Conditions: Metastatic Breast Cancer
Keywords: Brain Irradiation Tremelimumab 15-038
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if the combination of tremelimumab and durvalumab with brain radiation therapy can help treat this type of breast cancer that has spread to the brain.

Detailed description:
A Simon 2-stage single-arm design (n=17) will be employed to evaluate for preliminary efficacy. A maximum of 17 subjects will be accrued to the efficacy arm. After the first 3 patients are enrolled in the efficacy arm, a 6 week enrollment hold will be conducted in order to ensure safety before additional patients are enrolled. An interim assessment will then occur after the first 9 subjects have enrolled, and the accrual to this arm will proceed only if a pre-specified futility threshold is met. Patients not requiring continuation of HER2 directed therapy, such as trastuzumab, will be enrolled in this arm.

Arms:
arm 1: Subjects will get either whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered every 28 days. Patients, for whom concurrent HER2 directed therapy trastuzumab is indicated, as determined by the treating investigator, will be enrolled in a parallel HER2 directed therapy trastuzumab safety cohort. Protocol Expansion: Dose 1 of tremelimumab \& durvalumab (75 mg \& 1500 mg, respectively) will ideally be administered 2 days prior to initiation of brain radiotherapy (or between 5 days prior \& 3 days after initiation of radiotherapy). Subjects will get either WBRT or SRS, depending on the number \& size of their brain metastases. Following the 1st dose, tremelimumab \& duvralumab will be administered q28 days from the date of 1st tremelimumab \& durvalumab administration, plus or minus 1 week, for 4 cycles. After the 4th cycle, durvalumab will be administered alone until progression of disease or unacceptable toxicity.

Interventions: intervention 1: Brain radiotherapy or Stereotactic Radiosurgery intervention 2: Tremelimumab intervention 3: HER2 directed therapy intervention 4: Durvalumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Page 1 of 98 
 
 
Approval date: 29-Jun-2018 
A Pilot Study of Brain Irradiation and Tremelimumab in Metastatic 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOC 
Principal  Investigator/Department: 
Shanu Modi, MD 
Breast Cancer 
OL 
Medicine/Breast 
Co-Principal 
Kathryn Beal, M 
Investigator(s)/Department: 
D 
Radiation Oncology 
Investigator(s)/Department: 
Sujata Patil, PhD 
Thomas Kaley, MD 
Gary Ulaner, MD 
Maxine Jochelson, MD 
Robert Young, MD 
John Lyo, MD 
Darragh Halpenny, MD 
Jedd Wolchok, MD, PhD 
Larry Norton, MD 
Nancy T. Sklarin, MD 
Mark E. Robson, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD, PhD 
Sarat Chandarlapaty, MD, PhD 
Gabriella M. D’Andrea, MD 
Chau T. Dang, MD 
Maura N. Dickler, MD 
Monica N. Fornier, MD 
Teresa A. Gilewski, MD 
Ayca Gucalp, MD 
Diana E. Lake, MD 
Mary Ellen Moynahan, MD 
Andrew D. Seidman, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Neil Iyengar, MD 
Ting Bao, MD 
Komal Jhaveri, MD 
Lillian Smyth, MD 
Pedram Razavi, MD, PhD 
Rachel Sanford, MD 
Christopher Klebanoff, MD 
Linda Vahdat, MD 
Simon N. Powell, MD 
Michael J. Zelefsky, MD 
Beryl McCormick, MD 
Christopher Barker, MD 
Marisa Kollmeier, MD 
Nancy Lee, MD 
Abraham Wu, MD 
Epidemiology / Biostatistics 
Neurology 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology Medicine 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
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Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
 


Page 2 of 98 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
 
 
 
 
 
Yoshiya Yamada, MD 
Radiation Oncology 
Paul Romesser, MD 
Radiation Oncology 
Nadeem Riaz, MD 
Radiation Oncology 
Kaled Alektiar, MD 
Radiation Oncology 
Timothy Chan, MD, PhD 
Radiation Oncology 
Christopher Crane, MD 
Radiation Oncology 
Daniel Higginson, MD 
Radiation Oncology 
Andreas Rimner, MD 
Radiation Oncology 
Adam Schmitt, MD 
Radiation Oncology 
Suzanne Wolden, MD 
Radiation Oncology 
Karen Schupak, MD 
Radiation Oncology 
Annemarie Shepherd, MD 
Radiation Oncology 
Daniel Gorovets, MD 
Radiation Oncology 
Carla Hajj, MD 
Radiation Oncology 
Jillian Tsai, MD 
Radiation Oncology 
Marsha Reyngold, MD 
Radiation Oncology 
Daniel Shasha, MD 
Radiation Oncology 
Boris Mueller, MD 
Radiation Oncology 
Borys Mychalczak, MD 
Radiation Oncology 
John Cuaron, MD 
Radiation Oncology 
Daphna Gelblum, MD 
Radiation Oncology 
Melissa Zinovoy, MD 
Radiation Oncology 
Atif Khan, MD 
Radiation Oncology 
Lior Braunstein, MD 
Radiation Oncology 
Erin Gillespie, MD 
Radiation Oncology 
Richard Gewanter, MD 
Radiation Oncology 
Pinaki Dutta, MD 
Radiation Oncology 
Nursing 
Karen Drucker, NP 
Nursing 
Maureen Cannon, NP 
Nursing 
Valentina Sterlin, NP 
Nursing 
Lauren Wood, RN 
Nursing 
Tina Alano, RN 
Nursing 
Emer Heaney, RN 
Nursing 
Aimee Rogado, RN 
Nursing 
Odessa Williams, NP 
Nursing 
Danielle Alleva, NP 
Nursing 
Nicole Jimenez, NP 
Nursing 
Catherine Keane, NP 
Nursing 
Renee Wisniewski, NP 
Nursing 
Nora Messinger, NP 
Nursing 
Veronica Fitzpatrick, NP 
Nursing 


Page 3 of 98 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
 
 
 
 
 
Consenting 
Professional(s)/Department: 
Larry Norton, MD 
Nancy T. Sklarin, MD 
Mark E. Robson, MD 
Victoria S. Blinder, MD 
Jacqueline F. Bromberg, MD, PhD 
Sarat Chandarlapaty, MD 
Gabriella M. D’Andrea, MD 
Chau T. Dang, MD 
Maura N. Dickler, MD 
Monica N. Fornier, MD 
Teresa A. Gilewski, MD 
Ayca Gucalp, MD 
Diana E. Lake, MD 
Shanu Modi, MD 
Mary Ellen Moynahan, MD 
Andrew D. Seidman, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Neil Iyengar, MD 
Ting Bao, MD 
Komal Jhaveri, MD 
Lillian Smyth, MD 
Pedram Razavi, MD, PhD 
Rachel Sanford, MD 
Christopher Klebanoff, MD 
Linda Vahdat, MD 
Simon N. Powell, MD 
Michael J. Zelefsky, MD 
Beryl McCormick, MD 
Kathryn Beal, MD 
Christopher Barker, MD 
Marisa Kollmeier, MD 
Nancy Lee, MD 
Abraham Wu, MD 
Yoshiya Yamada, MD 
Paul Romesser, MD 
Nadeem Riaz, MD 
Kaled Alektiar, MD 
Timothy Chan, MD, PhD 
Christopher Crane, MD 
Daniel Higginson, MD 
Andreas Rimner, MD 
Adam Schmitt, MD 
Suzanne Wolden, MD 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
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Radiation Oncology 
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Radiation Oncology 
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Radiation Oncology 
Radiation Oncology 
Radiation Oncology 


Page 4 of 98 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
 
 
 
 
 
 
Participating  Institutions 
PI's Name 
Site's Role 
Cedars-Sinai Medical Center 
Heather L. McArthur, MD/ MPH 
Data Collection 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects Education 
and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 5 of 98 
 
 
 
 
Table of Contents 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................................................... 7 
1.2 Brief Rationale .............................................................................................................................................. 7 
1.3 Protocol Summary........................................................................................................................................ 7 
1.2 Efficacy Arm ........................................................................................................................................... 9 
1.3 HER2 directed therapy Co-administration Arm ...................................................................................... 9 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ......................................................................................................... 10 
3.0 
BACKGROUND AND RATIONALE ................................................................................................................... 11 
3.3 
Current Standard of Care for Treating Brain Metastases .................................................................. 12 
3.4 
Rationale for Immunotherapy in Breast Cancer Brain Metastases ..................................................... 12 
3.5 
Anti-CTLA-4 therapy ............................................................................................................................ 13 
3.6 
Safety and Efficacy of Tremelimumab ................................................................................................ 13 
3.7 
Combination of anti-CTLA-4 antibody with radiotherapy: Background ........................................... 25 
3.8 Combination of anti-CTLA-4 therapy with anti-HER2 therapy: background .......................................... 27 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................................................... 30 
4.2 
Design ............................................................................................................................................. 30 
4.3 
Intervention .......................................................................................................................................... 33 
5.1 
THERAPEUTIC/DIAGNOSTIC  AGENTS .................................................................................................... 35 
5.2 
Brain radiotherapy ............................................................................................................................... 35 
5.3 
Tremelimumab ..................................................................................................................................... 35 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ....................................................................................................... 42 
6.2 
Subject Inclusion Criteria ..................................................................................................................... 42 
6.3 
Subject Exclusion Criteria .................................................................................................................... 44 
7.0 
RECRUITMENT PLAN .......................................................................................................................... 46 
8.0 
PRETREATMENT EVALUATION ................................................................................................................ 47 
9.1 
TREATMENT/INTERVENTION  PLAN ............................................................................................................ 48 
9.2 Concomitant Steroid Administration for symptomatic CNS disease ...................................................... 48 
9.3 HER2 directed therapy co-administration arm safety run-in and expansion schedule ......................... 49 
9.4 Determining when to reinitiate systemic therapy ................................................................................... 51 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ............................................................................. 52 
11.0 
TOXICITIES/SIDE EFFECTS ........................................................................................................................ 56 
11.2 Adverse event management ......................................................................................................................... 57 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 6 of 98 
 
 
12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................................................ 65 
12.2 
Evaluation of Primary Endpoint ........................................................................................................... 65 
12.3 
Evaluation of Secondary Endpoints ................................................................................................. 67 
12.4 Exploratory assessments .......................................................................................................................... 69 
13.1 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................................................... 71 
13.2 
Premature Patient Withdrawal ............................................................................................................. 72 
13.3 Very Premature Patient Withdrawal ............................................................................................................. 72 
14.1 
BIOSTATISTICS ........................................................................................................................................... 72 
14.2 
Sample Size Determination .............................................................................................................. 73 
14.3 
Subjects for analysis ......................................................................................................................... 75 
14.4 
Definitions of endpoints ................................................................................................................... 75 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ..................................... 76 
15.2 
Research Participant Registration ........................................................................................................ 76 
15.3 
Randomization ..................................................................................................................................... 76 
16.1 
DATA MANAGEMENT ISSUES ................................................................................................................... 77 
16.2 
Quality Assurance ....................................................................................................................................... 77 
16.3 
Data and Safety Monitoring ........................................................................................................... 77 
17.1 
PROTECTION OF HUMAN SUBJECTS ........................................................................................................ 77 
17.2 
Privacy ............................................................................................................................................ 78 
17.3 
Serious Adverse Event (SAE) Reporting ............................................................................................... 78 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................................................ 81 
19.0 
REFERENCES .............................................................................................................................................. 82 
20.1 
APPENDICES .............................................................................................................................................. 86 
20.2 Guidance on Contraception ..................................................................................................................... 86 
20.3 
Management Algorithms ................................................................................................................. 87 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 7 of 98 
 
 
 
 
1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
1.2 Brief Rationale 
 
Breast cancer brain metastases commonly arise following multiple lines of cytotoxic chemotherapy. The 
standard-of-care is to suspend cytotoxic therapy, treat with brain radiotherapy (either whole brain or 
stereotactic), and subsequently treat with additional cytotoxic chemotherapy. Based on the premise that 
radiation therapy induces tumor antigen release, concurrent treatment with tremelimumab—a 
therapeutic immune checkpoint antibody—may induce anti-tumor immunity and systemic disease control. 
Thus, the overarching goal of this study is to utilize brain irradiation as a “window of opportunity” to 
provide effective immunotherapy, which may provide a period of respite from the cumulative toxicities of 
cytotoxic chemotherapy and potentially induce clinically significant systemic disease control in a patient 
population forwhom few or no alternative effective therapies remain. 
1.3 Protocol Summary 
 
A single institution pilot study evaluated the combination of tremelimumab (treme) plus brain irradiation 
+/- HER2 directed therapy in breast cancer patients with brain metastasis (BCBM) for whom post-brain 
irradiation cytotoxic chemotherapy was planned. Subjects received either whole brain radiation treatment 
(WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab administered at 
10mg/kg every 28 days. All breast cancer subtypes were eligible for enrollment: subjects not requiring 
concurrent HER2 directed therapy such as trastuzumab (tras), were enrolled in a Simon 2-stage efficacy 
arm, whereas subjects with HER2-positive (i.e. HER2 overexpressing and/or amplified) disease requiring 
continuation of HER2 directed therapy were enrolled in a HER2 directed therapy safety arm designed to 
evaluate the safety of HER2 directed therapy and tremelimumab/RT co-administration. As of 3/1/2017, 
the 12 week disease control rate was 2/10 (10%) in the efficacy arm and 2/6 (33%) in the safety arm. One 
patient treated with concurrent HER2-directed therapy had a 57% partial response by RECIST v1.1 that 
was durable at 6 months. Overall, the regimen was well tolerated with 15 Grade 3 and no Grade 4 
attributable toxicity events reported. The most comment treatment related AEs were diarrhea (12.9%), 
fatigue (9.7%), and colitis (6.5%). Thus, an expansion of the HER2 arm is planned in a parallel Simon two- 
stage design to evaluate efficacy of brain RT with checkpoint blockade and concurrent HER2-directed 
therapy. However, because of the diarrhea and colitis associated with tremelimumab mediated CTLA4 
blockade when administered at 10mg/kg monthly (a well described class effect), a lower dose of 
tremelimumab will be co-administered with trastuzumab in the expansion study in combination with 
durvalumab, a PD-L1 directed antibody that is currently US FDA approved for other indications. 
1.2.1 Protocol Expansion Summary 
 
Given the safety and response demonstrated in the safety arm of patients treated with brain RT, 
checkpoint and HER2-directed therapy, this arm will be expanded to evaluate efficacy in a Simon two- 
stage design. In this expansion, we will evaluate the combination of tremelimumab (treme), durvalumab 
(durva), and HER2 directed therapy plus brain irradiation in breast cancer patients with brain metastases 
(BCBM) for whom post-brain irradiation cytotoxic chemotherapy is planned. Subjects will receive either 
whole brain radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with 
tremelimumab administered at 75 mg and durvalumab administered at 1500mg every 28 days for 4 cycles. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 8 of 98 
 
 
 
 
After the 4th  cycle, patients will continue to receive 1500mg durvalumab every 28 days. Patients will 
continue to receive HER2 directed therapy at a NCCN-guideline-endorsed dose and schedule, as 
determined by the treating investigator. The same study design parameters will be applied to the 
expansion (Fig 1.2-2) as were previously applied to the completed efficacy cohort not requiring concurrent 
HER2 directed therapy (Fig 1.2-1). 
 
Figure 1.2-1: Design Schematic 
 
 
 
SAE: Serious adverse event requiring tremelimumab discontinuation 
*Sa fety run-in: 6 week intra-subject enrollment hold across fi rs t 3subjects 
 
Figure 1.2-2 Study Expansion Design Schematic 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 9 of 98 
 
 
 
 
1.4 Efficacy Arm (Completed as of 3/1/2017) 
 
The primary objective of the trial will be to evaluate non-CNS disease control of tremelimumab plus brain 
irradiation at 12 weeks, defined as either complete response (CR), partial response (PR), or stable disease 
(SD) by RECIST1.1 criteria. A Simon 2-stage design will be employed. A maximum of 17 subjects will be 
accrued to the efficacy arm. After the first 3 patients are enrolled in the efficacy arm, a 6 week enrollment 
hold will be conducted in order to ensure safety before additional patients are enrolled. An interim 
assessment will then occur after the first 9 subjects have enrolled, and the accrual to this arm will proceed 
only if a pre-specified futility threshold is met. Patients not requiring continuation of  HER2  directed 
therapy will be enrolled in this arm. 
 
After the first 3 patients in the efficacy arm complete the 6 week enrollment hold, safety will be assessed 
on a continuous basis, and enrollment will be suspended if toxicities exceed the pre-defined safety 
threshold. 
 
1.5 HER2 directed therapy Co-administration Arm (Completed as of 3.1.2017) 
 
Women with HER2-overexpressing breast cancer for whom continuation of HER2 directed therapy is 
indicated will be eligible to enroll in an arm that will enroll concurrently with the efficacy arm, but will 
evaluate the safety of HER2 directed therapy and tremelimumab co-administration. 
 
Subjects in the co-administration arm will receive RT and tremelimumab at the same schedule and dose as 
the efficacy arm, but will continue to receive HER2 directed therapy at a NCCN-guideline-endorsed dose 
and schedule, as determined by the investigator. For heightened safety monitoring, a safety run-in will be 
performed, whereby each of the first 3 subjects will require a 6-week hold prior to enrollment of the 
subsequent subject.  Accrual will follow a modified 3+3 design, to minimize drug exposure if the treatment 
is not tolerable. 
1.6 Protocol Expansion (Planned as of 3.1.2017) 
 
Subjects in the study expansion will be enrolled in a Simon two-stage arm, designed to evaluate the safety 
and efficacy of tremelimumab, durvalumab, HER2 directed therapy, and RT co-administration. A maximum 
of 17 patients will be accrued to this stage. After the first 3 patients are enrolled, a 6 week enrollment 
hold will be conducted in order to ensure safety before additional patients are enrolled. An interim 
assessment will then occur after the first 9 subjects have enrolled, and the accrual to this arm will proceed 
only if a pre-specified futility threshold is met. After the first three patients in this stage complete the 6 
week enrollment hold, safety will be assessed on a continuous basis, and enrollment will be suspended if 
toxicities exceed the pre-defined safety threshold. 
1.7 Drug administration and Radiation Initiation 
 
1.6.1 Efficacy and HER2-directed Safety Arms (Completed as of 3.1.2017) 
 
In both the efficacy arm and HER2 directed arms, tremelimumab was administered intravenously at 
10mg/kg 2 days prior to the initiation of radiotherapy. In cases where this was not feasible, tremelimumab 
was administered at any time during a period of 5 days preceding the initiation of radiotherapy, to 3 days 
following initiation of radiotherapy. Subsequent doses of tremelimumab were administered every 28 days 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 10 of 98 
 
 
 
 
+/- 1 week until progression or intolerable toxicity. The dosing schedule was based on a patient’s first 
dose of tremelimumab. 
1.6.1 HER2 Expansion (Planned as of 3.1.2017) 
 
In the protocol expansion, tremelimumab will be administered at 75 mg and durvalumab will be 
administered at 1500 mg 2 days prior to the initiation of radiotherapy. In cases where this is not feasible, 
tremelimumab and durvalumab may be administered at any time during a period of 5 days proceeding 
initiation of radiotherapy to 3 days following initiation of radiotherapy. Subsequent doses  of 
tremelimumab and durvalumab will be administered every 28 days +/- 1 week for 4 cycles. After the 4th 
cycle, durvalumab 1500 mg will be administered until disease progression or intolerable  toxicity.  The 
dosing schedule will be based on the patient’s first dose of tremelimumab and durvalumab. Patients will 
receive HER2 directed therapy at the NCCN-guideline-endorsed dose and schedule, as determined by the 
investigator. 
 
 
 
 
During tremelimumab +/- durvalumab administration, systemic therapy  beyond  HER2-directed therapy 
will be suspended until confirmed radiographic progression or clinical deterioration, at which ti me 
tremelimumab +/- durvalumab will be discontinued and systemic therapy may be initiated. Subjects who 
initiate non-study cancer-directed systemic therapy before the imaging assessment will be considered 
treatment failures when determining the primary endpoint. 
 
Concurrent administration of bone modifying agents (i.e. Denosumab or zoledronic acid) is permitted on 
study. 
Week 1 is the week of first treatment. Response assessment will occur 12 weeks thereafter (i.e. at week 
13 +/- 1 week), with a confirmatory scan at 16 weeks (i.e. week 17 +/- 1 week ) in patients with evidence 
of radiographic progression at week 13 (Table 10.0-1). Responses will be determined by standard-of-care 
whole body imaging contrast-enhanced CT chest abdomen pelvis. For patients with bone metastases or 
with an appropriate clinical indication, concurrent bone scan or PET scan is recommended. Other imaging 
modalities will be performed as clinically indicated at the discretion of the investigator. 
 
When feasible, subjects with symptomatic brain metastases will be managed conservatively without the 
use of steroids. Subjects requiring steroids for symptom management will be eligible for enrollment as 
outlined in section 9. CNS and systemic response assessments will be evaluated every 12 weeks starting at 
week 13 (i.e. 12 weeks after treatment in week 1). Research bloods will be obtained for immune 
monitoring. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective 
 
• 
To  determine   12  week  non-CNS  disease   control  (CR  +  PR  +  SD)   of   the   combination  of 
tremelimumab plus brain irradiation (SRS or WBRT) by RECIST 1.1 criteria 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 11 of 98 
 
 
 
 
• 
To determine 12 week non-CNS disease control (CR + PR + SD) of the combination of 
tremelimumab, durvalumab, and HER2 directed therapy plus brain irradiation (SRS or WBRT) by 
RECIST 1.1 criteria. 
 
Secondary Objectives 
 
• 
To determine the safety profile of tremelimumab +/- durvalumab and HER2 directed therapy co- 
administration plus brain irradiation 
• 
To determine 12 week non-CNS objective response and disease control rate by immune related 
response criteria 
• 
To  determine  non-CNS  objective  response,  and  progression  free  survival  (PFS)  by  RECIST  1.1 
criteria 
• 
To determine overall survival 
• 
To determine 24-week CNS objective response rate, 24-week CNS PFS, and CNS median PFS 
Exploratory Objectives 
• 
To evaluate the effect of tremelimumab +/- durvalumab + RT on: lymphocyte phenotype and 
serum cytokines, disease related biomarkers, humoral and cellular responses to tumor antigens 
and recall non-tumor antigens 
• 
To evaluate serological and cellular immune correlates of toxicity and/or clinical activity 
• 
To explore the radiologic changes by PET/CT with tremelimumab +/- durvalumab and RT 
administration 
• 
To evaluate the efficacy of tremelimumab +/- durvalumab and HER2 directed therapy co- 
administration plus brain irradiation 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 
Epidemiology of breast cancer brain metastases 
 
Breast cancer is a global public health burden with more than 200,000 new cases diagnosed each year in 
the United States and more than one million new cases diagnosed worldwide each year (Society 2012). 
Despite effective screening and treatment, about one-third of women diagnosed with early stage disease 
develop lethal distant metastases. Furthermore, brain  metastases  are a relatively common  and 
devastating complication of breast cancer. Hence, more effective approaches are needed. The uniqueness 
of tumors and hosts provides an opportunity for individualized treatment. Because the synergistic effect 
of radiotherapy (RT) and immunotherapy has been demonstrated in multiple preclinical studies and 
because RT combined with immunotherapy may confer an abscopal effect with regression of distant 
metastases, our proposed strategy uses immune stimulation to augment the therapeutic impact of whole 
brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) on clinical outcomes for women with 
breast cancer brain metastases (BCBM). Thus, the central goal for this project is to make a major advance 
for women with BCBM by augmenting an effected individual’s immune response to their existing tumor. 
 
Brain metastasis is a relatively common and devastating complication of breast cancer. In fact, breast 
cancer is the second most common cancer associated with brain metastasis in the United States 
(Barnholtz-Sloan, Sloan et al. 2004). Both the incidence and prevalence of BCBM are rising (Frisk, Svensson 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 12 of 98 
 
 
 
 
et al. 2012). Although brain metastases are diagnosed in approximately 15% of breast cancer patients, 
autopsy data suggest a prevalence of up to 30%-40% (Tsukada, Fouad et al. 1983). Brain metastasis 
secondary to breast cancer is an independent poor prognostic factor, with variable outcomes depending 
on histologic subtype. 
 
3.2 
Breast Cancer Brain Metastases at MSKCC 
 
Because published outcomes data for women with BCBM treated in the modern treatment era are 
limited, we performed a retrospective study of our recent experience with this disease at Memorial Sloan- 
Kettering Cancer Center (MSKCC) (Morikawa, Diab et al. 2013). For women with newly diagnosed BCBM 
and treated with brain RT at MSKCC between January 2009 and December 2011, the median time from 
brain metastases to death for all patients was 15.3 months (10.9-18.2mo, 95% CI). The distribution by 
subtype was as follows: 28/113 (25%) HER2-positive (HER2+); 59/113 (52%) hormone receptor-positive, 
HER2-negative (HR+HER2-); and 26/113 (23%) hormone receptor-negative, HER2-negative, or “triple 
negative” (HR-HER2-). The majority (70%) were treated with WBRT. By subtype, the median time from 
brain metastases to death was 32.8 months for women with HER2+ disease; 12.7 months for women with 
HR+HER2- disease; and 11.3 months for women with HR-HER2- disease (p=0.001). The median time to 
death was 12.0 months for women treated with WBRT, and 23.0 months for women treated with SRS. 
These outcomes represent significant improvements when compared with published historical data, 
thereby implying that improvements in systemic and/or local therapeutic strategies have translated into 
improved survival for women with BCBM. However, despite these improvements, the prognosis for these 
women remains poor and further inroads are desperately needed. 
 
