatment Phase ................................................................................................. 8583 
8.1.3 
End of Treatment ............................................................................................... 8785 
8.2 
Description of study procedures ........................................................................ 8785 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and 
vital signs ........................................................................................................... 8785 
8.2.2 
Clinical laboratory tests ..................................................................................... 8886 
8.3 
Biological sampling procedures ......................................................................... 8987 
8.3.1 
Fresh tumor biopsies before starting therapy ..................................................... 9088 
8.3.1.1 
Tumor tissue from surgical resection ................................................................. 9088 
8.3.2 
Withdrawal of informed consent for donated biological samples ..................... 9088 
9. 
DISEASE EVALUATION AND METHODS .................................................. 9189 
9.1.1 
Pathologic Complete Response (pCR) ............................................................... 9189 
10. 
ASSESSMENT OF SAFETY ............................................................................ 9189 
10.1.1 
Safety Parameters ............................................................................................... 9189 
10.1.1.1 Definition of adverse events .............................................................................. 9189 
10.1.2 
Definition of serious adverse events .................................................................. 9290 
10.1.3 
Definition of adverse events of special interest (AESI) ..................................... 9391 
10.1.3.1 Pneumonitis ........................................................................................................ 9591 
10.1.3.2 Hypersensitivity Reactions ................................................................................ 9592 
10.1.3.3 Hepatic function abnormalities (hepatotoxicity) ............................................... 9692 
10.2 
Assessment of safety parameters ....................................................................... 9793 
10.2.1 
Assessment of severity ....................................................................................... 9793 
10.2.2 
Assessment of relationship ................................................................................ 9894 
10.3 
Recording of adverse events and serious adverse events ................................... 9995 
10.3.1 
Study recording period and follow-up for adverse events and serious 
adverse events .................................................................................................. 10096 
10.3.2 
Reporting of serious adverse events................................................................. 10197 
10.3.2.1 Reporting of deaths .......................................................................................... 10399 
10.3.3 
Other events requiring reporting ...................................................................... 10399 
10.3.3.1 Overdose .......................................................................................................... 10399 
10.3.3.2 Hepatic function abnormality ........................................................................ 104100 
10.3.3.3 Pregnancy ....................................................................................................... 104100 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .... 105101 
11.1 
Description of analysis sets ............................................................................ 105101 
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Clinical Study Protocol 
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Edition Number 15 
Date: 05-Jun-2020 
Page 19 of 117 
 
 
11.1.1 
Safety analysis set .......................................................................................... 105101 
11.1.2 
Efficacy analysis set ....................................................................................... 105101 
11.2 
Methods of statistical analyses ....................................................................... 106102 
11.2.1 
Safety Analyses .............................................................................................. 106102 
Analysis of safety endpoint ............................................................................................ 106102 
11.2.2 
Efficacy Analyses .......................................................................................... 108104 
11.2.3 
Exploratory Analyses ..................................................................................... 108104 
11.2.4 
Interim analyses ............................................................................................. 109105 
11.3 
Determination of sample size ......................................................................... 109105 
12. 
ETHICAL AND REGULATORY REQUIREMENTS ................................. 110106 
12.1 
Ethical conduct of the study ........................................................................... 110106 
12.2 
Ethics and regulatory review.......................................................................... 110106 
12.3 
Informed consent ........................................................................................... 110106 
12.4 
Changes to the protocol and informed consent form ..................................... 110106 
12.5 
Audits and inspections ................................................................................... 111107 
13. 
STUDY MANAGEMENT ............................................................................ 111107 
13.1 
Training of study site personnel ..................................................................... 111107 
13.2 
Monitoring of the study ................................................................................. 111107 
13.2.1 
Source data ..................................................................................................... 111107 
13.3 
Study timetable and end of study ................................................................... 111107 
14. 
DATA MANAGEMENT ............................................................................... 112108 
15. 
LIST OF REFERENCES ............................................................................... 112108 
 
 
 
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Edition Number 15 
Date: 05-Jun-2020 
Page 20 of 117 
 
 
 
LIST OF TABLES 
 
Table 1 
Dosing modification and toxicity management guidelines for 
immune-mediated reactions associated with MEDI4736 ............... …50-68 
Table 2 
Dosing modification and toxicity management guidelines for 
infusion-related reactions associated with MEDI4736 ............................. 69 
Table 3 
Dosing modification and toxicity management guidelines for non-
immune-mediated reactions associated with MEDI4736 ......................... 70 
 
Table 4 
Effective methods of contraception (two methods must be used) ............ 73 
Table 5 
Hematology laboratory tests ..................................................................... 79 
Table 6 
Clinical chemistry laboratory tests ........................................................... 79 
Table 7 
Urinalysis tests .......................................................................................... 80 
Table 8 
Estimate of volume of blood to be collected ............................................ 80 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 33 
 
LIST OF APPENDICES 
 
Appendix A 
MEDI4736 Dose Calculations………………………………………….106 
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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APC 
antigen-presenting cells 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
CDC 
Complement dependent cytotoxicity 
CI 
confidence interval 
CL 
clearance 
C82T82T82Tmax 
peak concentration 
C82T82T82Tmax,ss 
peak concentration at steady state 
C82T82T82Tmin 
trough concentration 
C82T82T82Tmin,ss 
trough concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
DC 
disease control 
ddAC 
Dose dense doxorubicin  and cyclophosphamide chemotherapy 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
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Abbreviation or 
special term 
Explanation 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
disodium edetate dihydrate 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FTIH 
first-time-in-human 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HCl 
hydrochloride 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 
IgG2 
immunoglobulin G2 
IGSF 
immunoglobulin superfamily 
IHC 
immunohistochemistry  
IL 
interleukin 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
MAb 
monoclonal antibody 
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Abbreviation or 
special term 
Explanation 
MDSC 
Myeloid derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
micro ribonucleic acid 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
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Abbreviation or 
special term 
Explanation 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
QoL 
quality of life 
QTc 
the time between the start of the Q wave and the end of the T wave 
corrected for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
sPD-L1 
soluble programmed cell death ligand 1 
SOCS3 
suppressor of cytokine signaling 3 
SUSAR 
suspected unexpected serious adverse reaction 
t82T82T82T½ 
half-life 
TEAE 
treatment-emergent adverse event 
TIL 
tumor infiltrating lymphocyte 
T82T82T82Tmax 
time to peak concentration 
T82T82T82Tmax,ss 
time to peak concentration at steady state 
TNBC  
Triple Negative Breast Cancer 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
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1. 
INTRODUCTION 
1.1 
Background 
Triple negative breast cancer 
Each year approximately 40-45,000 women are diagnosed with clinical stage I-III TNBC 
which has the least favorable prognosis among the different breast cancer subtypes. The only 
systemic treatment option for patients with early stage TNBC to improve their chance of 
survival is chemotherapy. The last new chemotherapy agent approved by the US FDA as 
adjuvant therapy to improve survival of this disease was paclitaxel close to 20 years ago. While 
TNBC includes some of the most chemotherapy sensitive tumors, pCR rates do not exceed 35-
40 % with the most widely used third generation neoadjuvant chemotherapy regimens that 
include a taxane (with or without a platinum agent) and anthracycline (Rouzier et al, 2005). 
Pathologic complete response is associated with excellent long term disease free and overall 
survival in this disease subset (Liedtke et al, 2008). On the other hand, patients with TNBC and 
residual cancer after neoadjuvant therapy have poor prognosis with 3-year recurrence rates 
around 50% (Symmans et al, 2007). The US FDA has recently recognized this strong 
association between pCR and long term survival in TNBC and HER2 positive breast cancers 
and expressed interest in accepting this endpoint for accelerated drug approval in these cancers 
(FDA guidance, 2012). In September 2013, Pertuzumab (PerjetaPPPTM
PPP) was approved for HER2 
positive breast cancer in combination with trastuzumab and docetaxel as neoadjuvant therapy 
on the basis of increased pCR rates (US FDA, 2013). The goal of this research is to estimate if 
inclusion of an immune checkpoint inhibitor could increase pCR rate above historical rates. 
1.2 
MEDI-4736 Background 
Investigators should be familiar with the current MEDI4736 Investigator Brochure (IB). 
MEDI4736 is being developed as a potential anticancer therapy for patients with advanced 
solid tumors. MEDI4736 is a human monoclonal antibody (MAb) of the immunoglobulin G1 
kappa (IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 
homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; 
CD279) and CD80 (B7-1). MEDI4736 is composed of 2 identical heavy chains and 2 identical 
light chains, with an overall molecular weight of approximately 149 kDa. MEDI4736 contains 
a triple mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain that 
reduces binding to complement protein C1q and the fragment crystallizable gamma (Fcγ) 
receptors involved in triggering effector function. 
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1.2.1 
Summary of non-clinical experience 
The non-clinical experience is fully described in the current version of the MEDI4736 
Investigator’s Brochure (IB).    
In general, treatment with MEDI4736 was not associated with any serious drug-related 
adverse effects in cynomolgus monkeys. Adverse findings in a non-GLP (good laboratory 
practice) pharmacokinetic/pharmacodynamic (PK/PD) and dose range-finding study, and in a 
separate GLP compliant 4-week repeat-dose toxicity study were both consistent with antidrug 
antibody (ADA)-associated morbidity and mortality in cynomolgus monkeys. The death of a 
single animal in the PK/PD and dose range-finding study was consistent with an 
ADA-associated acute anaphylactic reaction. The spectrum of findings, especially the 
microscopic pathology, in a single animal in the 4-week repeat-dose study indicated ADA-
mediated pathologic effects including immune complexes in tissues identified by 
immunohistochemistry. The NOAEL (No Observed Adverse Effect Level) of MEDI4736, the 
highest dose level at which chronic exposure to the substance shows no adverse effects, was 
100 mg/kg that corresponds to the highest dose tested in preclinical toxicity studies. 
The IB may be updated during the conduct of this trial; each update will be reviewed and 
submitted to the HIC. Any new drug-related human toxicity information, or preclinical 
toxicity that is relevant for humans, will be incorporated into the informed consent form. 
1.2.2 
Summary of clinical experience 
Clinical experience with MEDI4736 is fully described in the current version of the MEDI4736 
Investigator’s Brochure (IB). 
As of the data cutoff date of 14 Jul 2014, a total of 509 subjects have been enrolled and treated 
with MEDI4736 in 10 ongoing clinical studies: 5 employing MEDI4736 as monotherapy and 
5 as combination therapy. No studies have yet been completed.  
The IB may be updated during the conduct of this trial; each update will be reviewed and 
submitted to the HIC. Any new drug-related human toxicity information, or preclinical 
toxicity that is relevant for humans, will be incorporated into the informed consent form. 
Pharmacokinetics and Product Metabolism  
MEDI4736 monotherapy exhibited nonlinear (dose-dependent) PK. The area under the 
concentration-time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-
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Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
Page 27 of 117 
 
 
proportional manner over the dose range of 0.1 to 15 mg/kg and approached linearity at ≥ 3 
mg/kg, suggesting that the nonlinear PK of MEDI4736 is likely due to saturable target-
mediated clearance. Exposures following multiple doses (currently up to a maximum of 26 
doses) demonstrated accumulation consistent with PK parameters estimated from the first 
dose.  
Suppression of free soluble PD-L1 (sPD-L1) was correlated with MEDI4736 PK 
concentrations. Following administration of MEDI4736 monotherapy, free sPD-L1 levels 
were below the lower limit of quantitation (LLOQ) in the majority of subjects with available 
data (n = 38) at all time points following IV doses ≥ 1 mg/kg every 2 weeks (Q2W).   
Overall, a low incidence of ADA was observed. Of the 220 subjects who received MEDI4736 
monotherapy and for whom PK/ADA data were available, 5 were detected ADA positive, 
with an impact on PK/pharmacodynamics reported in 1 subject.  
Safety  
As of 14Jul2014, no identified risks are clearly associated with the use of MEDI4736. 
Important potential risks based on the mechanism of action of MEDI4736 and its related 
molecules include immune-mediated reactions such as enterocolitis, dermatitis, 
hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, and neuropathy. Additional important 
potential risks include infusion-related reactions, hypersensitivity, serious allergic reactions, 
serious infections, and immune complex disease.  
The majority of the safety data are from the monotherapy study, CD-ON-MEDI4736-1108, 
specifically the 10 mg/kg Q2W cohort (N = 393). In this cohort, the most frequently reported 
(≥ 10% of subjects) adverse events (AEs; all grades, regardless of causality) were fatigue 
(29.8%), nausea (20.1%), dyspnea (19.6%), decreased appetite (19.1%), constipation (14.0%), 
diarrhea and vomiting (12.5% each), cough (11.5%), pyrexia and back pain (10.4% each), and 
rash (10.2%). In approximately half of the subjects, the highest AE severity was Grade 1 
(25.2% of subjects) or Grade 2 (22.9% of subjects). Most of these events were managed 
clinically without the need for dose modifications or delays. Grade 3 or higher AEs that 
occurred in > 1% of subjects were dyspnea (5.1%), increased gamma-glutamyltransferase 
(3.3%), fatigue, general physical health deterioration, increased aspartate aminotransferase, 
and back pain (2.3% each), anemia and dehydration (1.8% each), and abdominal pain, 
vomiting, sepsis, syncope, and hypotension (1.3% each). Treatment-related Grade 3 AEs in 2 
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Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
Page 28 of 117 
 
 
or more subjects were fatigue (4 subjects), increased gamma-glutamyltransferase (3 subjects), 
and vomiting, increased alanine aminotransferase, increased aspartate aminotransferase, and 
arthralgia (2 subjects each). There were 2 subjects with treatment-related Grade 4 events 
(hypercalcemia, fatigue) and 1 subject with a treatment-related Grade 5 event (angiopathy). In 
general, Grade 3 or higher AEs were manageable and reversible with standard toxicity 
management guidelines.  
Serious adverse events (SAEs) and other significant AEs occurred in fewer than one-third of 
subjects treated with MEDI4736 10 mg/kg Q2W in Study CD-ON-MEDI4736-1108. The 
most frequently reported SAEs (regardless of causality; > 5 subjects) were dyspnea (15 
subjects), general physical health deterioration (9 subjects), pyrexia (8 subjects), back pain 
and abdominal pain (7 subjects each), and dehydration and pleural effusion (6 subjects each). 
One subject (with Stage IV lung cancer and a history of cardiac disease) died due to 
angiopathy considered by the investigator as related to MEDI4736. Adverse events that 
resulted in permanent discontinuation of MEDI4736 in ≥ 2 subjects were dyspnea (7 subjects), 
general physical health deterioration (5 subjects), and death, increased transaminases, 
pulmonary embolism, and respiratory failure (2 subjects each).  
No dose-limiting toxicities (DLTs) have been reported in any of the dose-escalation cohorts of 
the monotherapy studies. Overall, the AE profile of MEDI4736 was consistent with the 
pharmacology of the target. No tumor types appeared to be associated with unique AEs. 
Efficacy  
As of 14Jul2014, partial efficacy data are available for 2 monotherapy studies (CD-ON-
MEDI4736-1108 and D4190C00002) and 1 combination therapy study of MEDI4736 plus 
tremelimumab (D4190C00006). Tumor assessments were based on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 guidelines (Eisenhauer et al, 2009).  
Clinical activity has been observed across the 3 studies. In Study CD-ON-MEDI4736-1108, 
169 of 414 subjects treated with MEDI4736 (all dose levels) were evaluable for response 
analysis, which included subjects who had at least 24 weeks of follow-up as of the data cutoff 
date and had either at least 1 post-baseline tumor assessment or experienced clinical 
progressive disease (PD) or death. Nineteen subjects (11.2%) had a best overall response of 
complete response (CR)/partial response (PR; confirmed and unconfirmed). The disease 
control rate (DCR; CR + PR + stable disease [SD] ≥ 12 weeks) was 32% (54 of 169 subjects). 
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Investigational Drug Substance: MEDI4736 MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
Page 29 of 117 
 
 
Tumoral programmed cell death ligand 1 status was known for 143 of the 169 evaluable 
subjects, of whom 30 had tumors that were PD-L1 positive. A best overall response of CR/PR 
(confirmed and unconfirmed) was observed in 7 of 30 (23.3%) PD-L1-positive subjects and in 
6 of 113 (5.3%) PD-L1-negative subjects. By tumor type, responses were observed in subjects 
with non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck 
(SCCHN), hepatocellular carcinoma (HCC), cutaneous melanoma, gastroesophageal cancer, 
and pancreatic adenocarcinoma. In Study D4190C00002, 12 of 18 subjects had at least 1 post-
baseline tumor assessment. One subject had a best overall response of PR (unconfirmed) and 6 
subjects had SD (irrespective of tumoral PD-L1 expression). In Study D4190C00006, 13 of 18 
subjects had at least 1 tumor assessment. Five subjects had best overall responses of PR (1 
confirmed and 4 unconfirmed) and 3 subjects had SD (again irrespective of tumoral PD-L1 
expression). 
Drug Interactions 
There are no known clinically significant interactions of MEDI4736 with other medicinal 
products, but no formal drug-drug interaction studies have been conducted with MEDI4736.  
Pregnancy and Lactation 
Nonclinical assessment of the potential reproductive and developmental toxicity of MEDI4736 
has not been conducted.  It is not known whether MEDI4736 is excreted in breast milk. 
1.3 
Research hypothesis 
Our hypotheses are that MEDI4736 administered concomitantly with weekly nab-paclitaxel and 
dose-dense AC (ddAC) neoadjuvant chemotherapy will induce higher pathologic complete 
response (pCR) rate (>55%) in triple negative breast cancer than historical pCR rates (30-40%) 
observed with the same chemotherapy regimen chemotherapy alone. We also hypothesize that 
MEDI4736 can be administered safely at full dose concomitant with nab-paclitaxel (100mg/m2) 
and ddAC (60 mg/mPPP2
PPP and 600 mg/mPPP2
PPP respectively) 
 
