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Official Title: S1400F, "A Phase II Study of MEDI4736 (Durvalumab) Plus Tremelimumab as Therapy for Patients with Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell Lung Cancer (Lung-MAP Non-Match Sub-Study)"
NCT Number: 03373760 Version Date: 10/21/2019 Description:
S1400 [NCT 02154490] is the parent study to **S1400F** [NCT 03373760].  
The **S1400** Lung-MAP study is considered one study under one IND consisting of:
- S1400 Version Control Protocol
- S1400 Main Screening Protocol Component - Multiple Sub-Studies (or sub-protocols) Components Each component is contained in its own separate document.  
S1400F **is one of these components. Each "component" consists of the protocol**
document and its associated informed consent document(s). Since each screening and sub-study component operates independently from the other components contained in Lung-MAP, each has its own version date and NCT number. This is due to the complexity of the study and how it must be entered into different computer programs.  
S1400F: (Non-Match sub-study): Anti-PD-1/PD-L1 Resistant - MEDI4736 (Durvalumab) plus Tremelimumab TITLE
A BIOMARKER-DRIVEN MASTER PROTOCOL FOR PREVIOUSLY
TREATED SQUAMOUS CELL LUNG CANCER
A MASTER PROTOCOL TO EVALUATE BIOMARKER-DRIVEN THERAPIES AND
IMMUNOTHERAPIES IN PREVIOUSLY-TREATED NON-SMALL CELL LUNG CANCER
A PHASE II STUDY OF MEDI4736 (DURVALUMAB) PLUS TREMELIMUMAB AS THERAPY FOR
PATIENTS WITH PREVIOUSLY TREATED ANTI-PD-1/PD-L1 RESISTANT STAGE IV SQUAMOUS
CELL LUNG CANCER (LUNG-MAP NON-MATCH SUB-STUDY)
NCT \# 03373760 This is an FDA registration study. There will be additional centralized and on-site monitoring conducted in addition to routine audits. Sites must also maintain a study specific Trial Master File for this study.  
Lung-MAP **and its sub-studies are being conducted under SWOG IND 119672 and CIRB. The LungMAP Study is considered a single study under one IND, consisting of the Screening Protocol and**
multiple sub-studies. Each sub-study protocol operates independently and has its own version date. However, for regulatory purposes, all Lung-MAP sub-study protocols should be processed as a single study for Continuing Review.  
| SUB-STUDY CHAIRS:                                    | STUDY AGENTS:                                                                          |
|------------------------------------------------------|----------------------------------------------------------------------------------------|
| Natasha Leighl, BSc, MMSc, M.D.                      | Available from Pharmaceutical Collaborator:                                            |
| (Medical Oncology)                                   | SWOG Held IND:                                                                         |
| NCTN Group: CCTG                                     | MEDI4736 (Durvalumab) (NSC 778709)                                                     |
| Univ. Health Network-Princess Margaret Hospital      | (IND-119672)                                                                           |
| 610 University Avenue                                | Tremelimumab (NSC 744483) (IND-119672)                                                 |
| Toronto, Ontario, Canada M5G 2M9 Phone: 416/946-4645 | BIOSTATISTICIANS:                                                                      |
| FAX: 416/946-6546 E-mail: Natasha.leighl@uhn.ca      | Mary Redman, Ph.D. Katherine Minichiello, M.S.                                         |
| Naiyer Rizvi, M.D.                                   | Jieling Miao, M.S.                                                                     |
| (Medical Oncology)                                   | James Moon, M.S.                                                                       |
| NCTN Group: SWOG                                     | SWOG Statistics & Data Management Center                                               |
| Columbia University Medical Ctr                      | 1100 Fairview Ave N, M3-C102                                                           |
| Division of Hematology-Oncology                      | P.O. Box 19024                                                                         |
| 177 Fort Washington Ave, Ste 6GN435                  | Seattle, WA 98109-1024                                                                 |
| New York, NY 10032                                   | Phone: 206/667-4623                                                                    |
| Phone: 646/317-6344                                  | FAX: 206/667-4408                                                                      |
| FAX: 212/305-3035                                    | E-mail: mredman@fredhutch.org                                                          |
| E-mail: nar2144@cumc.columbia.edu                    | E-mail: kgriffin@fredhutch.org E-mail: jmiao@fredhutch.org E-mail: jmoon@fredhutch.org |  
Version Date 10/21/19
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table of contents

| TABLE OF CONTENTS                                                 |                                                                                                                                                  |
|-------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| TITLE                                                             | ..                                                                                                                                               |
| TABLE OF CONTENTS                                                 |                                                                                                                                                  |
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION |                                                                                                                                                  |
| SCHEMA                                                            |                                                                                                                                                  |
| OBJECTIVES .                                                      |                                                                                                                                                  |
| 1.0                                                               |                                                                                                                                                  |
| 1.1                                                               | Primary Objective                                                                                                                                |
| 1.2                                                               | Secondary and Exploratory Objectives .                                                                                                           |
| 1.3                                                               | Translational Medicine Objectives                                                                                                                |
| 2.0                                                               | BACKGROUND                                                                                                                                       |
| 3.0                                                               | DRUG INFORMATION .                                                                                                                               |
| 3.1                                                               | MEDI4736 (Durvalumab) - Liquid (NSC 778709) (IND-119672)                                                                                         |
| 3.2                                                               | Tremelimumab (NSC 744483) (IND 119672) .                                                                                                         |
| 3.3                                                               | DRUG ORDERING & ACCOUNTABILITY .                                                                                                                 |
| 4.0                                                               | STAGING CRITERIA                                                                                                                                 |
| 5.0                                                               | ELIGIBILITY CRITERIA .                                                                                                                           |
| SUB-STUDY SPECIFIC Disease Related Criteria                       |                                                                                                                                                  |
| 5.1                                                               |                                                                                                                                                  |
| 5.2                                                               | Sub-Study Specific Clinical/Laboratory Criteria                                                                                                  |
| Common Eligibility Criteria for all Sub-Studies                   |                                                                                                                                                  |
| 5.3                                                               |                                                                                                                                                  |
| 6.0                                                               | STRATIFICATION FACTORS                                                                                                                           |