3.3 
Current Standard of Care for Treating Brain Metastases 
 
Brain metastases are a particularly challenging clinical manifestation of breast cancer. Conventional 
systemic therapies have demonstrated limited effectiveness in preventing and treating brain metastases, 
as least in part because of the blood-brain barrier. For example, the successful development of 
trastuzumab in HER2+ breast cancer translated into an approximately 50% reduction in the risk of distant 
metastases when administered in the adjuvant setting (Slamon, Eiermann et al. 2011).  However,  in 
women with HER2+ metastatic breast cancer (MBC) treated with chemotherapy and trastuzumab, 
approximately 30% develop central nervous system (CNS) metastases (Gori, Rimondini et al. 2007). It was 
hoped that the small size of lapatinib, a tyrosine kinase inhibitor of EGFR and HER2, would permit CNS 
penetration and therefore, provide effective systemic treatment of brain metastases. However, studies of 
single agent lapatinib and lapatinib in combination with chemotherapy did not confer significant benefits 
(Lin, Carey et al. 2008). Response rates to systemic therapies have been similarly disappointing for other 
histologic subtypes. Consequently radiotherapy remains the cornerstone for  the treatment of BCBM, 
palliating neurologic symptoms and potentially prolonging survival (Wong, Hird et al. 2009). 
3.4 
Rationale for Immunotherapy in Breast Cancer Brain Metastases 
 
Despite promising initial response rates with brain radiotherapy, CNS failure is common (Ogura, Mitsumori 
et al. 2003). Therefore, local control in the brain could potentially be improved by combining radiotherapy 
with a systemic strategy that augments and prolongs the host immune response to radiotherapy- 
generated tumor-specific antigens. One such systemic strategy is the use of a therapeutic immunologic 


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checkpoint blockade antibody such as ipilimumab or tremelimumab. In melanoma patients with brain 
metastases, the anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, generated 14% 
disease control as monotherapy. (Margolin, Ernstoff et al. 2012) 
 
Immunotherapy for the treatment of metastatic breast  cancer has long  been a goal of scientists and 
clinicians. However, numerous challenges to successful implementation have included limited numbers of 
viable targets as a consequence of tumor heterogeneity, limited efficacy of available agents, and the lack 
of sustained anti-tumor effects even in the face of increased immune responses. Despite these challenges, 
a recent and growing literature indicates that immune therapy for the treatment of breast cancer is a 
viable strategy. Studies have demonstrated the prognostic and predictive impact of tumor tissue 
infiltration by T effector (Teff) and T regulatory (Treg) cells in curable breast cancer (Bates, Fox et al. 2006, 
Ladoire, Mignot et al. 2011, Mahmoud, Paish et al. 2011). Furthermore, in the retrospective MSKCC study 
of outcomes after BCBM diagnosis in the modern treatment era, an absolute lymphocyte count ≥0.7/ul 
was associated with improved survival (Morikawa, Diab et al. 2013). Together, these  data suggest that 
there is a critical relationship between the immune system and breast cancers, thereby supporting the 
pursuit of tumor-specific immunotherapy in this setting. 
 
 
3.5 
Anti-CTLA-4 therapy 
 
CTLA-4 is a homolog of the co-activation receptor CD28 that, when bound to B7 ligands (CD80 and CD86), 
inhibits T-cell function by both intrinsic and extrinsic mechanisms (Krummel and Allison 1995). CTLA-4 
induces inhibitory downstream T-cell receptor signaling, but also leads to up-regulation of CTLA-4 
expression and competitive inhibition of CD28-mediated co-activation. CTLA-4 is also highly expressed on 
CD25+FOXP3+ T-regulatory (Treg) cells and is instrumental in Treg function. CTLA-4 blockade been shown to 
promote T-cell activation, as well as depletion of intratumoral Tregs (Quezada and Peggs 2013) Ipilimumab 
(IgG1) and tremelimumab (IgG2) are the two human anti-CTLA-4 antibodies that have undergone clinical 
evaluation. 
 
3.6 
Safety and Efficacy of Tremelimumab 
 
3.6.1 Product Derivation 
 
Tremelimumab is a human IgG2 mAb directed against CTLA-4. Tremelimumab has an overall molecular 
weight of approximately 149 kDa including oligosaccharides. Cytotoxic T lymphocyte-associated antigen 4 
is a critical regulatory signal for T-cell expansion and activation following an immune response, and it 
serves as a natural braking mechanism that maintains T-cell homeostasis. During T-cell activation, T cells 
upregulate CTLA-4, which binds to B7 ligands on antigen-presenting cells, sending an inhibitory signal that 
limits T-cell activation. Tremelimumab blocks the inhibitory signal resulting from CTLA-4 binding to B7, 
leading to prolongation and enhancement of T-cell activation and expansion. 
 
3.6.2 Summary of Nonclinical Experience 
In vitro, specific mAbs directed against CTLA-4 enhance T cell function, measured by increased production 
of IL-2, IFN-γ, and other cytokines. In CTLA-4 knock-out mice, extensive, polyclonal lymphoproliferation 


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develops that is consistent with dysregulated activation of lymphocytes. Treatment of tumor-bearing mice 
with anti-mouse CTLA-4 mAb (9H10) can induce antitumor immunity and markedly enhance T cell- 
mediated killing of various mouse solid tumors. At a concentration of approximately 30 μg/mL 9H10, anti- 
tumor activity of 9H10 was observed in vivo. Thus, a concentration of ~ 30 μg/mL was identified as the 
target plasma concentration. 
 
3.6.2.1 Pharmacokinetics 
The pharmacokinetics (PK) of tremelimumab were evaluated in cynomolgus  monkeys  following  single 
(0.75, 10, 30, and 100 mg/kg) and multiple (5 to 50 mg/kg weekly) intravenous (IV) administrations. The 
PK of tremelimumab is characterized by a low plasma clearance (CL = 4.32 mL/day/kg), small volume of 
distribution at steady-state (Vss = 53.8 mL/kg), and long half-life (t½ = 9.1 days). In toxicologic studies in 
cynomolgus monkeys, systemic exposures of tremelimumab, assessed by the mean peak observed 
concentration (Cmax) and mean area under the concentration-time curve (AUC), increased dose-
proportionally within the dose ranges examined following single or multiple IV administrations. No 
evidence of nonlinear PK or gender-related differences in exposures was observed. Anti-drug antibody 
(ADA) responses were detected in some animals from all dose groups following single or multiple IV 
administrations of tremelimumab. Finally, PK and ADA responses of clonally- and nonclonally-derived 
tremelimumab were comparable. 
 
Population PK analysis of tremelimumab was performed on combined data from Phase 1, Phase 2, and 
Phase 3 studies (N = 654) in subjects with metastatic melanoma using nonlinear mixed-effects modeling in 
NONMEM software. A 2-compartment population PK model adequately described the plasma 
concentrations of tremelimumab following various dosing regimens. The population estimate for CL and 
central volume of distribution (V1) was 0.26 L/day and 3.97 L, respectively. The inter-individual variability 
in CL and V1 was modest (31.8% and 20.4%, respectively). Clearance was faster in males, subjects with 
higher values of creatinine clearance and endogenous Ig, and subjects  with relatively poor baseline 
prognostic factors. Central volume of distribution was higher in males and subjects with higher body 
weight. No dose adjustment was needed based on the magnitude of the change inL(< 30%; Wang et al, 
 
201 4). Preliminary population PK of tremelimumab was performed using data from two second-line, 
single-arm investigator-initiated Phase 2 studies (NCT01 649024 /N CT0 1655888) in subjects with malignant 
mesothelioma. A total of 40 subjects provided evaluable PK data following 15 mg/kg Q90D [NCT01649024] 
or 10 mg/kg Q4W for 6 months followed by 10 mg/kg Q12W [NCT01655888] dosing regimens. 
Tremelimumab PK exposure in mesothelioma subjects was similar to previous melanoma studies following 
15 mg/kg Q90D. Following  the 15 mg/kg Q90D, PK exposure was below the target trough level of 
approximately 30 µg/mL for about half of the dosing interval with almost all subjects below the lowerlimit 
of quantitation at the end of the 90-day dosing interval. Following more frequent dosing of 10 mg/kg 
Q4W, PK exposure was increased and maintained at or above the target level in the majority of subjects 
over the entire dosing interval. Tremelimumab PK was best described using a 2-compartment linear model 
with first order elimination. Following IV dosing, the typical CL and V1 were 0.2 L/day and 3.5 L, 
respectively. The between-subject variability for CL and V1 were 22% and 7%, respectively. The estimated 
typical PK parameters were similar to other mAbs without target mediated elimination. The baseline body 
weight and Eastern Cooperative Oncology Group (ECOG) performance status were identified as significant 


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covariates for CL, whereas only baseline body weight was significant covariate for volume of distribution. 
These correlations will be further validated using data from larger clinical studies. 
 
3.6.2.2 To xico logy 
The toxicology program conducted for tremelimumab consisted of in vivo general toxicology studies in 
cynomolgus monkeys for up to 6 months duration, an embryo-fetal development study in monkeys, tissue 
cross-reactivity studies in  both  monkey and human tissues, and  blood  compatibility studies. The 
cynomolgus monkey was considered to be the only pharmacologically relevant species  for nonclinical 
safety testing of tremelimumab, based on similar binding and potency against cynomolgus monkey and 
human CTLA-4 and lack of binding to rodent CTLA-4-Ig. Overall, tremelimumab toxicities were consistent 
with inhibition of CTLA-4 and  with clinical safety findings, and indicated that chronic clinical use of 
tremelimumab may lead to adverse effects on the gastrointestinal tract, skin, lymphoid organs, thyroid 
tissues, and hematological systems. Dose-limiting toxicities (DLTs) were identified in chronic  toxicity 
studies in monkeys and include persistent diarrhea microscopically correlated with mononuclear cell 
inflammation in the cecum, colon, and/or duodenum, weight loss, and development of adverse skin 
conditions (scabbed areas; open sores; swollen eyelids; dry, scaly, or crusted skin; rash or reddened skin; 
yellowish skin) accompanied histologically with mononuclear cell inflammation. Most toxicities were 
reversible or showed a trend towards reversibility. 
 
An embryo-fetal development study was conducted in pregnant cynomolgus monkeys during the period of 
organogenesis. Tremelimumab was administered IV once weekly from Day 20 to 50 of gestation at doses 
of 0 (control), 5, 15, or 30 mg/kg. Tremelimumab did not elicit maternal toxicity, developmental toxicity, 
or teratogenicity. 
 
3.6.3 Summary of Clinical Experience: Monotherapy 
As of November 12, 2014 (for all studies except D4190C00006 that has a cutoff date of December 4, 2014), 
22 sponsored clinical studies have been conducted as part of the tremelimumab clinical development 
program. Of these studies, 13 have been completed and 9 are ongoing. Tremelimumab has been 
administered as monotherapy to 973 subjects participating in 10 of the 22 clinical studies, 2 of which are 
ongoing. An additional 497 subjects have received tremelimumab or placebo in the ongoing  double- 
blinded, Phase 2b mesothelioma study, D4880C00003 (DETERMINE; data remain blinded). Tremelimumab 
in combination with other anticancer agents has been administered to 208 subjects with a variety of tumor 
types in 12 of the 22 clinical studies, 7 of which are ongoing. 
 
3.6.3.1 Efficacy 
 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged, also 
observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to be consistent across tumor 
types for this mechanism of action. Response rates to anti-CTLA-4 antibodies are generally low, 
approximately 10%. However, in patients who respond, the responses are generally  durable,  lasting 
several months even in those with aggressive tumors such as refractory metastatic melanoma. Moreover, 
survival benefit was reported even in subjects without radiographic regression in tumor burden. In a 
single-arm Phase 2 study (Study A3671008) of tremelimumab administered at 15 mg/kg Q90D to subjects 
with refractory melanoma, a response rate of 7% and median OS of 10 months in the second-line setting 


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(as compared to approximately 6 months with BSC reported from a retrospective analysis; (Korn, Liu et 
al. 2008) was observed (Kirkwood, Lorigan et al. 2010). In a randomized, open-label, first-line Phase 3 
study of tremelimumab (administered at 15 mg/kg Q90D) versus chemotherapy (DTIC or temozolomide) 
in advanced melanoma (Study A3671009), results of the final analysis showed a response rate of 11% and 
median OS of 12.58 months in this first-line setting (as compared to 10.71 months with standard 
chemotherapy)(Ribas, Kefford et al. 2013). Additionally, in a Phase 2 maintenance study in NSCLC, PFS at 
3 months was 22.7% in the tremelimumab arm compared with 11.9% in the BSC arm (Study A3671015). 
 
Survival analysis of 293 subjects treated with tremelimumab in a Phase 3 study in melanoma showed 
better OS in subjects with higher exposure. The median OS was 18.4 months for the high AUC (≥ 123,665 
μg·hour/mL) group compared to 9.0 months for the low AUC (< 123,665 μg·hour/mL) group (HR 0.5; p < 
0.001) as shown in Figure 3.6.3.1. Higher rates of 1-year survival (67% vs 56%) and 2-year survival (16% vs 
5%) were observed in the high versus low AUC groups, respectively. It is possible that the lower OS in the 
low AUC90 group is due to less favorable prognostic features in that group. Subjects who had an AUC90 
below the median were more likely to have baseline characteristics that predict poor prognosis, including 
M1c (67% vs 47%), LDH > ULN (30% vs 17%), ECOG performance status > 0 (42% vs 21%), and CRP > 1.5 × 
ULN (40% vs 18%). However, subjects who were able to achieve a higher AUC despite the presence of 
poor prognostic features had a better survival outcome than those who did not, suggesting that 
maximizing exposure could improve the survival outcome with tremelimumab. 
 
Preliminary data are available for the ongoing study, D4190C00006, which is evaluating MEDI4736 in 
combination with tremelimumab. As of the data cutoff date of 04Dec2014, a total of 31 of 61 subjects 
were evaluable for efficacy with at least 8 weeks of follow-up. Of these, 8 subjects had PR, 11 subjects 
had stable disease, and 12 subjects had PD. 
 
Figure 3.6.3.1: Kaplan-Meier curve of survival stratified by drug exposure in a phase III melanoma trial 


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3.6.3.2 Safety 
 
 
The profile of adverse events (AEs) and the spectrum of event severity have remained stable across the 
tremelimumab clinical program and are consistent with the pharmacology of the target. Based on 
integrated data from the completed and rollover tremelimumab monotherapy studies (N = 973), AEs (all 
grades, regardless of severity) reported in > 10% of subjects were diarrhea (45.3%), fatigue (37.5%), 
nausea (32.5%),  rash (28.8%), pruritus  (27.3%),  decreased  appetite (22.8%), vomiting (22.5%),  pyrexia 
(15.3%), cough (15.0%), constipation (14.4%), abdominal pain (13.9%), headache (13.8%), dyspnea 
(12.4%), and decreased weight (10.2%; see Section 5.3.2.1 for details). Integrated data from completed 
studies of tremelimumab in combination with other agents (N = 116) showed that AEs (all grades, 
regardless of causality) reported in > 15% of subjects (all grades, regardless of causality) included diarrhea 
(54.3%);  nausea (40.5%);  fatigue  (38.8%);  rash  (35.3%);  pruritus,  decreased  appetite  (30.2%  each); 
vomiting (27.6%); pyrexia (26.7%); influenza like illness (20.7%); arthralgia (19.8%); constipation (19.0%); 
thrombocytopenia, injection site reaction (18.1% each); and increased aspartate aminotransferase 
(15.5%). Most of these events occurred at a higher rate with tremelimumab plus sunitinib than with other 
combinations. 
 
Events reported in > 5% of subjects treated with tremelimumab monotherapy and assessed by the 
investigator as treatment related (listed in descending order of frequency) were diarrhea, rash, pruritus, 
fatigue, nausea, vomiting, decreased appetite, headache, abdominal pain, and colitis. 


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In an integrated analysis of tremelimumab monotherapy studies, 944 of the 973 subjects (97.0%) treated 
with tremelimumab monotherapy experienced at least 1 AE (Table 3.6.3.2). The events resulted in 
discontinuation of tremelimumab in 10.0% of subjects, were serious in 36.5%, were ≥ Grade 3 in severity 
in 49.7%, were fatal in 67.7%, and were considered to be treatment related in 79.1% of subjects. 
 
The frequency of any AEs and ≥ Grade 3 AEs was generally similar across the tremelimumab dose groups. 
However, a higher percentage of subjects in the 10 mg/kg Q28D and 15 mg/kg Q90D groups compared 
with the All Doses < 10 mg/kg group experienced treatment-related AEs, SAEs, AEs resulting in 
discontinuation of investigational product, and deaths. 
 
A total of 944 subjects (97.0%) experienced at least 1 event for a total of 10,341 events. Adverse events 
(all grades) reported in > 10% of subjects (in decreasing order of frequency) were diarrhea,  fatigue, 
nausea, rash, pruritus, decreased appetite, vomiting, pyrexia, cough, constipation, abdominal pain, 
headache, dyspnea, and decreased weight. The frequencies of these AEs were higher in the 10 and 15 
mg/kg dose groups than the All Doses < 10 mg/kg group. Notably, for all of these frequent AEs (all grades), 
except for diarrhea, abdominal pain, headache, and dyspnea, the incidence was higher in the 10 mg/kg 
group than the 15 mg/kg group. 
 
Approximately half of the subjects experienced AEs of ≥ Grade 3 severity. The most frequent ≥ Grade 3 
AEs reported in ≥ 2% of subjects (in decreasing order of frequency) were diarrhea, fatigue, colitis, disease 
progression, dyspnea, dehydration/nausea/vomiting, abdominal pain, decreased appetite, and asthenia. 
The events of diarrhea, abdominal pain, and colitis occurred at a higher rate in the 10 mg/kg group, 
whereas fatigue, disease progression, dehydration, nausea, vomiting, decreased appetite, and asthenia 
were reported more frequently in the 15 mg/kg group. 
 
Adverse events were considered to be treatment related in 770 subjects (79.1%). Treatment related AEs 
were reported at similar rates in the 10 and 15 mg/kg groups (81.8% and 80.0%, respectively), and were 
mostly Grade 1 or 2 in severity (≥ Grade 3 treatment-related AEs reported in 26.1% of subjects). The most 
frequent treatment-related AEs (in > 5% of subjects) were diarrhea (41.2%), rash (27.2%), pruritus (25.1%), 
fatigue (23.8%), nausea (21.9%), vomiting (13.5%), decreased appetite (11.3%), headache (7.2%), pyrexia 
(7.0%), abdominal pain (6.7%), and colitis (5.5%). 


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Table 3.6.3.2: Adverse Events Associated with Tremelimumab 
 
System Organ Class 
Preferred Term (MedDRA V 16. 0) 
Tremelimumab ( m g/k g ) 
All <1 0 
(n = 33 ) 
n (%)  
10 
(n = 77 ) 
n (%)  
15 
(n = 866) a 
n (%)  
Total 
(N = 973 ) 
n (%)  
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
Total number of events 
23 8 
30 
1088 
10 7 
9021 
1107 
10347 
1244 
Subjects reporting ≥ 1 event 
32 (97.0) 
13 (39.4) 
77 (100) 
35 (45.5) 
837 (96.7) 
437 (50.5) 
944 (97.0) 
485 (49.8) 
Blood and Lymphatic S ystem 
Disor ders 
4 (12.1) 
1 (3.0) 
15 (19.5) 
1 (1.3) 
94 (10.9) 
28 (3.2) 
113 (11.6) 
30 (3.1) 
Anemia 
2 (6.1) 
1 (3.0) 
12 (5.6) 
0 (0.0) 
52 (6.0) 
15 (1.7) 
66 (6.8) 
16 (1.6) 
Gastrointestinal  Disorders 
21 (63.6) 
6 (18.2) 
61 (79.2) 
21 (27.3) 
614 (70.9) 
175 (20.2) 
696 (71.5) 
202 (20.8) 
Dia rrhea 
10 (30.3) 
3 (9.1) 
32 (41.6) 
15 (19.5) 
399 (46.1) 
108 (12.5) 
441 (45.3) 
126 (12.9) 
Nausea 
10 (30.3) 
0 (0.0) 
33 (42.9) 
2 (2.6) 
273 (31.5) 
26 (3.0) 
316 (32.5) 
28 (2.9) 
Vomit ing 
5 (15.2) 
0 (0.0) 
26 (33.8) 
2 (2.6) 
188 (21.7) 
26 (3.0) 
219 (22.5) 
28 (2.9) 
Constipation 
2 (6.1) 
1 (3.0) 
16 (20.8) 
1 (1.3) 
122 (14.1) 
4 (0.5) 
140 (14.4) 
6 (0.6) 
Abdominal pain 
1 (3.0) 
0 (0.0) 
7 (9.1) 
3 (3.9) 
127 (14.7) 
23 (2.7) 
135 (13.9) 
26 (2.7) 
Colitis 
0 (0.0) 
0 (0.0) 
9 (11.7) 
4 (5.2) 
49 (5.7) 
32 (3.7) 
58 (6.0) 
36 (3.7) 
Abdominal pain upper 
0 (0.0) 
0 (0.0) 
4 (5.2) 
0 (0.0) 
47 (5.4) 
0 (0.0) 
51 (5.2) 
0 (0.0) 
General Disorders and Admi nistrati on 
Site Conditions 
19 (57.6) 
1 (3.0) 
53 (68.8) 
5 (6.5) 
543 (62.7) 
133 (15.4) 
614 (63.1) 
139 (14.3) 
Fatigue 
8 (24.2) 
0 (0.0) 
40 (51.9) 
1 (1.3) 
317 (36.6) 
46 (5.3) 
365 (37.5) 
47 (4.8) 
Pyrexia 
4 (12.1) 
0 (0.0) 
14 (18.2) 
1 (1.3) 
131 (15.1) 
9 (1.0) 
149 (15.3) 
10 (1.0) 
edema peripheral 
5 (15.2) 
0 (0.0) 
14 (18.2) 
2 (2.6) 
78 (9.0) 
8 (0.9) 
97 (10.0) 
10 (1.0) 
Asthenia 
6 (18.2) 
0 (0.0) 
6 (7.8) 
0 (0.0) 
71 (8.2) 
19 (2.2) 
83 (8.5) 
19 (2.0) 
Chills 
0 (0.0) 
0 (0.0) 
7 (9.1) 
1 (1.3) 
48 (5.5) 
0 (0.0) 
55 (5.7) 
1 (0.1) 
Disease  progression 
0 (0.0) 
0 (0.0) 
1 (1.3) 
1 (1.3) 
32 (3.7) 
32 (3.7) 
33 (3.4) 
33 (3.4) 


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Table 3.6.3.2 (continued): Adverse Events Associated with Tremelimumab Monotherapy 
 
 
System Organ Class 
Preferred Term (MedDRA V 16. 0) 
Tremelimumab ( m g/k g ) 
All <1 0 
(n = 33 ) 
n (%)  
10 
(n = 77 ) 
n (%)  
15 
(n = 866) a 
n (%)  
Total 
(N = 973 ) 
n (%)  
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
Investigations 
8 (24.2) 
1 (3.0) 
23 (29.9) 
4 (5.2) 
205 (23.7) 
49 (5.7) 
236 (24.3) 
54 (5.5) 
Weight decreased 
4 (12.1) 
0 (0.0) 
12 (15.6) 
1 (1.3) 
83 (9.6) 
6 (0.7) 
99 (10.2) 
7 (0.7) 
Metabolism and Nutri tion Disorders 
3 (9.1) 
0 (0.0) 
38 (49.4) 
6 (7.8) 
287 (33.1) 
76 (8.8) 
328 (33.7) 
82 (8.4) 
Decreased  appetite 
3 (9.1) 
0 (0.0) 
29 (37.7) 
0 (0.0) 
190 (21.9) 
23 (2.7) 
222 (22.8) 
23 (2.4) 
Dehydration 
0 (0.0) 
0 (0.0) 
13 (16.9) 
4 (5.2) 
61 (7.0) 
24 (2.8) 
74 (7.6) 
28 (2.9) 
Musculoskeletal and Connecti ve 
Tissue Disorders 
13 (39.4) 
1 (3.0) 
31 (40.3) 
3 (3.9) 
309 (35.7) 
50 (5.8) 
353 (36.3) 
54 (5.5) 
Arthralgia 
4 (12.1) 
0 (0.0) 
8 (10.4) 
1 (1.3) 
79 (9.1) 
8 (0.9) 
91 (9.4) 
9 (0.9) 
Back pain 
1 (3.0) 
0 (0.0) 
7 (9.1) 
2 (2.6) 
75 (8.7) 
13 (1.5) 
83 (8.5) 
15 (1.5) 
Pain in e xtre mity 
1 (3.0) 
0 (0.0) 
8 (10.4) 
0 (0.0) 
69 (8.0) 
11 (1.3) 
78 (8.0) 
11 (1.1) 
Myalgia 
2 (6.1) 
0 (0.0) 
11 (14.3) 
0 (0.0) 
57 (6.6) 
3 (0.3) 
70 (7.2) 
3 (0.3) 
Musculoskeletalpain 
2 (6.1) 
1 (3.0) 
3 (3.9) 
2 (2.6) 
50 (5.8) 
7 (0.8) 
55 (5.7) 
10 (1.0) 
Ner vous S ystem Disor ders 
13 (39.4) 
3 (9.1) 
26 (33.8) 
1 (1.3) 
274 (31.6) 
40 (4.6) 
313 (32.2) 
44 (4.5) 
Headache 
7 (21.2) 
1 (3.0) 
10 (13.0) 
0 (0.0) 
117 (13.5) 
8 (0.9) 
134 (13.8) 
9 (0.9) 
Dizziness 
4 (12.1) 
0 (0.0) 
5 (6.5) 
1 (1.3) 
61 (7.0) 
2 (0.2) 
70 (7.2) 
3 (0.3) 
Psychiatric Disor ders 
9 (27.3) 
0 (0.0) 
15 (19.5) 
1 (1.3) 
154 (17.8) 
19 (2.2) 
178 (18.3) 
20 (2.1) 
Insomnia 
5 (15.2) 
0 (0.0) 
6 (7.8) 
0 (0.0) 
77 (8.9) 
0 (0.0) 
88 (9.0) 
0 (0.0) 
Respiratory, Thoracic and 
Mediastinal Disor ders 
9 (27.3) 
4 (12.1) 
30 (39.0) 
5 (6.5) 
316 (36.5) 
55 (6.4) 
355 (36.5) 
64 (6.6) 
Cough 
3 (9.1) 
0 (0.0) 
12 (15.6) 
0 (0.0) 
131 (15.1) 
4 (0.5) 
146 (15.0) 
4 (0.4) 
Dyspnea 
2 (6.1) 
1 (3.0) 
9 (11.7) 
2 (2.6) 
110 (12.7) 
26 (3.0) 
121 (12.4) 
29 (3.0) 
Oropharyngealpain 
2 (6.1) 
0 (0.0) 
5 (6.5) 
0 (0.0) 
51 (5.9) 
0 (0.0) 
58 (6.0) 
0 (0.0) 


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Table 3.6.3.2 (continued): Adverse Events Associated with Tremelimumab Monotherapy 
 
 
 
System Organ Class 
Preferred Term (MedDRA V 16. 0) 
Tremelimumab ( m g/k g ) 
All <1 0 
(n = 33 ) 
n (%)  
10 
(n = 77 ) 
n (%)  
15 
(n = 866) a 
n (%)  
Total 
(N = 973 ) 
n (%)  
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
All Grades 
≥ Grade 3 
Skin and Subcutane ous Tissue 
Disor ders 
14 (42.4) 
0 (0.0) 
53 (68.8) 
2 (2.6) 
504 (58.2) 
22 (2.5) 
571 (58.7) 
24 (2.5) 
Rash 
7 (21.2) 
0 (0.0) 
29 (37.7) 
2 (2.6) 
244 (28.2) 
10 (1.2) 
280 (28.8) 
12 (1.2) 
Pruritus 
3 (9.1) 
0 (0.0) 
33 (42.9) 
1 (1.3) 
230 (26.6) 
3 (0.3) 
266 (27.3) 
4 (0.4) 
MedDRA = Medical Dictionary for Regulatory Activities. 
Note:  This  table  includes  data  from Studies  A3671001  (single-dose  study),  A3671002,  A3671008,  A3671009,  A3671011  (single-dose  study),  A3671014, 
A3671015, A3671022, and A3671024 (D4881C00024). 
a 
Includes 3 subjects who were in itia lly treated at 10 mg/ kg in one of the legacy studies and subsequently treated at 15 mg/kg in the rollover study 
(D4881C00024). 