1.4 
Rationale for conducting this study 
There are few molecular prognostic markers for survival and predictive markers for 
chemotherapy sensitivity for Stage I-III TNBC. High level of lymphocytic infiltration in the 
primary tumor (TIL) is the only consistent prognostic marker for better survival in the absence 
of any systemic therapy and it also serves as a predictive marker for higher pCR to 
neoadjuvant chemotherapy in these cancers (Bianchini et al, 2010; Loi et al, 2013; Denkert et 
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Investigational Drug Substance: MEDI4736 MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
Page 30 of 117 
 
 
al, 2010). These observations raise the possibility that antitumor immune response may 
contribute to the better clinical outcome. Multiple different preclinical studies indicate that 
immune cells in the tumor microenvironment, particularly activated cytotoxic T cells, partially 
mediate chemotherapy response (Bracci et al, 2014, Zitvogel et al, 2008). The CD80/CTLA4 
and PD1/PD-L1/L2 receptor-ligand interactions play a major role in suppressing cytotoxic T 
cell activity. In the lymph nodes, PD-L1 expressed on antigen-presenting cells binds to PD-1 
or CD80 on activated T cells and inhibits their activity (Keir et al, 2008; Park et al, 2010). In 
the tumor microenvironment, PD-L1 is also expressed on tumor cells and can suppress anti-
tumor immunity (Zou et al, 2008).  Several studies using different immunohistochemistry 
methods and in situ mRNA measurements have demonstrated that PD-L1 is expressed by 
breast cancer cell lines and also by 20-60% of TNBC (Schalper et al, 2014; Soliman et al, 
2014; Mittendorf et al, 2014; Ghebeh et al, 2008). The relationship between PD-L1 expression 
and response to MEDI4736 is currently unclear, objective tumor response in lung cancer and 
melanoma appear to be more common in PD-L1 positive cancers (defined as > 1% IHC 
positivity) but is also seen in PD-L1 negative cases (Antonio et al, ESMO 2014 abstract 
7629). Currently, there is no agreed upon standard clinical test to determine PD-L1 
expression, and different research groups and companies often use different methods. For 
these reasons, this study will not restrict eligibility based on PD-L1 expression. 
In the past few years new drugs emerged that can boost local anti-tumor immune response by 
inhibiting the PD1 mediated immune checkpoints. Antibodies that target the interaction 
between PD1 and its ligands can enhance the cytotoxic activity of antitumor T cells by 
removing the inhibitory signal (Blank et al, 2006).  Multiple different drugs that block the 
PD1 ligand interaction has been shown to induce objective and lasting tumor responses in 
multiple different tumor types including lung cancer, melanoma, head and neck cancer and 
bladder cancer (Brahmer et al, 2012; Hamid et al, 2013; Herbst et al, 2013; Kirskwood et al, 
2010). PD1-targeted drugs as single agent therapy in Phase I trials also showed objective 
responses in 15-20% of metastatic TNBC (San Antonio Breast Cancer Symposium, 2014, Abs 
#S1-09) . 
1.5 
Benefit/risk and ethical assessment 
All patients who participate in this trial will receive the currently most effective sequential 
taxane and anthracycline combination neoadjuvant chemotherapy, which is considered 
standard of care in this patient population. Long-term disease-free and overall survival are the 
same for patients who receive the same chemotherapy, regardless if the treatment is given 
preoperatively (neoadjuvant treatment) or postopratively (adjuvant therapy).  Administration 
of chemotherapy preoperatively provides an opportunity to directly assess the cytotoxicity of a 
treatment regime. It also yields personal benefits for patients in the form of tumor shrinkage 
that allows smaller resection and providing important prognostic information that resides in 
the pathologic tumor stage. Patients with TNBC and extensive residual cancer after 
chemotherapy have very poor prognosis which could motivate patients to seek out further 
adjuvant clinical trials to improve outcome. It is widely held that increasing the pCR rate in 
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Investigational Drug Substance: MEDI4736 MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
Page 31 of 117 
 
 
TNBC may increase long-term survival. However, there is considerable controversy about 
what degree of increase in pCR rate would translate to what level of improvement in survival. 
The ultimate goal of this trial is to attempt to improve pCR rate beyond what the current best 
regimens can accomplish, we hope that the magnitude of improvement will be sufficient to 
increase long-term survival which can be demonstrated in the future, in a much larger 
randomized trial.  
The risk inherent to this clinical study is increased toxicity due to inclusion of MEDI4736 in 
the treatment. MEDI4736 monotherapy at the 10 mg/kg dose administered every two weeks 
was well tolerated. No dose limiting toxicities were reached in any of the dose escalation 
trials. However, the most frequent adverse events, including fatigue, dyspnea, decreased 
appetite and liver enzyme elevations, are also adverse events that can be caused by the 
chemotherapy drugs used in this trial. Safety monitoring and dose reduction guidelines are 
built into the trial to minimize harm. 
Currently there are no known clinically significant drug interactions with MEDI4736 and 
other drugs. Humanized monoclonal antibodies, as a drug class, have also not demonstrated 
significant interactions with chemotherapy drugs. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective(s) 
 
The primary objective of the Phase I portion of the trial is to assess the safety of MEDI4736 
combined with chemotherapy and determine if full dose of MEDI4736 can be administered in 
combination with weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in 
combination with ddAC x 4 treatments.   
The primary objective of the Phase II portion of the study is to estimate the pCR rate, defined 
as no invasive cancer in the resected breast tissue and lymph nodes (ypT0/Tis, N0), after 
neoadjuvant (pre-operative) therapy with MEDI4736 in combination with weekly nab-
paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 treatments 
for estrogen receptor (ER), progesterone receptor (PR) and HER2 negative (triple negative, 
TNBC), clinical stage I-III breast cancer.  
 
2.2 
Secondary objective(s) 
To assess the toxicity of adding anti-PD-L1 antibody, MEDI4736 to neoadjuvant chemotherapy 
with standard of care nab-paclitaxel and ddAC. Safety will be assessed by adverse experiences 
using Common Terminology Criteria for Adverse Events, Version 4.0. and will also monitor for 
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Clinical Study Protocol 
Investigational Drug Substance: MEDI4736 MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
Page 32 of 117 
 
 
events of special clinical interest with a suspected auto-immunologic etiology including grade 
≥3 colitis, hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash and anti-drug-
antibody (ADA) immune complex disease (manifested as symptoms of arthralgia, serum-
sickness, abdominal pain, back pain, and vasculitis). Acute toxicities will be reported for the 
entire 20-week duration of therapy for patients included in the Phase II portion of the trial and 
also separately for the combination with nab-paclitaxel and dose dense AC respectively. Late 
toxicities will also be collected and reported separately for 90 days after completion of treatment. 
 
2.3 
Exploratory objective(s) 
Exploratory correlative science objectives include correlation of baseline and post-treatment 
residual cancer immune parameters of the tumor with pCR.  
The following immune parameters, in order of priority in case of limited tissue availability, will 
be assessed using quantitative immunohistochemistry in base line core needle biopsies: PD1 
(programmed death receptor 1) and PD-L1 and -L2 (programmed death receptor ligands 1 and 
2), CD3+, CD4+, CD8+, CD137, FOXP3, OX40, CTLA4 and GITR. Tumor infiltrating 
lymphocyte (TIL) count will be estimated from an H&E section and quantified as the percent of 
stromal cells that are lymphocytes.  
RNA expression profiling will also be performed on all base line core needle biopsy 
samples using RNA sequencing to assess associations between pCR and published immune gene 
signatures. The 6 immune gene signatures are metagenes corresponding to the average 
expression of sets of highly co-expressed genes.  These metagenes represent semi-quantitative 
estimates of distinct cell types including plasma cells (IGG metagene), T-cells (CD8A metagene) 
and antigen-presenting cells (MHC2 metagene) and also capture important immune regulatory 
pathways such as MHC1 gene expression (MHC1 metaene), STAT1 co-expressed genes 
(STAT1 metagene), interferon-inducible genes (IF-I metagene) and chemokine signaling 
through CXCL9 and CXCL1. These metagenes were selected because they were repeatedly 
observed in gene expression data, can be assessed reliably and carry prognostic value.  
Whole exome DNA sequencing will also performed to identify somatic mutations and 
other alterations that could be potential novel predictive markers of response. These will 
represent exploratory analysis. Sequencing will be performed at the Yale Center for Genome 
analysis with average depths of UUU> UUU150x. 
Blood will be collected at baseline before starting therapy and after completion of all 
neoadjuvant treatment for future studies.   
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3. 
STUDY DESIGN 
3.1 
Overview of study design 
 
The study will have an initial lead in safety portion that follows a 3+3 Phase I trial design with 
two dose levels of MEDI4736 (3mg/kg and 10mg/kg). The subsequent efficacy assessment 
portion will follow a Simon’s two stage Phase II trial design including patients from the Phase I 
portion of the trial who have received at least 12 weeks of therapy with the recommended Phase 
II dose of MEDI4736.  
 
3.2 
Study schema 
Figure 1 Trial Schema 
 
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3.3 
Study Oversight for Safety Evaluation 
 
During the Phase I portion of the trial, the first 3 patients will be enrolled at dose level of 3 mg/kg 
MEDI4736 concomitant with chemotherapy. The DLT evaluation period will extend from Cycle 1 Day 
1 through to the end of the 20-week treatment period.  Accrual will be halted after the 3PPPrd
PPP patient 
enters the trial and until all 3 patients have had toxicity assessment at the end of the DLT evaluation 
period (20 weeks). If 1 patient experiences DLT during the entire treatment period (20 weeks), 3 
additional patients will be enrolled at the 3 mg/kg dose-level. If 2 or more patients experience DLT 
among the first 6 patients treated at the 3 mg/kg dose level, the study will be halted and dose de-
escalation will be considered as an amendment to the trial after consultation with the sponsor. Also, if 
2 or more patients experienced DLT among the first 3 patients treated at 3 mg/kg dose level, the study 
will be halted and dose de-escalation will be considered as an amendment to the trial.  
 
During the Phase II portion of the trial the following toxicities require permanent discontinuation 
of MEDI4736: Any grade >3 toxicity (non-hematologic or hematologic) that is unexpected or probably 
casually related to MEDI4736 including infusion reaction. Grade > 3 colitis. Grade > 3 events of 
potential immunologic etiology including but not limited to nephritis, pneumonitis, pancreatitis, non-
infectious myocarditis, Guillain-Barré syndrome, or myasthenia gravis. Grade > 3 endocrinopathy that 
is symptomatic despite adequate hormone replacement therapy. AST or ALT >5 x ULN. Total serum 
bilirubin >3 x ULN. Steven-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration or necrotic, bullous or hemorrhagic manifestations. 
4. 
SUBJECT SELECTION  
4.1 
Inclusion criteria 
For inclusion in the study, patients must fulfill all of the following criteria: 
1. Newly diagnosed histologically confirmed stage I-III, ER, PR and HER2 negative 
invasive breast cancer as defined by ASCO CAP guidelines for whom systemic 
chemotherapy would be indicated based on physician judgment following standard 
NCCN practice guidelines (Theriault et al, 2013). 
2. Patients with prior history of stage I-III breast cancer currently without evidence of 
metastatic disease are eligible if can tolerate further chemotherapy, patients with newly 
diagnosed synchronous bilateral breast cancers are also eligible if at least one tumor is 
triple negative (response will be assessed in both breasts if invasive cancer is present 
in both). 
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Page 35 of 117 
 
 
3. Willing and able to provide written informed consent for voluntary participation in the 
trial. 
4. Willing to undergo a baseline tumor core needle biopsy for correlative science studies. 
This study does not restrict eligibility based on PD-L1 expression because the 
relationship between PD-L1 expression and response is not fully understood and there 
are no standardized and validated clinical tests to assess PD-L1 expression. 
5. Eighteen years of age or older on the day of signing informed consent.  
6. Female subjects must either be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical cause; 
OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of 
bilateral oophorectomy) or must have a negative urine or serum pregnancy test upon 
study entry.   
7. Patients should have adequate organ function to tolerate chemotherapy, as defined by: 
- 
peripheral granulocyte count of > 1,500/mmPPP3
PPP  
- 
platelet count > 100,000/mmPPP3 
- 
hemoglobin >9 g/dL 
- 
total bilirubin < 1.5 x upper limit of normal (ULN) 
- 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) each < 1.5 x 
ULN  
- 
serum creatinine < 1.5 x ULN or serum creatinine clearance > 50mL/min 
- 
INR/PT/PTT each < 1.5 x ULN 
-   TSH within normal limits 
 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Patients who underwent partial excisional biopsy or lumpectomy, segmental 
mastectomy or modified radical mastectomy or sentinel node biopsy are not eligible 
because they cannot be assessed accurately for pathologic response. 
 
2. Patients for whom anthracycline, paclitaxel or antibody therapies are contraindicated: 
- 
Hypersensitivity reactions to any of the medications or to humanized monoclonal 
antibodies 
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- 
History of congestive heart failure 
- 
Myocardial infarction within the past 12 months 
- 
Pre-existing peripheral neuropathy > grade 2 
- 
Prior anthracycline therapy with > cumulative dose of 240 mg/m2 
3. Patients with active autoimmune disease or documented autoimmune disease within 2 
years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, 
vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, 
vasculitis, or glomerulonephritis. 
 
4. Patients with hypothyroidism that is clinically stable and have normal TSH levels with 
hormone replacement, or patients with vitiligo or psoriasis not requiring treatment 
remain eligible for the study. 
 
5. Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative 
colitis).  
 
6. Patients with known active hepatitis B or C or HIV infection or with history of 
tuberculosis.  
 
7. Patients with a syndrome that requires administration of chronic systemic steroids or 
immunosuppressive agents. However, patients that require intermittent use of 
bronchodilators or local steroid injections are eligible.   
 
8. Attenuated vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, 
rabies, BCG, and typhoid vaccine. 
 
9. Female patients who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing effective methods of birth control for at 
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least 6 months after completion of the last dose of MEDI4736 and AC chemotherapy. 
(see section 7.1).   
 
10. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736. 
 
11. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Bazett’s Correction. 
 
12. Current or prior use of immunosuppressive medication within 28 days before the first 
dose of MEDI4736, 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. 
 
13. History of primary immunodeficiency. 
 
14. History of allogeneic organ transplant. 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric 
illness/social situations that would limit compliance with study requirements or 
compromise the ability of the subject to give written informed consent. 
 
16. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results. 
 
4.3 
Withdrawal of Patients from Study Treatment and/or Study 
Permanent discontinuation of study treatment 
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An individual patient will not receive any further investigational product if any of the 
following occur: 
1. 
Withdrawal of consent for any reason 
2. 
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing 
3. 
Patient is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk 
4. 
Pregnancy or intent to become pregnant 
5. 
Any patient showing clinical or radiological sign of progression of her disease during 
therapy. Further treatment will be individualized for these patients by their primary 
treating physician. Options include more chemotherapy with different agents, surgery 
or preoperative radiation. For analysis purposes these patients will be considered as 
residual disease (RD). 
 
6. 
Any patient developing dose limiting toxicity (as defined in Section 6.5) or 
unacceptable toxicity (as defined in section 6.6) will discontinue therapy in the study. 
Further treatment will be individualized for these patients by their primary treating 
physician. Options include more chemotherapy with different agents, surgery or 
preoperative radiation. 
 
7. 
Grade ≥ 3 infusion reaction 
8. 
Patient noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
9. 
Initiation of alternative anticancer therapy including another investigational agent 
Patients who received at least one dose of MEDI4736 but subsequently were permanently 
discontinued from receiving investigational product will be followed for safety per Section 
10.3.1.   
 
Withdrawal of consent 
If consent is withdrawn, the patient will not receive any further investigational product or 
further study observation. 
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4.4 
Replacement of patients 
 