| 7.0                                                               | TREATMENT PLAN .                                                                                                                                 |
| 7.1                                                               | Pre-Medication and Supportive Care                                                                                                               |
| 7.2                                                               | Treatment - MEDI4736 (Durvalumab) plus Tremelimumab                                                                                              |
| 7.3                                                               | Criteria for Removal from Protocol Treatment .                                                                                                   |
| 7.4                                                               | D Discontinuation of Treatment .                                                                                                                 |
| 7.5                                                               | Follow-Up Period                                                                                                                                 |
| 8.0                                                               | TOXICITIES TO BE MONITORED AND DOSE INTERRUPTIONS .........................................................31                                    |
| 8.1                                                               | NCI Common Terminology Criteria for Adverse Events .                                                                                             |
| 8.2                                                               | General Considerations .                                                                                                                         |
| 8.3                                                               | Dose Interruptions - MEDI4736 (Durvalumab) or in Combination with Tremelimumab                                                                   |
| 8.4                                                               | Dose Modification Contacts .                                                                                                                     |
| 8.5                                                               | Adverse Event Reporting                                                                                                                          |
| 9.0                                                               | STUDY CALENDAR                                                                                                                                   |
| MEDI4736 (Durvalumab) plus Tremelimumab                           |                                                                                                                                                  |
| 9.1                                                               |                                                                                                                                                  |
| 10.0                                                              |                                                                                                                                                  |
| 10.1                                                              | Measurability of Lesions                                                                                                                         |
| 10.2                                                              | Objective Status at Each Disease Evaluation                                                                                                      |
| 10.3                                                              | Best Response                                                                                                                                    |
| 10.4                                                              | Performance Status .                                                                                                                             |
| 10.5                                                              | Time to Death                                                                                                                                    |
| 10.6                                                              | irRC-Progression                                                                                                                                 |
| 10.7                                                              | Investigator-Assessed Progression-Free Survival ..............................................................................................60 |
| 10.8                                                              | Progression-Free Survival by Central Review                                                                                                      |
| 10.9                                                              | Duration of Response (DoR)                                                                                                                       |
| 10.10                                                             | irRC Investigator-Assessed Duration of Response (irRC-IA-DoR)........................................................61                          |
| 1.0                                                               | STATISTICAL CONSIDERATIONS .                                                                                                                     |
| 11.1                                                              | Primary Objective                                                                                                                                |
| 11.2                                                              | Secondary Objectives .                                                                                                                           |
| 1.3                                                               | Sample Size with Power Justification .                                                                                                           |
| 1.4                                                               | Analysis Plan                                                                                                                                    |
| 1.5                                                               | Accrual Information                                                                                                                              |
| 1.6                                                               | Data and Safety Monitoring Committee .                                                                                                           |
| 12.0                                                              | DISCIPLINE REVIEW                                                                                                                                |
| 13.0                                                              | REGISTRATION GUIDELINES                                                                                                                          |
| 13.1                                                              | Registration Timing                                                                                                                              |
| 14.0                                                              | DATA SUBMISSIÕN SCHEDULE .                                                                                                                       |
| 14.1                                                              | Data Submission Requirements .                                                                                                                   |  
Page 2  
| Appended 4/12/17             | S1400F                                                                                                                                                  |
|------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| Page 3                       |                                                                                                                                                         |
| Version Date 10/21/19        |                                                                                                                                                         |
| 14.2                         | Master Forms .                                                                                                                                          |
| DATA Submission Procedures . |                                                                                                                                                         |
| 14.3                         | Data Submission Overview and Timepoints .....................................................................................................65         |
| 14.4                         | SPECIAL INSTRUCTIONS                                                                                                                                    |
| 15.0                         | SWOG Specimen Tracking System (STS)                                                                                                                     |
| 15.1                         |                                                                                                                                                         |
| 15.2                         |                                                                                                                                                         |