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The highest incidence of serious AEs (SAEs) occurred in the 10 mg/kg group (42.9%), followed by the 15 
mg/kg (36.0%) and All Doses < 10 mg/kg (30.3%) groups. Serious adverse events experienced by > 1% of 
subjects were diarrhea, colitis, vomiting, disease progression, dehydration, pyrexia, nausea, abdominal pain, 
dyspnea, pneumonia, and confusional state. The majority of these events was ≥ Grade 3 in severity and 
reported at a higher rate in the 15 mg/kg group. A total of 451 SAEs in 197 subjects (20.2%) were assessed as 
related to investigational product by the investigator. Treatment-related SAEs were reported in  more 
subjects in the 10 mg/kg group compared with the 15 mg/kg group (29.9% vs 20.0%, respectively), and were 
≥ Grade 3 in severity in the majority of subjects (84.8%). The most frequent treatment related  SAEs 
(occurring in > 1% of subjects) were diarrhea (9.2%), colitis (3.6%), vomiting (2.3%), and nausea and 
dehydration (1.8% each). 
 
 
A total of 97 subjects (10.0%) experienced 140 AEs that resulted in discontinuation of tremelimumab. The 
highest frequency of such AEs occurred in the 10 mg/kg group (16.9%) followed by the 15 mg/kg (9.8%); 
none of the AEs reported in the All Doses < 10 mg/kg group resulted in discontinuation of tremelimumab. 
Adverse events that resulted in discontinuation of tremelimumab in ≥ 3 subjects (≥ 0.3%) were diarrhea, 
colitis, abdominal pain, dehydration, hypophysitis, renal failure, and asthenia. Of the 97 subjects with AEs 
resulting in treatment discontinuation, 72 subjects (74.2%) had 98 events that were ≥ Grade 3 in severity and 
84 subjects (86.6%) had 118 events that were assessed as treatment related by the investigator. Treatment- 
related AEs resulting in discontinuation of tremelimumab in ≥ 3 subjects (≥ 0.3%) were diarrhea (3.4%), colitis 
(1.4%), asthenia (0.5%), and hypophysitis, dehydration, and abdominal pain (0.3% each). As of August 2013, 
659 subjects (67.7%) who received tremelimumab monotherapy have died due to a number of causes, 
including 0.5% which was attributed to tremelimumab. 
 
 
3.6.4 Summary of Clinical Experience: Combination Therapies 
116 subjects with a variety of tumor types have received tremelimumab in combination with other 
anticancer agents in 5 of the 15 clinical studies. Overall, 114 of 116 subje cts (98.3%) treated with 
tremelimumab in combination with other agents experienced at least 1 adverse event. The frequency of 
events overall was similar across the combination therapy arms. Adverse events resulted in discontinuation 
of tremelimumab in 25.9% of subjects, and were serious in 39.7%, fatal in 45.7%, ≥ Grade 3 in severity in 
62.9%, and considered to be treatment related in 70.7% of subjects. Adverse events reported in > 10% of 
subjects overall were diarrhea, nausea, fatigue, rash, decreased appetite, pruritus, vomiting, pyrexia, 
influenza-like 
illness, arthralgia, constipation, 
injection site reaction, thrombocytopenia, aspartate 
aminotransferase increased, peripheral edema, alanine aminotransferase increased, back pain, dysgeusia, 
headache, dyspnea, and cough. Most of these events occurred at a higher rate with tremelimumab + 
sunitinib compared with the other combinations. 
 
Of the subjects who experienced AEs, 73 (62.9%) had events of ≥ Grade 3 severity. The most frequently 
reported ≥ Grade 3 treatment emergent AEs (TEAEs) (in > 3% of subjects) were diarrhea (14.7%), fatigue 
(7.8%), hypertension (5.2%), disease progression and dyspnea (4.3% each), and nausea, alanine 
aminotransferase increased, lipase increased, and dehydration (3.4% each). Adverse events were considered 
to be treatment related in 82 subjects (70.7%). The most frequent treatment-related TEAEs (occurring in > 
10%  of  subjects)  were  diarrhea (44.0%),  pruritus  (25.0%), fatigue  (24.1%),  rash  (23.3%),  nausea (19.8%), 


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decreased appetite (18.1%), vomiting and pyrexia (12.9% each), and thrombocytopenia  (10.3%). Of note, 
thrombocytopenia was reported with tremelimumab + sunitinib (10 subjects) and tremelimumab + 
gemcitabine (2 subjects). 
 
A total of 30 subjects (25.9%) experienced 52 AEs that resulted in discontinuation of tremelimumab. The 
highest frequency of such AEs occurred with tremelimumab + sunitinib and tremelimumab + neoadjuvant 
androgen ablation (42.9% each). Adverse events that resulted in discontinuation of tremelimumab in ≥ 2 
subjects (> 1%) were diarrhea, pyrexia, acute renal failure, colitis, rash, disease progression, dyspnea, and 
edema. A total of 25 subjects (21.6%) had 32 AEs that were ≥ Grade 3 in severity and 19 subjects (16.4%) had 
35 AEs that were assessed as treatment related by the investigator. Treatment related AEs that resulted in 
discontinuation of investigational product in ≥ 2 subjects (> 1%) were diarrhea (6.0%), pyrexia (3.4%), colitis 
(2.6%), and rash, edema, and acute renal failure (1.7% each). The cause of death was ascribed to the 
investigation product in 0.9%. 
 
 
3.6.4.1 Summary of Tremelimumab in Breast Cancer 
In the only reported study of anti-CTLA-4 therapy in breast cancer, tremelimumab with exemestane proved 
safe in women with heavily pre-treated hormone receptor-expressing advanced breast cancer, conferring a 
42% 12-week disease control rate across multiple doses (Vonderheide, LoRusso et al. 2010). The MTD was 
determined to be 6mg/kg q90d, however, dose escalation at the q28d schedule was aborted when the first 
subject receiving 6mg/kg q28d developed dose-limiting diarrhea. The effect of exemestane on the rate of 
adverse effect profile, or the disease control rate, is unknown. 
 
3.6.5 Tremelimumab Dose & Schedule 
For future clinical studies, tremelimumab will be administered IV at a dose of 10 mg/kg Q4W for the first 6 
doses, followed by one dose Q12W until disease progression. The proposed dose and schedule is informed 
by PK, safety, and efficacy data on tremelimumab. 
In an early small Phase 2 study (A3671002), 2 dosing regimens of tremelimumab were compared in subjects 
with melanoma: 15 mg/kg Q90D (N = 45) and 10 mg/kg Q28D (N = 44). Comparable efficacy and overall AE 
rates were observed in both arms; however, the rate of treatment-related CTCAE Grade 3 or 4 AEs was 
higher in the 10-mg/kg Q28D arm (27%) compared to the 15-mg/kg Q90D arm (13%). 
 
Subsequently, 2 pivotal tremelimumab studies (Phase 2 Study A3671008 and Phase 3 Study A3671009) in 
subjects with melanoma used the regimen 15 mg/kg Q90D. Although neither study met its primary endpoint, 
the observed response rate and OS clearly indicate activity of tremelimumab in melanoma. Retrospective 
exposure-survival analyses of these studies suggest better OS in subjects with higher tremelimumab 
exposure (see Section 3.6.3.1). In the Phase 3 trial, there was no difference in the incidence of ≥ Grade 3 AEs 
between low and high exposure groups of tremelimumab. 
 
Tremelimumab at a concentration of 30 μg/mL enhanced IL-2 release (in vitro) and showed antitumor activity 
(in vivo), and was consequently identified as the target concentration. Pharmacokinetic simulations indicate 
that following a dose of 10 mg/kg Q28D for 6 months, approximately 90% of subjects are expected to be 
above the target level of 30 μg/mL during the induction phase (See figure 3.6.5.1). In the Phase 3 melanoma 


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trial with less frequent dosing of 15 mg/kg Q90D, only approximately 50% of the subjects treated with 
tremelimumab were above the target concentration, for only half of the dosing interval. 
 
 
 
Q28D = once every 28 days; Q90D = once every 90 days. 
 
Note: The horizontal line represents the target level of 30 µg/mL. 
 
 
 
Tremelimumab at a dose of 10 mg/kg QM for 6 months followed by 10 mg/kg Q3M is expected to yield PK 
exposures similar to those of the related anti-CTLA-4 mAb ipilimumab at a dose of 10 mg/kg every 3-weeks 
followed by 10 mg/kg Q3M, the dosing regimen that was tested in the pivotal first-line melanoma trial 
(Robert, Thomas et al. 2011). The ipilimumab data suggest that the long-term benefits of anti-CTLA-4 therapy 
may be sustained with a reduced frequency of dosing in patients who are benefiting from therapy. 
 
Based on these data, tremelimumab will be administered at a dose of 10 mg/kg Q4W for 6 doses. Following 
the first 6 doses, in the absence of confirmed disease progression, the interval will be increased to Q12W. 
Dosing will continue as long as the subject is deriving clinical benefit. 
 
3.6.5 Benefit-risk and Ethical Assessment 
In the nonclinical setting, treatment of tumor-bearing mice with anti-mouse CTLA-4 mAb (9H10) induced 
antitumor immunity and markedly enhanced T cell-mediated killing of various mouse solid tumors. Clinical 
trials of tremelimumab, and of the related anti-CTLA-4 antibody ipilimumab, in melanoma suggest activity 
(improved  survival)  of  these  agents  in  melanoma.  Tremelimumab  has  al so  shown  activity  (objective 
Figure 3.6.5.1: Predicted Plasma Tremelimumab Concentration-time Profiles 
for 10 mg/kg Q28D (induction phase) followed by 10 mg/kg Q90D 
(maintenance phase), versus 15 mg/kg Q90D 


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responses and disease stabilization) in the malignant mesothelioma setting, with preliminary results 
suggesting that tremelimumab may lead  to improved  survival with 45.5%  of subjects  alive at 1 year and 
5 subjects were alive at 2 years. 
 
Overall, tremelimumab nonclinical toxicities were consistent with inhibition of CTLA -4, with adverse effects 
noted for the gastrointestinal tract, skin, lymphoid organs, thyroid tissues, and hematological systems. Dose- 
limiting toxicities identified in chronic toxicity studies in monkeys included skin rash and gastrointestinal 
effects. Most toxicities were reversible or showed a trend towards reversibility. 
 
The profile of AEs from > 1000 treated subjects and the spectrum of event severity are consistent with the 
pharmacologic class and with the signal observed in nonclinical toxicology studies. Adverse events have been 
observed in every organ system and are mainly due to the inflammation caused by tremelimumab’s 
mechanism of action. The most common AEs involve skin, the gastrointestinal tract, and endocrine system, 
and are usually mild in nature. Events reported at a frequency of ≥ 5% and assessed by the investigator as 
related to treatment (listed in descending order of frequency) were diarrhea, rash, pruritus, fatigue, nausea, 
vomiting, anorexia, headache, abdominal pain, and colitis. Infusion-related AEs were rare. 
 
Overall, the observed benefit-risk profile supports the further investigation of tremelimumab in the patient 
population chosen for this study. 
 
3.7 
Combination of anti-CTLA-4 antibody with radiotherapy: Background 
 
A recent phase II study of patients with melanoma brain metastases treated with ipilimumab showed that 
the primary endpoint of disease control was achieved in a approximately 25% of patients  at 12 weeks 
without unexpected toxicities (Margolin, Ernstoff et al. 2012).These data are corroborated by a retrospective 
analysis of melanoma patients receiving ipilimumab in the earliest phase II trials (Weber, Amin et al. 2011). In 
this study, 5/12 identified patients had CNS clinical benefit, with a median survival of 14 months, and 3 
patients living longer than 4 years. 
 
Combining an anti-CTLA-4 antibody with radiation therapy (RT), which potentially releases antigenic stimuli 
and inflammatory cytokines and alters the tumor microenvironment, may allow for synergistic activity (Shiao 
and Coussens 2010). This could result in improved clinical outcomes and could lead to an entirely new 
treatment approach for patients with brain metastases in breast and other cancers. 
 
The synergistic effect of RT and immunotherapy has been demonstrated in multiple preclinical studies. The 
combination of ionizing radiotherapy and anti-CTLA-4 antibody delayed growth of irradiated tumor, inhibited 
lung metastases, and improved survival in a 4T1 murine carcinoma model (Demaria, Kawashima et al. 2005). 
These findings were confirmed in a 9H10 model, in which combination therapy enhanced primary tumor 
regression, and produced abscopal regression of non-irradiated lesions (Dewan, Galloway et al. 2009). 
Importantly, this study suggested that delays in immunotherapy beyond 2 days may reduce  anti -tumor 
activity; additionally, the fractionated radiotherapy was more effective compared to single-dose. Another 
murine model demonstrated that the combination of radiotherapy and antibodies against CD137 + PD-1 was 
curative, and associated with tumor-antigen specific CD8+ T-cell infiltration (Verbrugge, Hagekyriakou et al. 
2012) 


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To date, our clinical experience of combined radiotherapy with CTLA -4 blockade comes from retrospective 
analyses of melanoma. The historical median survival of melanoma patients requiring brain radiosurgery is 4- 
6 months. Our colleagues in Radiation Oncology at MSKCC have reported a retrospective experience of 45 
melanoma patients receiving concurrent ipilimumab + brain SRS (Kiess, Wolchok et al. 2012). Patients treated 
with stereotactic radiosurgery (SRS) during ipilimumab administration demonstrated better overall survival, 
less neurologic deaths and a trend toward fewer local recurrences than those treated with SRS before or 
after CTLA-4 blockade. A follow-up evaluation demonstrated overall survival of 9 months and 39 months in 
melanoma subjects receiving non-brain RT during ipilimumab induction and maintenance, respectively 
(Barker, Postow et al. 2013). The possible synergy between RT and CTLA-4 blockade was also corroborated by 
retrospective reviews at other institutions (Knisely, Yu et al. 2012). These results indicate that RT and CTLA-4 
blockade are well tolerated in patients with brain metastases and that the timing of CTLA-4 blockade to RT 
administration could be critical. Furthermore, a recent case report indicates that RT combined with CTLA -4 
blockade may confer an abscopal effect, whereby regression of metastases is observed distant to the 
irradiated site (Postow, Callahan et al. 2012). 
 
3.7.1 Safety of combination CTLA-4 blockade/RT 
In the aforementioned studies, the safety of combination CTLA-4 blockade/RT was evaluated. In a single- 
institution evaluation of 29 subjects receiving non-brain radiotherapy, grade ≥3 immune related AE’s 
occurred in 22% of patients receiving ipilimumab 3mg/kg, and 43% of patients receiving ipilimumab 10mg/kg. 
These rates were not significantly different compared to monotherapy historical controls, and included grade 
III cytokine release (n=2), grade III diarrhea (n=1), grade III transaminase elevation (n=4) , grade III 
rash/pruritus (n=3), grade 3 radiculitis (n=1), grade 3 thrombocytopenia (n=1), and grade IV uveitis (n=1). 
Grade ≥3 AE’s in irradiated organs was 15%. 77% of patients experienced improvement in symptoms with 
therapy (Barker, Postow et al. 2013). 
 
In the retrospective evaluation of patients treated with concurrent brain SRS and ipilimumab, patients 
receiving concurrent SRS and ipilimumab (n=14) experienced grade ≥3 toxicities including rash/pruritus (7%), 
cardiopulmonary (7%), CNS bleeding of treated brain metastases (14%), and seizure (14%). On MRI, 40% of 
metastases treated during or before ipilimumab increased in size to greater than 150%, of which only 
ultimately 7% reflected recurrence. The majority of CNS bleeds or increased tumor size was asymptomatic, 
but some were associated with seizure or headache. CNS bleeds did not interfere with completion of 
ipilimumab (Kiess, Wolchok et al. 2012). In a  separate retrospective evaluation, melanoma patients who 
received both SRS and ipilimumab did not experience increases in toxicity or intracerebral disease control, 
however the timing of SRS compared to ipilimumab in these patients was not reported, and may not have 
been delivered concurrently (Mathew, Tam et al. 2013). In an additional retrospective series of 13 melanoma 
patients, combination ipilimumab + WBRT was safe, with only 1 patient experiencing a grade III/IV acute CNS- 
related toxicity (cognitive change). (Gerber, Young et al. 2014) Finally, the concordant toxicity profiles of 
tremelimumab and ipilimumab suggest that toxicities are mediated by class-effect (CTLA-4 blockade), and 
that tremelimumab+RT may have a similar safety profile as ipilimumab+RT. 
 
A related strategy is to combine potential tumor-antigen releasing therapeutic modalities with anti-CTLA-4 
therapy. For example, thermal ablation leads to immediate tissue destruction and necrosis secondary to 
crystallization, osmotic changes, and vascular stasis. This promotes a release of tumor antigen that could 
activate a specific immune  response (Sabel 2009). At MSKCC, we have conducted a pilot study in humans, 


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evaluating ipilimumab and/or cryoablation in 18 subjects. The prespecified safety endpoint was met, with no 
subjects experiencing a delay in planned standard-of-care mastectomy. With a median followup of  15 
months, no treatment-related grade III/IV toxicities were reported (Diab, Solomon et al. 2013). 
 
In summary, the incidence and prevalence of BCBM continues to increase and these patients need new and 
effective therapies. We hypothesize, based on the compelling clinical and  pre-clinical  evidence  outlined 
above, that the combination of tumor-targeted brain RT with systemic CTLA-4 blockade with tremelimumab 
will induce disease control and ultimately permit a clinically meaningful delay in cytotoxic chemotherapy. We 
therefore propose a Simon 2-stage study of tremelimumab with brain RT in women with BCBM for whom 
cytotoxic therapy is planned. 
3.8 Combination of anti-CTLA-4 therapy with anti-HER2 therapy: background 
 
Trastuzumab is a therapeutic human antibody against human epidermal growth factor 2 (HER2), and is 
commonly used to treat metastatic breast cancer in patients with HER2-overexpressing tumors (Hudis 2007). 
The therapeutic mechanism of trastuzumab is multifold, with activity attributed to inhibition of downstream 
HER2 signaling as well as immune modulation. The immune activity of trastuzumab is pleiotropic, dependent 
on both antibody-dependent cell-mediated cytotoxicity, antibody production, and T-cell activation  (Page, 
Naidoo et al. 2014). 
 
While trastuzumab has limited efficacy as monotherapy, clinical benefit is maximized when trastuzumab is 
combined with a cytotoxic backbone (Hudis 2007). Based upon expert opinion and retrospective data, it is 
now standard practice to continue trastuzumab at the time of progression, when a switch in the cytotoxic 
backbone is required (von Minckwitz, du Bois et al. 2009, Hamberg, Bos et al. 2011). In patients with newly 
diagnosed brain metastasis, trastuzumab is often continued during and after brain irradiation, whereas 
systemic therapy is suspended for several weeks to minimize the risk of exacerbating radiotoxicity. 
 
Trastuzumab is generally well tolerated. However, <5% of patients experience cardiotoxicity, which is 
generally reversible upon discontinuation of therapy (Hudis 2007). Other potential adverse effects include 
infusion reaction and rash. The mechanism of cardiotoxicity is thought to be related to inhibition of 
downstream HER2 signaling, which is integral to growth, repair and survival of cardiac myocytes (Fedele, 
Riccio et al. 2012). No data suggests an immune-based mechanism of cardiotoxicity. 
 
Because of the immune-mediated mechanism of trastuzumab, combination with anti-CTLA-4 may produce 
synergistic clinical benefit. In mice, combination anti-CTLA-4 with anti-HER2 and AKT blockade generated 
synergistic tumor regression (Wang, Li et al. 2012). Additionally, anti-HER2 antibody has been shown to 
synergize with otherimmunotherapies, including vaccine therapy and anti-PD-1 (Stagg, Loi et al. 2011), with 
no reports of unanticipated adverse events. Anti-CTLA-4 has been safely combined with other therapeutic 
antibodies in humans (Wolchok, Kluger et al. 2013). 
 
3.9 Durvalumab 
 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobin G (igG) 1 kappa subclass that 
blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 T cells and CD80 (B7.1) 
on immune cells (IC). It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. 
(MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as 


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AstraZeneca throughout this document.) Durvalumab has been engineered to reduce antibody-dependent 
cellular cytotoxicity and complement-dependent cytotoxicity. In vitro studies demonstrate that durvalumab 
antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in their restored proliferation 
and release of interferon gamma (IFNγ; Stewart et al. 2015). 
 
As of the DCO date (12 July 2016), a total of 2878 patients have been exposed to 1 or more doses of 
durvalumab in ongoing open-label AstraZeneca- or MedImmune-sponsored Phase I-III monotherapy and 
combination therapy studies across all indications. Refer to the current duvalumab Investigator’s Brochure 
for a complete summary of non-clinical and clinical information including safety, efficacy, and 
pharmacokinetics. 
 
3.9.1 Durvalumab in combination with tremelimumab 
 
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012) because the 
mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, AstraZeneca is also investigating the 
use of durvalumab + tremelimumab combination therapy for the treatment of cancer. Combination 
CTLA-4 and PD-1 directed therapies have demonstrated synergy compared with either strategy alone in other 
settings including metastatic melanoma (Wolchok JDNEJM 2013, Postow AACR 2016). 
 
The durvalumab + tremelimumab doses and regimen selected for this study are based on the goal of 
selecting an optimal combination dose of durvalumab and tremelimumab that would yield sustained target 
suppression (sPD-L1), demonstrate promising efficacy, and have an acceptable safety profile. 
 
3.9.2 Fixed Dosing for durvalumab and tremelimumab 
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 study ( study 
1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK analysis indicated 
only minor impact of body weight (WT) on PK of durvalumab (coefficient of ≤ 0.5). The impact of body WT- 
based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5
th, median and 95
th  percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concent rations with slightly less 
overall between-subject variability with fixed dosing regimen. 
 
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 through Phase 3 
(N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) [Wang et al. 2014]. Population PK 
model indicated minor impact of body WT on PK of tremelimumab (coefficient of ≤ 0.5). The WT-based (1 
mg/kg Q4W) and fixed dosing (75 mg/kg Q4W; based on median body WT of ~75 kg) regimens  were 
compared using predicted PK concentrations (5th, median and 95th  percentiles) using population PK model in 
a simulated population of 1000 patients with body weight distribution of 40 to 120 kg. Similar to durvalumab, 
simulations indicated that both body WT-based and fixed dosing regimens of tremelimumab yield similar 
median steady state PK concentrations with slightly less between-subject variability with fixed dosing 
regimen. 


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Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 2012,Narwal et al 
2013]. Wang and colleagues investigated 12 monoclonal antibodies and found that fixed and body size-based 
dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies. In addition, they investigated 
18 therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 18 in terms of 
reducing the between-subject variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 
2012]. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible to 
switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W MEDI4736 
(equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W 
tremelimumab (equivalent to 1 mg/kg Q4W) is included in the current study. 
 
Fixed dosing of durvalumab and tremelimumab is recommended only for subjects with > 30kg body weight 
due to endotoxin exposure. Patients with a body weight less than or equal to 30 kg should be dosed using a 
weight-based dosing schedule. 
 
3.9.3 Safety of durvalumab 
 
Risks with durvalumab include diarrhea, colitis, pneumonitis /ILD, endocrinopathies (hypo- and hyper- 
thyroidism, type I diabetes mellitus, diabetes insipidus, hypophysitis and adrenal insufficiency) 
hepatitis/hepatotoxicity/increases in transaminases, neurotoxicities, nephritis/increases in creatinine, 
pancreatitis,  rash/pruritus/dermatitis,  myocarditis, infusion-related  reactions,  anaphylaxis,  hypersensitivity 
or allergic reactions, and immune complex disease. 
 
Further information on these risks can be found in the current version of the durvalumab IB. 
 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥10% of patients)  are fatigue, 
nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, pyrexia, abdominal 
pain, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. Approximately 8% of patients 
experienced an AE that resulted in permanent discontinuation of durvalumab and approximately 5%  of 
patients experienced an SAE that was considered to be related to durvalumab by the study investigator. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and in 
the case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity (see the Dosing Modification and Toxicity Management Guidelines in Error! 
Reference source not found.). 
 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of the 
durvalumab IB. 
3.9.4 Safety of durvalumab + tremelimumab 
 
The safety of durvalumab + tremelimumab combination therapy is being evaluated in the ongoing dose 
escalation and dose expansion Study 006, in patients with NSCLC, and has so far shown a manageable safety 
and tolerability profile. 


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The potential risks with the combination of durvalumab + tremelimumab are similar to those for durvalumab 
and tremelimumab monotherapy. Emerging data from study 006 and from combinations of other agents in 
the same class indicate an increased frequency and/or severity of some of these potential immune-mediated 
toxicities. 
 