Replacement of patient, lost due to withdrawal of consent or lost for follow up for reasons 
other than toxicity or progression (e.g. transfer of care to other institutions) is allowed.  
5. 
INVESTIGATIONAL PRODUCT(S) 
5.1 
MEDI4736 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
MEDI4736 to the investigator as a concentrate for solution for infusion. 
5.1.1 
Formulation/packaging/storage 
MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.  
The investigational product is supplied as a vialed liquid solution in clear 10R glass vials 
closed with an elastomeric stopper and a flip-off cap overseal. Each vial contains 500 mg 
(nominal) of active investigational product at a concentration of 50 mg/mL (500 mg/vial). The 
solution will be diluted with 0.9% (w/v) saline for IV infusion.  
Unopened vials of liquid MEDI4736 must be stored at 2°C to 8°C (36°F to 46°F).  MEDI4736 
must be used within the individually assigned expiry date on the label. 
In use storage and stability 
Total in-use storage time from needle puncture of MEDI4736 vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2-8°C (36-46°F). 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. MEDI4736 does not contain preservatives and any unused portion must be 
discarded. 
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5.1.2 
Doses and treatment regimens 
MEDI4736 will be administered every 2 weeks at doses of either 3 mg/kg or 10 mg/kg during 
the phase I portion of this study.  The dose of MEDI4736 in the phase II portion will be either 
3 mg/kg or 10 mg/kg, as determined in the phase I portion. 
There will be no intra-patient dose escalation permitted.   
5.1.3 
Study drug preparation 
Calculate the dose volume of MEDI4736 and number of vials needed for the subject to 
achieve the accurate dose according to Appendix A. 
Preparation of infusion bags 
The preparation of infusion bags should be done under aseptic conditions by trained 
personnel; it should not be prepared on the ward. 
An additional volume of 0.9% (w/v) saline equal to the calculated volume of MEDI4736 to be 
added to the IV bag must be removed from the bag prior to addition of MEDI4736.  
The calculated volume of MEDI4736 is then added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Prior to the start of the infusion, ensure that the bag contents are at room temperature to avoid 
an infusion reaction due to the administration of the solution at low temperatures. 
Vials should be used for specific subjects and should not be shared between subjects. 
5.1.4 
Dose administration 
MEDI4736 will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral vein.   
Following preparation of MEDI4736, the entire contents of the IV bag should be administered 
as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm in-line filter.  
The IV line will be flushed with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
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infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.  
Since the compatibility of MEDI4736 with other IV medications and solutions, other than 
normal saline (0.9% [weight/volume] sodium chloride for injection), is not known, the 
MEDI4736 solution should not be infused through an IV line in which other solutions or 
medications are being administered. 
5.1.5 
Monitoring of dose administration 
Subjects will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment (see Section 8.2).  
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 subjects 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. 
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 subjects to an intensive care unit if necessary. 
5.1.6 
Accountability and dispensation 
Study drug will be shipped to the Oncology Investigational Drugs Pharmacy and dispensed 
under the supervision of Thomas M. Ferencz R.Ph., BCOP, Senior Clinical Pharmacy 
Specialist, Oncology Investigational Drugs, Smilow Cancer Hospital at Yale New Haven 
Hospital Oncology Pharmacy, 8th floor, room 8-110, 35 Park St., New Haven, CT 06510. 
Phone (203)-200-4455, Fax (203)-200-4445, email: 59T59T59TThomas.Ferencz@ynhh.org59T59T59T. 
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5.1.7 
Disposition of unused investigational study drug 
Unused drugs will be destroyed as per the policy of the Oncology Investigational Drugs 
pharmacy of Smilow Cancer Hospital. 
5.2 
Nab-paclitaxel 
Nab-paclitaxel (Abraxane®, NDC 68817-134-50) is an albumin-bound form of paclitaxel with 
a mean particle size of approximately 130 nanometers.  Paclitaxel is the active anti-tumor 
agent in the particles that disrupts microtubule dynamics and induce cell death. 
5.2.1 
Formulation/packaging/storage 
Nab-paclitaxel is supplied as a white to yellow, sterile, lyophilized powder for reconstitution 
with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each 
single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 
900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). 
Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.  Nab-paclitaxel is 
considered standard of care chemotherapy and will be stored and dispensed following the 
pharmacy policies of Smilow Cancer Hospital. 
5.2.2 
Doses and treatment regimens 
Nab-paclitaxel 100mg/m IV will be administered together with, but prior to, MEDI4736 
following standard chemotherapy administration practice of Smilow cancer hospital.  No 
steroid premedication is required for this drug in routine practice. Patients will receive 12 
weekly treatments and subsequently on week 13 will start the ddAC part of their treatment. 
5.2.3 
Product preparation 
Preparation and administration of nab-paclitaxel will follow standard hospital policy for 
routine chemotherapy.  
5.2.4 
Dose administration 
Nab-paclitaxel 100 mg/mPPP2
PPP will be administered as a 30 minute IV infusion once every week for 
12 treatments (through weeks 1-12) following institutional treatment guidelines.  
5.2.5 
Monitoring of dose administration 
Each patient will be monitored for vital signs and assessed for symptoms by the chemotherapy 
nurse before, during and after administration of treatment as per institutional guidelines.  
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5.2.6 
Accountability and dispensation  
Accountability and dispensation of nab-paclitaxel will follow oncology pharmacy policy for 
routine chemotherapy. 
5.2.7 
Disposition of unused drug 
Disposition of nab-paclitaxel will follow oncology pharmacy policy for routine chemotherapy.  
5.3 
Doxorubicin combined with Cyclophosphamide (AC) 
Doxorubicin is an antineoplastic antibiotic. It has multiple mechanisms of action including 
inhibition of topoisomerase II, generation of free oxygen radicals and induction of apoptosis.  
Cyclophosphamide is a synthetic antineoplastic drug chemically related to nitrogen mustard. 
Cyclophosphamide is metabolized in the liver to active alkylating compounds by the 
microsomal oxidase system. These metabolites induce DNA cross links which lead to cell 
death.  
Doxorubicin and cyclophosphamide are used in combination due to synergistic anticancer 
activity and have been shown to improve survival of early stage breast cancer in randomized 
clinical trials.  
5.3.1 
Formulation/packaging/storage 
Doxorubicin Hydrochloride Injection: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 
mL, 150 mg/75 mL, and 200 mg/100 mL Doxorubicin hydrochloride as a clear red solution. 
Lyophilized Doxorubicin Hydrochloride for Injection: Vials contain 10 mg, 20 mg, 50 mg, 
and 150 mg Doxorubicin hydrochloride as a red-orange lyophilized powder. 
Cyclophosphamide is supplied in 500 mg, 1000mg and 2000mg vials (as anhydrous 
cyclophosphamide). 
5.3.2 
Doses and treatment regimens 
One week after completion of nab-paclitaxel,  4 additional courses of chemotherapy consisting 
of Doxorubicin 60 mg/mPPP2
PPP IV and Cyclophosphamide 600 mg/m PPP2
PPP IV once every 14 days 
(through weeks 13-20) will be administered. Approximately 24 hours after each AC 
chemotherapy, pegfilgrastrim 6 mg (NeulastaPPPTM
PPP) will be administered subcutaneously followed 
by MEDI4736 intravenously as described in section 5.1.  
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5.3.3 
Product preparation 
Preparation and administration of will follow standard hospital policy for routine 
chemotherapy.  
5.3.4 
Dose administration 
Doxorubicin 60 mg/mPPP2
PPP and cyclophosphamide 600 mg/mPPP2
PPP will be administered following 
institutional treatment guidelines for routine chemotherapy.  The first course of treatment will 
be administered without decadron pre-medication. If clinically significant nausea or vomiting 
occurs subsequent courses will be administered with decadron pre-medication as per 
institutional practice.   
5.3.5 
Monitoring of dose administration 
Each patient will be monitored for vital signs and assessed for symptoms by the chemotherapy 
nurse before, during and after administration of treatment as per institutional guidelines.  
5.3.6 
Accountability and dispensation  
Accountability and dispensation of doxorubicin and cyclophosphamide will follow oncology 
pharmacy policy for routine chemotherapy. 
5.3.7 
Disposition of unused drug 
Disposition of doxorubicin and cyclophosphamide will follow oncology pharmacy policy for 
routine chemotherapy. 
6. 
TREATMENT PLAN 
6.1 
Subject enrollment 
Patients will be enrolled sequentially into this open-label, non-randomized phase I/II study.  The 
phase I portion of the trial will include 2 dose levels, described in Section 6.2 and 6.3. 
Patients will be enrolled into the phase II portion of the trial after the MTD/RP2D has been 
determined.   
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6.2 
Dosage and Administration 
MEDI4736 will be administered at two dose levels of either 
UUU3 mg/kgUUU (1PPPst
PPP dose level) or 
UUU10 
mg/kgUUU (2PPPnd
PPP dose level) over 60 minute IV infusion every 2 weeks during the Phase I portion of 
the trial to establish the RP2D which will be used in the Phase II portion of the trial.  
MEDI4736 will be administered immediately after administration of Nab-paclitaxel 100 mg/mPPP2
PPP  
IV on Day 1 of chemotherapy on weeks 1, 3, 5, 7, 9, 11 (every two weeks). Nab-paclitaxel will 
be administered on day 1 weekly x 12 treatments.   
After completion of the 12 courses of nab-paclitaxel / MEDI3476, doxorubicin and 
cyclophosphamide (AC) will be administered at 60 mg/mPPP2
PPP and 600 mg/mPPP2
PPP dose respectively, 
once every two weeks x 4 treatments as described in section 5.2. Pegfilgrastim 6 mg will be 
given as IM injection 24 hours (Day 2) after each AC chemotherapy. MEDI4736 is administered 
at the R2PD (or assigned dose cohort in the phase I portion) on Day 2 immediately after the 
administration of pegfilgrastim during each course of AC (weeks 13,15,17 and 19).  
6.3 
Dose Escalation Decision Rules 
Phase I safety portion of the trial  
Two dose levels will be assessed including 3mg/kg and 10mg/kg MEDI4736 in combination with 
weekly nab-paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 
treatments.  
UUU3 mg/kg MEDI4736 dose level 
The first 3 patients will be enrolled at dose level of 3 mg/kg MEDI4736 concomitant with 
chemotherapy. Further accrual will be halted after the first 3 patients are enrolled until the DLT 
assessment is complete for a given treatment part of the two-part (weekly nab-paclitaxel x 12 + AC x 
4) chemotherapy regimen. If no patients experience a DLT during the weekly nab-paclitaxel treatment 
period (12 weeks), the next 3 patients will start weekly nab-paclitaxel at the next dose level, 10 mg/kg, 
while the previous cohort is still receiving AC chemotherapy (with MEDI4736 at 3 mg/kg).  If 1 
patient experiences DLT during either the nab-paclitaxel or AC parts of the therapy, 3 additional 
patients will be enrolled at the 3 mg/kg dose-level in combination with the chemotherapy part of 
interest. If none of these 3 additional patients experience DLT (i.e. the final observed DLT rate is 1 of 
6), the dose is escalated to 10 mg/kg for the given chemotherapy part. If 2 or more patients experience 
DLT among the first 6 patients treated at the 3 mg/kg dose level, the study will be halted and dose de-
escalation will be considered as an amendment to the trial after consultation with the sponsor. If 2 or 
more patients experience DLT among the first 3 patients treated at 3 mg/kg dose level, the study will 
also be halted and dose de-escalation will be considered as an amendment to the trial.  
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Using the above design, the probabilities of halting dose escalation, in each treatment part, for true 
rates of DLT ranging from 5% to 70% are as follows: 
True rate of DLT: 
 
 
5%   10%    20%    30%   40%   50%   60%   70%  
Probability of halting dose escalation: 
0.03  0.09   0.29     0.51    0.69   0.83    0.92   0.97 
UUU10 mg/kg MEDI4736 dose level 
If dose escalation is feasible, the next cohort of patients will receive MEDI4736 at 10 mg/kg dose 
concomitant with chemotherapy. Accrual will be halted after the first 3 patients are enrolled at the 10 
mg/kg dose until DLT assessment is complete for nab-paclitaxel (i.e. all 3 patients have completed 12 
weeks of nab-paclitaxel chemotherapy). If only 1 patient experiences DLT after the first 3 patients are 
treated at this dose level, the study will proceed to enroll 3 additional patients at the 10 mg/kg dose 
level in combination with nab-paclitaxel. If none or only 1 of these additional 3 patients show DLT 
(final observed DLT 1 of 6), this dose level will be moved forward to the Phase II portion for efficacy 
assessment and accrual will start on the nab-paclitaxel part of treatment while patients are completing 
the AC part of their therapy. If 2 or more patients experience DLT among the first 6 patients treated at 
the 10 mg/kg dose level, the dose will be de-escalated to 3 mg/kg and this dose is designated as the 
RP2D for the subsequent Phase II portion of the trial. If 2 or more patients out of the first 3 experience 
DLT, the dose will be de-escalated to 3 mg/kg dose and this dose will be moved forward to the Phase 
II portion for efficacy assessment. DLT will be assessed similarly and the same expansion rules will be 
followed during the AC part of the treatment. 
Phase II portion of the trial  
The interim efficacy and toxicity analysis will be performed after the first 22 two patients have 
completed chemotherapy therapy, undergone surgery and are eligible for efficacy assessment. Patients 
are eligible for efficacy assessment if they received at least 12 weeks of MEDI4736 at the 
recommended phase 2 dose concomitant with chemotherapy.  Patients who received lower than the 
RP2D during the Phase I portion of the trial will not be included in the efficacy analysis. Patients who 
discontinued MEDI4736 within 12 weeks of initiation of therapy for any reason are also not eligible 
for efficacy analysis, but will be included in the toxicity assessment. Trial accrual will continue while 
efficacy and toxicity data is accumulating for the 22 patients. 
The trial will terminate for lack of efficacy if < 7 patients out of the first 22 experience pCR (Alpha = 
beta = 10%, probability of early termination if the response rate is 30%=0.67). If > 7 patients 
experience pCR, accrual will continue until a maximum of 50 patients are accrued. 
Safety analysis: If > 2/22 patients experience DLT or a serious treatment related adverse event (SAE) 
during the full 20 week treatment period, the MEDI4736 dose schedule will be re- evaluated. If futility 
criteria is not met (i.e. >7/22 patients have pCR), the trial will continue after the MEDI4736 dose and 
schedule is amended to improve safety. With 22 patients in the first stage, there is > 90% chance of 
observing at least 1 DLT event, if the true underlying rate of the adverse event is > 10%.  
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If the study proceeds to full accrual after the interim analysis, the final efficacy analysis will be as 
follows: 
If >20 patients have pCR (i.e. at least 40% observed pCR rate) then the treatment will considered 
successful and recommended for further study in a randomized trial. With 50 patients included in the 
efficacy phase of the study, for the targeted pCR rate of 50% the corresponding 95% confidence 
interval ranges from 38% to 69%. 
 
6.4 
Definition of DLT 
Dose limiting toxicities (DLT) to establish RP2D will be evaluated during the entire 20 weeks 
of therapy. Any DLT encountered during the 20 week treatment period will be considered DLT. 
Grading 
of 
toxicities 
will 
be 
according 
to 
NCI 
CTCAE 
v5.0 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/T59T59T). The following toxicities will be considered 
DLT that require permanent discontinuation of MEDI4736: 
• Any Grade 4 immune-mediated adverse event (imAE) defined as adverse events (AEs) 
of immune nature (ie, inflammatory) in the absence of a clear alternative etiology. In 
the absence of clinical abnormality, repeat laboratory testing will need to be performed 
to confirm a significant laboratory finding prior to designating it as a DLT. 
• Any > Grade 3 colitis irrespective of duration 
• Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
• Any Grade 2 or greater pneumonitis that does not resolve to ≤ Grade 1 within 3 days 
of the initiation of maximal supportive care. 
• Any Grade 3 imAE, (except colitis or pneumonitis, see above), that does not resolve to 
Grade 2 within 3 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline 
within 14 days. 
• Any ≥ Grade 3 non-imAE deemed by the treating physician to be probably causally 
related to MEDI4736 except those listed below which are NOT considered dose 
limiting: 
o Grade 3 fatigue lasting ≤ 7 days 
o 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 subject is asymptomatic 
o Grade 3 inflammatory reaction attributed to a local antitumor response (eg, 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc) 
o Concurrent vitiligo or alopecia of any AE grade 
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o Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
o 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 
o Grade 3 or 4 lymphopenia 
o 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 
o 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 
 
6.5 
Dose Modification and Toxicity Management 
6.5.1 
MEDI4736 
For adverse events (AEs) that are considered at least partly due to administration of 
MEDI4736 the following dose adjustment guidance may be applied: 
• Treat each of the toxicities 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 MEDI4736 along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for 
MEDI4736 (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 MEDI4736 should be permanently 
discontinued. 
 
Following the first dose of MEDI4736, subsequent administration of MEDI4736 can be 
modified based on toxicities observed (see Table 1, 2, and 3 below).   
 
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Based on the mechanism of action of MEDI4736 leading to T-cell activation and proliferation, 
there is the possibility of observing immune mediated Adverse Events (imAEs) during the 
conduct of this study.  Potential imAEs include immune-mediated enterocolitis, dermatitis, 
hepatitis, and endocrinopathies. Subjects should be monitored for signs and symptoms of 
imAEs.  In the absence of an alternate etiology (e.g., infection or PD) signs or symptoms of 
enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be immune-
related.   
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Tables 1, 2, and 3, respectively.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3.  
 
 
 
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Table 1 - Dosing modification and toxicity management guidelines for immune-mediated reactions associated with MEDI4736 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management For 
toxicities not noted 
below) 
Drug administration modifications of study drug/study regimen will be 
made to manage potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per NCI CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of study 
drug/regimen based on CTC grade/severity (table below) , permanently 
discontinue study drug/study regimen for  the following conditions:  
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of 
prednisone per day (or equivalent) within 12 weeks of the start of 
immune-mediated adverse event (imAE) 
• 
Grade 3 recurrence of a previously experienced Grade 3 treatment-
related imAE following resumption of dosing 
It is recommended that management of immune-mediated adverse events 
(imAEs) follow the guidelines presented in this table: 
- 
It is possible that events with an inflammatory or immune-mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
- 
Whether specific immune-mediated events (and/or laboratory indicators 
of such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, infections, etc.) to a possible 
immune-mediated event. In the absence of a clear alternative etiology, 
all such events should be managed as if they were immune related. 
General recommendations follow. 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 PO or IV 
equivalent 
- 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted 
in the guidelines – should progress rapidly to high dose IV 
corticosteroids (methylprednisolone at 2 to 4 mg/kg/day) even if the 
event is Grade 2, and if clinical suspicion is high and/or there has been 
clinical confirmation. Consider, as necessary, discussing with the study 
physician, and promptly pursue specialist consultation.  
- 
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 PO or IV equivalent]) until stabilization or improvement of 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen 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 after completion of steroid 
taper 
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement can be 
retreated with study drug/study regimen 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 


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Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below 
symptoms, then resume corticosteroid tapering at a slower rate (> 28 
days of taper). 
 
- 
More potent immunosuppressives such as TNF inhibitors (e.g. 
infliximab) – (also refer to the individual sections of the imAEs for 
specific type of immunosuppressive) should be considered for events not 
responding to systemic steroids. Progression to use of more potent 
immunosuppressives should proceed more rapidly in events with high 
likelihood for morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the guidelines – 
when these events are not responding to systemic steroids. 
- 
With long-term steroid and other immunosuppressive use, consider need 
for Pneumocystis jirovecii pneumonia (PJP, formally known as 
Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal 
protection, and glucose monitoring.  
- 
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 upon a 
benefit/risk analysis for that patient.  
 
 
 
 
 
Grade 4 
Permanently discontinue study drug/study regimen  
 
 
Note: For Grade ≥3 asymptomatic amylase or lipase levels of >2X ULN, 
hold study drug/study regimen, and if complete work up shows no evidence 
of pancreatitis, study drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in 
Grade 3 events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in 
the guidelines. Similarly, consider whether study drug/study regimen should 


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be permanently discontinued in Grade 2 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other similar events even 
if they are not currently noted in the guidelines – when they do not rapidly 
improve to Grade ‹1 upon treatment with systemic steroids and following 
full taper. 
Note: There are some exception to permanent discontinuation of study drug 
for Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes 
mellitus). 
 