| 15.3                         | PD-L1 IHC Testing                                                                                                                                       |
| 15.4                         | Specimen Flow Diagram                                                                                                                                   |
| 15.5                         | Radiology Review (Required)                                                                                                                             |
| 16.0                         | ETHICAL AND REGULATORY CONSIDERATIONS                                                                                                                   |
| 16.1                         | Adverse Event Reporting Requirements .                                                                                                                  |
| 17.0                         | BIBLIOGRAPHY                                                                                                                                            |
| 18.0                         | APPENDIX                                                                                                                                                |
| 18.1                         | Background of Adverse Events of Special Interest (AESIs) ...........................................................................80                  |
| 18.2                         | Biomarker Analysis of Immunotherapy Resistance ....................................................................................81                   |
| 18.3                         | PD-L1 IHC Testing                                                                                                                                       |
| 18.4                         | Instructions for the SWOG Biospecimen Bank ..........................................................................................................83 |  
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| For regulatory                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | For patient                                                                                                                                                                                                                           | For study data submission:                                                                                                                                                                                                                                                                                                                                          |
| requirements:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | enrollments:                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                     |
| Regulatory documentation  must be submitted to the  CTSU via the Regulatory  Submission Portal: (Sign in at www.ctsu.org,  and select the Regulatory  Submission sub-tab under  the Regulatory tab.)  Institutions with patients  waiting that are unable to  use the Portal should alert  the CTSU Regulatory Office  immediately at 866-651- 2878 to receive further  instruction and support. Contact the CTSU  Regulatory Help Desk at  866-651-2878 for regulatory  assistance.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Please refer to the patient  enrollment section of the  protocol for instructions on  using the Oncology Patient  Enrollment Network  (OPEN) which can be  accessed at  https://www.ctsu.org/OPEN _SYSTEM/ or  https://OPEN.ctsu.org. | Data collection for this study will be done  exclusively through Medidata Rave. Please  see the data submission section of the  protocol for further instructions.  Other Tools and Reports:  Institutions participating through the CTSU  continue to have access to other tools and  reports available on the SWOG Workbench via the SWOG website (www.swog.org). |
| Contact the CTSU Help  Desk with any OPENrelated questions at  ctsucontact@westat.com.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                     |
| The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific Web page of the CTSU Member Web site located at  https://www.ctsu.org. Access to the CTSU members' website is managed through the Cancer Therapy  and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires  user log on with CTEP-IAM username and password. Permission to view and download this protocol and  its supporting documents is restricted and is based on person and site roster assignment housed in the  CTSU RSS. For patient eligibility or data submission questions contact the SWOG Statistics and Data  Management Center by phone or email: 206/652-2267 LUNGMAPquestion@crab.org For treatment or toxicity related questions contact the S1400FMedicalQuery@swog.org.  For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data  submission) contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line: 1-888-823-5923 S1400contact@westat.com All calls and correspondence will be triaged to the appropriate CTSU representative. The CTSU Web site is located at https://www.ctsu.org |                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                     |
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schema screening/pre-screening registrationa

Common Broad Platform CLIA Biomarker Profiling b If NOT eligible for biomarker driven sub-studies, Pure Squamous AND have progressed on or after an **anti-PD-1/PD-L1** c Cohort 1 (acquired resistance) Cohort 2 (primary resistance)
MEDI4736 (Durvalumab) plus Tremelimumab MEDI4736 (Durvalumab) plus Tremelimumab a Patients may have screened/pre-screened on S1400 or **LUNGMAP**
NOTE: At the time of **LUNGMAP** activation, **S1400** screening will close to accrual. Please see the Lung-MAP protocol training webpage for additional information (https://www.swog.org/requiredlung-map-s1400-training).  
b Archival formalin-fixed paraffin-embedded (FFPE) tumor, fresh core needle biopsy if needed c Notification of sub-study assignment will be provided by the SWOG Statistics and Data Management Center (see Section 11.0 in S1400 or LUNGMAP for details).
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WKHUDSHXWLFRSSRUWXQLWLHVIRUWKHEURDGHUSRSXODWLRQRIVTXDPRXVFDUFLQRPDSDWLHQWVQRWHOLJLEOH for biomarker-driven studies through non-match sub-studies, to date focusing on immune checkpoint inhibitors.  
After **S1400** was developed and began accrual, the standard of care for platinum-treated advanced lung cancer patients with squamous carcinoma evolved from docetaxel chemotherapy to PD-1 checkpoint inhibitor therapy. Several Phase III randomized trials have demonstrated improved survival, progression-free survival, response and even quality of life with the use of PD-1 checkpoint inhibitors compared to docetaxel in advanced pre-treated non-small cell lung cancer. Nivolumab improved survival (HR 0.59, 95% CI 0.44-0.79, p<0.001; median 9.2 versus 6.0 months), PFS (HR
0.62, 95% CI 0.47 - 0.81, p<0.001, median 3.5 versus 2.8 months) and, response (20% versus 9%, p=0.008) and quality of life compared to docetaxel in patients with advanced squamous carcinoma. *(1)* Longer duration of response (median not reached versus 8 months with chemotherapy) and significantly fewer Grade 3 or 4 treatment-related AEs (7 versus 55%) were also seen in the nivolumab arm. (2) Nivolumab has also been approved for use in non-squamous lung cancer based on a similar trial demonstrating improved survival, response rate and less toxicity compared to docetaxel. (3) Pembrolizumab, another PD-1 checkpoint inhibitor, also demonstrated significantly better survival, PFS and response compared to docetaxel in pretreated non-small cell lung cancer patients with PD-L1 tumor expression (including 21% squamous carcinoma patients). (4) Despite the progress of immune checkpoint inhibition in this population, a significant number of patients will not derive long-term benefit from second-line therapy with single agent PD-1 or PD-L1 inhibitors. For this group, the next step in therapy is undefined. Many will receive docetaxel as subsequent therapy, with significant treatment-associated toxicity, response rate in the range of 10% and median survival time of 6 months or less. Better options are needed for this newly emerging population, and whether this group has the potential to benefit from further immune targeted therapy is unknown.  
Both PD-1 and CTLA-4 checkpoint inhibitors have demonstrated clinical activity across a range of tumor types, including melanoma, prostate cancer and lung cancer, both small cell and non-small cell subtypes. While both CTLA-4 and PD-1 checkpoint receptors are negative regulators of T cell activation and function, they use distinct mechanisms to block T cell activity. CTLA-4 inhibition impairs T-cell activation, while PD-1 inhibition results in T cell effector dysfunction. Blockade of one T-cell checkpoint may lead to reliance on other immune mechanisms, potentially making cells more sensitive to alternate checkpoint inhibitors. Preclinical studies suggest synergistic anti-cancer activity between PD-1 and CTLA-4 receptor inhibitors.  
In a relevant mouse model of melanoma, single blockade of either CTLA-4 or PD-1 enhanced the infiltration of activated T-cells into tumors, but the T-cells accumulated high levels of unblocked negative co-receptors that eventually limited their expansion. Blocking CTLA-4, PD-1 and PD-L1 simultaneously allowed T-cells to continue to survive and proliferate, and resulted in enhanced infiltration, activation and cytokine production, thereby reducing tumor-induced immune suppression and promoting tumor rejection. *(5)* In a study by Curran et al, vaccination with irradiated B16 melanoma cells expressing the Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell co-stimulatory receptor CTLA-4 promoted rejection of pre-implanted tumors.  
However, despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of PD-1 with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B71. The study showed that the combination of CTLA-4 and PD-1 blockade was more than twice as effective as either agent alone in promoting the rejection of B16 melanomas in conjunction with Fvax. *(6)* In clinical studies, combination of PD-1 and CTLA-4 inhibitors has led to exciting response data although greater toxicity. Larkin *et al* compared combination nivolumab/ipilimumab with either agent alone (1:1:1 randomization) as first-line therapy in advanced melanoma. Those receiving combination therapy had the longest PFS (median 11.5 v. 2.9 months with ipilimumab, HR 0.42, 99.5% CI 0.31-0.47, p<0.001; 6.9 months with nivolumab), as well as the highest response rate
(57.6%). Patients with PD-L1- expressing tumors had similar PFS with either nivolumab or combination therapy (14.0 months median), although combination therapy yielded a higher response rate (72.1%, 57.5% nivolumab, 21.3% ipilimumab). However in the group with PD-L1 negative tumors, the combination yielded the best PFS (median 11.2 v. 5.3 months in the nivolumab arm), and response rate (54.8%, 41.3% nivolumab, 17.8% ipilimumab). Treatment-related Grade 3 or 4 AEs occurred more commonly in the combination arm (55%) compared to nivolumab alone (16.3%) or ipilimumab (27.3%). The most common severe events in the combination arm were diarrhea (44%), fatigue (35%) and pruritus (33%). Investigators deemed the safety profile of the combination greater than either single agent but still manageable. *(7)*
A recent report from a Phase I/II study of nivolumab plus ipilimumab in small cell lung cancer suggests higher response rates with combination therapy, 32.6% versus 18% with nivolumab alone. (8) Other reports of significant activity with combination therapy have also emerged from early phase trials in NSCLC, including a Phase I combination study of tremelimumab with MEDI4736 (Durvalumab) (PD-L1 inhibitor), demonstrating a 33% response rate in those with PDL1 expressing tumors and a 27% response rate in those with PD-L1 negative tumors. *(9)*
Based on these data, a trial examining whether the addition of CTLA-4 blockade to PD-L1 blockade would improve outcome in the growing population of advanced squamous patients that progress on second-line PD-1 checkpoint inhibitor therapy would be appropriate. MEDI4736 (Durvalumab)
is a human IgG1 monoclonal antibody that inhibits PD-L1 binding without induction of antibodydependent cellular nor complement-dependent cytotoxicity, has shown clinical activity and safety across a range of solid tumors, including NSCLC. Tremelimumab, an IgG2 monoclonal antibody targeting CTLA-4 (CD152), has also shown activity across solid tumors including mesothelioma with manageable toxicity. A Phase I combination study of these two agents, both being developed by AstraZeneca, has been completed demonstrating efficacy and manageable toxicity at the recommended Phase III dose. (10)
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clinical summary

Study D4190C00006, a Phase Ib dose-escalation and dose-expansion study of MEDI4736  
 (Durvalumab) in combination with tremelimumab in patients with advanced NSCLC, included patients with ECOG performance status of 0-1, and no more than three prior lines of metastic therapy. Two dosing schedules were evaluated using Q4W and alternative Q2W dosing. As of 6/1/15, a total of 102 patients have been treated in the study across 5 US centers with a median follow-up of 18.8 weeks (range 2-68). Dosing cohorts are detailed below:  
| D10−20 q4/2w + T1                                                                                                                                          | D10-20 q4/2w + T3   | D15 q4w + T10   | Al cohort   |          |         |          |          |        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|-----------------|-------------|----------|---------|----------|----------|--------|
| Event, n (%)                                                                                                                                               | (n=56)              | (n=34)          | (N=102)     |          |         |          |          |        |
| 41 (73)                                                                                                                                                    | 32 (94)             | B (89)          | 82 (80)     |          |         |          |          |        |
| Related Grade 3/4 AE                                                                                                                                       | 17 (30)             | 19 (56)         | 7 (78)      | 43 (42)  |         |          |          |        |
| Related death'                                                                                                                                             | 2 (4)               | 1 (3)           | 3 (3)       |          |         |          |          |        |
| Related SAE                                                                                                                                                | 12 (21)             | 18 (53)         | 7 (78)      | 37 (36)  |         |          |          |        |
| Related AE leading to disc                                                                                                                                 | 9 (16)              | 15 (44)         | 5 (56)      | 29 (28)  |         |          |          |        |
| Any grade                                                                                                                                                  | 2Grade 3            | Any grade       | 2Grade 3    | Any grad | :Grade  | Ay grade | 2Grade 3 |        |
| Diarrhe                                                                                                                                                    | 13 (23)             | 4 (7)           | 16 (47)     | 6 (18)   | 4 (44)  | 1 (11)   | 3 (32)   | 1 (11) |
| Colitis                                                                                                                                                    | 2 (4)               | 1 (2)           | 8 (24)      | 6 (18)   | 2 (22)  | 2 (22)   | 12 (12)  | 9 (9)  |
| Enteritis                                                                                                                                                  | 1 (2)               | 1 (2)           | 0           | 1 (1)    | 1 (1)   |          |          |        |
| 0                                                                                                                                                          | 0                   |                 |             |          |         |          |          |        |
| Pruritus                                                                                                                                                   | 1 (20)              | 0               | 7 (21)      | 0        | 3 (33)  | o        | 21 (21)  | 0      |
| Rash                                                                                                                                                       | 6 (11)              | 0               | 7 (21)      | 0        | 2 (22)  | o        | 15 (15)  | 0      |
| Hypothyroidism                                                                                                                                             | 5 (9)               | 1 (2)           | 4 (12)      | 0        | 1 (11)  | 0        | 10 (10)  | 1 (1)  |
| Pneumonitis                                                                                                                                                | 0                   | 0               | 3 (9)       | 2 (6)    | 2 (22)  | 2 (22)   | 5 (5)    | 4 (4)  |
| Amylase increased                                                                                                                                          | 9 (16)              | 1 (2)           | 5 (15)      | 2 (6)    | 2 (22)  | 0        | 17 (17)  | 3 (3)  |
| Lipase increased                                                                                                                                           | 7 (13)              | 5 (9)           | 4 (12)      | 2 (6)    | 1 (11)  | 1 (11)   | 12 (12)  | 8 (8)  |
| AT increased                                                                                                                                               | 6 (11)              | 2 (4)           | 4 (12)      | 1 (3)    | 10 (10) | 3 (3)    |          |        |
| AT increased                                                                                                                                               | 4 (7)               | 3 (5)           | 3 (9)       | 1 (3)    | 7 (7)   | 4 (4)    |          |        |
| Data cut-off: June 1, 2015. "Excludes D3 q4w T1 cohort (n=3).                                                                                              |                     |                 |             |          |         |          |          |        |
| ↑ These patients also had Grade 3/4 AEs. Deaths: D10/T1 = polymyositis, D20/T1 = pericardial effusion, D20/T3 = neuromuscular disorder                     |                     |                 |             |          |         |          |          |        |
| AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; D, durvalumab; q#w, every # weeks; SAE, serious adverse event; T, tremelimumab. |                     |                 |             |          |         |          |          |        |  
As of 6/1/15, adverse events deemed related to protocol therapy led to treatment discontinuation in 28% of patients (29/102). Three treatment-related deaths occurred, include a case of polymositis
(D10/T1), pericardial effusion (D20/T1) and myasthenia gravis/neuromuscular disorder (D20/T3).  