In durvalumab + tremelimumab combination studies at the dose of durvalumab 20mg/kg and tremelimumab 
1mg/kg AEs (all grades) reported very commonly (≥10% of patients) are fatigue, diarrhea, nausea, dyspnea, 
decreased appetite, pruritus, vomiting, anemia, constipation, cough, abdominal pain, pyrexia, back pain 
hyponatremia and rash. 
 
Approximately 13% of patients experienced an AE that resulted in permanent discontinuation of study drug 
and approximately 13% of patients experienced an SAE that was considered to be related to durvalumab and 
tremelimumab by the study investigator. 
A detailed summary of durvalumab + tremelimumab combination AE data can be found in the  current 
version of the durvalumab IB. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
4.1.1 Efficacy and safety cohort study (completed as of 3/1/2017) 
 
In this pilot single institution study, breast cancer patients with brain metastasis (BCBM) and measurable 
systemic disease for whom whole brain radiation treatment or stereotactic radiosurgery is indicated received 
tremelimumab 10mg/kg q28 days, with the first dose initiated during or in proximity to administration of 
radiotherapy. The primary objective was to evaluate non-CNS disease control at 12 weeks. Secondary 
objectives were to characterize safety and to evaluate anti-tumor efficacy using  other metrics including 
overall survival (OS), CNS 24 week objective response, and CNS and non-CNS progression free survival (PFS). 
Additionally, the safety of tremelimumab and HER2 directed therapy co-administration will be evaluated in a 
parallel safety cohort. 
 
Eligible patients were ≥18 years with good functional status (ECOG 0-2) and life expectancy ≥12weeks, with 
pathologically confirmed invasive breast carcinoma (any histologic subtype), radiologically confirmed brain 
metastases for which standard-of-care brain  RT (either SRS or WBRT) was planned, and RECIST1.1 
measurable non-CNS metastases with recent progression of disease as determined by the investigator, for 
which a change in systemic therapy is planned. Alternatively, patients who had stable disease to their current 
systemic therapy were also eligible if a  treatment holiday was planned. Subjects with CNS complications 
requiring urgent neurosurgical intervention or intrathecal therapy / intravenous methotrexate for 
leptomeningeal disease were excluded. 
 
A Simon 2-stage single-arm design (n=17) was employed to evaluate for preliminary efficacy. A maximum of 
17 subjects will be accrued to the efficacy arm. After the first 3 patients were enrolled in the efficacy arm, a 6 
week enrollment hold was conducted in order to ensure safety before additional patients were enrolled. An 
interim assessment occurred after the first 9 subjects were enrolled, and the accrual to this arm continued, 


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as it met a pre-specified futility threshold. Patients not requiring continuation of HER2 directed therapy, such 
as trastuzumab, were enrolled in this arm. 
The first dose of tremelimumab was administered at 10mg/kg two days prior to initiation of radiotherapy. If 
not feasible, tremelimumab was administered any day from 5 days prior to 3 days post the first dose of 
radiotherapy. 
 
Because brain irradiation is often performed to palliate symptoms, no washout period for cytotoxic therapy 
was mandated. This will preserve feasibility of enrollment, but  may introduce the possibility  that  some 
patients may have non-negligible serum chemotherapy levels at the time of tremelimumab administration. 
Thus, we will exclude enrollment of patients with ongoing reversible ≥CTCAE grade II chemotherapy-related 
toxicities. We believe the risk of unfavorable drug-drug interactions is acceptably low, as the safety of anti- 
CTLA-4 therapy combined with various cytotoxic therapies has been demonstrated in humans (Reck, 
Bondarenko et al. 2013, Weber, Hamid et al. 2013). Concurrent administration of cytotoxic therapy with 
tremelimumab will not be permitted. Concurrent bone-directed therapies such as denosumab or 
bisphosphonates will be permitted. 
 
Subsequent tremelimumab doses were administered at 10mg/kg every 28 days +/- 1 week until radiographic 
progression or until treatment was no longer tolerated. 
Patients for whom concurrent HER2 directed therapy is indicated, as determined by the treating investigator, 
were enrolled in a parallel HER2 directed therapy safety arm. As described in section 3.8, the combination of 
tremelimumab and HER2 directed therapy with brain irradiation was anticipated to be safe, with possible 
synergistic benefit. However, because HER2 directed therapy had not yet been evaluated in combination 
with tremelimumab in humans, additional precautions were taken to monitor for overlapping toxicities. A 
modified 3+3 design was adopted to minimize exposure in the event of unanticipated toxicities. In a safety 
run-in, the first 3 subjects each required 6 weeks of follow-up from the first dose of tremelimumab before 
the subsequent HER2-positive patient could be enrolled. As detailed in section 9, additional subjects will be 
enrolled if the therapy is tolerated in 2 of more of the first three subjects. If the HER2 directed therapy safety 
arm completes accrual prior to completion of the Simon 2-stage efficacy arm, an expansion cohort will be 
considered under a protocol amendment. Similarly, if concurrent HER2 directed therapy /tremelimumab/RT 
is not tolerated at the specified dose, a dose de-escalation cohort may be considered under a protocol 
amendment. 
 
Steroids and anti-seizure medications are permitted on study. However, because steroid administration 
practices vary in clinical practice, and because of the potential impact on immune modulation, 
recommendations for steroid use will be provided (section 9.1). Serum levels of anti-seizure medications will 
be monitored at the discretion of the treating neurologist. 
As of 3/1/17, the primary endpoint was established for the efficacy arm without HER2-directed therapy and 
the safety arm with HER2-directed therapy. Specifically, the 12 week disease control rate was 2/20 (10%) in 
the efficacy arm and 2/6 (33%) in the safety arm. One patient treated with concurrent HER2-directed therapy 
had a 57% partial response by RECIST v1.1 that was durable at 6 months. Overall, the regimen was well 
tolerated with 15 grade 3 and no grade 4 attributable toxicity events reported. The most common treatment 
related AEs were diarrhea (12.9%), fatigue (9.7%), and colitis (6.5%). Thus, an expansion of the HER2 arm is 
planned in a parallel Simon two-stage design to evaluate efficacy of brain RT with checkpoint blockade and 


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concurrent HER2-directed therapy. However, because of the diarrhea and colitis associated with 
tremelimumab mediated CTLA4 blockade when administered at 10mg/kg monthly (a well described class 
effect), a lower dose of tremelimumab will be co-administered with trastuzumab in the expansion study in 
combination with durvalumab, a PD-L1 directed antibody that is currently US FDA approved for other 
indications. 
 
4.1.2 Expansion Study (planned as of 3/1/2017) 
 
The expansion cohort for the HER2+ breast cancer patients who are also undergoing concurrent HER2 
directed therapy is designed as a Simon’s two-stage optimal study with design parameters similar to that 
used to study patients not requiring continuation of HER2 directed therapy. Specifically, a maximum of 17 
HER2+ breast cancer patients will be enrolled in a Simon 2-stage design to evaluate for preliminary efficacy. 
 
As described in section 3.8, the combination of tremelimumab and HER2 directed therapy with brain 
irradiation was safe, with possible synergistic benefit. However, because  HER2 directed therapy has not yet 
been evaluated in combination with tremelimumab and durvalumab in humans, additional precautions will 
be taken to monitor for overlapping toxicities. A modified 3+3 design is adopted to minimize exposure in the 
event of unanticipated toxicities. In the first stage, three patients will be enrolled, and a 6 week enrollment 
hold will be conducted in order to ensure safety before additional patients are enrolled. An interim 
assessment will then occur after the first 9 subjects have enrolled, and the accrual to this arm will proceed 
only if a pre-specified futility threshold is met. Specifically, as detailed in section 9, additional subjects will be 
enrolled if the therapy is tolerated in 2 of more of the first three subjects. Similarly, if concurrent HER2 
directed therapy /tremelimumab/durvalumab/RT is not tolerated at the specified dose, a dose de-escalation 
cohort may be considered under a protocol amendment. 
 
Patients in this expansion will have two biopsies attempted. The first tissue biopsy will be collected 
(attempted) at baseline, within 28 days prior to starting study treatment. A second, optional, biopsy will be 
performed at times such as disease progression, prior to starting a new systemic cancer treatment and if the 
patient’s condition allows it, or at the time of radiographic response, at the investigator’s discretion and in 
discussion with the patient. Tissue biopsy will be taken by core needle or surgical biopsy. For each core 
needle biopsy, an attempt should be made to collect at least 3 core needle samples; however, if it is not 
medically feasible to collect 3 samples, the investigator or designee should attempt to collect as much tumor 
tissue as is deemed medically feasible. 
 
 
Eligible patients will be ≥18 years with good functional status (ECOG 0-2) and life expectancy ≥12weeks, with 
pathologically confirmed HER2-positive invasive breast carcinoma (3+ by IHC and/or > 2.0 by FISH), 
radiologically confirmed brain metastases for which standard-of-care brain RT (either SRS or WBRT) is 
planned, and RECIST1.1 measurable non-CNS metastases with recent progression of disease as determined 
by the investigator, for which a change in systemic therapy is planned. Alternatively, patients who have 
stable disease to their current systemic therapy will also be eligible if a treatment holiday is planned. Subjects 
with CNS complications requiring urgent neurosurgical intervention or intrathecal therapy / intravenous 
methotrexate for leptomeningeal disease will be excluded. 


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The first dose of tremelimumab and durvalumab will be administered at 75mg and 1500mg, respectively, two 
days prior to initiation of radiotherapy. If not feasible, tremelimumab and durvalumab will be administered 
any day from 5 days prior to 3 days post the first dose of radiotherapy. Subsequent tremelimumab and 
durvalumab doses will be administered every 28 days +/- 1 week for 4 cycles. After the 4th cycle patients will 
receive durvalumab 1500 mg every 28 days +/- 1 week until radiographic progression or treatment is not 
tolerated. 
 
Because brain irradiation is often performed to palliate symptoms, no washout period for cytotoxic therapy 
will be mandated. This will preserve feasibility of enrollment, but may introduce the possibility that some 
patients may have non-negligible serum chemotherapy levels at the time of tremelimumab and durvalumab 
administration. Thus, we will exclude enrollment of patients with ongoing reversible ≥CTCAE grade II 
chemotherapy-related toxicities. We believe the risk of unfavorable drug-drug interactions is acceptably low, 
as the safety of anti-CTLA-4 and PD-1/L1 therapy combined with various cytotoxic therapies has been 
demonstrated in humans (Reck, Bondarenko et al. 2013, Weber, Hamid et al. 2013). Concurrent 
administration of cytotoxic therapy on study will not be permitted. Concurrent bone-directed therapies such 
as denosumab or bisphosphonates will be permitted. 
 
Steroids and anti-seizure medications are permitted on study. However, because steroid administration 
practices vary in clinical practice, and because of the potential impact on immune modulation, 
recommendations for steroid use will be provided (section 9.1). Serum levels of anti-seizure medications will 
be monitored at the discretion of the treating neurologist. 
 
4.2 
Intervention 
 
4.2.1 Tremelimumab and Radiotherapy administration 
Dose 1 of tremelimumab (at 10mg/kg) will ideally be administered 2 days prior to initiation of brain 
radiotherapy (or between 5 days prior and 3 days after initiation of radiotherapy if administration 2 days 
prior to initiation of brain radiotherapy is not feasible). Subjects will receive either WBRT or SRS, depending 
on the number and size of their brain metastases, as per the standard of care. 
 
Following dose 1, tremelimumab will be administered q28 days from the date of first tremelimumab 
administration, plus or minus 1 week. Immune monitoring blood draws will occur as outlined in section 10. 
 
4.2.2 Concurrent trastuzumab and other HER2 directed therapies 
The current accepted dosing schedules of maintenance trastuzumab are 2mg/kg IV weekly, or 6mg/kg IV 
every three weeks. Because both schedules are acceptable and regarded as equivalent, the  dose  and 
schedule for trastuzumab will be administered at the discretion of the treating physician. Cardiac monitoring 
with transthoracic echocardiogram (TTE) or MUGA is recommended every 12 weeks for patients receiving 
concurrent trastuzumab. Other HER2 directed therapies are also allowed, such as lapatinib and pertuzumab 
and will be administered as per standard practice at the discretion of the treating physician. 
 
4.2.3 Protocol   Expansion:   Tremelimumab,   durvalumab,   and   HER2   directed   therapies   with 
concurrent RT. 
 
Dose 1 of tremelimumab and durvalumab (75 mg and 1500 mg, respectively) will ideally be administered 2 
days  prior  to  initiation  of  brain  radiotherapy  (or  between  5  days  prior  and  3  days  after in itiation  of 


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radiotherapy). Subjects will receive either WBRT or SRS, depending on the number and size of their brain 
metastases, as per the standard of care. 
Following the first dose, tremelimumab and durvalumab will be administered q28 days from the date of first 
tremelimumab and durvalumab administration, plus or minus 1 week, for 4 cycles. After the fourth cycle, 
durvalumab will be administered alone until progression of disease or unacceptable toxicity. HER2 directed 
therapy will be administered per the NCCN-guideline-endorsed dose and schedule, as determined by the 
investigator. 
 
Immune monitoring blood draws will occur as outlined in section 10.1. 
 
4.2.4 Duration of treatment and criteria for retreatment 
 
For patients receiving durvalumab + tremelimumab, retreatment is allowed (once only) for patients meeting 
the retreatment criteria below. The same treatment guidelines followed during the initial treatment period 
will be followed during the retreatment period, including the same dose and frequency of treatments and 
the same schedule of assessments. 
 
Patients receiving the combination of durvalumab and tremelimumab may undergo retreatment  in  the 
clinical scenario, described below: 
1. Patients who complete the 4 dosing cycles of the combination of durvalumab and tremelimumab 
portion of the regimen (with clinical benefit per Investigator judgment), but subsequently have 
evidence of PD during the durvalumab monotherapy portion of the combination regimen, with or 
without confirmation according to RECIST 1.1, may restart treatment with the combination. 
 
For the durvalumab + tremelimumab treatment group, before restarting their assigned treatment, the 
Investigator should ensure that the patient: 
 
1. Does not have any significant, unacceptable, or irreversible toxicities that indicate continuing 
treatment will not further benefit the patient 
 
2. Still fulfils the eligibility criteria for this study, including re-consenting to restart durvalumab and 
tremelimumab 
 
3. Has not received an intervening systemic anticancer therapy after their assigned treatment 
discontinuation. 
 
4. Has had a baseline tumor assessment within 28 days of restarting their assigned treatment; all 
further scans should occur with the same frequency as during the initial treatment period until 
study treatment is stopped. 
 
During the retreatment period, patients receiving durvalumab + tremelimumab may resume durvalumab 
dosing at 1500 mg q4w with 75 mg of tremelimumab q4w for 4 doses each. After the 4th dose, the treating 
investigator and site PI will review the patient’s clinical and radiographic status to confirm if the patient 
should continue on the tremelimumab + durvalumab combination, or if they should continue with 
durvalumab monotherapy at 1500 mg q4w. 


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Treatment through progression is at the Investigator’s discretion, and the Investigator should ensure that 
patients do not have any significant, unacceptable, or irreversible toxicity that indicate that continuing 
treatment will not further benefit the patient.  A patient with a confirmed progression receiving 
durvalumab + tremelimumab cannot continue therapy or obtain retreatment if dosing is ongoing in the 
combination portion of therapy (q4w dosing) and progression occurs in a target lesion that has previously 
shown a confirmed response. 
 
 
 
4.2.5 Toxicity Monitoring 
Subjects will be followed with regular physical examination and toxicity assessment using the NCI CTCAE 4.0, 
as outlined in sections 10-11. They will follow with regular radiation oncology assessments as  per  the 
standard of care. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 
Brain radiotherapy 
 
Subjects will receive either WBRT or SRS, at the discretion of the treating radiation oncologist. 
 
5.2.1 Whole Brain Radiotherapy 
As determined by the radiation oncologist, subjects will receive multiple fractions of WBRT, most commonly 
10 days in fractions of 3Gy. Treatment will be delivered with right and left lateral equally weighted fields with 
the dose calculated on the central ray at mid-separation of the beams. Megavoltage LINAC with 6 MV or 
higher should be used. 
 
5.2.2 Stereotactic Radiosurgery 
Eligibility for SRS will be determined by the treating radiation oncologist. At MSKCC, SRS is generally 
administered in cases of oligometastatic disease, with ≤3 foci of disease measuring  less than 4cm each. 
Dosing is dependent on a number of factors including lesion size and location, but is usually delivered in one 
fraction. 
 
5.2.3 Rationale for including both SRS and WBRT study populations 
The dose and fractionation of radiotherapy may be relevant in determining response to therapy. One murine 
mammary carcinoma model demonstrated that only fractionated dosing was capable of producing an 
abscopal effect with combined RT+ anti-CTLA-4 (Dewan, Galloway et al. 2009). This was corroborated by a 
murine melanoma study which demonstrated optimal tumor control with 7.5Gy/fraction dosing, which 
generated the highest interferon production, and a favorable ratio of effector to regulatory T-cell 
proliferation (Schaue, Ratikan et al. 2012). The translatability of these findings to humans is unknown, and 
the relative immunogenicity of alternative radiotherapy regimens such as SRS and WBRT should be explored 
in a clinical trial. 
 
5.2 
Tremelimumab 
 
5.2.1 
Investigational Product 


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MedImmune  will  provide  the  investigator(s)  with  investigational  product  ( Table  5.2.1)  using  designated 
distribution centers. 
 
Table 5.2.1 
Identification of Investigational Product 
Investigational Product 
Manufacturer 
Concentration and Formulation as 
Supplied 
Tremelimumab 
MedImmune 
Formulated at a nominal concentration of 
20 mg/mL in 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose 
dihydrate, 0.2% (w/v) polysorbate 80, and 
0.27 mM disodium edetate dihydrate 
(EDTA), pH 5.5. 
 
Tremelimumab vials should be stored at refrigerated temperatures (2°C to 8°C), and should not be frozen. 
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines (such as GMP Annex 13 requirements for labeling). Label text will be translated into local 
languages, as required. 
Investigational product will be supplied to the site in containers in coded kits. Each kit has a unique number 
that is printed on all labels within the kit (i.e., the outer carton label and the label of each vial within the 
carton). 
 
5.2.2 Other Study Medications 
 
In the parallel concurrent safety arm and in the protocol expansion, subjects will continue to receive HER2 
directed therapy such as trastuzumab. No other study medications were specified for use in the first part of 
this clinical protocol. In the protocol expansion, subjects will receive tremelimumab, durvalumab, and 
concurrent HER2 directed therapy for the first 4 cycles. After the 4
th cycle, subjects will continue on 
durvalumab and HER2 directed therapy. Best supportive care (including antibiotics, nutritional support, 
correction of metabolic disorders, optimal symptom control and pain management [including palliative 
radiotherapy on non-target lesions, etc]) should be used when necessary for all subjects with the exception 
of prohibited concomitant medications. 
 
5.2.3 Treatment Regimen 
 
In the first part of this clinical protocol, tremelimumab was administered as an IV solution of 10 mg/kg at a 
rate of 250 mL/hr, followed by observation. Subjects received one dose of investigational product Q4W until 
disease progression. 
 
5.2.4 Investigational Product Dose Preparation 
 
Tremelimumab is supplied as a sterile IV solution, filled in 20 mL clear glass vials with a rubber stopper and 
aluminium seal. Each vial contains 20 mg/mL (with a nominal fill of 20 mL accounting to 400 mg/vial) of 
tremelimumab, in  an  isotonic solution  at  pH 5.5.  Vials  containing  tremelimumab  must  be  stored in  the 


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8 
 
 
refrigerator at 2- oC. The 20 mg/mL solution will be diluted into a saline bag for IV infusion. Vials containing 
tremelimumab may be gently inverted for mixing, but should not be shaken. 
 
For dose preparation steps, the following ancillary items are required: 
 
• 
IV infusion bags of 0.9% sodium chloride injection (250 mL size). Saline bags must be latex-free 
and can be made of polyvinyl chloride (PVC) or polyolefin (e.g., polyethylene), manufactured with 
bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free. 
• 
IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate (TOTM) or polyethylene or 
polyurethane. All DEHP-containing or DEHP-free lines are acceptable. Lines should contain a 0.22 
or 0.2 µm in-line filter. The in-line filter can be made of polyethersulfone (PES) or polyvinylidine 
fluoride DRF (PVDF). Lines containing cellulose -based filters should not be used with 
tremelimumab. 
• 
Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and stainless steel 
and/or PVC components. 
• 
Syringes made of polypropylene and latex-free. Polycarbonate syringes should not be used with 
tremelimumab. 
• 
Needles made of stainless steel. 
5.2.4.1 Dose Calculation 
Subject weight at baseline should be used for dosing calculations unless there is a ≥ 10% change in weight. 
The dose will be calculated using the following formula: 
Dose (mL) = [subject weight (kg) × dose level (10 mg/kg)] 
drug concentration (20 mg/mL) 
The corresponding volume of investigational product should be rounded to the nearest tenth mL (0.1 mL). 
Each vial contains a small amount of overage and the overage should be utilized as much as possible before 
using another vial. 
 
The number of vials required for dose preparation is the next greatest whole number of vials from the 
following formula: 
 
Number of vials = Dose (mL) ÷ 20 (mL/vial) 
 
5.2.4.2 Dose Preparation Steps 
Tremelimumab does not contain preservatives and any unused portion must be discarded. Preparation of 
tremelimumab and preparation of the IV bag are to be performed aseptically. Total in-use storage time for 
the prepared  final IV bag should  not exceed 24 hours at 2-8°C or 4 hours at room temperature (25°C). 
However, it is recommended that the prepared final IV bag be stored in the dark at 2-8°C until needed. The 
refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room temperature for 
about 2 hours prior to administration. If storage time exceeds these limits, a new dose must be prepared 
from new vials. 
 
The investigational product manager or qualified personnel will be responsible for preparing the IV doses 
using the following steps: 


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1) All investigational product vials should be equilibrated to room temperature for 30 minutes prior 
to dose preparation. 
2) To prepare the IV bag, first, calculate the dose volume of investigational  product required. 
Second, remove the volume of 0.9% sodium chloride IV solution equivalent to the  calculated 
dose volume of investigational product from the IV bag. Lastly, add the calculated dose volume of 
investigational product to the IV bag. Gently mix the solution in the bag by inverting up and 
down. Avoid shaking the IV bag to prevent foaming. 
 
 
Example: A subject weighing 85 kg will require 42.5 mL (3 vials) of investigational product. Remove 42.5 mL 
of saline from the commercial IV bag. Add the 42.5 mL of investigational product to the IV bag and gently mix 
by inverting up and down. 
 
5.2.5 Treatment Administration 
 
The first day of dosing is considered Day 1. Each dose of investigational product should be administered using 
the following guidelines: 
1) 
Investigational product must be administered at room temperature (25°C) by controlled 
infusion via an infusion pump into a peripheral vein. 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. 
2) A physician must  be present at the site or immediately available to respond to emergencies 
during all administrations of investigational product. Fully functional resuscitation facilities 
should be available. 
3) Investigational product must not be administered via IV push or bolus but as a slow IV infusion. 
The entire content of each IV bag will be infused using an infusion pump. 
4) The infusion lines should be attached only at time of use. Lines used for infusion during dose 
administration will need to be equipped with 0.22 or 0.2 μm in-line filters. 
5) If there are no requirements to slow, interrupt, or permanently stop the infusion, the anticipated 
infusion time to deliver each dose (250 mL) is anticipated to be at least 60 minutes. 
6) Some investigational product may remain in the IV line after the infusion has completed. Fif teen 
to 30 mL of 0.9% sodium chloride IV solution should be added to the infusion bag after the 
investigational product has been administered to flush the line. The infusion rate should not be 
changed. 
 
 
The duration of the investigational product administration will be recorded. 
 
5.2.6 Monitoring of Dose Administration 
Vital signs (blood pressure, temperature, pulse, and respiration rate) will be collected before investigational 
product infusion, every 30 minutes +/- 10 minutes during infusion, at completion of infusion, and 30 and 60 
minutes +/- 10 minutes post infusion. 
As with any antibody, allergic reactions to dose administration are possible. Therefore, 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, as per local institutional guidelines. 


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5.3 Durvalumab + tremelimumab combination therapy 
 
5.3.1 Investigational Product 
 
MedImmune will provide the investigator(s) with investigational product (Table 5.3.1) using designated 
distribution centers. 
 
Table 5.3.1 
Identification of Investigational Product 
Investigational Product 
Manufacturer 
Concentration and Formulation as 
Supplied 
Durvalumab 
MedImmune 
Formulated at a minimal concentration of 
50 mg/mL in 26 mM histidine/histidine- 
hydrochloride, 275 mM trehalose 
dihydrate, 0.02% (w/v) polysorbate 80, 
pH 6.0. 
Tremelimumab 
MedImmune 
Formulated at a nominal concentration of 
20 mg/mL in 20 mM histidine/histidine 
hydrochloride, 222 mM trehalose 
dihydrate, 0.2% (w/v) polysorbate 80, and 
0.27 mM disodium edetate dihydrate 
(EDTA), pH 5.5. 
 
 
Durvalumab vials should be stored at refrigerated temperatures (2°C to 8°C), and should not be frozen. 
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines (such as GMP Annex 13 requirements for labeling). Label text will be translated into local 
languages, as required. 
 
5.3.2 Durvalumab + Tremelimumab Combination Therapy Treatment Regimen 
 
Patients in the protocol expansion will receive 1500 mg durvalumab via IV infusion and 75 mg tremelimumab 
via IV infusion q4w for up to 4 doses/cycles. Patients will then continue 1500 mg durvalumab q4w, starting 
on Week 17, until disease progression or unacceptable toxicity. The first durvalumab monotherapy dose at 
1500mg Q4W will be 4 weeks after the final dose of durvalumab in combination with tremelimumab. Dosing 
outside the window should be discussed with the Study Physician.  Tremelimumab will be administered first. 
Durvalumab infusion will start approximately 1 hour (maximum 2 hours) after the end of tremelimumab 
infusion.  The duration of each infusion should be 60 minutes (+/- 5 minutes). Less than 55 minutes is 
considered a deviation. In the event that there are interruptions during infusion, the total allowed time 
should not exceed 8 hours at room temperature. A 1-hour observation period is required after the first 
infusion of durvalumab and tremelimumab.  If no clinically significant infusion reactions are observed during 
or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion 
(suggested 30 minutes aftereach durvalumab and tremelimumab infusion). 
 