Pediatric Considerations 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of the start of the immune-mediated event (imAE) 
− 
All recommendations for specialist consultation should occur with a pediatric specialist in the specialty 
recommended. 
− 
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG and plasmapheresis that are 
provided for adult patients should also be used for pediatric patients. 
− 
The infliximab 5 mg/kg IV dose recommended for adults is the same as recommended for pediatric 
patients ≥ 6 years old.  For dosing in children younger than 6 years old, consult with a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult with a pediatric specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for PJP prophylaxis, 
gastrointestinal protection, and glucose monitoring. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 53 of 117 
 
 
Adverse Events 
Severity Grade of 
the Event (NCI 
CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Intersti
tial Lung Disease 
(ILD) 
Any Grade 
General Guidance 
For Any Grade: 
- 
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 1  
(Asymptomatic, 
clinical or diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. 
However, consider holding study 
drug/study regimen dosing as clinically 
appropriate and during diagnostic 
work-up for other etiologies 
For Grade 1 (Radiographic Changes Only) 
-      Monitor and closely 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 consults 
Grade 2  
(Symptomatic, 
medical intervention 
indicated, limiting 
instrumental ADL)  
 Hold study drug/study regimen dose 
until Grade 2 resolution to ≤ Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• If toxicity improves to ≤ Grade 1, 
then the decision to reinitiate study 
drug/regimen will be based upon 
treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day PO or IV 
equivalent) 
- 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2-4mg/kg/day started  
- 
If still no improvement within 3-5 days despite IV methylprednisolone at 2-
4/g/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors 
(e.g. infliximab at 5mg/kg every 2 weeks). Caution: Important to rule out sepsis 
and refer to infliximab label for general guidance before using infliximab  


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 54 of 117 
 
 
 
1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects”  
- 
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 infectionsP0FP0FP0F1 
- 
Consider Pulmonary and Infectious Disease Consults 
- 
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 study 
drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life threatening)  
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent  
- 
Obtain Pulmonary and Infectious disease consult; consider, as necessary, 
discussing with study physician. 
- 
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 (please 
refer to current  NCCN guidelines for treatment of  cancer-related infections a 
Diarrhea/ Colitis 
Large intestine 
perforation/Intestine 
perforation 
 
 
 
 
 
Grade of Diarrhea 
(CTCAE version 5.0) 
General Guidance 
- 
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) 
- 
When symptoms or evaluation indicate a perforation is suspected, consult a surgeon experienced 
in abdominal surgery immediately without any delay.  
- 
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 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 55 of 117 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
low grade events, in order to prevent potential progression to higher grade event, 
including perforation 
- 
Use analgesics carefully; they can mask symptoms of perforation and peritonitis 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: 
asymptomatic; 
clinical or diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification 
For Grade 1: 
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including hydration, electrolyte replacement, 
dietary changes (e.g., American Dietetic Association colitis diet), and loperamide. 
Use of probiotics as per treating physician’s clinical judgment. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 56 of 117 
 
 
 
2 ASCO Educational Bcatook 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects   
 
 
 
Grade 2 
(Diarrhea: stool 
frequency of 4-6 over 
baseline per day; 
intervention not 
indicated) 
(Colitis: abdominal 
pain; mucus or blood 
in stool) 
(Perforation: invasive 
intervention not 
indicated) 
 
 
 
  
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to ≤ Grade 1, 
then study drug/study regimen can 
be resumed after completion of 
steroid taper 
For Grade 2: 
- 
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 event is 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 
weeksP1FP1FP1F2
PPP). Caution: Important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab 
- 
Consider, as necessary, discussing with 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 (please refer to 
current  NCCN guidelines for treatment of  cancer-related infections.PPPa 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 57 of 117 
 
 
 
Grade 3 or 4 diarrhea  
 
(Grade 3 diarrhea: 
stool frequency of ≥7 
over baseline per day; 
limiting self care 
ADL 
 
Grade 4 diarrhea: life 
threatening 
consequences) 
 
(Grade 3 colitis: 
severe abdominal 
pain, change in bowel 
habits, medical 
intervention 
indicated, peritoneal 
signs; Grade 4 colitis: 
life threatening 
consequences, urgent 
intervention 
indicated) 
(Grade 3 Perforation:   
invasive intervention 
indicated;  
Grade 4 Perforation: 
life-threatening 
consequences; urgent 
intervention 
indicated) 
Grade 3 
 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study 
drug/study regimen can be 
resumed after completion of 
steroid taper. 
 
Grade 4 
 
Permanently discontinue study 
drug/study regimen. 
 
For Grade 3 or 4: 
- 
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 to 
4mg/kg/day or equivalent, promptly start further immunosuppressives (e.g. 
infliximab at 5mg/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 (please refer to current NCCN 
guidelines for treatment of  cancer-related infections.PPPa 
 
 
 
 
 
 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 58 of 117 
 
 
Hepatitis  
(elevated LFTs) 
 
Infliximab should 
not be used for 
management of 
immune-related 
hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
- 
Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications). 
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5-
3.0×baseline if 
baseline abnormal; 
and/or TB >ULN and 
≤1.5×ULN if baseline 
normal, >1.0-
1.5×baseline if 
baseline abnormal) 
• No dose modifications. 
• If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 59 of 117 
 
 
Grade 2  
(AST or  
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-
5×baseline if baseline 
abnormal; and/or  
TB >1.5×ULN and 
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if 
baseline abnormal) 
 
 
 
 
 
 
• Hold study drug/study regimen dose 
until Grade 2 resolution to Grade 
≤1. 
• If toxicity worsens, then treat as 
Grade 3. 
• If toxicity improves to Grade ≤1, 
resume study drug/study regimen 
after completion of steroid taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) until elevations of 
these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider, as necessary, discussing with 
study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone 
PO or IV equivalent, consider additional workupwork up and start prompt treatment with 
IV methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (i.e., mycophenolate mofetil).a 
Discuss with study physician if mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
− 
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections).PPPa 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 60 of 117 
 
 
Grade 3 or 4 
(AST or  
ALT >5.0×ULN and 
≤20×ULN if baseline 
normal, >5-20× 
baseline if baseline 
abnormal; and/or  
TB >3.0×ULN  and  
≤10.0×ULN if 
baseline normal, 
>3.0-10.0× baseline if 
baseline abnormal) 
(Grade 4: (AST or 
ALT >20×ULN if 
baseline normal, 
>20×baseline if 
baseline abnormal; 
and/or  
TB >10×ULN if 
baseline normal, 
>10.0×baseline if 
baseline abnormal)   
 
 
Grade 3: 
For elevations in transaminases ≤8 × 
ULN, or elevations in bilirubin ≤5 × 
ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 
or baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For evaluations in transaminases >8 × 
ULN or elevations in bilirubin >5 × 
ULN, discontinue study drug/study 
regimen. 
Permanently discontinue study 
drug/study regimen 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.PPPb 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or 
equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, promptly start treatment with immunosuppressive 
therapy (i.e., mycophenolate mofetil). Discuss with study physician if mycophenolate is not 
available. Infliximab should NOT be used. 
− 
Perform hepatology consult, abdominal workup, and imaging as appropriate. 
− 
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections).PPPa 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 61 of 117 
 
 
Hepatitis 
(elevated LFTs) 
  
Infliximab should 
not beused for 
management of 
immune-related 
helpatitis. 
 
See instructions at 
bottom of shaded 
area if transaminase 
rise is not isolated 
but (at any time) 
occurs in setting of 
either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
Any Grade 
General Guidance 
For Any Grade: 
- 
Monitor and evaluate liver function test: AST, ALT, ALP, and TB. 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications, worsening of liver cirrhosis [e.g., portal vein thrombosis]). 
- 
For HBV+ patients: evaluate quantitative HBV viral load, quantitative HBsAg, or 
HBeAg 
- 
For HCV+ patients: evaluate quantitative HCV viral load 
- 
onsider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral medications for any patient with an elevated 
HBC viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious disease specialist regarding 
change/implementation in/of antiviral medications  for any patient with an elevated HBV 
viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious Disease specialist regarding change/implementation 
in/of antiviral HCV medications if HCV viral load increased by ≥2-fold 
- 
 
- 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as above 
 
 
 
 
 
 
• 
 
 
 
(Isolated AST or ALT 
>ULN and <5.0 x 
ULN, whether normal 
or elevated at 
baseline. 
• 
No dose modifications 
• 
If ALT/AST elevations represents 
significant worsening based n 
investigator assessment, then treat  
event as described for elevations in 
the row below.  
For all transaminase elevations, see 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 62 of 117 
 
 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at 
any time) occurs in stetting of either 
increasing bilirubin or signs of 
DILI/liver decompensation 
 
 
(Isolated AST or AST 
or ALT >5.0×ULN 
and ≤8.0×ULN, if 
normal at baseline) 
 
 
(Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline) 
• 
Hold study drug/study regimen 
dose until resolution to AST or 
ALT ≤5.0×ULN. 
• 
If toxicity worsens, then treat as 
described for elevations in the rows 
below. 
 
If toxicity improves to  AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid 
taper. 
 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) until elevations of 
these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal ultrasound, including Doppler 
assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and investigator suspects toxicity to be 
immune-mediated AE, recommend to start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 2 mg/kg/day of prednisone PO 
or IV equivalent, consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, consider additional abdominal workup (including liver biopsy) 
and imaging (i.e., liver ultrasound), and consider starting immunosuppressives (i.e., 
mycophenolate mofetil). Discuss with study physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used. 
 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 63 of 117 
 
 
 
 
(Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if 
normal at baseline) 
 
(Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN at 
baseline) 
 
 
• 
 Hold study drug/study regimen 
dose until resolution to  AST or 
ALT ≤5.0×ULN. 
• 
Resume study drug/study regimen 
if elevations downgrade to AST or 
ALT ≤5.0×ULN within 14 days 
and after completion of steroid 
taper. 
• 
Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
AST or ALT ≤5.0×ULN  within 14 
days 
 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause. 
 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) until elevations of these 
are improving or resolved. 
− 
Consult hepatologist (unless investigator is hepatologist); obtain abdominal ultrasound, 
including Doppler assessment of liver perfusion; and consider liver biopsy. 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day methylprednisolone IV 
or equivalent, obtain liver biopsy (if it has not been done already) and promptly start 
treatment with immunosuppressive therapy (mycophenolate mofetil). Discuss with 
study physician if mycophenolate is not available. Infliximab should NOT be used. 
− 
Once the patient is 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). a 
 
 
 
 
 
 
 
 
(Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline) 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
If transaminase rise is not isolated (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if >ULN at baseline) or 
signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if 
elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and 
≤20.0×ULN, if  elevated >ULN at baseline) 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 64 of 117 
 
 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
Nephritis or Renal 
Dysfunction  
 
(Elevated Serum 
Creatinine)  
Any Grade  
General Guidance 
 
 
For Any Grade: 
- 
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 1  
[Serum Creatinine >  
ULN to 1.5X ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any accompanying symptoms 
• 
If creatinine returns to baseline, resume its regular monitoring per study 
protocol. 
• 
If creatinine worsens, depending on the severity, treat as Grade 2 or 
Grade 3 or 4  
-      Consider symptomatic treatment including hydration, electrolyte replacement, 
diuretics, etc. 
− 
If baseline serum creatinine is elevated above normal, and there is a rise to > 1 to 
1.5 × baseline, consider following recommendations in this row. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 65 of 117 
 
 
Grade 2  
[Serum 
Creatinine>1.5-3.0X 
baseline; >1.5X-
3.0XULN] 
 
Hold study drug/study regimen 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 then resume study 
drug/study regimen after 
completion of steroid taper   
For Grade 2 elevated creatinine:  
- 
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 to 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 (please refer to 
current NCCN guidelines for treatment of cancer-related infections) a.  
- 
When event returns to baseline, resume study drug/study regimen and routine 
serum creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 X 
ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN)  
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4: 
- 
Carefully monitor serum creatinine on daily basis 
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
Promptly start prednisone 1 to 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 2-4mg/kg/day started.  
- 
Once improving, gradually taper steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP treatment (please refer to current NCCN 
guidelines for treatment of  cancer-related infections. a  
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin Rash  
(Please refer to NCI 
CTCAE version 5.0 
for definition of 
General Guidance 
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  IF SUSPECT 
STEVENS-JOHNSON SYNDROME OR TOXIC EPIDERMAL 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 66 of 117 
 
 
severity/grade 
depending on  type of 
skin rash)  
NECROLYSIS.** 
Grade 1  
No dose modification 
For Grade 1: 
- 
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 scheduled study 
drug/study regimen until resolution 
to ≤ Grade 1 or baseline  
• 
If toxicity worsens then treat 
as Grade 3  
• 
If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper    
For Grade 2 : 
- 
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 of rash/skin lesions occurs within 3-5 days or is worsening 
despite symptomatic treatment and/or use of moderate strength topical steroid, 
consider, as necessary, discussing with study physician and promptly start 
systemic steroids prednisone 1-2 mg/kg/day PO or IV equivalent.  If > 30% body 
surface area is involved, consider initiation of systemic steroids promptly.   
- 
Consider skin biopsy if persistent for >1-2 weeks or recurs 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
 If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin 
rash to ≤ Grade 1 or baseline within 
30 days, then permanently 
discontinue Study drug/study 
regimen  
For Grade 3 or 4 (or life-threatening): 
- 
Consult Dermatology  
- 
 Promptly initiate empiric IV methylprednisolone 1 to 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 (please refer to current NCCN 
guidelines for treatment of cancer-related infections)a 
- 
Consider, as necessary, discussing with Study Physician 
Grade 4 (or life-
threatening) 
Permanently discontinue study 
drug/study regimen  


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 67 of 117 
 
 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
thyroiditis, Type 1 
diabetes mellitus, 
hypophysitis, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section) 
 
 
 
 
 
 
 
 
 
 
 
Any Grade  
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 5.0 for 
defining the CTC 
grade/severity)  
General Guidance 
- 
Consider consulting an Endocrinologist for endocrine events. 
- 
Consider, as necessary, discussing with study physician. 
- 
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, polydipsia, polyuria, hypotension 
and weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression including brain metastases, infections, etc.) 
- 
Depending on the suspected endocrinopathy, monitor and evaluate thyroid 
function tests: TSH, free T RRR3
RRR and free TRRR4 
RRRand other relevant endocrine and related 
labs (e.g., blood glucose and ketone levels, HgA1c). 
- 
For asymptomatic elevations in serum amylase and lipase >ULN and <3×ULN, 
corticosteroid treatment is not indicated as long as there are no other signs or 
symptoms of pancreatic inflammation.  
- 
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 1 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 5.0 for 
defining the CTC 
grade 1) 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- 
Monitor patient with appropriate endocrine function tests 
- 
For suspected hypophysitis/hypopituitarism, consider consultation of an 
endocrinologist to guide assessment of early-morning ACTH, cortisol, TSH and 
free T4; also consider gonadotropins, sex hormones, and prolactin levels, as well 
as cosyntropin stimulation test (though it may not be useful in diagnosing early 
secondary adrenal insufficiency). 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of range in 2 
subsequent measurements, include FT4 at subsequent cycles as clinically 
indicated and consider consultation of an endocrinologist. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 68 of 117 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 2  
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 5.0 for 
defining the CTC 
grade/severity 2) 
  
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study 
regimen dose until  subject is 
clinically stable 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper 
   Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement can be retreated 
with study drug/study regimen 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. 
For Grade 2: (including those with symptomatic endocrinopathy) 
- 
Consult endocrinologist to guide evaluation of endocrine function and, as 
indicated by suspected endocrinopathy and as clinically indicated by suspected 
endocrinopathy and as clinically indicated, consider pituitary scan. 
- 
For all patients with abnormal endocrine work up, except those with isolated 
hypothyroidism or Type 1 DM, and as guided by an endocrinologist, 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. hydrocortisone, sex hormones). 
- 
Isolated hypothyroidism may be treated with replacement therapy, without study 
drug/study regimen interruption, and without corticosteroids.  
- 
Isolated Type 1 diabetes mellitus (DM) may be treated with appropriate diabetic 
therapy, without study drug/study regimen interruption, and without 
corticosteroids. 
- 
Once patients on steroids are improving, gradually taper immunosuppressive 
steroids (as appropriate and with guidance of endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP treatment (please refer 
to current NCCN guidelines for treatment of cancer-related infectionsPPPa 
- 
For patients with normal endocrine work up (lab or MRI scans), repeat labs/MRI 
as clinically indicated. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 69 of 117 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 5.0 for 
defining the CTC 
grade/severity 3 or 4)  
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study drug/study 
regimen dose until endocrinopathy 
symptom(s) are controlled. 
Study drug/study regimen can be 
resumed once event stabilizes and after 
completion of steroid taper. 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insuffiency) can be retreated wth study 
drug/study regimen 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. 
3. Doses of prednisone are <10 
mg/day or equivalent. 
 
For Grade 3 or 4: 
- 
Consult endocrinologist to guide evaluation of endocrine function and, as 
indicated by suspected endocrinopathy and as clinically indicated by suspected 
endocrinopathy and as clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
- 
For all patients with abnormal endocrine work up, except those with isolated 
hypothyroidism  or Type 1 DM, and as guided by an endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
- 
or adrenal crisis, severe dehydration, hypotension, or shock: immediately initiate 
intravenous corticosteroids with mineralocorticoid activity. 
- 
Isolated hypothyroidism may be treated with replacement therapy, without study 
drug/study regimen interruption, and without corticosteroids. 
- 
Isolated Type 1 diabetes mellitus may be treated with appropriate diabetic therapy, 
without study drug/study regimen interruption, and without corticosteroids. 
- 
Once improving, gradually taper immunosuppressive steroids (as appropriate and 
with guidance of endocrinologist) over ≥28 days consider prophylactic antibiotics, 
antifungals and anti PCP treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections) 
Neurotoxicity 
(to include but not 
be limited to limbic 
encephalitis and 
autonomic 
Andy Grade 
(depending on the 
type of neurotoxicity, 
refer to NCI CTCAE 
v5.0 for defining the 
General Guidance 
For Any Grade: 
- 
Patient should be evaluated to rule out any alternative etiology (e.g., disease 
progression, infections, metabolic syndromes, or medications). 
- 
Monitor patient for general symptoms (headache, nausea, vertigo, behavior 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 70 of 117 
 
 
neuropathy, 
excluding 
Myasthenia Gravis 
and Guillain-Barre) 
 
CTC grade/severity) 
change, or weakness). 
- 
Consider appropriate diagnostic testing (e.g., electromyogram and nerve 
condition investigations). 
- 
Perform symptomatic treatment with neurological consult as appropriate. 
Grade 1 
No dose modifications 
For Grade 1: 
See “Any Grade” recommendations above. 
− 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep tendon reflexes or 
paresthesia) 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to ≤ 
Grade 1. 
For sensory neuropathy/neuropathic 
pain, consider holding study drug/study 
regimen dose until resolution to ≤ 
Grade 1. 
If toxicity worsens then treat as Grade 3 
or Grade 4 
Study drug/study regimen can be 
resumed once event improves to Grade 
≤1 and after completion of steroid 
taper. 
For Grade 2: 
- 
Consider, as necessary, discussing 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 or 4 
For Grade 3: 
Hold Study drug/study regimen dose 
until resolution to Grade ≤ 1 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤ 1 within 30 
days. 
 