Adverse events were considered related to treatment in 82 patients (80%) and are presented in the table below. The majority of these events were <Grade 3 with Grade ≥3 events reported in 43 patients (42%).  (11) Grade 1 and 2 AEs have been managed clinically without requiring dose modifications or delays. Grade 3 treatment-related AEs have been manageable and reversible with standard toxicity management guidelines, including steroids, with the exception of Patient 200062006 who experienced myasthenia gravis and polymyositis.  
As of 2/20/15, MEDI4736 (Durvalumab) PK (n = 55) and tremelimumab PK (n = 26) data were available from 10 cohorts following MEDI4736 (Durvalumab) every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W regimens. An approximately dose-proportional increase in PK exposure (C max and area under the concentration-time curve from 0 to 28 days [AUC 0-28 ]) of both MEDI4736 (Durvalumab) and tremelimumab was observed. While steady state PK parameters were based on a limited number of patients, the observed PK exposures of MEDI4736
(Durvalumab) and tremelimumab in combination were consistent with monotherapy data of each agent, indicating no PK interaction.  
As of 2/20/15, ADA data were available from 60 patients for MEDI4736 (Durvalumab) and 53 patients for tremelimumab in Study D4190C0006. Four of 60 patients were ADA positive for anti-MEDI4736 (Durvalumab) antibodies and 1 of 53 for anti-tremelimumab antibodies post treatment. There was no clear relationship between ADA and safety, efficacy nor dose of either agent. Efficacy updates are available from the 2015 Annual Meeting of the Society for Immunotherapy of Cancer (data cut-off 6/1/15). (12) Of 84 response evaluable patients, 21 (25%) had confirmed or unconfirmed response to therapy. In those with PD-L1 expression in ≥ 25% of cells, responses were seen in 35% (7/20). In those with PD-L1 expression in 1-24% of cells, responses were seen in 22% and in those with PD-L1 negative tumors, responses were seen in 33% (9/27). Median time to response was 7.1 weeks (range 5.0 -37.4), with a median duration of 16.7 weeks (0.1-49.1). At data cut-off on 6/1/15, responses were ongoing in 14 of 21 patients (66%).  
Page 9 The dose recommended for Phase III was MEDI4736 (Durvalumab) 20 mg/kg q4weeks plus tremelimumab 1 mg/kg q4weeks, based on aggregate safety, PK, PD and efficacy data. No doselimiting toxicities were reported. Efficacy data suggested that the 20 mg/kg MEDI4736
(Durvalumab) + 1 mg/kg tremelimumab dose cohort may demonstrate equivalent clinical activity to other dose combinations. The response rate in all patients treated with tremelimumab 1 mg/kg was 28% (11/39), similar to the 25% overall response rate across doses. In those with ≥ 25% PD-L1+
tumors, responses were seen in 3/9 (33%), 1-24% PD-L1 positive tumors, the response rate was 26% (6/23) and in those with PD-L1 negative tumors, half experienced tumor response (6/12).  
Fixed dosing for MEDI4736 (Durvalumab) and tremelimumab has been recommended by AstraZeneca for patients with >30 kg body weight. This is based on population PK models for each agent indicating similar steady stage PK concentrations with less inter-subject variability with fixed dosing regimens. Based on an average body weight of 75 kg, the fixed dose of MEDI4736
(Durvalumab) 1500 mg q4weeks is recommended (equivalent to 20 mg/kg q4weeks). Similarly, 75 mg q4weeks of tremelimumab (equivalent to 1 mg/kg q4 weeks) is recommended. Four cycles of combination MEDI4736 (Durvalumab)/tremelimumab are proposed, followed by MEDI4736 (Durvalumab) monotherapy until disease progression. This is based on melanoma data suggesting that patients responding to CTLA-4 inhibitor ipilimumab appear to derive long-term benefit with 22% of patients alive at 3 years. Other PD-1 targeting agents have been developed with protocol-mandated drug discontinuation after a specified treatment period. Despite stopping drug, ongoing prolonged responses have been described across multiple studies of multiple PD1/PD-L1 inhibitors, including combination nivolumab and ipilimumab. (13)
Sub-study **S1400I** tests whether combination CTLA-4 and PD-1 checkpoint inhibition will improve outcomes compared to PD-1 checkpoint inhibition alone in unmatched squamous patients as second-line therapy. By contrast, in the current sub-study **S1400F**, we hypothesize that a subgroup of patients that do not respond to single PD-1 checkpoint inhibition may benefit from combination checkpoint blockade, specifically the addition of a CTLA-4 inhibitor to ongoing PD-1 inhibitor therapy. Given the growing population of patients that will develop cancer progression during PD1 checkpoint blockade monotherapy, the proposed study design of adding CTLA-4 inhibition in this population to ongoing PD-1 inhibition is novel and appropriate. As outlined in Section 3.1, the combination of MEDI4736 (Durvalumab) and tremelimumab has shown activity and manageable toxicity, and is worthy of further study in this setting. It will also offer an opportunity to explore potential markers of benefit and/or toxicity.