If a patient’s weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 
mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to >30 kg, at which 


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point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg 
Q4W. 
5.3.3 Dose Calculation 
Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg 
Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) is included in the protocol expansion. 
5.3.4 Dose Preparation Steps – Durvalumab 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s designated IP 
manager using aseptic technique. Total time from needle puncture of the durvalumab vial to the start of 
administration should not exceed: 
 
24 hours at 2°C to 8°C (36°F to 46°F) 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion solutions 
must be allowed to equilibrate to room temperature prior to commencement of administration. 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been observed. 
Dose of 1500mg durvalumab for patients >30 kg will be administered using an IV bag containing 0.9% (w/v) 
saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab 
(ie, 1500 mg of durvalumab) to the IV bag. The IV bag size should be selected such that final concentration is 
within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
Weight-based dosing (for patients <30kg) will be administered using an IV bag containing 0.9% (w/v) saline of 
5% (w/v) dextrose, with a final durvalumab concentration ranging from 1-20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter. 
 
The IV line will be flushed with a volume of IV diluents equal to the priming volume of the infusion set used 
after the contents of the UV bag are fully administered, or complete the infusion according to institutional 
policy to ensure the full dose is administered and document if the line was not flushed. 
 
Standard infusion time is 1 hour. However, if there are interruptions during infusion, the total allowed time 
should not exceed 8 hours at room temperature. Durvalumab does not  contain  preservatives,  and  any 
unused portion must be discarded 
 
5.3.5 Dose Preparation Steps – Tremelimumab 
 
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s designated IP 
manager using aseptic technique. Total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed: 
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
 
• 
4 hours at room temperature 


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A dose of 75 mg (for patients >30kg in weight) will be administered using an IV bag containing 0.9% (w/v) 
saline or 5% (w/v) dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 3.8 mL (i.e.,75 mg of 
tremelimumab, with the dose volume rounded to the nearest tenth mL) to the IV bag. The IV bag size should 
be selected such that the final concentration is within 0.10 to 10 mg/mL. Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag. 
 
Weight-based dosing (for patients ≤30 kg) will be administered using an IV bag containing 0.9% (w/v) saline 
or 5% (w/v) dextrose, with a final tremelimumab concentration ranging from 0.10 to 10 mg/mL,  and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter. 
 
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) until needed. If 
storage time exceeds these limits, a new dose must be prepared from new vials. The refrigerated infusion 
solutions in the prepared final IV bag should be equilibrated at room temperature for about 2 hours prior to 
administration. Tremelimumab does not contain preservatives and any unused portion must be discarded. 
 
The IV line will be flushed with a volume of IV diluents equal to the priming volume of the infusion set used 
after the contents of the IV bag are fully administered, or complete the infusion according to institutional 
policy to ensure the full dose is administered and document if the line was not flushed. 
 
In the event that there are interruptions during infusion, the total allowed time should not exceed 8 hours at 
room temperature. If either preparation time or infusion time exceeds the time limits a new dose must be 
prepared from new vials. 
 
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have been observed. 
However, administration sets containing cellulose-based filters should not be used with tremelimumab. 
 
5.3.6 Durvalumab and Tremelimumab Administration 
 
The first day of dosing is considered Day 1. Each dose of investigational product should be administered using 
the following guidelines: 
1) Investigational product must be administered at room temperature (25°C) by controlled infusion 
via an infusion pump into a peripheral or central vein. 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. 
2) A physician must be present at the site or immediately available to respond to emergencies 
during all administrations of investigational product. Fully functional resuscitation facilities 
should be available. 
3) Investigational product must not be administered via IV push or bolus but as a slow IV infusion. 
The entire content of each IV bag will be infused using an infusion pump. 
4) The infusion lines should be attached only at time of use. Lines used for infusion during dose 
administration will need to be equipped with 0.22 or 0.2 μm in-line filters. 
5) If there are no requirements to slow, interrupt, or permanently stop the infusion, the anticipated 
infusion  time  to  deliver  each  dose  is  approximately  60 minutes  (±5  minutes).  Less  than  55 


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minutes is considered a deviation. If there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature. 
6) The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed. 
 
The duration of the investigational product administration will be recorded. 
 
5.3.7 Monitoring of Dose Administration 
Vital signs (blood pressure, temperature, pulse, and respiration rate) will be collected before investigational 
product infusion, every 30 minutes +/- 10 minutes during infusion, at completion of infusion, and 30 and 60 
minutes +/- 10 minutes post infusion. 
 
A 1-hour observation period is required after the first infusion of durvalumab and tremelimumab. 
 
If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion 
observation periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab and 
tremelimumab infusion). If the infusion takes longer than 60 minutes, then BP and pulse measurements 
should follow the principles as described above or be taken more frequently if clinically indicated. 
 
As with any antibody, allergic reactions to dose administration are possible. Therefore, 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, as per local institutional guidelines. 
 
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 and re-initiated at 50% of the initial rate until completion of the 
infusion.  For patients with a ≤Grade 2 infusion-related reaction, subsequent infusions may be administered 
at 50% of the initial rate. Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the treating investigator. If 
the infusion-related reaction is ≥Grade 3 or higherin severity, study drug will be discontinued. 
 
 
 
 
 
 
 
6.1 CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
Eligible subjects must fulfill all of the following criteria: 
 
1 
Diagnosis of CNS metastases for whom SRS or WBRT is indicated, as determined by radiation 
oncologist assessment; 
2 
Age 18 and older at the time of consent; 
3 
Written informed consent and authorization obtained from the subject/HIPAA-appointed legal 


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representative prior to performing any protocol-related procedures including screening 
evaluations; 
4 
ECOG performance of 0-2 with anticipated life expectancy of ≥12 weeks; 
5 
Histologically or cytologically confirmed invasive breast cancer that is HER2-positive (3+ by IHC 
and/or >2.0 by FISH) if concurrent HER2-directed therapy is planned; 
6 
Non-CNS progression of disease as assessed by the investigator/treating physician, forwhich a 
change in systemic therapy is planned OR achievement of stable or responsive non-CNS disease 
for which a holiday from the current systemic therapy is planned, as assessed by the 
investigator/treating physician. 
7 
Measurable non-CNS disease, defined by RECIST1.1 criteria (see section 12) 
8 
Recovered from all toxicities associated with prior treatment, to acceptable baseline status or 
grade 1 or less (for lab toxicities see below limits for inclusion, as per criterion 9), except for 
toxicities not considered a safety risk, such as alopecia or vitiligo. Peripheral neuropathy must be 
grade 2 or less. 
9 
Adequate organ and marrow function, as defined below: 
• 
platelets ≥ 75x 103/μL; 
• 
absolute neutrophil count (ANC) ≥ 1,000/μL; 
• 
hemoglobin ≥ 9.0 g/dL; 
• 
total bilirubin ≤1.5 x ULN (upper limit of normal) except subject with documented 
Gilbert’s syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin 
≤3.0 mg/dL; 
• 
AST and ALT ≤ 3 x ULN, unless associated with hepatobiliary metastases, in that case ≤5 x 
ULN 
• 
serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 50 ml/min as determined by 
the Cockcroft-Gault equation); 
10 
Negative hepatitis B serologic tests. If positive results are not indicative of active or chronic 
infection, the subjects can enter the study at the investigator’s discretion. 
11 
Females of childbearing potential who are sexually active with a non-sterilized male partner must 
use a highly effective method of contraception prior to the first dose of investigational product (as 
per appendix 20.1), and must agree to continue using such precautions for 6 months after the  
final dose of investigational product; cessation of contraception after this point should be 
discussed with a responsible physician. Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception. They must also refrain from  
egg cell donation for 6 months after the final dose of investigational product; 
• 
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause); 
• 
A highly effective method of contraception is defined as one that results in a low failure 
rate (i.e., less than 1% per year) when used consistently and correctly. The acceptable 
methods of contraception are described in appendix table 20.1; 
12 
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use a highly effective method of contraception (as per appendix 20.1) from Days 1 through 90 
post last dose. In addition, they must refrain from sperm donation for 90 days after the final dose 
of investigational product 
13 
LVEF ≥50% for patients enrolling in the HER2 directed therapy arm 
14 
Willing to attempt a baseline tumor biopsy procedure 


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6.3 
Subject Exclusion Criteria 
 
Patients may not enter the study if they fulfill any of the following criteria: 
 
1 
CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt 
placement); 
2 
Known leptomeningeal metastases not amenable to radiotherapy. Patients receiving radiotherapy 
for leptomeningeal metastases are eligible; 
3 
Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or 
programmed cell death 1 ligand 1 (PD-L1); 
4 
Subjects with a history of hypersensitivity to compounds of similar biologic composition to 
tremelimumab or any constituent of the product; 
5 
Subjects with a history of hypersensitivity to compounds of similar biologic composition to 
durvalumab or any constituent of the product; 
6 
Patients unable to obtain MRI for any reason (e.g., due to pacemaker, ferromagnetic implants, 
claustrophobia, extreme obesity); 
7 
Concurrent enrollment in another therapeutic clinical study or receipt of an investigational 
product within the last 4 weeks (participation in the survival follow-up period of a study is not an 
exclusion criterion); 
8 
Medical conditions (aside from newly-diagnosed brain metastases) for which the chronic use of 
corticosteroids or other immunosuppressive medications are indicated. Note: inhaled and topical 
steroids are permitted; 
9 
Use of immunosuppressive medications within 14 days before the first dose of study drug. The 
following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid 
injections (e.g. intra articular injection); systemic corticosteroids at physiological doses not to 
exceed 10mg/day of prednisone or its equivalent; steroids as premedication for hypersensitivity 
reactions (e.g. CT scan premedication). 
10 
Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting 
tremelimumab treatment; 
11 
Any condition that, in the opinion of the investigator, would interfere with evaluation of the 
investigational product or interpretation of subject safety or study results; 
12 
Any serious uncontrolled medical disorder or active infection that would impair the subject’s 
ability to receive investigational product, such as conditions associated with frequent diarrhea; 
13 
Active or history of autoimmune or inflammatory disorders, including inflammatory bowel disease 
(e.g., colitis, Crohn’s), diverticulitis (with the exception of diverticulosis), irritable bowel disease, 
celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active 
or history of systemic lupus erythematosus or Wegener’s granulomatosis, Sarcoidosis syndrome, 
Addison’s disease, multiple sclerosis, Graves’ disease, Hashimoto’s thyroiditis, rheumatoid 
arthritis, hypophysitis, uveitis, etc. Patients without active disease in the last 5 years may be 
included but only after consultation with the study physician. Note: the following are exceptions 
to this criterion: Vitiligo or alopecia; patients with hypothyroidism (i.e. following Hashimoto 
syndrome) stable on hormone replacement; any chronic skin condition that does not require 
systemic therapy; patients with celiac disease controlled by diet alone; 
14 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms 


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(ECGs) using Frederica’s Correction; 
15 
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart 
failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, intersti tial lung 
disease, serious chronic gastrointestinal conditions associated with diarrhea, active peptic ulcer 
disease or gastritis, and active bleeding diatheses; 
16 
Known history of previous clinical diagnosis of tuberculosis; 
17 
History of allogeneic organ transplant; 
18 
History of leptomeningeal carcinomatosis; 
19 
No active, second potentially life-threatening cancer. No history of another primary malignancy 
except for; malignancy treated with curative intent and no known active disease ≥5 years before 
the first dose of IP and of low potential risk for recurrence; adequately treated non-melanoma 
skin cancer or lentigo malignawithout evidence of disease; adequately treated carcinoma in situ 
without evidence of disease; 
20 
Pregnant or breast feeding at time of consent; 
21 
Any condition that would prohibit the understanding or rendering of information and consent and 
compliance with the requirements of this protocol; 
22 
Known positive for HIV, chronic or active hepatitis B or C. 
23 
Patient is unable to receive IV contrast. 
24 
Neuroimaging evidence of midline shift 
25 
Major surgical procedure, as defined by the investigator, within 28 days prior to the first dose of 
IP. Note: Local surgery or isolated lesions for palliative intent is acceptable. 
 
 
6.3 
Restrictions on Concomitant Therapies 
 
6.3.1 
Non-Permitted Concomitant Therapies 
 
The following medications are to be considered exclusionary by the investigator and are not permitted from 
signing of the informed consent form through the periods indicated. The investigator must be notified if a 
subject receives any of the following during the study: 
 
1 
Immunosuppressive   doses  of   steroids   or   other  immunosuppressive   medication,   Exceptions 
include : 1) inhaled and topical steroids when medically indicated as treatment for an acute illness 
or as a pretreatments before CT scans (for contrast allergies); 2) corticosteroids as treatment for 
infusion reactions and treatment-related adverse events as described in section 11; and 3) 
corticosteroids for the treatment of symptomatic brain metastases are permitted (refer to section 
9 for guidelines); 
2 
Other cancer therapy (chemotherapy or immunotherapy), with the exception of  HER2 directed 
therapies, which may be continued in subjects enrolled on the concurrent therapy arm. Surgery 
and radiation therapy  with palliative intent  are permitted at any time; 
3 
Live/attenuated vaccines 28 days prior to day 1 and for at least 6 months after the last dose of 
study therapy; 
4 
Sunitinib within 3 months after the last dose of study therapy; 
5 
Drugs with laxative properties and herbal or natural remedies for constipation should be avoided 


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if  possible  through  90  days  post  last  dose  during  the  study  because  of  the  potential  for 
exacerbation of diarrhea which is an identified risk for study therapy; 
6 
Inactivated vaccinations +/- 30 days around any dose of study therapy; 
7 
EGFR TKIs within 90 days post last dose; 
8 
mAbs against CTLA-4, PD-1, or PD-L1, and any investigational anticancer therapy, other than those 
under investigation, should not be given while the patient is on study therapy; 
9 
Herbal and natural remedies which may have immune-modulating effects. 
 
 
6.3.2 
Permitted Concomitant Therapies 
Patients may receive the following concomitant therapies during the study: 
 
1 
Inhaled or oral steroids for treating mild to moderate asthma or allergies, or topical steroids for 
localized (<5% of body surface area) dermatitis 
2 
NSAIDS, acetylsalicylic acid, and COX-2 inhibitors 
3 
Antihistamines and other non-steroidal anti-allergy medication 
4 
Previously-initiated bone metastases-directed therapies, including bisphosphonate therapy or 
denosumab. 
5 
At the discretion of the investigator, any drug or non-drug therapy necessary to treat any 
condition arising during the study, including high dose corticosteroids and TNF-α inhibitors to 
treat adverse reactions. 
6 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic or brand name, indication, dose, route, and dates 
of administration. All non-drug therapies must be recorded in the respective sections of the case 
report form or as adverse events. 
7 
HER2 directed therapies, such as trastuzumab is permitted in subjects enrolled on the concurrent 
therapy arm who have progressed on a trastuzumab or other HER2 directed-containing 
chemotherapy combination. 
 
 
7.0        RECRUITMENT PLAN 
 
7.1 Expansion recruitment plan 
 
The study will enroll at two locations, MSKCC and Cedars-Sinai Medical Center (CSMC) in Los Angeles. MSKCC 
and CSMC provide large referral bases, with approximately 25 women with HER2-positive breast cancer 
treated with WBRT or SRS across both sites each year (15 at MSKCC and 10 at CSMC). Notably, the completed 
efficacy and safety arms for this study enrolled briskly. Given that there are no competing trials at MSKCC or 
CSMC and given that this patient population is typically highly motivated, we anticipate an average accrual 
rate of 1-2 patients per month with accrual of 17 patients within 1 year (approx 10 at MSKCC and 7 at CSMC). 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team at both sites. If the investigator is a member of the treatment team, s/he will 
screen their patient’s medical records for suitable research study participants and discuss the study and their 
potential for enrolling in the research study. Potential subjects contacted by their treating physician will be 
referred to the investigator/research staff of the study. 


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The site principal investigator (PI) may also screen the medical records of patients with whom they do not 
have a treatment relationship for the limited purpose of identifying patients who would be eligible to enroll 
in the study and to record appropriate contact information in order to approach these numbers and patients 
regarding the possibility of enrolling in the study. 
 
In most  cases, the initial contact with the prospective subject will be conducted either by the treatment 
team, investigator or the research staff working in consultation with the treatment team, specifically the 
radiation oncology, medical oncology, or urgent care / inpatient departments. Potential patients may also be 
identified by the radiology department, who can identify breast cancer patients who demonstrate 
new/progressive CNS disease on MRI imaging. 
 
During the initial conversation between the investigator/research staff and the patient, the patient may be 
asked to provide certain health information that is necessary to the recruitment and enrollment process. The 
investigator/research staff may also review portions of their medical records in order to further assess 
eligibility. They will use the information provided by the patient and/or medical record to confirm that the 
patient is eligible and  to  contact the patient regarding study enrollment. If the patient turns out to  be 
ineligible for the research study, the research staff will destroy all information collected on the patient during 
the initial conversation and medical records review, except for any information that must be maintained for 
screening log purposes. 
 
Once patients are identified, an expedited consultation will be facilitated by the site PI or another consenting 
clinician, in order to obtain consent and assess for eligibility. Additionally, an expedited radiation oncology 
evaluation will be facilitated to evaluate for WBRT/SRS. Radiation therapy will then be administered as per 
standard of care, and tremelimumab/durvalumab will be administered at a scheduled primary investigator 
appointment or as an inpatient if the subject is hospitalized. 
 
The recruitment process outlined presents no more than minimal risk to the privacy of the patients who are 
screened and minimal PHI will be maintained as part of a screening log. For these reasons, we seek a (partial) 
limited waiver of authorization for MSK patients for the purposes of (1) reviewing medical records to identify 
potential research subjects and obtain information relevant to the enrollment process; (2) conversing with 
patients regarding possible enrollment; (3) handling of PHI contained within those records and provided by 
the potential subjects; and (4) maintaining information in a screening log of patients approached (if 
applicable). Cedars Sinai will obtain a limited waiver from their IRB/privacy board separately. 
8.1 
PRETREATMENT EVALUATION 
 
A signed written, informed consent form must be obtained prior to screening assessments and before any 
study-specific assessments are initiated. 
 
The following will be obtained prior to enrollment: 
Within 4 weeks (28 days) of enrollment: 
• 
Patients must  undergo  MRI  of the  brain  as well  as either contrast-enhanced  PET/CT or contrast- 
enhanced CT of the chest, abdomen, and pelvis with bone scan for baseline assessment 
• 
For subjects continuing trastuzumab or other HER2 directed therapies, a baseline TTE or MUGA must 
be obtained 


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• 
A baseline biopsy will be performed (attempted) for all patients 
Within 2 weeks (14 days) of enrollment: 
• 
Medical History 
• 
Height,  body weight,  ECOG PS,  and  vital signs including  blood  pressure, pulse,  temperature,  and 
respiration rate. 
• 
Physical exam will be  completed.  Any changes in the patients’ mental or physical  condition  since 
screening that would make him/her ineligible for the study should be considered 
• 
Clinical  safety labs (CBC  with differential,  CMP,  magnesium,  phosphorus,  INR/PT,  amylase/lipase, 
LDH, TSH with reflexive free T3/free T4, gamma glutamyltransferase) 
• 
A serum HCG test will be obtained for all women of childbearing potential 
• 
Urinalysis 
• 
A baseline electrocardiogram (ECG) in triplicate, 2-5 minutes apart 
• 
A baseline CA15-3 and CEA 
• 
Baseline peripheral  blood for immune  monitoring (for flow cytometric analysis, circulating soluble 
factors, baseline serologic evaluation, and T-cell repertoire analysis) 
• 
Screening HIV, Hepatitis B and C studies 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Tremelimumab +/- durvalumab + WBRT/SRS will be administered as per the schedule delineated in section 
4.0. 
9.1 Concomitant Steroid Administration for symptomatic CNS disease 
 
Subjects with newly-diagnosed CNS metastases frequently benefit from steroids for symptomatic relief. 
Current practices are founded on level 3 evidence alone, with no randomized studies demonstrating superior 
benefit of higher steroid dose over lower steroid dose. (Ryken, McDermott et al. 2010) Therefore, it is 
reasonable to treat patients with lower-dose steroids at the onset of radiation therapy and titrate up if 
needed, in order to minimize the immunosuppression associated with steroids. 
 
We defer to the discretion of the treating physician; however, in an effort to standardize steroid use as much 
as possible, we offer the following recommendations, which were developed in collaboration with radiation 
oncology and neurology co-investigators. 
 
 
Table 9.1-1: Standardized Recommendations for Steroid Use for CNS Mets 
 
Scenario 
Dexamethasone Induction 
Dexamethasone Taper 
SRS 
Asymptomatic 
None 
None 
Mild-Moderate Symptoms 
Conservative management with 
analgesics. 
If needed, 2mg PO BID x 7d 
1.5mg PO BID x 2d 
1.0mg PO BID x 2d 
0.5mg PO BID x 2d 
0.5mg PO daily x 2d 


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Severe Symptoms (or) 
Insufficient response to 2mg 
regimen 
4mg PO BID x 7d 
2mg PO BID x 7d 
1.5mg PO BID x 3d 
1.0mg PO BID x 3d 
0.5mg PO BID x 3d 
0.5mg PO daily x 3d 
Adverse effect to SRS 
2mg PO BID x 7d 
1.5mg PO BID x 2d 
1.0mg PO BID x 2d 
0.5mg PO BID x 2d 
0.5mg PO daily x 2d 
WBRT 
Asymptomatic 
None 
None 
Mild-Moderate Symptoms 
Conservative management with 
analgesics. 
If needed, 2mg PO BID x 7d 
1.5mg PO BID x 2d 
1.0mg PO BID x 2d 
0.5mg PO BID x 2d 
0.5mg PO daily x 2d 
Severe Symptoms (or) 
Insufficient response to 2mg 
regimen 
4mg PO BID x 7d 
2mg PO BID x 7d 
1.5mg PO BID x 3d 
1.0mg PO BID x 3d 
0.5mg PO BID x 3d 
0.5mg PO daily x 3d 
Adverse effect to WRBT 
2mg PO BID x 10d 
1.5mg PO BID x 2d 
1.0mg PO BID x 2d 
0.5mg PO BID x 2d 
0.5mg PO daily x 2d 
 
9.2 Efficacy arm safety analysis (completed as of 3.1.17) 
 
A maximum of 17 subjects were accrued to the efficacy arm. After the first 3 patients were enrolled in the 
efficacy arm, a 6 week enrollment hold was conducted in order to ensure safety before additional patients 
were enrolled. Thereafter, stopping rules (based on a repeated significance testing method) were employed 
to continuously assess safety. (Ivanova, Qaqish et al. 2005) These criteria were based on assumptions that a 
toxicity rate of 50% is deemed unacceptable, and a rate of 20% is deemed acceptable. The boundaries to stop 
the study were given as follows: 
 
• 
If 3 of the first 5 patients have a SAE attributable to the experimental intervention, stop the 
study. 
• 
If 5 of the first 10 patients have a SAE attributable to the experimental intervention, stop the 
study. 
• 
If 6 of the first 17 patients have a SAE attributable to the experimental intervention, stop the 
study. 
 
With these parameters, there is a 0.94 probability of crossing the boundary if the true toxicity rate is .50, and 
there is a 0.14 probability of .14 probability of crossing the boundary if the true toxicity rate is .20.” 


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9.3 HER2 directed  therapy co-administration arm safety  run-in and  expansion 
schedule 
In the HER2 directed therapy safety arm, each of the first 3 HER2-positive subjects treated with both HER2 
directed therapy and tremelimumab required 6 weeks of follow-up from the first dose of tremelimumab 
before additional HER2-positive patients were enrolled. 
 
During the safety run-in, the following were criteria that would prompt discontinuation of enrollment of 
subsequent patients in the HER2 directed therapy safety arm: 
 
• 
Any subject experiencing symptomatic CHF requiring therapeutic intervention. The CHF must be 
attributable to the experimental intervention. The diagnosis should be confirmed by a TTE 
demonstrating evidence of heart failure. A cardiology consultation should be obtained in cases of 
diagnostic uncertainty. 
• 
Any subject with a cardiac event requiring therapy, including myocardial infarction or 
myocarditis/pericarditis, if the cardiac event is attributable to the experimental intervention. 
• 
SAE’s attributable to the experimental intervention, requiring  treatment  discontinuation, 
occurring in two of three subjects. If a serious adverse event (SAE) attributable to the 
experimental intervention occurs in 1/3 subjects a discussion and consensus will be required 
amongst the principal investigator before enrollment continues. 
• 
Closure of the tremelimumab/RTefficacy arm related to toxicity concerns. 
 
If cardiac toxicity or additional SAEs occur in patients following the safety run-in, the decision to continue 
enrollment of additional patients requiring concurrent therapy will be made by the principal investigator. If 
enrollment is discontinued for safety concerns, the decision of whether to halt therapy in previously enrolled 
patients will be made on a case-by-case basis by the principle investigator in discussion with the sponsor. 
 
Patients who tolerate therapy are defined as patients who do not discontinue tremelimumab for safety- 
related reasons within 6 weeks of initiating tremelimumab. 
Following the safety run-in, additional subjects were enrolled according to table 9.2.1. During the safety run- 
in, if none or one subject out of the three subjects enrolled experience unacceptable toxicity; we will expand 
to enroll 3 more patients. If either 0/6 or 1/6 subjects tolerate therapy, the combination will be deemed 
safe. Depending on availability of resources, if the combination is deemed safe, we may consider enrollment 
of additional subjects in an expansion cohort, to be defined under a protocol amendment. Similarly, if the 
combination is deemed not  tolerable, we may consider enrollment of additional subjects in a dose de- 
escalation cohort. 
 
Cardiac monitoring with TTE or MUGA is recommended at baseline and every 12 weeks (+/- 1 week ) for 
patients receiving concurrent HER2 directed therapy while on study. Left  ventricular  dysfunction, 
symptomatic or not, should be treated and followed according to standard medical practice. 
 