For Grade 3 or 4: 
- 
Consider, as necessary, discussing with study physician 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 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)  


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 71 of 117 
 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen 
- 
Once stable, gradually taper steroids over ≥28 days 
Peripheral 
neuromotor 
syndromes  
(such as Guillain-
Barre and 
Myasthenia Gravis) 
Any Grade 
General Guidance 
For Any Grade:  
- 
The 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  
It is 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 1 
(Guillain-Barre [GB]:  
mild symptoms) 
(Myasthenia gravis 
[MG]: asymptomatic or 
mild symptoms; clinical 
or diagnostic 
No dose modification 
For Grade 1: 
- 
Consider, as necessary, discussing 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 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 72 of 117 
 
 
observations only; 
intervention not 
indicated)    
Grade 2 
(GB: moderate 
symptoms; limiting 
instrumental ADL) 
(MG: moderate; 
minimal, local or 
noninvasive intervention 
indicated; limiting age-
appropriate instrumental 
ADL) 
Hold study drug/study regimen dose 
until resolution to Grade ≤ 1 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤ 1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic 
instability 
 
For Grade 2: 
- 
Consider, as necessary, discussing 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 
o 
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. 
o 
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. 
o 
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:  
o 
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 3 or 4 
(Grade 3 GB: severe 
symptoms; limiting self 
care ADL;  
For Grade 3: 
Hold study drug/study regimen dose 
until resolution to Grade ≤ 1 
Permanently discontinue study 
For Grade 3 or 4 (severe or life-threatening events): 
For severe or life threatening (Grade 3 or 4) events:  
- 
Consider, as necessary, discussing with study physician. 
- 
Recommend hospitalization 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 73 of 117 
 
 
Grade 4 GB: life-
threatening 
consequences; urgent 
intervention indicated; 
intubation) 
(Grade 3 MG: severe or 
medically significant but 
not immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated; limiting self 
care ADL;  
Grade 4 MG: life-
threatening 
consequences; urgent 
intervention indicated) 
drug/study regimen if Grade 3 imAE 
does not resolve to ≤ Grade 1 within 30 
days or if there are signs of respiratory 
insufficiency or autonomic instability 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia Gravis.  They 
should typically be administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for treatment with 
plasmapheresis or IV IG. 
o 
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 IV IG and followed by 
plasmapheresis if not responsive to IV IG 
Grade 4 
Permanently discontinue study 
drug/study regimen 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade: 
- 
The prompt diagnosis of immune-mediated myocarditis is important, particularly 
in patients with baseline cardiopulmonary disease and reduced cardiac function. 
- 
Consider, as necessary, discussing with the study physician. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 74 of 117 
 
 
- 
Monitor patients for signs and symptoms of myocarditis (new onset or worsening 
chest pain, arrhythmia, shortness of breath, peripheral edema). As some symptoms 
can overlap with lung toxicities, simultaneously evaluate for and rule out 
pulmonary toxicity as well as other causes (e.g., pulmonary embolism, congestive 
heart failure, malignant pericardial effusion). A Cardiology consultation should be 
obtained early, with prompt assessment of whether and when to complete a 
cardiac biopsy, including any other diagnostic procedures. 
- 
Initial work-up should include clinical evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting 
and exertion), and additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion abnormalities when 
needed. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., 
disease progression, other medications, or infections) 
 
Grade 1 
(asymptomatic or 
mild symptoms*; 
clinical or diagnostic 
interventions only; 
intervention not 
indicated(treat 
myocarditis with mild 
symptoms as Grade 
2) 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen 
is held, resume after complete 
resolution to Grade 0. 
For Grade 2-4: 
- 
Monitor and closely follow up in 2 to 4 days for clinical symptoms,  BNP, cardiac 
enzymes, ECG, ECHO, pulse oximetry (resting and exertion), and laboratory work-
up as clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to Grade 
0. If toxicity rapidly improves to Grade 
For Grade 2-4: 
- 
Monitor symptoms daily, hospitalize. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 75 of 117 
 
 
(Grade 2: Symptoms 
with moderate 
activity or exertion) 
 
(Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention 
indicated; new onset 
of symptoms) 
 
(Grade 4: Life 
threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic 
support)) 
0, then the decision to reinitiate study 
drug/study regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid taper. If 
toxicity does not rapidly improve, 
permanently. discontinue study 
drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
- 
Promptly start IV methylprednisolone 2 to 4mg/kg/day or equivalent after 
Cardiology consultation has determined whether and when to complete diagnostic 
procedures including a cardiac biopsy. 
- 
If no improvement within 3 to 5 days despite IV methylprednisolone at 2 to 
4mg/kg/day, promptly start immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5mg/kg every 2 weeks). Caution: It is important to rule out sepsis 
and refer to infliximab label for general guidance before using infliximab.  
- 
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections.a 
Myositis / 
Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal muscles including upper arms, thighs, 
shoulders, hips, neck and back, but rarely affects the extremities including hands 
and fingers; also difficulty breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of tiredness and fatigue may occur, 
and there can be new-onset falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, and/or reaching up. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 76 of 117 
 
 
− 
If poly/myositis is suspected, a Neurology consultation should be obtained early, 
with prompt guidance on diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) autoimmune disorder, 
consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up as indicated, including a number of 
possible rheumatological/antibody tests (i.e., consider whether a rheumatologist 
consultation is indicated and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal-
recognition particle antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of the muscles, and/or a muscle 
biopsy. Consider Barium swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical symptoms and initiate 
evaluation as clinically indicated. 
− 
Consider Neurology consult. 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently 
discontinue 
study 
drug/study regimen if it does not resolve 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 77 of 117 
 
 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
− 
If clinical course is rapidly progressive (particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids UUUalong with receiving input UUU from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no improvement within 3 to 
5 days, continue additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infections.PPPa 
 
Grade 3 or 4 
Grade 3: pain 
associated with severe 
weakness; limiting 
self-care ADLs 
Grade 4: life-
threatening 
consequences; urgent 
intervention indicated 
For Grade 3: 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic steroids UUUalong 
with receiving inputUUU from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, consider start of immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 


APPROVED BY THE YALE UNIVERSITY IRB 2/26/2021
Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 78 of 117 
 
 
PPPa
PPPASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
PPPb
PPPFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea 
nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV 
Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive 
Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF 
Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
Once the patient is improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, or anti-PJP treatment (refer to current NCCN guidelines 
for treatment of cancer-related infectionsPPPa 


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Table 2 - Dosing modification and toxicity management guidelines for infusion-related reactions associated with MEDI4736 
Severity Grade 
of the Event 
(NCI CTCAE 
version 5.0) 
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 study drug/study regimen 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 study drug/study regimen may 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 study drug/study regimen 
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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Non-immune Mediated Reactions 
 
(Note: As applicable, for early phase studies, the following sentence may be added:  
“Any event greater than or equal to Grade 2, please discuss with Study Physician” 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
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; imAE = immune-mediated 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. 
PPPa
PPP ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD  
PPPib
PPP NCI CTCAE version 5.0 


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6.5.2 
Nab-paclitaxel 
Nab-paclitaxel dose will be reduced for 
- 
Grade 3 peripheral neuropathy (i.e. sensory alteration or paresthesia interfering with normal daily 
activities); treatment with nab-paclitaxel will be held for a maximum of 14 days. If symptoms 
improve within this time period to grade 2 or less, resume nab-paclitaxel at 80 mg/mPPP2
PPP dose. If 
neuropathy does not resolve to grade 2, discontinue nab-paclitaxel and start the 
doxorubicin/cyclophosphamide phase of the treatment. 
 
- 
Absolute neutrophil count (ANC) is below < 1000/microliter or platelet count < 100,000/microliter 
on the day of chemotherapy administration, nab-paclitaxel should be held and complete blood count 
repeated 24 hours later. Resume administration of nab-paclitaxel at full dose once ANC >1000 and 
Plt > 100,000. Use G-CSF with subsequent treatments to prevent dose delays should follow NCCN 
practice guidelines (18). 
 
6.5.3 
Dose dense doxorubicin/cyclophosphamide (ddAC) 
The dose of doxorubicin/cyclophosphamide will be reduced for 
- 
Absolute neutrophil count (ANC) is below < 1000/microliter or platelet count < 100,000/microliter 
on the day of chemotherapy administration, ddAC should be held and complete blood count repeated 
24 hours later. Resume administration of ddAC at 20% reduced dose for both drugs for all 
subsequent cycles. 
 
6.5.4 
Toxicity management guidelines for combination treatment regimen 
MEDI4736 and nab-paclitaxel or doxorubicin and cyclophosphamide are not expected to have overlapping 
toxicities other than fatigue and nausea. These side effects, as well as all other chemotherapy related side 
effects, will be managed following routine clinical practice (i.e. antiemetics, growth factors, dose delays and 
dose reductions as described in sections 6.5.1-3).   
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7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S) 
7.1 
Restrictions during the study 
Contraception must be practiced 
Non-sterilised male patients who are sexually active with a female partner of childbearing potential and female 
patients of childbearing potential who are sexually active with a non-sterilised male partner must use 2 methods 
of effective contraception from screening, and must agree to continue using such precautions for 6 months after 
the final dose of MEDI4736 and AC chemotherapy.  Females of childbearing potential are those who are (i) not 
surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or (ii) 
postmenopausal defined as 12 months with no menses without an alternative medical cause. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 
• All subjects, male or female, with childbearing potential as defined above must use a combination of two 
acceptable methods of effective contraception. Effective methods of contraception are listed in Table 4. 
Table 4. Effective methods of contraception (a combination of two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal 
Methods 
Male condom plus spermicide 
Copper T 
Implants 
 
Cap plus spermicide 
 
Progesterone T 
 
Hormone shot or 
injection 
 
Diaphragm plus spermicide 
 
Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena84TP84TP84TP®
PPP84T84T84T) 
 
Combined pill 
Minipill 
Patch 
 
Blood donation 
Subjects should not donate blood while participating in this study, or for at least 90 days following the last 
infusion of MEDI4736. 
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7.2 
Concomitant treatment(s) 
7.2.1 
Permitted concomitant medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, diphenhydramine) 
deemed necessary to provide adequate prophylactic or supportive care except for those medications identified as 
“excluded” as listed in Section 7.2.2. 
7.2.2 
Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies 
2. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment, 
other than any stated combination regimens. 
3. 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 
subjects 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).    
4. Live attenuated vaccines within 30 days of MEDI4736 dosing (ie, 30 days prior to the first dose, during 
treatment with MEDI4736 and for 30 days post discontinuation of MEDI4736).  Inactivated viruses, 
such as those in the influenza vaccine, are permitted. 
8. 
STUDY PROCEDURES 
8.1 
Schedule of study procedures 
Clinical evaluations and laboratory studies may be repeated more frequently if clinically indicated.  The 
Schedules of Assessments during the screening and treatment period is provided following the Protocol 
Synopsis. 
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8.1.1 
Screening Phase 
UUUWithin 6 weeks of study entry: 
1. 
Assessment of the primary tumor with bilateral mammograms and if clinically indicated also with 
ultrasonograms or MRI to determine the clinical T and N stage of the disease. The most recent breast 
imaging that provides tumor size estimate has to be within 12   weeks of study entry.  
 
2. 
If the tumor is less than 2 cm, the tumor site will need to be identified with radiopaque marker via 
ultrasound guidance or tattooing of the skin before starting treatment. This procedure is not necessary for 
patients who have microcalcifications in the breast corresponding to the tumor. 
 
3. 
Obtain 3 core needle biopsies for correlative science studies and blood collection for research (5 ml blood 
will be collected into 1 red-top and 1 green-top tube respectively) 
 
4. 
Systemic staging should follow standard NCCN practice guidelines as appropriate for clinical stage 
(Theriault et 2013). 
 
5. 
Female patients with childbearing potential or must have a negative urine or serum pregnancy test upon 
study entry. 
 
UUUWithin 14 days of starting therapy: 
NOTE: If any of the bellow laboratory assessments are abnormal at time of screening but still within the ranges 
allowed for edibility, these tests will need to be repeated on Day 1 before treatment could commence. 
 
6. 
Complete blood count and differential  
 
7. 
serum creatinine, creatinine clearance   
 
8. 
total bilirubin, AST , ALT 
  
9. 
PT, PTT, INR 
  
10. 
TSH (free T4 if TSH is elevated) 
 
11. 
Patients with elevated liver functions or clinical symptoms or history of hepatitis will also have hepatitis 
panel 
 
(e.g. 
HAV 
Ab; 
HBsAb;  
HBsAg; HBcAb; HCV Ab) to rule out acute hepatitis.  
 
12. 
ECG ( x 3 reads within 5 minutes) 
 
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UUUWithin 7 days of starting therapy 
 
13. 
Complete physical examination  
 
14. 
Review of all systems and medical history 
 
15. 
Patients of childbearing potential must also have urine pregnancy test within 7 days of starting therapy. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required for 
confirmation. 
 
8.1.2 
Treatment Phase  
During neoadjuvant therapy patients must be assessed as follows: 
UUUWeekly before each Nab-paclitaxel therapy and every two-weeks before each AC chemotherapy: 
1. Complete blood count and differential (as per institutional chemotherapy orders) 
2. Nursing assessment as per institutional protocol 
 
UUUEvery Two weeks (before each MEDI4736 treatment): 
1. 
All patients must be seen by the treating physician or advance practice nurse every 2 weeks during the 
treatment (i.e. on the day or 1-2 days before administration of therapy). 
a. Complete history, review of systems and physical exam must be performed including clinical tumor 
measurements. Patients will be monitored for clinical symptoms of immune-mediated adverse reactions 
including enterocolitis, dermatitis, hepatotoxicity, endocrinopathy, pneumonitis, and neuropathy, and 
development of serious infection, infusion related reactions, hypersensitivity reactions. 
b. Toxicity will be graded following the NCI CTCAE version 5.0 criteria. The full text is available online 
at: (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/59T59T59T) 
c. If during therapy the tumor becomes no longer palpable because of response, it is recommended that 
the tumor site is marked with radiopaque marker via ultrasound guidance. This procedure is not 
necessary for patients who have microcalcifications in the breast corresponding to the tumor or already 
have markers placed before starting therapy.  
d. Breast imaging may be repeated any time during therapy if clinically indicated for suspicion of 
progression.  
 
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UUUOnce every 4 weeks (+/- 1 week) after starting therapy and whenever clinically indicated: 
1. Serum creatinine, total bilirubin, AST, and ALT. 
2. Serum TSH and if TSH is elevated free T3 and T4. 
3. Urinalysis 
 
UUUECGs (single trace) will be repeated on week 6 UUU (+/- 1 week) during the Nab-paclitaxel therapy UUUand on week 17UUU (+/- 
1 week) during the AC part of the chemotherapy. 
 
UUUAfter completion of all preoperative chemotherapy but before surgery 
1. Repeat blood collection for research will be performed 2 weeks (+/- 1 week) after completion of the last dose 
of neoadjuvant therapy (5 ml blood will be collected into 1 red-top and 1 green-top tube respectively). 
 
Surgery: 
It is recommended that surgery be performed within 4 weeks of completion of the last chemotherapy unless 
medical contraindications exist. Surgical resection of the tumor bed and axillary sampling should follow standard 
clinical practice. 
In patients who have residual invasive cancer, 10 FFPE sections (5 micron each) will be collected for correlative 
science studies after routine pathology examination of the surgical specimen is completed. 
 
Post-treatment follow-up: 
Three delayed toxicity assessments will be performed after completion of neoadjuvant therapy. Each visit will 
include complete medical history, toxicity assessment, physical examination and serum AST, ALT, total Bilirubin 
and complete blood count assessment. 
The first is 2 weeks (+/- 1 week) after completion of the last MEDI4736 therapy. 
The second, at 6 weeks (+/- 1 week) after completion of therapy (approximately 2 weeks after surgery). 
The third is 13 weeks, approximately 90 days (+/- 14 days), after completion of therapy. 
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Delayed toxicities will be reported separately from acute toxicities while on treatment and will not be included in 
the DLT assessment. 
 
8.1.3 
End of Treatment 
End of treatment is defined as the last planned dosing visit prior to surgery.  
 
8.2 
Description of study procedures 
8.2.1 
Medical history and physical examination, electrocardiogram, weight and vital signs 
Findings from medical history (obtained at screening) and physical examination shall be given a baseline grade 
according to the procedure for AEs. Increases in severity of pre-existing conditions during the study will be 
considered AEs, with resolution occurring when the grade returns to the pre-study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the following (as 
clinically indicated): general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including 
ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and extremities), 
genital/rectal, and neurological systems and at screening only, height.   
ECGs are required during screening, within 14 days prior to starting study treatment and will be repeated on 
week 6 (+/- 1 week) during the Nab-paclitaxel therapy and on week 17 (+/- 1 week) during the AC part of the 
chemotherapy, and may be repeated any time if clinically indicated. ECGs recorded during the screening period 
will be obtained in triplicate (all 3 within a 5-minute time period at least 1 minute apart); ECGs recorded during 
the treatment phase will be single tracing. All 12-lead ECGs should be recorded while the subject is in the 
supine position. A 12-lead ECG will be recorded for all subjects on study days noted in Section 8.1. The same 
method of assessment should be used throughout the study. Twelve-lead ECGs will be obtained after the subject 
has been resting in a supine position for at least 5 minutes in each case.  
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on study days noted 
in the Schedule of Assessments. On MEDI4736 treatment days, vital signs will be measured within an hour 
prior to start of MEDI4736 administration, at 30 minutes during the infusion (± 5 minutes), at the end of 
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infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion.  If the 
infusion takes longer than 60 minutes, then temperature, blood pressure, pulse rate, and respiratory rate 
measurements should follow the principles described here, or more frequently if clinically indicated.  For 
subsequent doses (at dose levels of 10 mg/kg or less), the 1-hour observation period will not be required unless 
a subject experiences an infusion-related reaction.  
8.2.2 
Clinical laboratory tests 
Section 8.1.1 and 8.1.2 lists screening and on-treatment laboratory tests that are required during the study.  
Table 5 - Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular haemoglobin 
Total white cell count 
Mean corpuscular hemoglobin concentration 
 
 
 
 
Table 6 - Clinical chemistry (serum or plasma) Laboratory Tests 
Alanine aminotransferase 
PT 
Aspartate aminotransferase 
PTT 
Creatinine 
INR 
Total bilirubinPPPb 
TSH 
 
 
 
PPPa  
PPP If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  bilirubin 
 
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Table 7 - Urinalysis TestsPPPa 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
PPPa
PPP  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red blood cells 
 
8.3 
Biological sampling procedures 
Three pre-treatment core needle biopsies will be obtained and 10 x 5 micron FFPE sections of residual cancer 
tissues will be collected for correlative science research. Tissue samples will be stored de-identified and labelled 
with patient study ID number only in the Breast Cancer Translational Research Laboratory in room 786, 300 
George St, New Haven, CT. 
Blood collection for research  
10 mL blood will be collected for future research before starting therapy and 2 weeks (+/- 1 week) after completion 
of all neoadjuvant therapy but before surgery. Blood samples will be labelled with de-identified patient study 
number and will be picked up by a laboratory personnel and stored in the Breast Cancer Translational Research 
Laboratory in room 786, 300 George St, New Haven, CT. 
 