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hiv hbv and hcv exclusion

Patients with known HIV/HBV/HCV infection will be excluded from this study. Immune checkpoint inhibition is a relatively new class of therapy. While HIV patients have been studied with anti-CTLA4 therapy, the unique interactions of PD-1/PD-L1 inhibitors and HIV may be difficult to predict and require further study. Since many of these patients may already be highly suppressed with antiretroviral therapy, standard assays may not be sensitive enough to detect a safety signal of increasing viral load. Thus, these patients may need to be studied in trials with access to such sensitive assays to better inform drug development in this particular population. The impact of PD1/PD-L1 inhibition in HIV patients may be beneficial, which is of great interest in drug development in the field of chronic infections generally. We have elected not to complicate our trial with this added and important question at this time.
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Version 2.4, April 17, 20191  
| Adverse Events with Possible                                                                           |                                                                                                                                        |          |
|--------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------|
| Relationship to MEDI4736 (durvalumab) (CTCAE 5.0 Term) [n= 2833]                                       |                                                                                                                                        |          |
| Likely (>20%)                                                                                          | Less Likely                                                                                                                            | Rare but |
| (<=20%)                                                                                                | Serious (<3%)                                                                                                                          |          |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS                                                                   | Blood and  lymphatic system  disorders - Other  (idiopathic  thrombocytopenic  purpura)2 Thrombotic  thrombocytopenic  purpura2        |          |
| CARDIAC DISORDERS                                                                                      | Myocarditis2 Pericarditis2                                                                                                             |          |
| ENDOCRINE DISORDERS                                                                                    | Adrenal  insufficiency2 Endocrine  disorders - Other  (diabetes  insipidus) Endocrine  disorders - Other  (diabetes mellitus  type 1)2 |          |
| Hyperthyroidism2                                                                                       | Hypopituitarism2                                                                                                                       |          |
| Hypothyroidism2                                                                                        |                                                                                                                                        |          |
| EYE DISORDERS                                                                                          | Keratitis2 Uveitis2                                                                                                                    |          |
| GASTROINTESTINAL DISORDERS Abdominal pain                                                              | Colitis2                                                                                                                               |          |
| Diarrhea                                                                                               | Gastrointestinal  disorders -Other -  (gastrointestinal  perforation)2,3                                                               |          |
| Nausea                                                                                                 | Pancreatitis2                                                                                                                          |          |
| Vomiting                                                                                               |                                                                                                                                        |          |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue Fever HEPATOBILIARY DISORDERS |                                                                                                                                        |          |  
| Adverse Events with Possible                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                     |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|----------|
| Relationship to MEDI4736 (durvalumab) (CTCAE 5.0 Term) [n= 2833]                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                     |          |
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Less Likely                                                                                                         | Rare but |
| (<=20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Serious (<3%) Hepatobiliary  disorders - Other  (autoimmune  hepatitis)2                                            |          |
| IMMUNE SYSTEM DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Immune system  disorders - Other  (immune related  adverse events)2 Immune system  disorders - Other  (sarcoidosis) |          |
| INFECTIONS AND INFESTATIONS Infection4 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related  reaction INVESTIGATIONS Alanine  aminotransferase  increased2 Aspartate  aminotransferase  increased2 Creatinine  increased METABOLISM AND NUTRITION DISORDERS Anorexia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthritis2 Musculoskeletal  and connective  tissue disorder -  Other  (polymyositis)2 Myalgia Myositis2 NERVOUS SYSTEM DISORDERS Guillain-Barre  syndrome2,5 Myasthenia  gravis2 Nervous system  disorders - Other  (aseptic  meningitis)2 Peripheral sensory  neuropathy RENAL AND URINARY DISORDERS |                                                                                                                     |          |  
  
| Relationship to MEDI4736 (durvalumab) (CTCAE 5.0 Term) [n= 2833]                                                                                                                                                                                                                                                                                                                                                                                          |                                                                |          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|----------|
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                                                                                             | Less Likely                                                    | Rare but |
| (<=20%)                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Serious (<3%)                                                  |          |
| Dysuria                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Renal and urinary  disorders - Other  (autoimmune  nephritis)2 |          |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Dyspnea Pneumonitis2 Respiratory,  thoracic and  mediastinal  disorders - Other  (dysphonia) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Hyperhidrosis Pruritus Rash2,6 Skin and  subcutaneous  tissue disorders -  Other  (scleroderma) Skin and  subcutaneous  tissue disorders -  Other (severe  dermatitis)2,7 Skin  hypopigmentation NOTE: Cardiomyopathy, and graft versus host disease, while not |                                                                |          |  
NOTE: Cardiomyopathy, and graft versus host disease, while not observed on clinical trials of MEDI4736 (durvalumab) at this time, are known events with this class of agent (PD-L1 antagonist).  
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2 Immune-mediated adverse reactions (irAEs) have been reported in patients receiving MEDI4736 (durvalumab). irAEs can involve any of the organs or systems in the body. Most irAEs were reversible and managed with interruptions of MEDI4736 (durvalumab), administration of corticosteroids and supportive care, however, these events can be serious and fatal.  
3 Gastrointestinal perforations have been observed only in patients receiving MEDI4736 (durvalumab) in combination with tremelimumab (CP-675,206).  
4 Infections includes infection in the lungs, upper respiratory tract, dental and oral soft tissues and other organs under the INFECTIONS AND INFESTATIONS SOC. Infections generally are mild (Gr 1-2) but severe infections including sepsis, necrotizing fasciitis, and osteomyelitis have been reported.  