Table 9.2.1: Concurrent arm enrollment schema 
 
# pts 
with 
safety-related 
Next step 


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treatment discontinuation 
Safety run-in 
≤1/3 
Expand to 6 subjects 
≥2/3 
Therapy not tolerable; consider 
dose de-escalation cohort 
Expansion 
≤1/6 
Therapy tolerable, consider 
expansion cohort 
≥2/6 
Therapy not tolerable; consider 
dose de-escalation cohort 
 
 
9.4 Expansion of the HER2+ safety cohort 
 
As of 3/1/2017, the safety arm of patients with HER2-positive disease requiring continuation  of  HER2 
directed therapy met the criteria for treatment expansion per the above enrollment schema. As a result, this 
cohort of patients  will be expanded  in  order to  evaluate efficacy in a Simon  two-stage design. In  this 
expansion, we will evaluate the combination of tremelimumab (treme), durvalumab (durva), and  HER2 
directed therapy plus brain irradiation in breast cancer patients with brain metastases (BCBM) for whom 
post-brain irradiation cytotoxic chemotherapy is planned. Subjects will  receive either whole brain radiation 
treatment (WBRT) or stereotactic radiosurgery (SRS), as  per standard  of care, with tremelimumab 
administered at 75 mg and durvalumab administered at 1500 mg every 28 days for 4 cycles. After the 4th 
cycle, patients will continue to receive 1500 mg durvalumab every 28 days until disease progression or 
unacceptable toxicity. Patients will continue to receive HER2 directed therapy at a NCCN -guideline-endorsed 
dose and schedule, as determined by the investigator. Study design parameters and safety rules are 
consistent with those that were used to study subjects not requiring concurrent HER2 directed therapy. 
 
 
9.5 Determining when to reinitiate systemic therapy 
 
Subjects will be eligible to reinitiate cytotoxic therapy when any of the following criteria are met: 
 
• 
Subject is experiencing symptomatic progression of disease as determined by either the medical 
oncologist, radiation oncologist, or neurologist 
• 
Subject has confirmed progression of disease by irRC per section 12 
• 
At the discretion of the investigator 
 
Subjects requiring reinitiation of therapy before adjudication of the primary endpoint will be designated 
progressors, and will be included in calculating disease control rate, as per the intention to treat principle. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 52 of 98 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Subjects will require frequent monitoring which includes history and physical exam, toxicity grading, 
laboratory analyses, response assessment imaging (including body imaging), and ECG. Detailed monitoring 
schedules are provided in tables 10.0-1, 10.0-2, 10.1-1, and 10.1-2. 
 
Table 10.0 -1 Study Flowsheet for q4wk Treatment Period 
Study Flowchart 
Screening 
Q4wk Treatment Period 
Dose 1 
(4 weeks) 
Dose 2 
(4 
weeks) 
Dose 3 
(4 
weeks) 
Dose 4 
(4 
weeks) 
Dose 5 
(4 
weeks) 
Dose 6 
(4 
weeks) 
Dose 7 
(4 
weeks) 
Treatment week 
-2 to 0 
1 
3 
5 
9 
13 
17 
21 
25 
Treatment day 
-14 to 0 
1 
15 +/- 
1 
week 
29 +/- 1 
week 
57 +/- 1 
week 
85 +/- 1 
week 
113 +/- 1 
week 
141 +/- 1 
week 
169 +/- 
1 week 
Treatment Administration 
Tremelimumab 10mg/kg 
x3 
x 
x 
x 
x 
x 
x 
Radiotherapy 
x 
Tumor assessment 
MRI brain w/& w/o Gd 
X4 
X 
X2 
X 
CT CAP with PET or bone 
scan 
X4 
X 
X2 
X 
Study procedures 
Eligibility + Informed 
Consent 
x 
Demographics 
x 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG PS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs, including 
height(screening only) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
TTE or MUGA (in 
concurrent HER2 directed 
therapy) 
X4 
X 
X 
Medication reconciliation 
x 
x 
x 
x 
x 
X 
x 
x 
X 
CTCAE Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Labs 
Blood Hematology (CBC, 
diff) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (CMP) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tumor markers (CA15-3, 
CEA) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Magnesium, 
Amylase/Lipase, LDH 
x 
x 
x 
x 
x 
x 
x 
x 
Phosphorus 
x 
INR/PT 
x 
TSH ( with reflexive FT3, 
FT4) 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Pregnancy test 
x 
HIV and Hepatitis B,C 
virologies 
x 
Immune monitoring 
studies 
Circulating soluble factors 
(cytokines, chemokines) 
x 
x1 
x 
x 
x 
x 
x 
PBMC collection (flow, 
functional assay, immune 
repertoire) 
x 
x1 
x 
x 
x 
x 
x 
1 – Immune monitoring studies will be drawn on the day of tremelimumab administration 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 53 of 98 
 
 
 
 
2- Response assessment will occur at week 13 +/- 1 week, with a confirmatory scan at week 17 +/- 1 week in patients with evidence of radiographic 
progression 
3- The first dose of tremelimumab will ideally be administered 2 days prior to initiation of radiotherapy (but if not feasible, the first dose can be 
administered from 5 days preceding to 3 days followinginitiation of radiotherapy). 
4 – Can be within 4 weeks (28 days) of enrollment 
 
 
 
 
 
 
 
Table 10.0 -2: Study Flowsheet for q4week treatment period, end of treatment, and follow-up 
Study Flowchart 
Q4wk Treatment Period 
End of 
Treatment2 
(Within 30 
days post last 
dose) 
Short Term Follow up Visits2 
Dosing visits 
(dose 8, 9, 
10) 
(Dose 10, 
4wk +/- 1 
week after 
last dose3 
8wk +/- 1 
week after 
last dose 
12wk +/- 1 
week after 
last dose 
Treatment week 
29, 33, 37… 
Treatment day 
197, 
225,253+/- 1 
week … 
Treatment Administration 
Tremelimumab 10mg/kg 
x 
Radiotherapy 
Tumor Assessment 
MRI brain w/& w/o Gd 
X4 
X 
CT CAP with PET or bone scan 
X4 
x 
Study Procedures 
Eligibility + Informed Consent 
Demographics 
Physical Exam 
x 
x 
x 
x 
x 
Medical History 
x 
x 
x 
x 
x 
ECOG 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
Medication reconciliation 
x 
x 
x 
x 
x 
TTE or MUGA (in concurrent HER2 
directed therapy) 
X1 
X 
X 
CTCAE Adverse Events 
x 
x 
x 
x 
x 
Labs 
Blood Hematology (CBC, diff) 
x 
x 
x 
x 
x 
Chemistry (CMP, LDH, 
TSH with reflexive FT3, FT4) 
x 
x 
x 
x 
x 
Tumor markers (CA15-3, CEA) 
x 
x 
x 
x 
x 
Immune monitoring studies 
Circulating soluble factors 
(cytokines, chemokines) 
x 
PBMC collection (flow, functional 
assay, immune repertoire) 
x 
1- TTE or MUGA every 12 weeks (+/- 1 week ) while on concurrent HER2 directed therapy 
2 – End of treatment andshort term follow up visit assessments are to be performed onlyif clinicallyappropriate. 
3 – If the End of Treatment visit occurs within the 4 week Short Term Follow up visit window, the assessments performed can be used 
to satisfy both visits. 
4 – Imaging assessments are to be performed every 12 weeks (+/- 1 week) (e.g. Dose 10, Dose 13, Dose 16, ect) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 54 of 98 
 
 
 
 
Table 10.1 -1 Study Flowsheet for the HER2 Expansion Treatment Period 
 
Study Flowchart 
Screening 
Q4wk Treatment Period 
Dose 1 
(4 weeks) 
Dose 2 
(4 
weeks) 
Dose 3 
(4 
weeks) 
Dose 4 
(4 
weeks) 
Dose 5 
(4 
weeks) 
Dose 6 
(4 
weeks) 
Dose 7 
(4 
weeks) 
Treatment week 
-2 to 0 
1 
3 
5 
9 
13 
17 
21 
25 
Treatment day 
-14 to 0 
1 
15 +/- 
1 
week 
29 +/- 1 
week 
57 +/- 1 
week 
85 +/- 1 
week 
113 +/- 1 
week 
141 +/- 1 
week 
169 +/- 
1 week 
Treatment Administration 
Durvalumab 1500 mg 
x3 
x 
x 
x 
x 
x 
x 
Tremelimumab 75 mg 
x3 
x 
x 
x 
Radiotherapy 
x 
Tumor assessment 
MRI brain w/& w/o Gd 
x4 
x 
x2 
x 
CT CAP with PET or bone 
scan 
x4 
x 
x2 
x 
Tumor core needle or 
surgical biopsy8 
x 
Study procedures 
Eligibility + Informed 
Consent 
x 
Demographics 
x 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical History 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG PS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs5 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight (height at 
screening only) 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
x6 
TTE or MUGA (in 
concurrent HER2 directed 
therapy) 
x 4 
x 
x 
Medication reconciliation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CTCAE Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Labs 
Blood Hematology (CBC, 
diff) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (CMP) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tumor markers (CA15-3, 
CEA) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Amylase/Lipase 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Phosphorus 
x 
Gamma GTP, Magnesium7 
x 
x 
Lactate Dehydrogenase 
x 
x 
x 
x 
x 
x 
x 
x 
Uric Acid 
x 
x 
x 
x 
x 
x 
x 
x 
INR/PT 
x 
TSH ( with reflexive FT3, 
FT4) 
x 
x 
x 
x 
x 
x 
x 
x 
Serum Pregnancy test 
x 
Urinalysis 
x 
x 
x 
x 
x 
x 
x 
HIV and Hepatitis B,C 
virologies 
x 
Immune monitoring studies 
Circulating soluble factors 
(cytokines, chemokines) 
x 
x1 
x 
x 
x 
x 
x 
PBMC collection (flow, 
functional assay, immune 
repertoire) 
x 
x1 
x 
x 
x 
x 
x 
 
1 – Immune monitoring studies will be drawn on the day of tremelimumab administration 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 55 of 98 
 
 
 
 
2- Response assessment will occur at week 13 +/- 1 week, with a confirmatory scan at week 17 +/- 1 week in patients with evidence of radiographic 
progression 
3- The first dose of tremelimumab will ideally be administered 2 days prior to initiation of radiotherapy (but if not feasible, the first dose can be 
administered from 5 days proceeding to 3 days following initiation of radiotherapy). Concurrent HER2-directed therapy will be administeredat a dose 
and schedule consistent with NCCN guidelines at the treating physicians’ discretion 
4 – Can be within 4 weeks (28 days) of enrollment 
5 – Subjects will have their vital signs (BP, HR, RR, Temp) taken before, during, and after each infusion at the following times (based on a 60 -minute 
infusion): 
- 
At the beginning of the infusion (at 0 minutes) 
- 
At 30 minutes during the infusion (±10 minutes) 
- 
At the end of the infusion (at 60 minutes ±10 minutes) 
- 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the 
infusion) (±10 minutes). A 1-hour observation period is required after the first infusion. If no clinically significant infusion reactions 
are observed during orafter the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after each durvalumab and tremelimumab infusion). 
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should follow the principles as described above 
or more frequentlyif clinically indicated 
6 – During Screening, ECGs should be taken in triplicate 2-5 minutes apart. On Cycle 1 Day 1, ECGs should be taken withinan hour prior to the start of 
the infusion and at least one time point 0 to 3 hours after the infusion. Baseline and abnormal ECGs should be performed in triplicate. At all other 
times, single. After C1D1, ECGs should be performedas clinically indicated. 
7 – To be performedas clinically indicated after C1D1 
8 – The first tumor biopsy will be taken (attempted) at baseline, within 28 days prior to dosing or initiation of radiotherapy, whichever is first. An 
optional tumor biopsy will be performed at times such as disease progression, if the patient’s condition allows it, or at the time of radiographic 
response, at the investigator’s discretion and in discussion with the patient. 
 
 
Table 10.1 -2: Study Flowsheet for the HER2 Expansion Treatment Period, End of Treatment, and Follow-up 
 
Study Flowchart 
Q4wk Treatment Period 
End of 
Treatment2 
(Within 30 days 
post last dose) 
Short Term Follow up Visits2 
Dosing visits (dose 8, 9, 
10…) 
4wk +/- 1 
week after 
last dose3 
8wk +/- 1 
week after 
last dose 
12wk +/- 1 
week after 
last dose 
Treatment week 
29, 33, 37… 
Treatment day 
197, 225,253+/- 1 week … 
Treatment Administration 
Durvalumab 1500mg 
x 
Tumor Assessment 
MRI brain w/& w/o Gd 
CT CAP with PET or bone scan 
x4 
x 
Tumor core needle or surgical 
biopsy 
X6 
Study Procedures 
Physical Exam 
x 
x 
x 
x 
x 
Medical History 
x 
x 
x 
x 
x 
ECOG 
x 
x 
x 
x 
x 
Weight, Vital signs5 
x 
x 
x 
x 
x 
Medication reconciliation 
x 
x 
x 
x 
x 
TTE or MUGA (in concurrent HER2 
directed therapy) 
x1 
x 
CTCAE Adverse Events 
x 
x 
x 
x 
x 
Labs 
Blood Hematology (CBC, diff) 
x 
x 
x 
x 
x 
Chemistry (CMP) 
x 
x 
x 
x 
x 
Amylase/Lipase 
x 
Lactate Dehydrogenase 
x 
Uric Acid 
x 
TSH with reflexive FT3, FT4 
x 
x 
x 
x 
x 
Tumor markers (CA15-3, CEA) 
x 
x 
x 
x 
x 
Urinalysis 
x 
Immune monitoring studies 
Circulating soluble factors 
(cytokines, chemokines) 
x 
PBMC collection (flow, functional 
assay, immune repertoire) 
x 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 56 of 98 
 
 
 
 
 
 
1- TTE or MUGA every 12 weeks (+/- 1 week ) while on concurrent HER2 directed therapy 
2 – End of treatment andshort term follow up visit assessments are to be performed onlyif clinicallyappropriate. 
3 – If the End of Treatment visit occurs within the 4 week Short Term Follow up visit window, the assessments performed can be us ed 
to satisfy both visits. 
4 – Imaging assessments are to be performed every 12 weeks (+/- 1 week) (e.g. Dose 10, Dose 13, Dose 16, ect) 
5 - Subjects will have their vital signs taken before, during, and after each infusion at the following times (based on a 60-minute 
infusion): 
- 
At the beginning of the infusion (at 0 minutes) 
- 
At 30 minutes during the infusion (±10 minutes) 
- 
At the end of the infusion (at 60 minutes ±10 minutes) 
- 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the 
start of the infusion) (±10 minutes ). A 1-hour observation period is required after the first infusion. If no clinically 
significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can 
be at the Investigator’s discretion (suggested 30 minutes after each durvalumaband tremelimumab infusi on). 
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should follow the principles as 
described above or more frequently if clinicallyindicated 
6 – A second, optional tumor biopsy will be performed at times such as  disease progression, prior to starting a new anti -cancer 
regimen and if the patient’s condition allows it, or at the time of radiographic response, at the investigator’s discretion and in 
discussion with the patient. 
 
 
 
11.1 
TOXICITIES/SIDE EFFECTS 
 
11.1 Overview of Tremelimumab Toxicity Profile 
In the nonclinical setting, treatment of tumor-bearing mice with anti-mouse CTLA-4 mAb (9H10) induced 
antitumor immunity and markedly enhanced T cell-mediated killing of various mouse solid tumors. Clinical 
trials of tremelimumab, and of the related anti-CTLA-4 antibody ipilimumab, in melanoma suggest activity 
(improved survival) of these agents in melanoma. Tremelimumab has also shown activity (objective 
responses and disease stabilization) in the malignant mesothelioma setting, with preliminary results 
suggesting that tremelimumab may lead  to improved  survival with 45.5%  of subjects  alive at  1 year and 
5 subjects were alive at 2 years. 
 
Overall, tremelimumab nonclinical  toxicities were consistent with inhibition of CTLA-4, with adverse effects 
noted for the gastrointestinal tract, skin, lymphoid organs, thyroid tissues, and hematological systems. Dose- 
limiting toxicities identified in chronic toxicity studies in monkeys included skin rash and gastrointestinal 
effects. Most toxicities were reversible or showed a trend towards reversibility. 
 
The profile of AEs from > 1000 treated subjects and the spectrum of event severity are consistent with the 
pharmacologic class and with the signal observed in nonclinical toxicology studies. Adverse events have been 
observed in every organ system and are mainly due to the inflammation caused by tremelimumab’s 
mechanism of action. The most common AEs involve skin, the gastrointestinal tract, and endocrine system, 
and are usually mild in nature. Events reported at a frequency of ≥ 5% and assessed by the investigator as 
related to treatment (listed in descending order of frequency) were diarrhea, rash, pruritus, fatigue, nausea, 
vomiting, anorexia, headache, abdominal pain, and colitis. Infusion-related AEs were rare. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
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Page 57 of 98 
 
 
 
 
11.2 Adverse event management 
 
11.2.1 Dose modification and universal management guidelines for drug-related adverse events. 
 
No dose reduction is allowed. Dosing may be delayed up to + 3 days during the treatment phase to allow 
recovery from treatment-related toxicity. Toxicity management guidelines for anti-CTLA-4 monoclonal 
antibodies have been developed and published in the past 5 years (Weber, Kahler et  al. 2012). Detailed 
management guidelines have been created for diarrhea and/or colitis-related events (Appendix 20.1). 
However, for management of most other toxicities follow the guideline in table 11.2. 
 
 
Specific detailed management guidelines have been created for diarrhea and colitis-related events. However, 
for management of most other toxicities follow the guideline in Table 11.2 below. 
 
 
 
 
 
 
 
Table 11.2 General Toxicity Management Guideline 
Condition 
Management 
Onset of any toxicity 
• 
Rule out alternative etiology 
CTCAE Grade 1 
• 
Provide symptomatic treatment. 
• 
Possible topical steroids if applicable. 
• 
If symptoms resolve, continue tremelimumab dosing. 
• 
If symptoms persist >10 days, treat as CTCAE Grade 2. 
CTCAE Grade 2 
• 
Provide symptomatic treatment 
• 
Do not give scheduled dose; dosing may be resumed at next 
scheduled dose if symptoms are resolved. 
• 
Dosing delays are not permitted (except per protocol specified 
window of +3 days in treatment phase). 
• 
Consider oral or intravenous (IV) steroids at the onset of symptoms. 
Taper steroid over 4 weeks if symptoms improve 
• 
For persistent Grade 2 CTCAE events: treat as CTCAE grade 3 event, 
start high-dose IV steroids 
CTCAE Grade 3 
• 
Start high-dose IV steroids at the onset of the symptoms 
• 
Provide symptomatic treatment 
• 
Permanent discontinuation* of tremelimumab for CTCAE Grade 3 
events thought to be drug-related. 
• 
Exception are endocrinopathies that are asymptomatic and 
controlled with hormone replacement therapy, and rash or other 
skin disorders 


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Table 11.2 General Toxicity Management Guideline 
 
Condition 
Management 
CTCAE Grade 4 
• 
Start high dose IV steroids at the onset of the symptoms 
• 
Provide symptomatic treatment 
• 
Permanent discontinuation* of tremelimumab for all Grade 4 
events 
Steroid refractory 
toxicity (no 
improvement after 5 
days on high dose IV 
steroids) or relapse 
after reducing high 
dose steroids 
• 
Continue symptomatic treatment and steroids 
• 
Possible infliximab 5 mg/kg IV for gastro-intestinal toxicities unless 
contraindicated [consult with GI specialist]. Caution: rule out bowel 
perforation and refer to label before using infliximab. 
• 
For patients with increased AST/ ALT, or Total Bilirubin levels, 
consider Mycophenolate mofetil 
*Patients will not receive any subsequent dose, but will remain on study and follow the other procedures required from the study (e.g. follow up 
procedures, imaging follow-up, blood sample collections). 


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11.2.1.1 Guidelines  for hypersensitivity reactions 
In case of hypersensitivity reactions, the investigator should institute treatment measures deemed medically 
appropriate per institutional guidelines. 
 
• 
Grade 1 = Transient flushing or rash; drug fever < 38°C 
• 
Grade 2 = Rash; flushing; urticaria; dyspnea; drug fever ≥ 38°C 
• 
Grade 3 = Symptomatic bronchospasm with or without urticaria; parenteral medication(s) 
indicated; allergy-related edema/angioedema; hypotension; anaphylaxis 
• 
Grade 4 = Anaphylaxis 
• 
Grade 5 = Death 
 
11.2.1.1.1 Dose modification and delay for non-related adverse events 
 
Dosing delays for toxicities not related to treatment are at the discretion of the treating investigator. Any 
patient who has a treatment delay due to an unrelated toxicity will reinitiate treatment at the discretion of 
the treating investigator. 
 
 
11.2.2 Guidelines for skipping the next scheduled dose for drug-related adverse events. 
The following guidance (see Table 11.2.2.1 below) is for consideration when determining when to skip/hold 
the next scheduled dose of tremelimumab during management of drug-related toxicities. When a scheduled 
dose of tremelimumab is skipped; the dosing may be resumed at the next scheduled dose if the symptoms 
have resolved to CTCAE Grade ≤ 1. Dose delays are not allowed (except per protocol specified window of 2 
days in induction and 5 days in maintenance phase). No dose reductions are permitted for tremelimumab. 


Memorial Sloan Kettering Cancer Center 
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Table 11.2.2.1 Guidelines for skipping a tremelimumab dose 
Condition 
Action 
For persistent NCI CTCAE Grade 1 treatment-related toxicities (> 10 
days). 
Manage as a NCI CTCAE Grade 2 
Subjects with AST/ALT 5-8 × ULN or total bilirubin 3-5 × ULN. 
Subjects with any NCI CTCAE Grade 2 treatment-related laboratory 
abnormalities. 
For ongoing NCI CTCAE Grade 2 related toxicities, dosing may be 
resumed at next scheduled dose if the event is resolving and at 
Grade ≤ 1. 
Exceptions to this are: 
• 
Investigational product may be dosed for NCI CTCAE Grade 
≤ 3 endocrine disorders, if asymptomatic and controlled 
with hormone replacement therapy. Skip investigational 
product dose for Grade ≥ 2 endocrinopathies that are 
under treatment and remain symptomatic. 
• 
For hypersensitivity reactions and infusion reactions NCI 
CTCAE Grade ≤ 2: slow the infusion rate or temporarily 
pause the infusion, medicate the subject with symptomatic 
therapies (i.e. anti-histaminic drugs), and consider 
premedication perinstitutional guidelines. 
• 
Investigational product may be dosed for NCI CTCAE Grade 
2 rash or other skin disorders; skip dose for Grade 3 skin 
disorders, with the exception of vitiligo, for which 
tremelimumab may be continued. 
Skip 
scheduled 
tremelimumab 
dose 
ALT  =  alanine  transaminase;  AST  =  aspartate  transaminase;  NCI  CTCAE  = National  Cancer  Institute 
Common Terminology Criteria for Adverse Events; ULN = upperlimit of normal. 
 
 
 
During the study, patients may immunosuppressive medications such as steroids may be indicated for 
management of underlying disease, treatment-related toxicity, or unrelated conditions. If symptoms resolved 
to CTCAE Grade ≤1, tremelimumab dosing  may be resumed during  steroid taper. Patients with adrenal 
insufficiency may take daily prednisone or equivalent therapy for their endocrinopathy while receiving 
tremelimumab treatment. Topical and inhaled steroids in standard doses are allowed. 


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11.2.3 Guidelines for permanent dosing discontinuation (safety related) 
Table 11.2.3.1 below lists the safety related conditions when patients must be permanently discontinued 
from tremelimumab treatment. Additionally, tremelimumab should be permanently discontinued for any 
adverse event, which in the opinion of the investigator, contraindicate further dosing. When tremelimumab 
dosing is permanently discontinued, continue to follow the patient (e.g. they will follow the other procedures 
required from the study; follow up procedures, imaging follow-up, blood samples collection etc.). 
 
 
Table 11.2.3.1 Guideline for Permanent Discontinuation of tremelimumab 
 
Action 
Condition 
Permanent 
Discontinuation of 
tremelimumab 
CTCAE Grade ≥3 treatment-related diarrhea or colitis 
AST or ALT > 8 x ULN or total bilirubin > 5x ULN 
CTCAE Grade ≥3 hypersensitivity reaction or infusion reaction; 
Recurrent/persistent CTCAE Grade 2 hypersensitivity despite optimal 
premedication 
CTCAE Grade ≥ 3 related endocrine disorders, if symptomatic and not controlled 
with hormone replacement therapy. [Tremelimumab may de dosed for CTCAE 
Grade ≤ 3 endocrine disorders, if asymptomatic and controlled with hormone 
replacement therapy] 
CTCAE Grade 4 rash or other skin disorders [with the exception of vitiligo, which 
may be dosed regardless of severity] 
Any CTCAE Grade 4 event thought to be drug related 
Any patient who receives infliximab or any other TNF alfa inhibitor 
If 2 consecutive doses are missed due to on-going related toxicities 
Begins new investigational therapy, chemotherapy, cytokine therapy, or 
immunotherapy (including vaccines) must withdraw from treatment 
Patient becomes pregnant 
 
 
 
11.3 Toxicities/Side effects of durvalumab + tremelimumab combination therapy 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and non-immune- 
mediated reactions for durvalumab monotherapy and durvalumab + tremelimumab are provided in the 
Dosing Modification and Toxicity Management Guidelines in section 20.3. Patients should be thoroughly 
evaluated and appropriate efforts should be made to rule out neoplastic, infectious, metabolic,  toxin, or 
other etiologic causes of the imAE. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an imAE diagnosis. In the absence of a clear alternative etiology, events should be 
considered potentially immune related. 


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In addition, there are certain circumstances in which durvalumab and tremelimumab should be permanently 
discontinued (see  the Dosing Modification and Toxicity Management Guidelines in section 20.3). 
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity Management Guidelines in 
section 20.3. These guidelines apply to AEs considered causally related to durvalumab monotherapy and the 
durvalumab + tremelimumab regimen by the reporting investigator. 
 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing will resume as soon as 
feasible. Dosing intervals of subsequent cycles may be shortened as clinically feasible in order to gradually 
align treatment cycles with the schedule of tumor efficacy (RECIST) assessments. Subsequent time between 2 
consecutive doses cannot be less than 22 days, based on the half-lives of durvalumab and tremelimumab 
(see current Investigator Brochures for durvalumab and tremelimumab. 
Dose reductions are not permitted. 
 