Estimate of volume of blood to be collected. The total volume of blood that will be drawn from each 
subject in this study is as follows: 
Table 8 - Volume of blood to be drawn from each subject 
Assessment 
Sample volume (mL) 
No. of samples 
Total volume (mL) 
Safety 
Clinical chemistry 
10 ml 
5 
50 mL 
 
Hematology 
5 ml 
20 
100 mL 
For Future Research 
10 mL total (red- and green-top 
tubes, 5 mL each) 
4 (samples at 
baseline and two 
samples after 
treatment) 
20 mL 
Total 
 
 
170 mL 
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8.3.1 
Fresh tumor biopsies before starting therapy 
 
Three core needle biopsies of the cancer will be obtained for correlative science studies before starting the first 
course of therapy. Tissue collection will be performed by a breast surgeon (if the lesion is palpable) or by 
radiologist (for non-palpable lesions) or their designate following standard operating procedure for diagnostic 
biopsies. 
a. 
1 core biopsy sample will be placed into 1.5 ml plastic vials containing RNAlater™ (Qiagen). RNA 
later vial labeled with de-identified patient study number will be supplied by the Pusztai laboratory. 
The sample in RNAlater will be picked up by a laboratory personnel and stored in the Breast Cancer 
Translational Research Laboratory in room 786, 300 George St, New Haven, CT. 
 
b. 
1 biopsy sample will be placed in Corning 2 ml cryogenic vial and snap freeze in liquid nitrogen. 
The frozen sample will be picked up by a laboratory personnel and stored in the Breast Cancer 
Translational Research Laboratory in room 786, 300 George St, New Haven, CT. 
 
c. 
1 biopsy sample will be placed in formalin for fixation and will be embedded in paraffin following 
standard clinical operating procedure. Specimens will be labelled with de-identified patient study 
number and samples will be picked up by a laboratory personnel and stored in the Breast Cancer 
Translational Research Laboratory in room 786, 300 George St, New Haven, CT.. 
 
8.3.1.1 
Tumor tissue from surgical resection 
In patients who have residual invasive cancer, 10 FFPE sections (5 micron each) will be collected for correlative 
science studies to assess immune parameters and the genomic architecture of the cancer that survived therapy. The 
sections will be cut after completion of routine pathology assessment for pCR. Specimens will be labelled with 
de-identified patient study number and samples will be picked up by a laboratory personnel and stored in the Breast 
Cancer Translational Research Laboratory in room 786, 300 George St, New Haven, CT. 
 
8.3.2 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated samples, the samples will be disposed of/destroyed, and the 
action documented. The Principal Investigator: 
Ensures that biological samples from that subject, if stored at the study site, are immediately identified, 
disposed of /destroyed, and the action documented 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent immediately and 
that samples are disposed/destroyed, the action documented and the signed document returned to the study 
site 
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Ensures that the subject is informed about the sample disposal. 
9. 
DISEASE EVALUATION AND METHODS 
9.1.1 
Pathologic Complete Response (pCR) 
The primary efficacy endpoint is pathologic complete response (pCR). Pathologic response will be assessed in 
the surgically resected cancer and lymph nodes after completion of all chemotherapy by the local pathologist as 
part of routine care. Pathologic complete response is defined as no invasive cancer in the resected breast tissue 
and lymph nodes (ypT0/Tis, ypN0). This information will be extracted from the pathology report and patients 
will be assigned to one of two response categories, pCR or residual disease (RD) for the purpose of efficacy 
analysis. 
10. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff involved in the study is familiar with the 
content of this section. 
10.1.1 
Safety Parameters 
10.1.1.1 Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6(R1) 
defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-existing condition. 
An abnormal laboratory finding (including ECG finding) that requires an action or intervention by the 
investigator, or a finding judged by the investigator to represent a change beyond the range of normal 
physiologic fluctuation, should be reported as an AE. 
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Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational product) or 
nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or other untoward 
medical event that begins after written informed consent has been obtained but before the subject has received 
investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the subject being 
enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, is not 
considered an AE (serious or nonserious). An untoward medical event occurring during the prescheduled 
elective procedure or routinely scheduled treatment should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
10.1.2 
Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, treatment, wash-out, 
follow-up), at any dose of the study drugs that fulfils one or more of the following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability or incapacity  
Is a congenital abnormality or birth defect in offspring of the subject 
Is an important medical event that may jeopardize the patient or may require medical intervention to prevent 
one of the outcomes listed above. 
• 
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the 
investigator(s) and communicated to AstraZeneca. 
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10.1.3 
Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is an event of scientific and medical interest specific to the further 
understanding of the MEDI4736 safety profile and require close monitoring and rapid communication by the 
investigator to the sponsor. MEDI4736 AESIs may be serious or non-serious. The rapid reporting of these 
AESIs allows ongoing analysis of these events in order to characterize and understand them in association with 
the use of this investigational product. 
If the Investigator has any questions in regards to an event being an imAE, the Investigator should promptly 
contact the Study Physician. 
MEDI4736, an anti-PD-L1 antibody, and belongs to a new class of anticancer therapies, called “checkpoint-
inhibitors” that amplify antitumor immune responses by blocking inhibitory signaling pathway modulated by 
the co-inhibitory or co-stimulatory receptors, CTLA-4 and PD-1, expressed on T cells (Callahan and Wolchok, 
2013). This class of drugs can have a wide spectrum of immune-mediated reactions that have been considered 
inflammatory in nature and can affect any organs of the body.  
AESIs observed with durvalumab include: 
• 
Diarrhea / Colitis and intestinal perforation 
• 
Pneumonitis / ILD 
• 
hepatitis / transaminase increases 
• 
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypothyroidism and type I diabetes mellitus) 
• 
Rash / Dermatitis 
• 
Nephritis / Blood creatinine increases 
• 
Pancreatitis / serum lipase and amylase increases   
• 
Myocarditis 
• 
Myositis / Polymyositis 
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• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• 
Intestinal Perforations 
Other inflammatory responses that are rare/less frequent with a potential immune-mediated etiology include, but 
are not limited to: 
• 
Pericarditis 
• 
Sarcoidosis 
• 
Uveitis 
• 
Other events involving the eye and skin 
• 
Hematological events 
• 
Rheumatological events 
• 
Vasculitis 
• 
Non-infectious meningitis 
• 
Non-infectious encephalitis.  
It is possible that events with an inflammatory or immune mediated mechanism could occur in nearly all organs. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological aetiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the 
durvalumab Investigator’s Brochure. More specific guidelines for their evaluation and treatment are described 
in detail in the Dosing Modification and Toxicity Management Guidelines (please see Appendix 1). These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities.  These guidelines apply to AEs considered causally related to the 
study drug/study regimen by the reporting investigator. 
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10.1.3.1 Pneumonitis 
Immune-mediated pneumonitis is characterized by inflammation focally or diffusely affecting the lung 
parenchyma that may be result of off-target effects of checkpoint inhibitors against the normal lung 
parenchyma. (Chow, 2013) Presentations of pneumonitis range from asymptomatic lung infiltrates to a mimic 
of severe bacterial pneumonia. For symptomatic patients, complaints and findings may include dyspnea, cough, 
tachypnea, pleuritic chest pain, and hypoxia. 
The frequency of immune-mediated pneumonitis in clinical trials with immune checkpoint-inhibitors ranged 
from ≤1% to 4%. (Topalian et al, 2012; Brahmer et al, 2012)  
Because pneumonitis can quickly escalate and become fatal, early recognition is essential. Initial workup 
includes chest imaging; however, pneumonitis can have highly variable appearances on chest CT scans.  In 
patients with pulmonary metastases or cardiopulmonary comorbidities, evaluation can be particularly 
challenging as it can be difficult to differentiate between infection, early pulmonary edema, alveolar 
hemorrhage, immune-mediated pneumonitis, immune-related tumor inflammation, and tumor progression 
(Topalian et al, 2012). Pneumonitis has also been reported as a complication of cancer treatment associated with 
lung and breast cancer. 
Guidelines for the management of subjects with immune-mediated events including pneumonitis are outlined in 
Section 6.6.1. 
10.1.3.2 Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L1 and anti-
PD-1 therapy (Topalian et al, 2012; Brahmer et al, 2012). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of MAbs can be caused by various mechanisms, 
including acute anaphylactic (immunoglobulin E-mediated) and anaphylactoid reactions against the MAb, and 
serum sickness. Acute allergic reactions may occur, may be severe, and may result in death. Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) and 
infusion-related reactions are outlined in Section 6.6.1. 
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10.1.3.3 Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 antibodies (Brahmer et 
al 2012).  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with anti-CTLA-4 
monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of ipilimumab-treated subjects included 
general weakness, fatigue, nausea and/or mild fever and increased liver function tests such as AST, ALT, 
alkaline phosphatase, and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and concurrent 
increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other. Follow-up investigations and 
inquiries will be initiated promptly by the investigational site to determine whether the findings are reproducible 
and/or whether there is objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and 
bile duct obstruction with distended gallbladder) or an agent other than the investigational product. Guidelines 
for management of subjects with hepatic function abnormality are outlined in Section 6.6.1. 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to be reported as 
SAEs, These cases should be reported as SAEs if, after evaluation they meet the criteria for a Hy’s Law case or 
if any of the individual liver test parameters fulfill any of the SAE criteria. 
 
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Criteria for Hy’s Law (FDA Guidance 2009) 
• The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater 
elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or placebo  
• Among trial subjects showing such aminotransferase elevations, often with aminotransferases much 
greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x ULN, without 
initial findings of cholestasis (elevated serum alkaline phosphatase)  
• No other reason can be found to explain the combination of increased aminotransferases and total 
bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another drug capable 
of causing the observed injury. 
10.2 
Assessment of safety parameters 
The safety evaluation period during this study extends from date of first treatment until 90 days after completion 
of therapy with MEDI4736 or until resolution from all acute toxicities associated with the drug administration. 
 
10.2.1 
Assessment of severity 
There is a distinction between serious and severe AEs.  Assessment of seriousness will be made solely by the 
serious criteria listed above.  Therefore, serious events will not be automatically considered severe.  For example, 
a stroke that results in only a limited degree of disability may be considered a mild (not severe) stroke, but it would 
still meet serious criteria and thus, be captured as an SAE.  Similarly, severe events may not always be serious.  
An example would be an episode of severe, transient nausea which persists for several hours.  This would be 
classified as a “severe” episode of nausea, but if it did not require treatment, intervention, or somehow meet other 
serious criteria, it would not be considered an SAE. 
Severity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events v5.0.  If 
a certain event or symptom is not described in the CTCAE grades, use the following grading scale: 
Grade 1 (mild)  
 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
 
Grade 2 (moderate)  
An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
 
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Grade 3 (severe)  
An event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects the clinical status of the 
subject. 
 
Grade 4 (life threatening)  
Any adverse drug experience that places the patient or patient, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e. it 
does not include a reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Grade 5 (fatal)  
 
Death (loss of life) as a result of an event. 
 
 
Unexpected AE 
Any adverse drug experience, the specificity or severity of which is not consistent 
with the current investigator brochure; or, if an investigator brochure is not required 
or available, the specificity or severity of which is not consistent with the risk 
information described in the general investigational plan.  “Unexpected” as used in 
this definition, refers to an adverse drug experience that has not been previously 
observed (e.g., included in the investigator brochure) rather than from the 
perspective of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product. 
10.2.2 
Assessment of relationship 
Determination of causality between an adverse event and drug therapy will be made after consideration of all 
clinically relevant data prior to, during, and after occurrence of the event. Clinically relevant data include, but are 
not limited to; underlying disease, past and present medical history (all concurrent non-malignant disease), 
concurrent medications, and timing between event and drug administration. The mechanism of action and prior 
toxicology of the study drug should be considered. An adverse event is associated with the use of the drug when 
there is a reasonable possibility that the drug may have caused the event.  
The following attribution guidelines are recommended by the US National Cancer institute: 
        Unrelated:  The Adverse Event is clearly not related to the investigational agent (s) 
        Unlikely:     The Adverse Event is doubtfully related to the investigational agent(s) 
        Possible:      The Adverse Event may be related to the investigational agent(s) 
        Probable:    The Adverse Event is likely related to the investigational agent(s) 
        Definite:      The Adverse Event is clearly related to the investigational agent(s) 
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10.3 
Recording of adverse events and serious adverse events 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately reflects the event. 
Adverse events will be assessed by the investigator for severity, relationship to the investigational product, 
possible etiologies, and whether the event meets criteria of an SAE and therefore requires immediate 
notification to AstraZeneca/MedImmune Patient Safety. 
The following variables will be collected for each AE: 
AE (verbatim) 
The date and time when the AE started and stopped 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
Whether the AE is serious or not 
Investigator causality rating against MEDI4736 (yes or no) and against combination drug (yes/no) 
Action taken with regard to MEDI4736/comparator/combination agent 
Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
Date AE met criteria for serious AE 
Date Investigator became aware of serious AE 
AE is serious due to 
Date of hospitalization 
Date of discharge 
Probable cause of death 
Date of death 
Autopsy performed 
Description of AE 
Causality assessment in relation to Study procedure(s) 
Causality assessment in relation to Additional Study Drug 
 
 
Events, which are unequivocally due to disease progression, should not be reported as an AE during the study. 
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10.3.1 
Study recording period and follow-up for adverse events and serious adverse events 
Adverse events and serious adverse events will be recorded from time of signature of informed consent, 
throughout the treatment period and including the follow-up period (including a minimum of 90 days after the 
last dose of MEDI4736). 
During the course of the study all AEs and SAEs should be proactively followed up for each subject. Every 
effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. 
If a subject discontinues from treatment for reasons other than disease progression, and therefore continues to 
have tumor assessments, drug or procedure-related SAEs must be captured until the patient is considered to 
have confirmed PD and will have no further tumor assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to baseline 
status, or until the condition has stabilized with the expectation that it will remain chronic, even if this extends 
beyond study participation. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the investigator for as 
long as medically indicated, but without further recording.  After 90 days, only subjects with ongoing 
investigational product-related SAEs will continue to be followed for safety. 
AstraZeneca/MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Post study events 
 
After the subject has been permanently withdrawn from the study, there is no obligation for the investigator to 
actively report information on new AE or SAEs occurring in former study subjects after the 90-day safety 
follow-up period for patients treated with MEDI4736.  However, if an investigator learns of any SAEs, 
including death, at any time after the subject has been permanently withdrawn from study, and he/she considers 
there is a reasonable possibility that the event is related to study treatment, the investigator should notify the 
study sponsor and AstraZeneca/MedImmune Drug Safety. 
 