5 Guillain-Barre Syndrome has been reported in patients receiving MEDI4736 (durvalumab) in combination with tremelimumab (CP675,206) but can potentially occur after durvalumab monotherapy.
6Rash includes the terms: rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, and eczema.  
7 In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson syndrome, toxic epidermal necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or hemorrhagic manifectations.  
Adverse events reported on MEDI4736 (durvalumab) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that MEDI4736 (durvalumab) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders
- Other (coronary artery disease); Pericardial effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right ventricular dysfunction; Sinus tachycardia EAR AND LABYRINTH DISORDERS - Hearing impaired EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body)
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental caries; Gastrointestinal disorders - Other (gastrointestinal hemorrhage);
Mucositis oral; Proctitis; Small intestinal obstruction; Upper gastrointestinal hemorrhage GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Edema trunk; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Hepatic hemorrhage IMMUNE SYSTEM DISORDERS - Immune system disorders - Other
(drug-induced liver injury); Serum sickness INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound complication INVESTIGATIONS - Blood bilirubin increased; CPK increased; Electrocardiogram T wave abnormal; GGT increased; Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Serum amylase increased; Weight loss; White blood cell decreased 0(7$%2/,60 $1' 1875,7,21 ',625'(56  'HK\GUDWLRQ +\SHUFDOFHPLD +\SHUJO\FHPLD +\SHUNDOHPLD +\SHUPDJQHVHPLD +\SRDOEXPLQHPLD+\SRNDOHPLD+\SRPDJQHVHPLD+\SRQDWUHPLD
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2. Distribution: Following an IV infusion, tremelimumab exhibits a biphasic pharmacokinetics with the mean systemic exposure parameters
(maximum concertation [Cmax] and area under the plasma concentrationtime curve [AUC]) increase in an approximately dose-proportional manner.  
Tremelimumab mean volume of distribution at steady state (Vss) is 81.2mL/kg. This is typical of mAbs with limited distribution. To date, the human tissue distribution of tremelimumab has not been studied.  
3. Metabolism: Tremelimumab is likely to be cleared from circulation by endothelial cell uptake and proteolysis.  
4. Elimination: The mean clearance for tremelimumab is 0.132 mL/hour/kg and the terminal-phase half-life is 22.1 days. Since mAbs are not primarily cleared via hepatic/renal pathways, no impact of renal/hepatic functions is expected on tremelimumab elimination.
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c. adverse effects 1. adverse

The Comprehensive Adverse Events and Potential Risks list (CAEPR)
provides a single list of reported and/or potential adverse events (AE)
associated with an agent using a uniform presentation of events by body system. Frequency is provided based on 1642 *patients.* Below is the CAEPR for tremelimumab (CP-675,206).  
| Version 2.1, March 25, 20191                                                                                                                                                                                                                                                                                      |             |                  |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|------------------|
| Adverse Events with Possible                                                                                                                                                                                                                                                                                      |             |                  |
| Relationship to Tremelimumab (CP-675,206) (CTCAE 5.0 Term) [n= 1642]                                                                                                                                                                                                                                              |             |                  |
| Likely (>20%)                                                                                                                                                                                                                                                                                                     | Less Likely | Rare but Serious |
| (<=20%)                                                                                                                                                                                                                                                                                                           | (<3%)       |                  |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia2 CARDIAC DISORDERS Myocarditis3 ENDOCRINE DISORDERS Adrenal insufficiency2 Endocrine disorders - Other (thyroiditis)2 Hyperthyroidism2 Hypophysitis2 Hypothyroidism2 EYE DISORDERS Uveitis GASTROINTESTINAL DISORDERS Abdominal pain Colitis2 Diarrhea Enterocolitis2 |             |                  |  
Page 20  
Version Date 10/21/19  
| Version Date 10/21/19 Gastrointestinal disorders  - Other (intestinal  perforation)2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| Nausea                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Pancreatitis2 |
| Vomiting                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |               |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs Fatigue Fever HEPATOBILIARY DISORDERS Hepatobiliary disorders - Other (autoimmune  hepatitis)2 IMMUNE SYSTEM DISORDERS Anaphylaxis INJURY, POISONING AND PROCEDURAL COMPLICATIONS Infusion related  reaction INVESTIGATIONS Alanine  aminotransferase  increased2 Aspartate  aminotransferase  increased2 Lipase increased2 Lymphocyte count  decreased2 Neutrophil count  decreased2 Platelet count  decreased2 Serum amylase  increased2 White blood cell  decreased2 METABOLISM AND NUTRITION DISORDERS Anorexia Dehydration Hypokalemia Metabolism and nutrition  disorders - Other  (diabetes mellitus) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthritis2 Musculoskeletal and  connective tissue  disorders - Other  (Sjogren's syndrome) NERVOUS SYSTEM DISORDERS Guillain-Barre syndrome2 Headache2 Myasthenia gravis2,4 |               |  
Page 21  
Version Date 10/21/19  
| Version Date 10/21/19 Nervous system disorders  - Other (encephalitis)2   |                     |
|---------------------------------------------------------------------------|---------------------|
| Peripheral motor  neuropathy2 Peripheral sensory  neuropathy2             |                     |
| RENAL AND URINARY DISORDERS Acute kidney injury                           | Nephrotic syndrome2 |
| Renal and urinary  disorders - Other  (autoimmune  nephritis)2            |                     |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough Dyspnea Pneumonitis2 Respiratory, thoracic  and mediastinal  disorders - Other  (interstitial lung  disease)2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin2 Pruritus Rash maculo-papular2 Skin and subcutaneous  tissue disorders - Other  (cutaneous sclerodermalike syndrome) Skin and subcutaneous  tissue disorders - Other  (Grover's disease) Skin  hypopigmentation Urticaria2 VASCULAR DISORDERS Vascular disorders - Other (giant cell temporal  arteritis)21 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal Investigators at the time of                                                                           |                     |  
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2 Immune-related adverse events may occur in any organs including but not limited to the events listed in CAEPR table.  