11.3.1 Durvalumab + tremelimumab adverse events of special interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding 
of the Investigational Product and may require close monitoring and rapid communication by the investigator 
to the Study Physician. An AESI may be serious or non-serious. The rapid reporting of AESIs allows ongoing 
surveillance of these events in order to characterize and understand them in association with the use of this 
investigational product. 
 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential inflammatory 
or immune-mediated mechanism and which may require more frequent monitoring  and/or interventions 
such as steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune-related 
adverse event (irAE) is defined as an adverse event that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate etiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the irAE. 
 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the  Investigator 
should promptly contact the Study Physician. 
 
AESIs observed with durvalumab and tremelimumab include: 
• 
Diarrhea/Colitis 
• 
Pneumonitis/ILD 
• 
ALT/AST increases / hepatitis / hepatotoxicity 
• 
Neuropathy  /  neuromuscular  toxicity  (i.e.  events  of  encephalitis,  peripheral  motor  and  sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 


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• 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, diabetes insipidus, type I diabetes 
mellitus, and hyper- and hypothyroidism) 
• 
Rash/Dermatitis 
• 
Nephritis/Blood creatinine increases 
• 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , increased serum amylase) 
• 
Cardiac disorders (myocarditis) 
• 
Otherinflammatory responses that are rare with a potential immune-mediated aetiology include, but 
are not limited to, myocarditis, pericarditis, and uveitis. 
 
• 
In addition, infusion related  reactions and hypersensitivity,  anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the 
durvalumab and tremelimumab Investigator Brochure. For durvalumab and tremelimumab, AESIs will 
comprise the following: 
 
Pneumonitis 
AEs of pneumonitis are also of interest for AstraZeneca, as pneumonitis has been observed with use of anti- 
PD-1 mAbs (but not with anti-PD-L1 mAbs). Initial work-up should include a high-resolution CT scan, ruling 
out infection, and pulse oximetry. Pulmonary consultation is highly recommended. Gui delines for the 
management of patients with immune-related AEs (irAEs) including pneumonitis are provided in Table 20.3. 
 
Infusion reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to AstraZeneca and 
are defined, for the purpose of this protocol, as all AEs occurring from the start of IP infusion up to 48 hours 
after the infusion start time. For all infusion reactions, SAEs should be reported to AstraZeneca Patient safety 
as described in Section 11.2.1.1. 
 
Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-L1 and anti- 
PD-1 therapy (Error! Reference source not found.). As with the administration of any foreign protein and/or 
other biologic agents, reactions following the infusion of mAbs can be caused by various mechanisms, 
including acute anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAbs 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 the management of patients with hypersensitivity (including 
anaphylactic reaction) and infusion-related reactions are provided in Section 11.2.1.1. 
 
Hepatic function abnormalities (hepatotoxicity) 
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 


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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 (eg, 
cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other than the IP. Guidelines 
for management of patients with hepatic function abnormality are provided in Table 20.3. 
 
Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is used as 
monotherapy. In rare cases, colon perforation may occur that requires surgery (colectomy) or can lead to a 
fatal outcome if not  properly managed. Guidelines on management of diarrhea and colitis  in  patients 
receiving tremelimumab are provided in Table 20.3. 
Endocrine disorders 
Immune-mediated 
endocrinopathies 
include 
hypophysitis, 
adrenal 
insufficiency, 
and 
hyper- 
and 
hypothyroidism. Guidelines for the management of patients with immune-mediated endocrine events are 
provided in Table 20.3. 
 
Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase  elevation. 
Guidelines for  the management of patients with immune-mediated pancreatic disorders are provided in 
Table 20.3. 
 
Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory neuropathies, 
Guillain-Barré, and myasthenia gravis. Guidelines for the management of patients with immune-mediated 
neurotoxic events are provided in Table 20.3. 
 
Nephritis 
 
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. Guidelines for the management of 
patients with immune-mediated neurotoxic events are provided in Table 20.3. 
 
 
11.3.2 Immune-related adverse events 
Based on the mechanism of action of durvalumab and tremelimumab leading to T-cell activation and 
proliferation, there is a possibility of observing irAEs during the conduct of this study. Potential irAEs may be 
similar to those seen with the use of ipilimumab, BMS-936558 (anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 
mAb)  and may  include immune-mediated enterocolitis, dermatitis, hepatitis (hepatotoxicity),  pneumonitis, 


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and endocrinopathies (Error! Reference source not found., Error! Reference source not found., Error! 
Reference source not found.). These AEs are inflammatory in nature and can affect any organ. With anti- 
PD-L1 and anti-CTLA-4 combination therapy, the occurrence of overlapping or increasing cumulative 
toxicities that include irAEs could potentially occur at higher frequencies than with either durvalumab or 
tremelimumab monotherapy.  Patients should be monitored for signs and symptoms of irAEs.  In the absence 
of an alternate etiology (eg, infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy. In addition to the dose 
modification guidelines provided in Table 20.3, it is recommended that irAEs are managed according to the 
general treatment guidelines outlined for ipilimumab (Error! Reference source not found.). These guidelines 
recommend the following: 
 
• 
Patients should be evaluated to identify any alternative etiology. 
 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered immune related. 
 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
 
• 
Systemic corticosteroids should be considered for a persistent low-grade event or 
for a severe event. 
 
• 
More    potent   immunosuppressives   should   be   considered   for   events   not 
responding to systemic steroids (eg, infliximab or mycophenolate). 
 
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should immediately 
contact the Study Physician. 
 
 
 
 
 
 
 
 
 
 
12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.2 
Evaluation of Primary Endpoint 
 
12.2.1 Response Assessments 
Imaging assessments will be performed at baseline (within 28 days before randomization)  and every  3 
months +/- 1 week during the q28d treatment period until confirmed objective disease progression 
irrespective of whether the subject has discontinued investigational product. In the absence of progression, 
the next assessment should be performed at the next scheduled visit. In addition, when available, scans done 


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after disease progression in subjects who permanently discontinue investigational product will be obtained 
when possible to determine if there was any delayed tremelimumab +/- durvalumab activity unless consent 
is withdrawn or the subject is lost to follow-up or starts receiving another anticancer therapy. Additional 
scans can also be done at any time based on investigator discretion. 
 
An initial increase in tumor burden or the appearance of new lesions could precede immunotherapy-induced 
tumor regression (Wolchok, Hoos et al. 2009). According to this model of response, subjects initially assessed 
as PD by RECIST1.1 criteria, in the absence of significant clinical deterioration warranting discontinuation of 
study treatment will continue treatment and receive a confirmatory scan at least 4 weeks later. The following 
criteria will be used to determine if study treatment is continued: 
 
• 
If the tumor burden at the confirmatory scan is more than 20% larger than the tumor burden at the 
initial PD scan, the subject will be considered to have confirmed PD and will be discontinued from 
study treatment 
• 
If the tumor burden at the confirmatory scan is within 20% of the tumor burden at the initial PD scan, 
the subject will be considered to have SD and will continue treatment until the next scheduled scan 3 
months after the initial PD. Any subsequent scheduled tumor assessment visit showing that  the 
tumor burden is more than 20% larger than the tumor burden at the initial PD scan will be 
considered as confirmed PD, and the subject will be discontinued from study treatment 
• 
In subjects with new lesions in the setting of overall response, the decision to continue treatment will 
be discussed on a case by case basis between the principal investigator and study monitor 
• 
It is important to maintain the schedule of assessments every 3 months and subjects having 
confirmatory scans for PD must return for the next scheduled visit per protocol. 
 
12.2.2 RECIST1.1 Criteria 
Tumor burden will be assessed using RECIST criteria v1.1 (Eisenhauer, Therasse et al. 2009). To  assess 
objective response or future progression, it is necessary to estimate the overall tumor burden at baseline and 
use this as a comparator for subsequent measurements. Measurable disease is defined by the presence of at 
least one measurable lesion (10mm by CT scan [CT scan slice thickness no greater than 5mm], 10mm caliper 
measurement by clinical exam, or 20mm by chest x-ray). A lymph node must be at least 15mm in short axis 
when measured by CT scan. When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Remaining lesions will 
be considered non-target lesions. For full details of the RECIST1.1 criteria, refer to the Eisenhauer 
reference.(Eisenhauer, Therasse et al. 2009) 
The RECIST1.1 criteria response definitions are summarized as follows: 
 
• 
Complete response: Disappearance of all target lesions. Any pathological lymph  nodes  (whether 
target or non-target) must have reduction in short axis to <10mm. 
• 
Partial response: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
• 
Progressive disease:  At least a 20% increase in the sum  of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5mm. 


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• 
Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
• 
 
12.3 
Evaluation of Secondary Endpoints 
 
12.3.1 Objective response and disease control rate by irRC 
We will assess disease control at 12 weeks using immune-related response criteria (irRC) (Wolchok, Hoos et 
al. 2009). Response is defined as irCR, irPR or irSD over a period of at least 4 weeks. Imaging before the week 
12 time point will not be specified, to account for the possibility that a subset of patients will experience an 
immune-related response, by which responses are preceded by radiographic progression, related to delayed 
response kinetics and/or T-cell tumoral infiltration. 


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12.2.2 CNS Response Determination 
 
CNS response will not be included in the primary endpoint. Investigators may plan more frequent imaging as 
clinically indicated, including MRI imaging. 
 
Subjects who experience systemic disease control and CNS progression may continue receiving study 
medication at the discretion of the investigator. These subjects may receive additional brain-directed SRS if 
clinically warranted. 
 
Table 12.2.2.1: RANO Criteria for CNS response (Wen, Macdonald et al. 2010) 
Response 
Criteria 
Complete 
Response 
Requires all of the following: complete disappearance of all enhancing measurable and 
non measurable disease sustained for at least 4 weeks; no new lesions; stable or 
improved non enhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on 
physiologic replacement doses only); and stable or improved clinically. Note: Patients 
with non measurable disease only cannot have a complete response; the best  
response possible is stable disease. 
Partial 
Response 
Requires all of the following: ≥50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for 
at least 4 weeks; no progression of non measurable disease; no new lesions; stable or 
improved non enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan; the corticosteroid dose at the time of the scan 
evaluation should be no greater than the dose at time of baseline scan; and stable or 
improved clinically. Note: Patients with non measurable disease only cannot have a 
partial response; the best response possible is stable disease. 
Stable Disease 
Requires all of the following: does not qualify for complete response, partial response, 
or progression; stable non enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the corticosteroid dose 
was increased for new symptoms and signs without confirmation of disease 
progression on neuroimaging, and subsequent follow-up imaging shows that this 
increase in corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose. 
Progression 
Defined by any of the following: ≥25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or increasing 
doses of corticosteroids; significant increase in T2/FLAIR non enhancing lesion on 
stable or increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy not caused by comorbid events (e.g., radiation 
therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to 
other causes apart from the tumor (e.g., seizures, medication adverse effects, 
complications of therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose; failure to return for evaluation as a result of death or  
deteriorating condition; or clear progression of non measurable disease. 


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12.3 Exploratory assessments 
 
 
12.3.1 Immunologic correlatives 
 
Exploratory correlative studies will be performed to evaluate anti-tumor and immunological response pre- 
and post-treatment on individuals. Peripheral blood samples will be studied, and these tests will be done at 
the IMF (currently located in the Zuckerman building). The following exploratory endpoints are proposed: 
 
1) To evaluate the effect of tremelimumab +/- durvalumab + RT on: lymphocyte phenotype and 
serum cytokines, disease related biomarkers, and humoral and cellular responses to tumor 
antigens and recall non-tumor antigens; 
 
2) To evaluate serological and cellular immune correlates of toxicity and/or clinical activity; 
 
To this end, the specimens to be collected for IMF evaluation include research blood samples at time points 
as delineated in table 10.1-1 and 10.1-2. For each blood draw, 4 CPT tubes will be collected for: 
• 
Flow cytometric analysis: 
o T-cells: activation and memory markers 
o Dendritic cells: activation and maturation markers and markers of inhibitor/tolerogenic DCs 
• 
Intracellular cytokine assay (ICCA) and ELISPOT: to detect responses to specific tumor antigens 
(forexample, HER2 or MUC1) which are expressed in breast cancers 
• 
Serum cytokines: Soluble factors, such as interferon gamma, are detectable at increased levels 
following administration of anti-CTLA-4 plus cryotherapy in breast cancer patients (Page, Yuan et 
al. 2014), and may serve as a pharmacodynamic marker of immune activation and biomarker of 
response 
• 
Serology assays: Antibody levels to cancer testis antigens and breast tumor specific antigens will 
be assessed by multiplex assays and enzyme-linked immunosorbent assay (ELISA). 
• 
DNA deep sequencing T-cell repertoire analysis: Maintenance of peripheral T-cell clonal diversity 
has been described as a predictor of clinical benefit to anti-CTLA4. (Cha, Klinger et al. 2014) 
• 
CBC: to quantify absolute lymphocyte count (ALC) 
 
 
12.3.2 Imaging 
In subjects receiving PET/CT, radiographic response by PET will be compared to standard assessment with CT 
CAP. This comparison will help to evaluate whether metabolic uptake might be useful in distinguishing clinical 
response to immunotherapy in breast cancer patients, who frequently are evaluated off-protocol  with 
PET/CT. 
 
PET/CT is commonly used as a standard-of-care modality for evaluating response to palliative therapy in 
metastatic breast cancer off-study. However, on study, response to treatments  is often measured 
anatomically using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1. However, 
there are limitations in using anatomic response criteria alone, particularly when evaluating bone metastases 
without an extra-osseous component, which is common in breast cancer patients. Furthermore, while RECIST 


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criteria may be appropriate for evaluating response to conventional cytotoxic therapies, they may not be 
ideal for evaluating response in the setting of dynamic infiltration with immunotherapy. 
 
12. 3.2.1 PERCIST Criteria 
 
PERCIST (PET response criteria in solid tumors) is a commonly proposed method for measuring treatment 
response based on metabolic response criteria with PET. A limitation of PERCIST is that it only takes into 
account the single hottest lesion and it relies upon SUV peak measurements, which are not easily 
reproducible in lesions with low FDG-avidity, as are often found  in breast cancer. Since there are no 
standardized methods for quantifying FD G-tracer avidity in individual tumor lesions, we will use a 
modification of PERCIST criteria called “PET Response Criteria” (PRC) that is currently being utilized in other 
cancer protocols at MSK requiring metabolic assessment. In brief, up to 5 FDG-avid target lesions will be 
selected, SUVmax measured  for each lesion, and the sum of all lesions (Sum SUVmax) recorded. On 
subsequent studies, the same target lesions will be measured and Sum SUVmax recorded. Lesions where 
SUVmax is no greater than background will be recorded as zero. Response or progression will be graded as 
follows: 
 
• 
Complete Response: All lesions no greater than background SUVmax 
• 
Partial Response: Sum SUVmax decreased by >30% but still greater than background SUVmax 
• 
Stable Disease: Lesions that do not fit criteria for response or progression 
• 
Progressive Disease: Sum SUVmax increased by > 30% or development of a new lesion 
 
Thus, PET will be performed in conjunction with dedicated CT in this study in order to explore similarities and 
differences in the information conferred, ultimately in order to inform future studies. 
12.3.3 Tumor Biopsies 
 
Patients in the expansion  will have two biopsies collected (attempted). The first tissue biopsy will be 
attempted at baseline, within 28 days prior to starting treatment. A second, optional, tumor biopsy will be 
performed at times such as disease progression, prior to starting a new systemic cancer treatment and if the 
patient’s condition allows it, or at the time of radiographic response, at the investigator’s discretion and in 
discussion with the patient. For each core needle biopsy, an attempt should be made to collect at least 3 core 
needle samples; however, if it is not medically feasible to collect 3 samples, the investigator or designee 
should attempt to collect as much tumor tissue as is deemed medically feasible. 
 
Biopsy samples will be collected for exploratory biomarker research, to be used in understanding the effects 
of tremelimumab and durvalumab. 
 
 
 
 
12.4 Evaluable patients 
 
All patients who receive at least one dose of tremelimumab +/- durvalumab will be evaluable for toxicity and 
will be included in the intent to treat analysis. 


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Patients who complete 12 weeks on study and undergo protocol imaging will be evaluable for response . 
Subjects who clinically progress or die prior to the 12 week assessment will be included in the analysis as 
failures. 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Permanent 
discontinuation 
of 
the drug: An individual subject 
will not 
receive 
any further 
Tremelimumab/durvalumab if any of the following occur in the subject in question: 
a) 
Withdrawal of consent from further treatment with investigational product 
b) 
Lost to follow-up 
c) 
An AE that, in the opinion of the investigator, contraindicates further dosing 
d) 
Adverse  event  related  to  Tremelimumab/durvalumab  that  met  criteria  for  discontinuation  as 
defined in Section 11 
e) 
Subject who skips 2 consecutive doses because of ongoing treatment-related toxicity; 
f) 
Subject who has received any amount of infliximab or other tumor necrosis factor alpha (TNF-α) 
inhibitor. 
g) 
Subject is determined to have met one or more of the exclusion criteria or failed to meet all of 
the inclusion criteria for study participation at study entry and continuing investigational therapy 
might constitute a safety risk 
h) 
Pregnancy or intent to become pregnant 
i) 
Subject noncompliance that, in the opinion of the investigator, warrants withdrawal; e.g., refusal 
to adhere to scheduled visits 
j) 
Initiation of alternative anticancer therapy including another investigational agent 
k) 
Confirmation of progressive disease and investigator determination that the patient is no longer 
benefitting from treatment 
l) 
Grade ≥ 3 infusion reaction 
 
 
Subjects who are permanently discontinued from further receipt of investigational product, regardless of the 
reason (withdrawal of consent, due to an AE, other), will be identified as having permanently discontinued 
treatment. Subjects who permanently discontinue treatment may either be considered to have completed 
the study or not to have completed the study. 
 
Subjects, who are permanently discontinued because of toxicity and in the absence of disease progression, 
will be asked to come in for every protocol-specified visit and will follow all protocol procedures with the 
exception of dosing. For subjects refusing to return to the site, they should be contacted by phone unless 
consent is withdrawn. 
 
Subjects who are permanently discontinued from receiving investigational product will  be  followed  for 
safety, including the collection of any protocol-specified blood, or urine specimens, as specified in section 10, 
unless consent is withdrawn or the subject is lost to follow-up or enrolled in another clinical study. Subjects 
who decline to return to the site forevaluations will be offered follow-up by phone as an alternative. 


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Withdrawal of consent: If consent is withdrawn, the subject will not receive any further investigational 
product or further study observation. Note that the subject may need to undergo additional tests or tapering 
of treatment to withdraw safely. 
 
Withdrawal of treatment: at any time the subject may withdrawal the consent to further treatment, without 
withdrawing the consent to the study; in this case the subject will not receive any further investigational 
product, but he/she will continue to follow the study procedures. 
 
Lost to follow-up: Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed such that there is insufficient information to determine the subject’s status at 
that time. 
 
Note: For subjects refusing to continue participation in the study, they should be documented as “withdrawal 
of consent” rather than “lost to follow-up.” Investigators should document attempts to re-establish contact 
with missing subjects throughout the study period. If contact with a missing subject is re-established, the 
subject should not  be considered lost  to follow-up and any evaluations should resume according to the 
protocol. 
13.1 
Premature Patient Withdrawal 
 
A patient may withdraw from  the study at any time for any reason without prejudice to his/her future 
medical care by the physician  or at the study site. Likewise, the Investigator has the right to  withdraw 
patients from the study. Should a patient (or a patient’s legally authorized representative) decide to 
withdraw, all efforts will be made to complete the required study procedures and report the treatment 
observations as thoroughly as possible. 
 
A complete final evaluation should be made at the time of the patient’s withdrawal, the  Study  Status 
Outcome form in the case report form should be completed with an explanation of why the patient is 
withdrawing, and an attempt should be made to perform a follow-up evaluation. 
 
Reasons for a premature withdrawal of a patient include, but are not limited to, the following: 
 
• 
Significant protocol violation or noncompliance on the part of the patient or Investigator 
• 
Refusal of the patient to continue treatment or observations 
• 
Best medical interest of the patient (at the discretion of the Investigator) 
• 
Unrelated medical illness or complication 
• 
Lost to follow-up 
 
13.2 Very Premature Patient Withdrawal 
 
Patients who withdraw consent prior to the first dose of tremelimumab will be replaced, and will not be 
included in subsequent analysis. 
 
14.1 
BIOSTATISTICS 


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14.2 
Sample Size Determination 
 
The overarching goal of this pilot study is to evaluate preliminary efficacy of the combination of 
tremelimumab with brain irradiation, and to confirm safety of concurrent HER2 directed therapy + 
tremelimumab at the previously-defined recommended doses for these two agents. The  total  maximum 
accrual will be 23 patients, 17 in the efficacy cohort and 6 in the HER2 directed therapy co-administration 
safety cohort. If preliminary efficacy is ascertained, this will prompt a multi-institutional randomized trial 
which will more definitively evaluate efficacy. 
 
14.2.1 Primary Endpoint: Efficacy Cohort 
Because clinically there can be a discord between the response of brain metastases and non-CNS metastases 
to any given therapy, because there are no uniformly accepted criteria for evaluating brain metastases 
responses to immunotherapy, and because criteria for evaluating CNS and  non-CNS  responses differ, we 
have chosen to evaluate non-CNS disease control rate as the primary endpoint. 
 
In the efficacy cohort, a Simon two-stage design will test whether tremelimumab and brain irradiation yields 
a 12 week non-CNS disease control rate (CR + PR + SD per RECIST 1.1) that is of clinical interest. This design 
limits the expected number of subjects who receive treatment when the true 12 week non-CNS disease 
control rate is not of clinical value. 
 
The Simon design will test the null hypothesis that the true non-CNS disease control rate is ≤ 5% versus the 
alternative hypothesis that the true non-CNS disease control rate is > 25%. The 2-stage testing will target a 
Type I error rate of 5 % and will have 80 % power to reject the null hypothesis if the true non-CNS disease 
control rate is 25%. 
 
The Simon design requires 9 treated subjects assigned to treatment for the first stage and calls for 
termination of a cohort at stage 1 if there are 0 subjects with non-CNS disease control amongst the 9 
assigned subjects within the cohort. Otherwise, if 1 subjects with non-CNS disease control are identified in up 
to 9 subjects in a cohort, additional subjects will be assigned to a total of 17 subjects. The treatment will be 
considered of clinical interest if, at the end of the second stage, there are ≥ 3 subjects with non-CNS disease 
control amongst 17 assigned subjects. Subjects who withdraw consent prior to receiving the first dose of 
tremelimumab will be replaced, and will not be included in analysis, but will be documented and reported 
with the results of the study. 
 
14.2.1.1 Ration ale of Altern ative Hypothesis 
 
Tremelimumab + RT  is a novel treatment modality—unique from cytotoxic  chemotherapy—which could 
potentially provide clinical benefit in a heavily pre-treated patients for whom relatively few effective 
cytotoxic therapies remain. Another potential advantage of tremelimumab/RT is that patients may benefit 
from a “respite period” during which they may recover from the cumulative toxicities of cytotoxic 
chemotherapy, while still receiving active therapy. Because of these unique attributes, and because of the 
durability of clinical benefit observed in melanoma patients treated with anti -CTLA-4, we have selected an 
alternative hypothesis of 25% non-CNS disease control rate, which we believe would be of sufficient clinical 
value to consider further study. 


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14.2.1.2 Ration ale of Null Hypothesis 
 
By study criteria, women are eligible for study participation if, as determined by the investigator, they 
experienced a non-CNS progression of disease for which a change is  systemic  therapy  cytotoxic 
chemotherapy is planned  after brain irradiation. The null hypothesis, therefore, is based upon  the 
expectation of a 12-week non-CNS disease control rate of 5% or less off systemic therapy. 
 
In light of the potential intangible benefits of a “chemotherapy holiday,” the 5% null hypothesis establishes a 
conservative lower threshold by which the therapy should be abandoned from further study. In other words, 
should this strategy confer a 25% non-CNS disease control rate, a rate which is comparable to the expected 
benefits of chemotherapy in this setting, and also permit a “chemotherapy holiday,” then the strategy would 
warrant further study. 
 
14.2.1.3 Efficacy Cohort Continuous Safety Assessment 
In the tremelimumab efficacy arm, stopping rules (based on a repeated significance testing method) will be 
employed to continuously assess safety. (Ivanova, Qaqish et al. 2005) These criteria were based on 
assumptions that a toxicity rate of 50% is deemed unacceptable, and a rate of 20% is deemed acceptable. 
The boundaries to stop the study are given as follows: 
 
• 
If 3 of the first 5 patients have a SAE attributable to the experimental intervention, stop the 
study. 
• 
If 5 of the first 10 patients have a SAE attributable to the experimental intervention, stop the 
study. 
• 
If 6 of the first 17 patients have a SAE attributable to the experimental intervention, stop the 
study. 
With these parameters, there is a 0.94 probability of crossing the boundary if the true toxicity rate is .50, and 
there is a 0.14 probability of .14 probability of crossing the boundary if the true toxicity rate is .20.” 
14.1.2 HER2 directed therapy Co-administration Safety cohort 
In the HER2 directed therapy co-administration cohort, the safety of HER2 directed therapy and 
tremelimumab co-administration will be evaluated in a minimum of 3 subjects. The sample sizes and dose 
expansion algorithm is based upon a classical 3+3 dose escalation design, whereby the recommended dose is 
the dose at which treatment-limiting toxicity occurs in ≤1/6 subjects within the first 6 weeks of therapy. 
 
If the combination of HER2 directed therapy + tremelimumab + RT is deemed tolerable, a dose expansion 
cohort will be considered, to further evaluate overall safety and toxicity profile of the combination.  This 
cohort will accrue following a protocol amendment. Similarly, if time permits and the treatment is deemed 
too toxic, a dose de-escalation cohort may be considered under a separately filed protocol amendment. 
 
This cohort is not statistically  powered to evaluate for preliminary efficacy of the combination of 
tremelimumab + HER2 directed therapy + RT, however if data permit, we will conduct preliminary analyses to 
evaluate for differential clinical activity across the two cohorts. 


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In the event that accrual of the efficacy arm completes prior to completion of the HER2 directed therapy 
safety arm, the primary endpoint may be reported independently of the secondary and exploratory 
endpoints. 
 