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10.3.2 
Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the investigational product, or to the 
study procedure(s). The reporting period for SAEs is the period immediately following the time that written 
informed consent is obtained through 90 days after the last dose of MEDI4736 or until the initiation of 
alternative anticancer therapy.  The investigator and/or Sponsor are responsible for informing the Ethics 
Committee and/or the Regulatory Authority of the SAE as per local requirements. 
Yale Principal Investigator SAE Reporting Requirements 
The principal investigator (PI) will assess all expedited adverse events and will periodically review all adverse 
events observed on the trial. The PI will promptly investigate all safety information related to an adverse 
experience.  If the results of the PI’s investigation show an adverse drug experience not initially determined to be 
reportable (based on whether the event is serious, unexpected, and associated with drug administration) is 
reportable, the PI will report such experience.  Follow-up information to a safety report shall be submitted as soon 
as the relevant information is available. 
Yale Safety Reporting And Monitoring (DSMP) 
The PI will monitor the clinical trial for safety and follow the Yale Cancer Center standard operating procedures 
(SOPs) for assessment and reporting of adverse events. These procedures are in compliance with federal 
regulations;  21 CFR 312.32 and 312.22. The clinical trial data consisting of all required observations, AEs, and 
laboratory data are entered into OnCore computerized clinical trial database by Yale Cancer Center Clinical Trials 
Office personnel trained in clinical trial data management.  
The accuracy and completeness of the database, timely submission of SAEs and compliance with the protocol, is 
assured by periodic auditing conducted by the Yale Data Safety Monitoring Board (DSMB).  Safety data will be 
submitted to the DSMB at least once yearly or more often as required by the DSMP.  On a regular interval basis, 
status reports of all laboratory parameters, AEs and SAEs are reviewed by the PI to view composite data across 
all patients.  Regular meetings among the study team are held to discuss ongoing patient treatment and adverse 
events.   
Expedited SAE reports are copied to the Human Investigations Committee (HIC) within the timeframes required 
by Yale. The PI and designated personnel will distribute manufacturer-provided safety reports and updated 
Toxicity Lists to the institution’s HIC and all relevant personnel involved in the conduct of the study.  The Toxicity 
List, in addition to the Investigator’s Brochure, will be used as a reference for reporting any new SAE. 
Reporting of SAE to the Yale Human Investigation Committee 
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All SAEs, whether originating at Yale or a collaborating center, meeting the criteria for expedited reporting will 
be reported to the Yale University Human Investigation Committee (HIC) using HIC Form 6A within 48 hours of 
discovery.  
The HIC expedited reporting criteria are: 
a.   Serious AND unexpected AND possibly, probably or definitely related events; 
b.   Anticipated Adverse Events occurring with a greater frequency than expected. 
The HIC does not require reporting of any other Adverse Event type.  A copy of the HIC reporting policy is 
available at 59T59T59Thttp://info.med.yale.edu/hic/policy/AdverseEventPolicy.pdf  
Reporting of SAE to the FDA and AstraZeneca 
The sponsor must inform the FDA, via a MedWatch/AdEERs form, of any serious or unexpected adverse events 
that occur in accordance with the reporting obligations of 21 CFR 312.32, and will concurrently forward all 
such reports to AstraZeneca.  A copy of the MedWatch/AdEERs report must be faxed to AstraZeneca at the 
time the event is reported to the FDA.  It is the responsibility of the sponsor to compile all necessary 
information and ensure that the FDA receives a report UUUaccording to the FDA reporting requirement timelinesUUU 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
“Notification from an Investigator Sponsored Study” 
The investigator IND number assigned by the FDA 
The investigator’s name and address 
The trial name/title and AstraZeneca reference number (ESR-14-10265) 
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in relation to 
all study medications and if the SAE is related to disease progression, as determined by the principal 
investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s UUUdesignated mailbox:UUU    
59T59T59TAEMailboxClinicalTrialTCS@astrazeneca.com 59T 
 
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If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided to 
AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This information 
should be reported on a monthly basis and under no circumstance less frequently than quarterly.  
10.3.2.1 Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of MEDI4736 safety 
follow-up period must be reported as follows: 
Death that is clearly the result of disease progression should be documented but should not be reported 
as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under study, the AE causing the 
death must be reported to as a SAE within 24 hours (see Section 10.3.2 for further details).  The 
report should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.   
Deaths with an unknown cause should always be reported as a SAE.   
Deaths that occur following the protocol-defined 90-day post-last-dose of MEDI4736 safety follow-up period 
will be documented but will not be reported as an SAE. 
10.3.3 
Other events requiring reporting 
10.3.3.1 Overdose 
An overdose is defined as a subject receiving a dose of MEDI4736 in excess of that specified in the 
Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with MEDI4736, with or without associated AEs/SAEs, is required to be 
reported within 24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety 
or designee using the designated Safety e-mailbox (see Section 10.3.2 for contact information). If the overdose 
results in an AE, the AE must also be recorded as an AE (see Section 10.3). Overdose does not automatically 
make an AE serious, but if the consequences of the overdose are serious, for example death or hospitalization, 
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the event is serious and must be recorded and reported as an SAE (see Section 10.1.2 and Section 10.3.2). There 
is currently no specific treatment in the event of an overdose of MEDI4736.  
The investigator will use clinical judgment to treat any overdose. 
10.3.3.2 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 10.1.3.3) in a study subject, with or without associated 
clinical manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of knowledge 
of the event to the sponsor and AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox 
(see Section 10.3.2 for contact information), unless a definitive underlying diagnosis for the abnormality (e.g., 
cholelithiasis or bile duct obstruction) that is unrelated to investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated to investigational 
product, the decision to continue dosing of the study subject will be based on the clinical judgment of the 
investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject must be 
interrupted immediately. Follow-up investigations and inquiries must be initiated by the investigational site 
without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated by the 
sponsor and AstraZeneca/MedImmune.  
10.3.3.3 Pregnancy 
Pregnancy itself, or pregnancy of a subject’s partner, is not regarded as an adverse event unless there is a 
suspicion that the investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of any conception occurring from the date of the first dose until 90 days after the last dose 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was withdrawn from the study.  
Pregnancy in a female subject who has received investigational product is required to be reported within 24 
hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety or designee using 
the designated Safety e-mailbox (see Section 10.3.2 for contact information). 
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Subjects who become pregnant during the study period must not receive additional doses of investigational 
product but will not be withdrawn from the study. The pregnancy will be followed for outcome of the mother 
and child (including any premature terminations) and should be reported to AstraZeneca/MedImmune Patient 
Safety or designee after outcome. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 3 months 
following the last dose.   
Should the investigator become aware of a pregnancy in the partner of a male study subject who has received 
investigational product this should be reported within 24 hours of knowledge of the event to 
AstraZeneca/MedImmune Patient Safety or designee using the Safety Fax Notification Form. The sponsor will 
endeavor to collect follow-up information on such pregnancies provided the partner of the study subject 
provides consent. 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
11.1 
Description of analysis sets 
 
11.1.1 
Safety analysis set 
All patients enrolled in the Phase I portion of the trial will comprise the safety analysis set to determine the 
RP2D. 
Toxicities will also be reported as descriptive statistics for all patients who received MEDI3476 at the RP2D 
dose in the Phase I and Phase II portions of the study.  
Acute toxicities observed while on treatment will be reported separately from late toxicities that are observed 
during the 90-day post-treatment follow-up period. Acute toxicities will also be reported separately for the 
combination with nab-paclitaxel and with ddAC. 
 
11.1.2 
Efficacy analysis set 
The primary efficacy analysis will include all patients who received at least 12 weeks (i.e. 6 courses) of 
MEDI4736 therapy at the RP2D.  
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A secondary, intent to treat, efficacy analysis will include all patients who received at least one dose of 
MEDI4736 at RP2D. 
11.2 
Methods of statistical analyses 
 
11.2.1 
Safety Analyses 
MTD/RP2D determination 
In the Phase I safety portion of the trial 2 dose levels will be assessed including 3mg/kg and 10mg/kg 
concomitant with weekly Nab-paclitaxel and concomitantly with dose dense doxorubicin and 
cyclophosphamide.  Intra-patient dose escalation is not allowed. Dose limiting toxicities will be assessed over 
the entire 20 weeks of therapy with MEDI4736 to determine MTD/RP2D but will be monitored separately 
during the two parts of the chemotherapy regimen (nab-paclitaxel x 12 weeks and AC x 4 treatments every two-
weeks). Delayed toxicities (i.e. toxicity in the 90 day follow-up period after completion of neoadjuvant therapy) 
are not considered for DLT purposes. 
Analysis of safety endpoint 
Interim safety analysis of the Phase II portion of the trial will be performed when 22 patients are accrued who 
received at least one treatment with MEDI4736.  If > 2/22 patients experience DLT or a serious treatment related 
adverse event (SAE), the MEDI4736 dose schedule will be re-evaluated. If futility criteria is not met at the 
interim efficacy analysis, the trial will continue after the MEDI4736 dose and schedule is amended to improve 
safety.  With 22 patients in the first stage, there is > 90% chance of observing at least 1 DLT event, if the true 
underlying rate of the adverse event is > 10%.  
Final toxicity results will be reported as frequency statistics with 95% confidence intervals. All patients who 
received at last one dose of MEDI4736 at the RP2D will be included in the final toxicity analysis. Acute 
toxicities that occur during the treatment phase will be reported separately from late toxicities that are 
encountered during the 90-day follow up period after completion of all neoadjuvant therapy. Acute toxicities will 
also be reported separately for the combination with nab-paclitaxel and dose dense AC. 
Phase I safety portion of the trial  
Two dose levels will be assessed including 3mg/kg and 10mg/kg MEDI4736 in combination with weekly nab-
paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 treatments.  
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 107 of 117 
 
 
UUU3 mg/kg MEDI4736 dose level 
The first 3 patients will be enrolled at dose level of 3 mg/kg MEDI4736 concomitant with chemotherapy. Further 
accrual will be halted after the first 3 patients are enrolled until the DLT assessment is complete for a given 
treatment part of the two-part (weekly nab-paclitaxel x 12 + AC x 4) chemotherapy regimen. If no patients 
experience a DLT during the weekly nab-paclitaxel treatment period (12 weeks), the next 3 patients will start 
weekly nab-paclitaxel at the next dose level, 10 mg/kg, while the previous cohort is still receiving AC 
chemotherapy (with MEDI4736 at 3 mg/kg).  If 1 patient experiences DLT during either the nab-paclitaxel or 
AC parts of the therapy, 3 additional patients will be enrolled at the 3 mg/kg dose-level in combination with the 
chemotherapy part of interest. If none of these 3 additional patients experience DLT (i.e. the final observed DLT 
rate is 1 of 6), the dose is escalated to 10 mg/kg for the given chemotherapy part. If 2 or more patients 
experience DLT among the first 6 patients treated at the 3 mg/kg dose level, the study will be halted and dose de-
escalation will be considered as an amendment to the trial after consultation with the sponsor. If 2 or more 
patients experience DLT among the first 3 patients treated at 3 mg/kg dose level, the study will also be halted 
and dose de-escalation will be considered as an amendment to the trial.  
Using the above design, the probabilities of halting dose escalation, in each treatment part, for true rates of DLT 
ranging from 5% to 70% are as follows: 
True rate of DLT: 
 
 
5%   10%    20%    30%   40%   50%   60%   70%  
Probability of halting dose escalation: 
0.03  0.09   0.29     0.51    0.69   0.83    0.92   0.97 
UUU10 mg/kg MEDI4736 dose level 
If dose escalation is feasible, the next cohort of patients will receive MEDI4736 at 10 mg/kg dose concomitant 
with chemotherapy. Accrual will be halted after the first 3 patients are enrolled at the 10 mg/kg dose until DLT 
assessment is complete for nab-paclitaxel (i.e. all 3 patients have completed 12 weeks of nab-paclitaxel 
chemotherapy). If only 1 patients experiences DLT after the first 3 patients are treated at this dose level, the 
study will proceed to enroll 3 additional patients at the 10 mg/kg dose level in combination with nab-paclitaxel. 
If none or only 1 of these additional 3 patients show DLT (final observed DLT 1 of 6), this dose level will be 
moved forward to the Phase II portion for efficacy assessment and accrual will start on the nab-paclitaxel part of 
treatment while patients are completing the AC part of their therapy. If 2 or more patients experience DLT 
among the first 6 patients treated at the 10 mg/kg dose level, the dose will be de-escalated to 3 mg/kg and this 
dose is designated as the RP2D for the subsequent Phase II portion of the trial. If 2 or more patients out of the 
first 3 experience DLT, the dose will be de-escalated to 3 mg/kg dose and this dose will be moved forward to the 
Phase II portion for efficacy assessment. DLT will be assessed similarly and the same expansion rules will be 
followed during the AC part of the treatment. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 108 of 117 
 
 
11.2.2 
Efficacy Analyses 
The first efficacy will be performed after the first 22 two patients who are enrolled at the RP2D level have received 
at least 12 weeks (i.e. 6 courses) of MEDI4736, undergone surgery and are evaluated for pCR. Patients who 
received lower than the RP2D dose during the Phase I part of the study or did not receive a minimum of 6 courses 
(i.e. 12 weeks) of MEDI4736 will not be included in the interim primary efficacy analysis  
Efficacy analysis: The trial will terminate for lack of efficacy if < 7 out of the first 22 evaluable patients experience 
pCR (Alpha = beta = 10%, probability of early termination if the response rate is 30%=0.67). If > 7 patients 
experience pCR, accrual will continue until a maximum of 50 evaluable patients are accrued.  
If the study proceeds to full accrual after the first interim safety and efficacy analysis, the final efficacy analysis 
will be as follows: 
If >20 patients who are evaluable for efficacy have pCR (i.e. at least 40% observed pCR rate) then the treatment 
will considered successful and recommended for further study in a randomized trial. With 50 patients included in 
the efficacy phase of the study, for the targeted pCR rate of 50% the corresponding 95% confidence interval ranges 
from 38% to 69%. 
A secondary, intent to treat efficacy analysis including all patients who received at least one dose of MEDI4736 
at RP2D will also be performed and results will be presented as point estimate of pCR rate with 95% confidence 
intervals. 
11.2.3 
Exploratory Analyses 
Multivariate associations of immune markers as continuous variables and pCR as dichotomous variable will be 
evaluated with logistic regression using backward feature elimination (LR test <0.05). Clinical tumor size, clinical 
nodal status and age will also be included in the model. 
RNA expression profiling will also be performed on all base line core needle biopsy samples using RNA 
sequencing to assess associations between pCR and published immune gene signatures that represent the average 
expression of sets of highly co-expressed genes that correspond to distinct immune cell types and immune 
functions. Multivariate associations of the immune signatures as continuous variables and pCR as dichotomous 
variable will be evaluated with logistic regression using backward feature elimination (LR test <0.05). Clinical 
tumor size, clinical nodal status and age will also be included in the model. 
Whole exome DNA sequencing will also performed to identify somatic mutations and other alterations that could 
be potential novel predictive markers of response. These will represent exploratory analysis. We will use the Fisher 
Exact test, which evaluates the significance for over-representation of a specific genomic alteration in the pCR 
versus no-pCR groups including functional variants in immune genes, overall mutation and neo-antigen load. Due 
to the sparsely of data at individual variant level, when testing for associations we will aggregate high functional 
impact variants at gene level and also at pathway level.  
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 109 of 117 
 
 
Selected immune parameters will also be assessed in residual cancer specimens in cases with less than pCR to 
assess changes in the immune microenvironment in response to therapy using pair-wise t-test and Bonferroni 
adjustment of p-values for multiple testing. Correlation coefficients will also be calculated for immune 
parameters between baseline and residual disease samples.    
 
11.2.4 
Interim analyses 
One interim efficacy and safety analyses will be performed during the Phase II portion of the study following 
Simon’s two stage clinical trial design as described in sections 11.2.1 and 11.2.2. 
11.3 
Determination of sample size 
The sample size is dictated by the 3+3 and Simons two stage design as described in sections 11.2.1 and 11.2.2.  
During the Phase I portion of the trial a minimum of 6 and a maximum of 12 patients will be enrolled. 
During the Phase II portion of the trial, we allow replacement of patients for efficacy and safety analysis who 
are lost for follow up or withdraw from the study for any reasons other than toxicity or disease progression. We 
also assume that a few accrued patients will not be eligible for the primary efficacy analysis due to receiving 
fewer than 6 courses of MEDI4736 due to toxicity (all such patients will be included in the safety analyses and 
secondary efficacy analysis).  To allow for replacement and to accrue the required number of eligible patients 
for primary efficacy analysis, we increase the sample size by 10% to a total sample size 24 (with early stopping 
for lack of efficacy) or 55 patients (with full accrual) to be included in the Phase II portion of the study.  
The combined sample size including both the Phase I and Phase II portions of the trial can range from a 
minimum of 24 (6 in Phase I plus 18 in Phase II) to a maximum 61 patients (6 in Phase I and 55 in Phase II). 
African American extension cohort 
We will perform one additional efficacy analysis which includes assessing pCR rates in African America (AA) 
and non-AA patients separately in the Phase II portion of the trial. In order to make this exploratory analysis, 
we need at least N=20 AA patients accrued to the study. An AA only extension cohort will remain open until 
N=20 AA patients are accrued, this may extend the maximum sample size to a total of 71 (as of October 8, 
2018; 10 AA patients have been accrued and the total accrual number is 50). Assuming that the baseline 
pCR=35% for AA patients with TNBC, a cohort of 20 AA patients will have a 76% power to detect an 
improvement in pCR from 35% to 65% based on the exact binomial test. This is a similar magnitude of 
improvement, a near doubling of pCR rate, as was observed when trastuzumab was added to paclitaxel/AC 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 110 of 117 
 
 
neoadjuvant chemotherapy in HER2 positive breast cancers. The comparison of pCR rates between the two 
racial cohorts will be performed as exploratory analysis.   
12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regulatory requirements Subject 
data protection. 
12.2 
Ethics and regulatory review 
This study will be subject to a two-step peer review following the policies of Yale Comprehensive Cancer 
Center.  
The first step is scientific review by the Protocol Review Committee (PRC) which meets weekly. Further 
information on the function and membership of the PRC can be found at: 
59T59T59Thttp://medicine.yale.edu/cancer/research/trials/services/review.aspx 59T59T59T .  
The second step is review by the Human Investigations Committee (HIC) which is the Yale equivalent of an 
institutional review board. All cancer trials are reviewed by a special oncology HIC that meets bimonthly. 
Further information on human subject protection at Yale and the role of the HIC can be found at: 
59T59T59Thttp://www.yale.edu/hrpp/59T59T59T. 
12.3 
Informed consent 
All patients must be counseled about the risk and benefits of the trial and alternative treatment options and 
signed informed consent before entering the trial. The principal investigator, co-investigators and designated, 
trained clinical staff and research personnel may obtain the informed consent. 
12.4 
Changes to the protocol and informed consent form 
All changes to the protocol or informed consent will have to be reviewed and approved by the sponsor and the 
institutional review board before implementation. 
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Clinical Study Protocol 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 111 of 117 
 
 
12.5 
Audits and inspections 
This study will be monitored by the Yale Clinical Trial Office and Yale Data Safety Monitoring Committee.  
13. 
STUDY MANAGEMENT 
The Principal Investigator Dr Lajos Pusztai will oversee all aspects of the conduct of this trial. Data collection, 
study monitoring and management of the trial will be provided by the Yale Cancer Center Clinical Trial Office 
Breast Cancer Disease Team. 
 
13.1 
Training of study site personnel 
 
All clinical trials conducted at Yale Cancer center are supported by a central Clinical Trial Office (CTO). The 
CTO employs, trains and supervises all clinical trial assistants, research nurses, regulatory assistants, data 
managers. The CTO staff is organized into disease units. The breast CTO staff includes two research nurses, 
two data managers, a regulatory assistant, trial assistant and a project manager. Staffing of disease teams is 
dynamic and may change based on the needs of the disease unit. Further information on the CTO can be found 
at: 59T59T59Thttp://www.yalecancercenter.org/research/trials/services/index.aspx 59T59T59T.  
Barbara Fordyce serves as project manager for the breast cancer disease group, e-mail: 
Barbara.fordyce@yale.edu, telephone: 203-737-2226. 
13.2 
Monitoring of the study 
13.2.1 
Source data 
Source data is the electronic medical record system of Smilow Cancer Hospital.  
13.3 
Study timetable and end of study 
The anticipated completion of accrual to the Phase I portion of the trial is 6-9 months due to 20 week 
observation period for each dose escalation cohort.  Full accrual to the Phase II portion will take an additional 
20-24 months assuming an accrual rate of 2 per months.  
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Clinical Study Protocol 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 112 of 117 
 
 
Final efficacy analysis will be reported 6 months after accrual of the last patient to the Phase II portion of the 
trail. 
14. 
DATA MANAGEMENT 
Source data will be collected in the clinic by a research nurse dedicated to the trial and the information will be 
entered into an electronic data bases, ONCORE, by a trained data manager/clinical trial assistant. The data 
elements and case report forms will be designed by the principal investigator following the policy of the 
Clinical Trial Office. The ONCORE datadase will be used to generate reports. 
 