3 Myocarditis has been reported with other anti-CTLA4 agents; however, it has not yet been observed in clinical trials of tremelimumab (CP675,206).  
4 Myasthenia gravis was observed in trials of tremelimumab in combination with durvalumab.  
Adverse events reported **on tremelimumab (CP-675,206) trials, but** for which there is insufficient evidence to suggest that there was a reasonable possibility that tremelimumab (CP-675,206) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest EAR AND LABYRINTH DISORDERS - Tinnitus ENDOCRINE DISORDERS - Endocrine disorders - Other (Graves' disease with ophthalmopathy)
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Ileus; Mucositis oral; Rectal hemorrhage GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Malaise; Pain; Sudden death NOS
INFECTIONS AND INFESTATIONS - Conjunctivitis; Infections and infestations - Other (oral herpes); Lung infection; Sepsis INVESTIGATIONS - GGT increased; Weight loss METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Arthralgia; Generalized muscle weakness; Myalgia NERVOUS SYSTEM DISORDERS - Dizziness; Syncope PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS -
Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other (asthma)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Rash acneiform VASCULAR DISORDERS - Flushing; Hypertension; Thromboembolic event; Vascular disorders - Other (hemorrhage); Vasculitis Note: Tremelimumab (CP-675,206) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.  
2. Pregnancy and Lactation: In an embryo-fetal toxicity study in primates, tremelimumab did not result maternal toxicity, developmental toxicity, or teratogenicity.  
The effects of tremelimumab on a pregnant woman or human fetus have not been studied, and information on the safety for women of childbearing potential or for pregnant women cannot be derived from the existing clinical data. Guidance on contraception and on avoidance of egg or sperm collection is provided in the Investigator's Brochure.  
The levels of tremelimumab in breast milk have not been analyzed. Since tremelimumab is a mAb of the IgG2a type and it could potentially be secreted in breast milk, breastfeeding should be avoided.  
3. Drug Interactions: To date, no formal drug-drug interaction studies have been conducted with tremelimumab. In renal cell carcinoma studies, acute renal failure has been reported with the combination of tremelimumab and sunitinib. It is unknown whether a similar reaction will be observed when tremelimumab is combined with other tyrosine kinase inhibitors.  
d. DOSING & ADMINISTRATION
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see section 7.0 treatment plan

Tremelimumab is administered intravenously into a peripheral or central vein using an IV bag containing 0.9% sodium chloride or 5% dextrose and a 0.2 or 0.22-μm in-line filter. Standard infusion time is 60 minutes (± 5 minutes). Less than 55 minutes is considered a deviation. In the event that there are interruptions during infusion, the total allowed infusion time should not exceed 8 hours at room temperature. Flush the IV line at the completion of the infusion with a volume of diluent equal to the priming volume of the infusion set used to ensure the full dose is administered and document if the line was not flushed.  
MonitoringofDose Administration: Patients will be monitored during and after the infusion with assessment of vital signs.  
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be immediately available, and study personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate access to emergency resuscitation teams and equipment in addition to the ability to admit patients to an intensive care unit if necessary.
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e. how supplied

1. Tremelimumab is supplied free of charge by AstraZeneca, Inc. and distributed by the CTEP, DCTD, NCI  
2. Tremelimumab is formulated at 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v])
polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5. It is provided in a 20-mL clear glass vials with an elastomeric stopper and aluminum seal. Each vial contains 400 mg (nominal) of active investigational product.
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f. storage preparation & stability

Store unopened tremelimumab vials refrigerated at 2°C to 8°C (36°F to 46°F). Tremelimumab vials should be stored in original packaging. Do not freeze. Total time from needle puncture of the tremelimumab vial to the start of administration should not exceed:
4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F)
Infusion solution must be allowed to equilibrate to room temperature prior to commencement of administration. In the event that either preparation time or infusion time exceeds the time limits a new dose must be prepared from new vials. Tremelimumab does not contain preservatives, and any unused portion must be discarded. If a storage temperature excursion is identified, promptly return (tremelimumab or MEDI4736) to between 2-8°C and quarantine the supplies. Provide a detailed report of the excursion (including documentation of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.
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preparation of tremelimumab

Sites should follow standard and local aseptic procedures and the clinical study protocol for all activities. All dispensing activities should be documented according to local procedures.  
Withdraw the required volume of tremelimumab from the vial(s) and further dilute in an IV bag containing 0.9% sodium chloride or 5% dextrose to obtain a final concentration of 0.10 to 10 mg/mL. The IV bag should be administered with a 0.2 or 0.22 μm in-line filter. Infusion bags must be latex-free and can be made of polyvinyl chloride (PVC) or polyolefins (e.g., polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP free.
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3.3 drug ordering & accountability

a. Drug ordering: Sites may order initial agent supplies when a subject has been registered. Starter supplies will not be provided. NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee) at each participating institution. The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators at each participating institution must be registered with CTEP, DCTD
through an annual submission of FDA Form 1572 (Statement of Investigator), NCI
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution.  
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB's website for specific policies and guidelines related to agent management.  
1. Drug Handling and Accountability a. Drug Accountability: The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the Drug Accountability Record Form available on the NCI home page (http://ctep.cancer.gov).  
b. Electronic logs are allowed as long as a print version of the log process is the exact same appearance as the current NCI DARF.  
2. Drug Return and/or Disposition Instruction
a. Drug Returns: All unused drug supplies must be returned to the PMB. When it is necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock recovery letter),
investigators should return the study drug to the PMB using the 1&, 5HWXUQ $JHQW )RUP DYDLODEOH RQ WKH 1&, KRPH SDJH KWWSFWHSFDQFHUJRY
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