14.1.3 The HER2+ Protocol Expansion 
 
As of 3/1/17, the 12 week disease control rate was 2/20 (10%) in the efficacy arm and 2/6 (33%) in the safety 
arm. One patient treated with concurrent HER2-directed therapy had a 57% partial response by RECIST v1.1 
that was durable at 6 months. Overall, the regimen was well tolerated with 15 grade 3 and no  grade 4 
attributable toxicity events reported. The most common treatment related AEs  were  diarrhea  (12.9%), 
fatigue (9.7%), and colitis (6.5%). Thus, an expansion of the HER2 arm is planned in a parallel Simon two- 
stage design to evaluate efficacy of brain RT with checkpoint blockade and  concurrent  HER2-directed 
therapy. In this expansion, we will evaluate the combination of tremelimumab (treme), durvalumab (durva), 
and HER2 directed therapy plus brain irradiation in breast cancer patients with brain me tastases (BCBM) for 
whom post-brain irradiation cytotoxic chemotherapy is planned. Subjects will receive either whole brain 
radiation treatment (WBRT) or stereotactic radiosurgery (SRS), as per standard of care, with tremelimumab 
administered at 75 mg and durvalumab administered at 1500 mg every 28 days for 4 cycles. After the 4th 
cycle, patients will continue to receive 1500 mg durvalumab every 28 days until disease progression or 
unacceptable toxicity. Patients will continue to receive HER2 directed therapy at a NCCN-guideline-endorsed 
dose and schedule, as determined by the investigator.    Study design parameters and safety rules are similar 
to those that were used to the previously enrolled study subjects who did not require concurrent HER2 
directed therapy. 
 
 
 
14.2 
Subjects for analysis 
 
• 
All Enrolled Subjects: All subjects who signed an informed consent form and were registered into the 
IVRS. 
• 
All Treated Subjects: All subjects who received at least one dose of any study medication. 
• 
Biomarker Subjects: All assigned subjects with available biomarker data. 
 
14.3 
Definitions of endpoints 
 
14.3.1 Primary endpoint 
The primary endpoint  will be assessed by RECIST1.1 criteria as described in section 12.1. The  non-CNS 
disease control rate (CR+PR+SD) at 12 weeks will be calculated with a 95% confidence interval. Subjects who 
clinically progress or die prior to the 12 week assessment will be included in the analysis as failures. 
14.3.2 Secondary endpoints 
 
14.3.2.1 Immune-related respons e 
Objective response (CR + PR), disease control (CR + PR + SD), non-CNS objective response, and non-CNS 
disease control rates will be evaluated at 12 weeks utilizing the immune-related response criteria. (Wolchok, 


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Hoos et al. 2009) The irRC calls for confirmation of radiographic progression with a repeat scan 4 weeks after 
initial scan, and allows for the presence of new lesions when evaluating for possible response. These rates 
will be calculated with a 95% confidence interval. 
 
Immune-related progression free survival (irPFS) will be defined as the time from the first dose of 
tremelimumab until death or progressive disease, as measured by irRC. Non-CNS irPFS will also be measured. 
PFS endpoints will be evaluated using Kaplan-Meier methods, and if necessary, using a cumulative risk 
approach that adjusts for competing risks. 
 
14.3.2.2 Other response parameters using RECIST1.1 
In addition to the primary endpoint, RECIST1.1 will be used to assess the above listed response parameters 
(see section 14.3.2.1). 
 
14.3.2.3 CNS respons e 
CNS-only responses will be assessed using the RANO criteria as detailed in section 12.2.2. 
 
14.3.2.4 Overall  Survival 
Overall survival is defined as the time from first dose of tremelimumab until death from any cause. This will 
be evaluated using Kaplan-Meier methods. 
 
14.3.2.5 Exploratory  Endpoints 
All exploratory endpoints will be analyzed descriptively and graphically. Any statistical test will be performed 
using nonparametric methods and interpreted with caution. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain  informed  consent,  by  following  procedures  defined  in  section  entitled  Informed  Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
 
 
The individual signing the Eligibility Checklist is confirm ing whether or not the participant 
is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been 
completed. See related Clinical Research Policy and  Procedure  #401  (Protoc ol 
Participant  Registration). 
 
 
15.2 
Randomization 
 
In this single-arm study, no randomization will take place. 


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16.0 
DATA MANAGEMENT ISSUES 
 
A MSKCC Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA include 
project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, problem 
resolution and prioritization, and coordination of the activities of the study team. 
 
The Clinical Research Database (CRDB) will be used for data collection. The data will be report to the MSKCC 
(IRB) and the drug manufacturer(MedImmune) as appropriate. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals, protocol compliance, eligibility 
verification, informed consent procedure, data accuracy, and completeness of registration data.  Routine 
data quality reports will be generated to assess missing data and inconsistencies.  Accrual rates and extent 
and accuracy of evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study team, at a 
minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were approved by 
the National Cancer Institute in September 2001.  The plans address the new policies set forth by the NCI in 
the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical 
Trials” which can be found at: http://www.cancer.gov/clinicaltrials/learningabout/patientsafety/dsm -  
guidelines/page1.  The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research.  The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Quality%20Assurance 
%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf   . 
There are several different mechanisms by which clinical trials are monitored for data, safety and quality. 
There are institutional processes in place for quality assurance (e.g., protocol monitoring, compliance and 
data verification audits, therapeutic response, and staff education on clinical research QA) and departmental 
procedures for quality control, plus there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs.  The committees: Data and Safety Monitoring 
Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for 
Phase III clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be reviewed with 
the participant, including a discussion of the possible toxicities and side effects. Every effort will be made to 
keep study records private. Neither the patient's name nor anything else that could identify the patient will 
be used in any reports or publications that result from this study. Trained staff at Memorial Hospital, the 
Food and Drug Administration, or the study supporters will be able to review the medical records if 
necessary. The patient may terminate her participation in the study at any time during the trial. 


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17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health information 
will be limited to the individuals described in the Research Authorization form. A Research Authorization 
form must be completed by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is any undesirable sign, symptom or medical condition occurring after starting study drug, 
even if the event is not considered  to  be related to  study drug. Information  about all adverse events, 
whether volunteered by the subject, discovered by investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected, recorded and followed  as  appropri ate. 
Medical conditions/diseases present before starting study treatment are only considered adverse events if 
they worsen after starting study treatment (any procedures specified in the protocol). Adverse events 
occurring before starting study treatment but after signing the informed consent form are recorded. Once an 
adverse event is detected, it should be followed until its resolution or until it is judged to be permanent. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, require changes in study medication(s), or require therapy, and are recorded. Laboratory 
abnormalities that meet the criteria for Adverse Events should be followed until they have returned  to 
normal or an adequate explanation of the abnormality is found. 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• 
Death 
• 
A Life threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial  disruption of the ability to conduct normal life 
functions 
• 
Is a congenital abnormality or birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or requi re 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
• 
Note: Hospital admission for a planned procedure/disease treatment is not considered a SAE 
 
 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with  any 
deterioration in condition, 
• treatment, which was elective  or pre-planned, for a pre-existing condition  that  did not 
worsen, 
• treatment  on  an  emergency,  outpatient  basis  for  an  event  not  fulfilling  any  of  the 
definitions of serious given above and not resulting in hospital admission. 


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Pregnancy, although not itself a serious adverse event, should also be reported on a serious adverse event 
form or pregnancy form and be followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects or congenital abnormalities. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 30-days after 
the participant’s last investigational treatment or intervention. Any events that occur after the 30-day period 
and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the 
SAE report must be sent to the IRB office within 5 calendar days of the event. The IRB requires a Clinical 
Research Database (CRDB) SAE report to be submitted electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other 
reports should be sent to saemskind@mskcc.org 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
o If the SAE is an Unanticipated problem. 
 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number written at the top 
of the report. If appropriate, the report will be forwarded to the FFA by the SAE staff through the IND Office. 


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17.2.1 Serious Adverse Event (SAE) Reporting responsibilities to AstraZeneca/MedImmune 
 
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 foll owing the time that written 
informed consent is obtained through 30 days after the last dose of study drug 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. 
 
The investigator and/or sponsor must inform the FDA, via CRDB SAE 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 CRDB SAE form must be emailed 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 according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to AstraZeneca at the same time. 
 
* A cover page should accompany the CRDB SAE 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 ISS reference number (ESR-##-#####) 
* 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 designated mailbox: 
AEMailboxClinicalTrialTCS@astrazeneca.com 
 
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. 
 
Reporting of deaths to AstraZeneca 
 
All deaths that occur during the study, or within the protocol-defined 30-day post-last dose of study drug 
safety follow-up period must be reported to AstraZeneca as follows: 
 
• 
Death that is clearly the result of disease  progression should be 
documented per institutional standards but should not be reported as a 
SAE to AstraZeneca. 


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• 
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to AstraZeneca as 
a SAE within 24 hours. 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. 
 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of the 
protocol and study procedures as well as the risks involved to participants prior to their inclusion in the 
study. Participants will also  be informed that they are free to withdraw from the study at any time. All 
participants must sign an IRB/PB-approved consent form indicating their consent to participate. This consent 
form meets the requirements of the Code of Federal Regulations and the Institutional Review Board/Privacy 
Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational therapies. 
In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The  right of the  participant  to accept or refuse study interventions/interactions  and  to withdraw 
from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain the 
aspects of patient privacy concerning research specific information. In addition to signing the IRB Informed 
Consent, all patients must agree to the Research Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must receive a copy 
of the signed informed consent form. 


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20.1 
APPENDICES 
 
20.2 Guidance on Contraception 
 
Females of childbearing potential 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner must use 
a highly effective method of contraception prior to the first dose of investigational product, and must 
agree to continue using such precautions for 180 days after the final dose of investigational product; 
cessation of contraception after this point should be discussed with a responsible physician. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. They must also refrain from egg cell donation for 180 days after the final dose of 
investigational product; 
• 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause); 
• 
A highly effective method of contraception is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in table 20.1; 
 
Males 
 
Non-sterilized males who are sexually active with a female partner of childbearing potential must use 
a highly effective method of contraception (see Table ) from Days 1 through 90 post last dose. In 
addition, they must refrain from sperm donation for 90 days after the final dose of investigational 
product; 
 
 
Table 20.1: Highly Effective Methods of Contraception 
Barrier Methods 
Hormonal Methods 
• 
Male condom with spermicide 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine 
system (e.g., Mirena
®) 
a
 
• 
Implants 
• 
Hormone shot or injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a This is also considered a hormonal method. 
 
20.1.1 Blood donation 
Patients should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab or tremelimumab. 


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20.2 
Management Algorithms 
 
These recommendations have been provided by MedImmune LLC and constitute guidance to the 
investigator and may be supplemented by discussions with MedImmune LLC representatives. The 
recommendations are not a representation of benefit/risk. A general principle is that differential 
diagnoses should be diligently evaluated according to the standard medical practice. 
 
Non-inflammatory etiologies should be explored and appropriately treated. Corticosteroids are a 
primary therapy for immune related events. The oral equivalent of the recommended IV doses may 
be considered for ambulatory patients with low grade toxicity and good oral tolerance. Lower 
bioavailability of oral corticosteroids should be taken into account when switching to the equivalent 
dose of PO corticosteroids. Consultation with a medical or surgical specialist, especially prior to an 
invasive diagnostic or therapeutic procedure, is recommended. 
 
 
 
 
 
 
20.3 Dose Modification and Toxicity Management Guidelines 
 
Table 20.3. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, 
and Non  Immune-mediated Reactions 
Grade (NCI 
CTCAE 
version 
Dose  Modifications 
Toxicity  Management 


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4.03) 
Pneumonitis/ILD: 
- 
Monitor patients for signs and symptoms of pneumonitis or ILD (new onset or worsening shortness of 
breath or cough).  Patients should be evaluated with imaging and pulmonary function tests including 
other diagnostic procedures as described below 
- 
Initial work-up may include clinical evaluation, monitoring of oxygenation via pulse oximetry (resting and 
exertion), laboratory work-up and high-resolution CT scan. 
Grade 1 
- No dose modification required. 
However, consider holding study 
drug/study regimen dosing as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies 
- 
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 consult 
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 
- 
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. 
- 
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 
methylprednisone at 2-4/mg/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 
- 
Once improving, gradually taper steroids over ≥4 
weeks and consider prophylactic antibiotics, antifungal 
or anti PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation)iii1 
- 
Consider pulmonary and infectious  disease consult 
- 
Consider, as necessary, discussing with study physician 
Grade 3 or 4 
- Permanently  discontinue study 
drug/study regimen 
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent 
- 
Obtain pulmonary and infectious  disease consult 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional workup 
should be considered and prompt treatment with 
additional  immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 weeks 
dose) started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab 
- 
Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and 
in particular,  anti PCP treatment (please refer to 
1  ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects” 


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current  NCCN guidelines for treatment of  cancer- 
related infections  (Category 2B recommendation)
iii
 
Diarrhea/ E nterocolitis: 
- 
Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and ileus) 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, other 
medications, infections ) including testing for clostridium difficile toxin, etc. 
- 
Steroids should be considered in the absence of clear alternative etiology, even for low grade events, in order 
to prevent potential progression to higher grade event 
- 
Use analgesics carefully; they can mask symptoms of perforation and peritonitis 
Grade 1 
No dose modification 
- 
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. 
Grade 2 
- 
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. 
- 
Study drug/study regimen can 
be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 5-7 
days have passed after 
completion of steroid taper 
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes  (e.g., 
American Dietetic Association colitis diet), and 
loperamide and/or  budesonide 
- 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent 
- 
If 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 weeks 2. Caution: Important to rule out 
bowel perforation and refer to infliximab label for 
general  guidance before using infliximab 
- 
Consult study physician if no resolution to ≤ Grade 1 in 
3-4 days 
- Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
Grade 3 or 4 
- Permanently  discontinue study 
drug/study regimen 
- 
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 
2  ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-038 A(7) 
Approval date: 29-Jun-2018 
Page 90 of 98 
 
 
 
 
 
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 
[Category 2B recommendation]) 
Hepatitis ( Elev ated LFTs) - Infl iximab shou ld not be used for m anagement of Immune Rel ated Hepatitis : 
- 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin 
- 
Evaluate for alternative etiologies  (e.g., viral  hepatitis, disease progression, concomitant medications) 
Grade 1 
- No    dose    modification.    If    it 
worsens, treat as Grade 2 event 
- Continue LFT monitoring per protocol 
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 
- 
If improves to ≤ Grade 1, 
resume study drug/study 
regimen after completion of 
steroid taper. 
- 
Regular and frequent checking of LFTs (e.g. every 1-2 
days) until elevations of these are improving or 
resolved. 
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with 
study physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly 
start prednisone 1-2mg/kg/day PO or IV equivalent. 
- 
If still no improvement within 3-5 days despite 1- 
2mg/kg/day PO of prednisone or IV equivalent, 
consider additional  workup and prompt treatment 
with IV methylprednisolone 2-4mg/kg/day. 
- 
If still no improvement within 3-5 days despite 2- 
4mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives  (mycophenolate mofetil)3   . 
Discuss with study physician if mycophenolate mofetil 
is not available.  Inflixim ab should NOT be used. 
- 
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 
[Category 2B recommendation]) 
Grade 3 
For elevations in transaminases ≤8 x 
ULN, or elevated bilirubin ≤5 x 
ULN: 
- Hold study drug/study regimen 
dose until resolution to ≤ Grade 
- 
Promptly initiate empiric IV methylprednisolone at 1 
to 4 mg/kg/day or equivalent 
- 
If still no improvement within 3-5 days despite 1 to 4 
mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive 
3  ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by Michael Postow 
MD 


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1 or baseline 
- Resume study drug/study 
regimen administration 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 elevations in 
transaminases > 8 × ULN or 
elevations in bilirubin > 5 × ULN, 
discontinuestudy  drug/study 
regimen 
- Permanently  discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT > 3x ULN + bilirubin 
> 2x ULN without initial findings 
of cholestasis (i.e. elevated 
alkaline P04) and in the absence 
of any alternative cause
iv
 
therapy (mycophenolate mofetil) Discuss with study 
physician if mycophenolate is not available. Inflixim ab 
should NOT be used. 
- 
Hepatology consult, abdominal  workup, and imaging 
as appropriate. 
- 
Once improving, gradually taper steroids  over ≥28 days 
and consider prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
Grade 4 
- Permanently  discontinue study 
drug/study regimen 
Nephritis or Renal Dys functi on (E levated Serum Creatinine) : 
- 
Consult with Nephrologist 
- 
Monitor for signs and symptoms that may be related to changes in renal function (e.g. routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.) 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression, 
infections  etc.) 
- 
Steroids should be considered in the absence of clear alternative etiology even for low grade events (Grade 2), 
in order to prevent potential progression to higher grade event 
Grade 1 
- No dose modification 
- 
Monitor serum creatinine weekly and any 
accompanying symptom 
- 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
- 
If it worsens, depending on the severity, treat as Grade 
2 or Grade 3 or 4 
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement,  diuretics, etc. 
Grade 2 
- 
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 
- 
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 


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completion of steroid taper. 
- 
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 
[Category 2B recommendation]). 
- 
When event returns to baseline, resume study 
drug/study regimen and routine serum creatinine 
monitoring per study protocol. 
Grade 3 or 4 
- Permanently  discontinue study 
drug/study regimen 
- 
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 
[Category 2B recommendation] 
Ras h  (excludin g  B ullou s  s kin  formation s):  **IF  THERE  IS  ANY  BULLOUS  FORMATION,  THE  STUDY  PHYSICIAN 
SHOULD BE CONTACTED AND STUDY DRUG DISCON TINUED** 
- Monitor for signs and symptoms of dermatitis (rash and pruritus) 
Grade 1 
- No dose modification 
- Consider symptomatic treatment including oral 
antipruritics  (e.g., diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea cream) 
Grade 2 
- 
For persistent (> 1- 2 weeks) 
Grade 2 events, hold 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. 
- 
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, 
discuss with study physician and promptly start 
systemic steroids prednisone 1-2 mg/kg/day or IV 
equivalent 
- 
Consider skin biopsy if persistent for >1-2 weeks or 
recurs 
Grade 3 
- Hold study drug/study regimen 
until resolution to ≤ Grade 1 or 
- 
Consult  dermatology 
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 


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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 
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 
[Category 2B recommendation]) 
- 
Discuss with Study Physician 
Grade 4 
- Permanently  discontinue study 
drug/study regimen 
Endo crinop athy (e.g., hyperthyroidi sm, hy pothyroid ism, h ypopituit arism, adrenal insu ffi cien cy, etc.) : 
- 
Consult  Endocrinologist 
- 
Monitor patients for signs and symptoms of endocrinopathies.  Non-specific symptoms include headache, 
fatigue, behavior changes, changed mental status, vertigo, abdominal pain, unusual bowel habits, hypotension 
and weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease progression 
including brain metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: TSH, fr ee T3  and free T4 and other relevant endocrine labs 
depending on suspected endocrinopathy. 
- 
If a patient experiences an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, diabetes insipidus), the investigator should send a blood sample for appropriate 
autoimmune antibody testing 
Grade 1 
- No dose modification 
- 
Monitor patient with appropriate endocrine function 
tests 
- 
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  endocrinology consult. 
Grade 2 
- 
For Grade 2 endocrinopathy 
other than hypothyroidism, 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 judgment. 3) 
- 
Isolated hypothyroidism may be treated with 
replacement therapy without treatment interruption 
and without corticosteroids 
- 
Initiate hormone replacement as needed for 
management 
- 
Evaluate endocrine function, and as clinically 
indicated, consider pituitary scan 
- 
For patients with abnormal endocrine work up, except 
for those with isolated hypothyroidism, consider short- 
term, corticosteroids  (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (e.g. Levothyroxine, hydrocortisone, or 
sex hormones). 
- 
Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and 
anti PCP treatment (please refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 


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Doses of prednisone are at less 
than or equal to 10mg/day or 
equivalent. 
- For patients with normal endocrine work up (lab or 
MRI scans), repeat labs/MRI as clinically indicated. 
Grade 3 or 4 
- 
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism, 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. 
- 
Consult  endocrinologist 
- 
Isolated hypothyroidism may be treated with 
replacement therapy without treatment interruption 
and without corticosteroids 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent 
- 
Administer hormone replacement therapy as 
necessary. 
- 
For adrenal crisis, severe dehydration, hypotension, or 
shock: immediately initiate intravenous corticosteroids 
with mineralocorticoid activity 
- 
Once improving, gradually taper immunosuppressive 
steroids over ≥4 weeks and consider prophylactic 
antibiotics, antifungals and anti PCP treatment (please 
refer to current NCCN guidelines for treatment of 
cancer-related infections  [Category 2B 
recommendation]) 
- 
Discuss with study physician 
Neurotoxicity (to in clude but not lim ited to limbic en cepha litis  and autonomi c neuropathy , excludin g 
My asthenia Gravis and Guil lai n-B arre): 
- 
Patients  should  be  evaluated  to  rule  out  any  alternative  etiology  (e.g.,  disease  progression,  infections, 
metabolic syndromes  and medications, etc.) 
- 
Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. electromyogram and nerve conduction investigations) 
- 
Sympto matic treatment with neurological  consult as appropriate 
Grade 1 
- 
No dose modifications 
- See recommendations  above. 
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. 
- 
Discuss with the study physician 
- 
Obtain Neurology Consult 
- 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications  (e.g., 
gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids  prednisone 1- 
2mg/kg/day PO or IV equivalent 
- 
If no improvement within 3-5 days despite 1- 
2mg/kg/day prednisone PO or IV equivalent consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (e.g. IVIG) 
Grade 3 
- Hold Study drug/study regimen 
dose until resolution to ≤ Grade 
- Discuss with study physician 


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1 
- Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ Grade 
1 within 30 days. 
- 
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) 
- 
Once stable, gradually taper steroids over ≥4 weeks 
Grade 4 
- Permanently  discontinue study 
drug/study regimen 
Peripheral neuromotor syndromes, such as Gui llain-B arre and My astheni a Gravis: 
- 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. Sp ecial care should be taken for certain sentinel symptoms which may predict a more 
severe outcome, such as prominent dysphagia, rapidly progressive weakness, and signs of respiratory 
insufficiency or autonomic instability 
- 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, infections, 
metabolic syndromes and medications, etc.). It should be noted that the diagnosis of immune-mediated 
peripheral neuromotor syndromes can be particularly challenging in patients with underlying cancer, due to 
the multiple potential confounding effects of cancer (and its treatments) throughout the neuraxis. Given the 
importance of prompt and accurate diagnosis, it is essential to have a low threshold to obtain a neurological 
consult 
- 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction investigations, and 
“repetitive stimulation” if myasthenia is suspected) are routinely indicated upon suspicion of such conditions 
and may be best facilitated by means of a neurology consultation 
- 
Important to consider that the use of steroids as the primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be started with IVIG and followed by plasmapheresis 
if not responsive to IVIG 
Grade 1 
- No dose modification 
- 
Discuss with the study physician 
- 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above 
- 
Obtain a neurology consult unless the symptoms are 
very minor and stable 
Grade 2 
- 
Hold 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 
- 
Discuss with the study physician 
- 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above 
- 
Obtain a Neurology Consult 
- 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications  (e.g., 
gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
- 
Steroids may be successfully used to treat Myasthenia 
Gravis. Important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
- 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IVIG. Such 
decisions   are   best   made   in   consultation   with   a 


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neurologist,  taking  into  account the unique needs  of 
each patient. 
- 
If Myasthenia  Gravis-like  neurotoxicity  present, 
consider starting  acetylcholine  esterase  (ACh E) 
inhibitor therapy in addition to steroids. Such therapy, 
if successful, can also serve to reinforce the diagnosis. 
GUI LLAIN- BARRE : 
- 
Important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective. Patients  requiring treatment 
should be started with IVIG and followed by 
plasmapheresis if not responsive to IVIG. 
Grade 3 
- 
Hold study drug/study regimen 
dose until resolution to ≤ Grade 
1 
- 
Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ Grade 
1 within 30 days or if there are 
signs of respi ratory insufficiency 
or autonomic instability 
- 
Discuss with study physician 
- 
Recommend  hospitalization 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
- 
Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
- 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IVIG. 
- 
If Myasthenia  Gravis-like neurotoxicity present, 
consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids. Such therapy, 
if successful, can also serve to reinforce the diagnosis. 
GUI LLAIN- BARRE : 
- 
Important to consider here that the use of steroids as 
the primary treatment of Guillain-Barre is not typically 
considered effective. Patients  requiring treatment 
should be started with IVIG and followed by 
plasmapheresis if not responsive to IVIG 
Grade 4 
- Permanently  discontinue study 
drug/study regimen 
 
 
 
 
 
 
i  ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow 
MD 
ii  NCI CTCAE version 4.03 
iii  ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow 
MD 
iv FDA Liver Gu idance Document 2009 Gu idance for Industry: Drug Induced Liver In jury – Premarketing Clinical 
Evaluation 
 
 
20.3.1 Infusion Related Reactions 
 
 
Table 20.3.1 Dosing Modification and Management Guidelines for Infusion Related Reactions 


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Grade (NCI 
CTCAE 
version 
4.03) 
Dose  Modifications 
Toxicity  Management 
General Gu idelines: 
- 
Manage 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, or skin 
rashes) and anaphylaxis  (e.g., generalized urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 
The infusion rate of study drug/study 
regimen may be  decreased  by  50% 
or 
temporarily 
interrupted 
until 
resolution of the event. 
− Aceta minophen 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. 
− Aceta minophen 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 3 or 4 
Permanently  discontinue study 
drug/study  regimen. 
Manage severe infusion-related reactions  per 
institutional  standards  (e.g., IM epinephrine, followed 
by IV diphenhydramine and ranitidine, and IV 
glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM Intramuscular; IV Intravenous; NCI National Cancer Institute. 
 
20.3.2 Non-Immune Mediated Reactions 
 
Table 20.3.1 Dosing Modification and Management Guidelines for Non-Immune  Mediated Reactions 
Grade (NCI 
CTCAE 
version 
4.03) 
Dose  Modifications 
Toxicity  Management 
General Gu idelines: 
- Note: Dose modifications are not required for AEs 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. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 


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Grade 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. 
Grade 4 
Discontinue 
 
study 
 
drug/study 
regimen (Note: For Grade 4 labs, 
decision to discontinue should be 
based on accompanying  clinical 
signs/symptoms, 
the Investigator’s 
clinical judgment, and consultation 
with the Sponsor.). 
Treat accordingly, as per institutional standard. 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.