15. 
LIST OF REFERENCES 
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Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, et al. (2010) Molecular anatomy of breast cancer 
stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 28: 4316-4323 
 
Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, et al. Blockade of PD-L1 (B7 H1) augments 
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Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and 
activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 
28;366(26):2455-65. 
 
59T59T59TBracci L59T59T59T, 59T59T59TSchiavoni G59T59T59T, 59T59T59TSistigu A59T59T59T, 59T59T59TBelardelli F59T59T59T. Immune-based mechanisms of cytotoxic chemotherapy: 
implications for the design of novel and rationale-based combined treatments against cancer. 59T59T59TCell Death 
Differ.59T59T59T 2014 Jan;21(1):15-25. 
 
Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al.  The PD-1/PD-L1 axis contributes to T-cell 
dysfunction in chronic lymphocytic leukemia.  Haematologica. 2013 Jun; 98(6):953-963. 
 
Callahan MK and Wolchok JD. CTLA-4 and PD-1 blocking antibodies in cancer immunotherapy.  J Leukoc 
Biol. 2013; 94(1):41-53. 
 
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 113 of 117 
 
 
Chow LQ. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-
small cell lung cancer. Am Soc Clin Oncol Educ Book. 2013:280-5. 
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Denkert C, Loibl S, Noske A, Roller M, Muller BM, et al. (2010) Tumor-associated lymphocytes as an 
independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28: 105-113 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45:228-47. 
 
European Medicines Agency’s “Guideline on the evaluation of anti-cancer medicinal products in man” 
(EMA/CHMP/205/95/Rev.4) 
 
Food and Drug Administration Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: 
Premarketing clinical evaluation’.  Available from URL: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
.  Accessed 10 December 2013. 
Ghebeh, H., Barhoush, E., Tulbah, A., Elkum, N., Al-Tweigeri, T., & Dermime, S. (2008). FOXP3+ Tregs and 
B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for 
immunotherapy. BMC cancer, 2008; 8(1): 57 
 
Guidance for Industry, Pathologic complete Response in Neoadjuvant Treatment of High-Risk Early-Stage 
Breast Cancer:  Use as an Endpoint to Support Accelerated Approval. US Department of Health and Human 
Services Food and Drug Administation Center or Drug Evaluation and Research(CDER)  May (2012).  
Retrieved from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM305501.pdf 
 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Nat Acad Sci U S A. 2007;104(9):3360-5. 
 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 June 2;DOI: 10.1056/NEJMoa1305133. 
 
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of MPDL3280A, an 
engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
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Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and 
immunity. Annu Rev Immunol. 2008;26:677-704. 
 
Kirkwood J, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II Trial of Tremelimumab 
(CP-675,206) in Patients with Advanced Refractory or Relapsed Melanoma. Clin Cancer Res. 2010; 16(3): 
1042-1048. 
 
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. 
Survivin and B7-H1 are collaborative predictors of survival and represent potential 
therapeutic targets for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1749- 
56. 
 
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, et al. (2008) Response to neoadjuvant therapy and long-
term survival in patients with triple-negative breast cancer. J Clin Oncol 26: 1275-1281. 
 
Loi S, Sirtaine N, Piette F et al. (2013) Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a 
Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of 
Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98. J Clin Oncol 31:860–867 
 
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance 
and regulation of the costimulatory molecule B7-H1 in pancreatic adenocarcinoma. Cancer 
Lett. 2008;268(1):98-109. 
 
Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., et al. PD-L1 Expression in Triple-Negative Breast 
Cancer. Cancer Immunology Research, 214; 2(4): 361-370. 
 
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer 
may contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cells maturation. Med Oncol. 2011 Sep;28(3):682-8. 
 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS.  Developing a common 
language for tumor response to immunotherapy: immune-related response criteria using unidimensional 
measurements.  Clin Cancer Res.  2013 Jul; 19(14):3936-3943. 
 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
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interaction is required for the induction and maintenance of peripheral T-cell tolerance. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
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burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25: 4414-4422. 
 
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cancer.  2013; 19(5):1021-1034. 
 
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Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. 
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B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 116 of 117 
 
 
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Immunol. 2008;8(6):467-77. 
 
 
 
 
 
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Page 117 of 117 
 
 
APPENDIX A: MEDI4736 DOSE CALCULATIONS  
MEDI4736 Dosing 
The MEDI4736 dosing should be done depending on subject weight: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL) where 50 mg/mL is MEDI4736 nominal concentration  
The corresponding volume of MEDI4736 should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 80 kg 
3. Dose for subject: 800 mg = 10 (mg/kg) × 80 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 800 mg / 50 (mg/mL) = 16.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 16.0 (mL) / 10 (mL/vial) = 2 vial 
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SAP_001.pdf: 
NCT02489448 Neoadjuvant MEDI4736 Concomitant With Weekly Nab-paclitaxel and Dose-dense AC 
for Stage I-III Triple Negative Breast Cancer 
SAP 
Date: 2/26/2021 


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Page 105 of 117 
 
 
Subjects who become pregnant during the study period must not receive additional doses of investigational 
product but will not be withdrawn from the study. The pregnancy will be followed for outcome of the mother 
and child (including any premature terminations) and should be reported to AstraZeneca/MedImmune Patient 
Safety or designee after outcome. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 3 months 
following the last dose.   
Should the investigator become aware of a pregnancy in the partner of a male study subject who has received 
investigational product this should be reported within 24 hours of knowledge of the event to 
AstraZeneca/MedImmune Patient Safety or designee using the Safety Fax Notification Form. The sponsor will 
endeavor to collect follow-up information on such pregnancies provided the partner of the study subject 
provides consent. 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
11.1 
Description of analysis sets 
 
11.1.1 
Safety analysis set 
All patients enrolled in the Phase I portion of the trial will comprise the safety analysis set to determine the 
RP2D. 
Toxicities will also be reported as descriptive statistics for all patients who received MEDI3476 at the RP2D 
dose in the Phase I and Phase II portions of the study.  
Acute toxicities observed while on treatment will be reported separately from late toxicities that are observed 
during the 90-day post-treatment follow-up period. Acute toxicities will also be reported separately for the 
combination with nab-paclitaxel and with ddAC. 
 
11.1.2 
Efficacy analysis set 
The primary efficacy analysis will include all patients who received at least 12 weeks (i.e. 6 courses) of 
MEDI4736 therapy at the RP2D.  
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 106 of 117 
 
 
A secondary, intent to treat, efficacy analysis will include all patients who received at least one dose of 
MEDI4736 at RP2D. 
11.2 
Methods of statistical analyses 
 
11.2.1 
Safety Analyses 
MTD/RP2D determination 
In the Phase I safety portion of the trial 2 dose levels will be assessed including 3mg/kg and 10mg/kg 
concomitant with weekly Nab-paclitaxel and concomitantly with dose dense doxorubicin and 
cyclophosphamide.  Intra-patient dose escalation is not allowed. Dose limiting toxicities will be assessed over 
the entire 20 weeks of therapy with MEDI4736 to determine MTD/RP2D but will be monitored separately 
during the two parts of the chemotherapy regimen (nab-paclitaxel x 12 weeks and AC x 4 treatments every two-
weeks). Delayed toxicities (i.e. toxicity in the 90 day follow-up period after completion of neoadjuvant therapy) 
are not considered for DLT purposes. 
Analysis of safety endpoint 
Interim safety analysis of the Phase II portion of the trial will be performed when 22 patients are accrued who 
received at least one treatment with MEDI4736.  If > 2/22 patients experience DLT or a serious treatment related 
adverse event (SAE), the MEDI4736 dose schedule will be re-evaluated. If futility criteria is not met at the 
interim efficacy analysis, the trial will continue after the MEDI4736 dose and schedule is amended to improve 
safety.  With 22 patients in the first stage, there is > 90% chance of observing at least 1 DLT event, if the true 
underlying rate of the adverse event is > 10%.  
Final toxicity results will be reported as frequency statistics with 95% confidence intervals. All patients who 
received at last one dose of MEDI4736 at the RP2D will be included in the final toxicity analysis. Acute 
toxicities that occur during the treatment phase will be reported separately from late toxicities that are 
encountered during the 90-day follow up period after completion of all neoadjuvant therapy. Acute toxicities will 
also be reported separately for the combination with nab-paclitaxel and dose dense AC. 
Phase I safety portion of the trial  
Two dose levels will be assessed including 3mg/kg and 10mg/kg MEDI4736 in combination with weekly nab-
paclitaxel x 12 treatments followed by MEDI4736 in combination with ddAC x 4 treatments.  
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 107 of 117 
 
 
UUU3 mg/kg MEDI4736 dose level 
The first 3 patients will be enrolled at dose level of 3 mg/kg MEDI4736 concomitant with chemotherapy. Further 
accrual will be halted after the first 3 patients are enrolled until the DLT assessment is complete for a given 
treatment part of the two-part (weekly nab-paclitaxel x 12 + AC x 4) chemotherapy regimen. If no patients 
experience a DLT during the weekly nab-paclitaxel treatment period (12 weeks), the next 3 patients will start 
weekly nab-paclitaxel at the next dose level, 10 mg/kg, while the previous cohort is still receiving AC 
chemotherapy (with MEDI4736 at 3 mg/kg).  If 1 patient experiences DLT during either the nab-paclitaxel or 
AC parts of the therapy, 3 additional patients will be enrolled at the 3 mg/kg dose-level in combination with the 
chemotherapy part of interest. If none of these 3 additional patients experience DLT (i.e. the final observed DLT 
rate is 1 of 6), the dose is escalated to 10 mg/kg for the given chemotherapy part. If 2 or more patients 
experience DLT among the first 6 patients treated at the 3 mg/kg dose level, the study will be halted and dose de-
escalation will be considered as an amendment to the trial after consultation with the sponsor. If 2 or more 
patients experience DLT among the first 3 patients treated at 3 mg/kg dose level, the study will also be halted 
and dose de-escalation will be considered as an amendment to the trial.  
Using the above design, the probabilities of halting dose escalation, in each treatment part, for true rates of DLT 
ranging from 5% to 70% are as follows: 
True rate of DLT: 
 
 
5%   10%    20%    30%   40%   50%   60%   70%  
Probability of halting dose escalation: 
0.03  0.09   0.29     0.51    0.69   0.83    0.92   0.97 
UUU10 mg/kg MEDI4736 dose level 
If dose escalation is feasible, the next cohort of patients will receive MEDI4736 at 10 mg/kg dose concomitant 
with chemotherapy. Accrual will be halted after the first 3 patients are enrolled at the 10 mg/kg dose until DLT 
assessment is complete for nab-paclitaxel (i.e. all 3 patients have completed 12 weeks of nab-paclitaxel 
chemotherapy). If only 1 patients experiences DLT after the first 3 patients are treated at this dose level, the 
study will proceed to enroll 3 additional patients at the 10 mg/kg dose level in combination with nab-paclitaxel. 
If none or only 1 of these additional 3 patients show DLT (final observed DLT 1 of 6), this dose level will be 
moved forward to the Phase II portion for efficacy assessment and accrual will start on the nab-paclitaxel part of 
treatment while patients are completing the AC part of their therapy. If 2 or more patients experience DLT 
among the first 6 patients treated at the 10 mg/kg dose level, the dose will be de-escalated to 3 mg/kg and this 
dose is designated as the RP2D for the subsequent Phase II portion of the trial. If 2 or more patients out of the 
first 3 experience DLT, the dose will be de-escalated to 3 mg/kg dose and this dose will be moved forward to the 
Phase II portion for efficacy assessment. DLT will be assessed similarly and the same expansion rules will be 
followed during the AC part of the treatment. 
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 108 of 117 
 
 
11.2.2 
Efficacy Analyses 
The first efficacy will be performed after the first 22 two patients who are enrolled at the RP2D level have received 
at least 12 weeks (i.e. 6 courses) of MEDI4736, undergone surgery and are evaluated for pCR. Patients who 
received lower than the RP2D dose during the Phase I part of the study or did not receive a minimum of 6 courses 
(i.e. 12 weeks) of MEDI4736 will not be included in the interim primary efficacy analysis  
Efficacy analysis: The trial will terminate for lack of efficacy if < 7 out of the first 22 evaluable patients experience 
pCR (Alpha = beta = 10%, probability of early termination if the response rate is 30%=0.67). If > 7 patients 
experience pCR, accrual will continue until a maximum of 50 evaluable patients are accrued.  
If the study proceeds to full accrual after the first interim safety and efficacy analysis, the final efficacy analysis 
will be as follows: 
If >20 patients who are evaluable for efficacy have pCR (i.e. at least 40% observed pCR rate) then the treatment 
will considered successful and recommended for further study in a randomized trial. With 50 patients included in 
the efficacy phase of the study, for the targeted pCR rate of 50% the corresponding 95% confidence interval ranges 
from 38% to 69%. 
A secondary, intent to treat efficacy analysis including all patients who received at least one dose of MEDI4736 
at RP2D will also be performed and results will be presented as point estimate of pCR rate with 95% confidence 
intervals. 
11.2.3 
Exploratory Analyses 
Multivariate associations of immune markers as continuous variables and pCR as dichotomous variable will be 
evaluated with logistic regression using backward feature elimination (LR test <0.05). Clinical tumor size, clinical 
nodal status and age will also be included in the model. 
RNA expression profiling will also be performed on all base line core needle biopsy samples using RNA 
sequencing to assess associations between pCR and published immune gene signatures that represent the average 
expression of sets of highly co-expressed genes that correspond to distinct immune cell types and immune 
functions. Multivariate associations of the immune signatures as continuous variables and pCR as dichotomous 
variable will be evaluated with logistic regression using backward feature elimination (LR test <0.05). Clinical 
tumor size, clinical nodal status and age will also be included in the model. 
Whole exome DNA sequencing will also performed to identify somatic mutations and other alterations that could 
be potential novel predictive markers of response. These will represent exploratory analysis. We will use the Fisher 
Exact test, which evaluates the significance for over-representation of a specific genomic alteration in the pCR 
versus no-pCR groups including functional variants in immune genes, overall mutation and neo-antigen load. Due 
to the sparsely of data at individual variant level, when testing for associations we will aggregate high functional 
impact variants at gene level and also at pathway level.  
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Clinical Study Protocol 
Drug Substance MEDI4736 
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Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 109 of 117 
 
 
Selected immune parameters will also be assessed in residual cancer specimens in cases with less than pCR to 
assess changes in the immune microenvironment in response to therapy using pair-wise t-test and Bonferroni 
adjustment of p-values for multiple testing. Correlation coefficients will also be calculated for immune 
parameters between baseline and residual disease samples.    
 
11.2.4 
Interim analyses 
One interim efficacy and safety analyses will be performed during the Phase II portion of the study following 
Simon’s two stage clinical trial design as described in sections 11.2.1 and 11.2.2. 
11.3 
Determination of sample size 
The sample size is dictated by the 3+3 and Simons two stage design as described in sections 11.2.1 and 11.2.2.  
During the Phase I portion of the trial a minimum of 6 and a maximum of 12 patients will be enrolled. 
During the Phase II portion of the trial, we allow replacement of patients for efficacy and safety analysis who 
are lost for follow up or withdraw from the study for any reasons other than toxicity or disease progression. We 
also assume that a few accrued patients will not be eligible for the primary efficacy analysis due to receiving 
fewer than 6 courses of MEDI4736 due to toxicity (all such patients will be included in the safety analyses and 
secondary efficacy analysis).  To allow for replacement and to accrue the required number of eligible patients 
for primary efficacy analysis, we increase the sample size by 10% to a total sample size 24 (with early stopping 
for lack of efficacy) or 55 patients (with full accrual) to be included in the Phase II portion of the study.  
The combined sample size including both the Phase I and Phase II portions of the trial can range from a 
minimum of 24 (6 in Phase I plus 18 in Phase II) to a maximum 61 patients (6 in Phase I and 55 in Phase II). 
African American extension cohort 
We will perform one additional efficacy analysis which includes assessing pCR rates in African America (AA) 
and non-AA patients separately in the Phase II portion of the trial. In order to make this exploratory analysis, 
we need at least N=20 AA patients accrued to the study. An AA only extension cohort will remain open until 
N=20 AA patients are accrued, this may extend the maximum sample size to a total of 71 (as of October 8, 
2018; 10 AA patients have been accrued and the total accrual number is 50). Assuming that the baseline 
pCR=35% for AA patients with TNBC, a cohort of 20 AA patients will have a 76% power to detect an 
improvement in pCR from 35% to 65% based on the exact binomial test. This is a similar magnitude of 
improvement, a near doubling of pCR rate, as was observed when trastuzumab was added to paclitaxel/AC 
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Clinical Study Protocol 
Drug Substance MEDI4736 
Study Number ESR-14-10265 / Yale HIC 1409014537 
Edition Number 15 
Date: 05-Jun-2020 
 
 
Page 110 of 117 
 
 
neoadjuvant chemotherapy in HER2 positive breast cancers. The comparison of pCR rates between the two 
racial cohorts will be performed as exploratory analysis.   
12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regulatory requirements Subject 
data protection. 
12.2 
Ethics and regulatory review 
This study will be subject to a two-step peer review following the policies of Yale Comprehensive Cancer 
Center.  
The first step is scientific review by the Protocol Review Committee (PRC) which meets weekly. Further 
information on the function and membership of the PRC can be found at: 
59T59T59Thttp://medicine.yale.edu/cancer/research/trials/services/review.aspx 59T59T59T .  
The second step is review by the Human Investigations Committee (HIC) which is the Yale equivalent of an 
institutional review board. All cancer trials are reviewed by a special oncology HIC that meets bimonthly. 
Further information on human subject protection at Yale and the role of the HIC can be found at: 
59T59T59Thttp://www.yale.edu/hrpp/59T59T59T. 
12.3 
Informed consent 
All patients must be counseled about the risk and benefits of the trial and alternative treatment options and 
signed informed consent before entering the trial. The principal investigator, co-investigators and designated, 
trained clinical staff and research personnel may obtain the informed consent. 
12.4 
Changes to the protocol and informed consent form 
All changes to the protocol or informed consent will have to be reviewed and approved by the sponsor and the 
institutional review board before implementation. 
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