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abbreviated title immune checkpoint inhibition

| Version Date: 04/28/21                                                                                                    |                                                                                                                                                       |                                                                                                            |
|---------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|
| 4.2                                                                                                                       | Male patients with a Female Partner of Childbearing Potential .........................................44                                             |                                                                                                            |
| 4.3                                                                                                                       | Blood Donation ...........................................................................................................................45          |                                                                                                            |
| 4.4                                                                                                                       | Concomitant Treatment(s) .......................................................................................................45                    |                                                                                                            |
| 4.5                                                                                                                       | Permitted Concomitant Medications                                                                                                                     |                                                                                                            |
| Excluded Concomitant Medications ......................................................................................46 |                                                                                                                                                       |                                                                                                            |
| 4.6                                                                                                                       | BIOSPECIMEN COLLECTION.......................................................................................................47                       |                                                                                                            |
| S                                                                                                                         | 5.1                                                                                                                                                   | Correlative Studies for Research/Pharmacokinetic Studies ...............................................47 |
| 5.2                                                                                                                       | NCI Correlative Studies ........................................................................................................48                    |                                                                                                            |
| Immune monitoring (All cohorts)                                                                                           |                                                                                                                                                       |                                                                                                            |
| 5.2.1                                                                                                                     |                                                                                                                                                       |                                                                                                            |
| 5.2.2                                                                                                                     | Liver autoantibody panel for autoimmune hepatitis (AIH) .......................................49                                                     |                                                                                                            |
| 5.2.3                                                                                                                     | Hepatitis serology and viral load ..................................................................................49                                |                                                                                                            |
| Tumor-specific aFP responses                                                                                              |                                                                                                                                                       |                                                                                                            |
| 5.2.4                                                                                                                     | MDSC functional assay ............................................................................................................50                  |                                                                                                            |
| 5.2.5                                                                                                                     |                                                                                                                                                       |                                                                                                            |
| 5.2.6                                                                                                                     | Rectal Swab Collection, Storage and Analysis (optional) ...........................................50                                                 |                                                                                                            |
| 5.2.7                                                                                                                     | T TUMOR Biopsies                                                                                                                                      |                                                                                                            |
| MedImmune Planned Studies                                                                                                 |                                                                                                                                                       |                                                                                                            |
| 5.3                                                                                                                       |                                                                                                                                                       |                                                                                                            |
| 5.3.1                                                                                                                     | Pharmacokinetics .                                                                                                                                    |                                                                                                            |
| 5.3.2                                                                                                                     | Immunogenicity .                                                                                                                                      |                                                                                                            |
| 5.3.3                                                                                                                     | T CELL Activation/ICOS expression                                                                                                                     |                                                                                                            |
| 5.3.4                                                                                                                     | Plasma-based assays for circulating receptors/ligands e.g. PDL1............................52                                                         |                                                                                                            |
| 5.4                                                                                                                       | Sample Storage, Tracking and Disposition.......................................................................................52                     |                                                                                                            |
| 5.4.1                                                                                                                     | Samples Managed by Dr. Figg's Blood Processing Core (BPC) ...............................52                                                           |                                                                                                            |
| Dr Greten Lab Contact information                                                                                         |                                                                                                                                                       |                                                                                                            |
| 5.4.2                                                                                                                     |                                                                                                                                                       |                                                                                                            |
| 5.4.3                                                                                                                     | Protocol Completion/Sample Destruction ...............................................................................53                              |                                                                                                            |
| 6                                                                                                                         | DATA COLLECTION AND EVALUATION ........................................................................................53                             |                                                                                                            |
| 6.1                                                                                                                       | DATA COLLECTION                                                                                                                                       |                                                                                                            |
| DATA SHARING Plans                                                                                                        |                                                                                                                                                       |                                                                                                            |
| 6.2                                                                                                                       |                                                                                                                                                       |                                                                                                            |
| 6.2.1                                                                                                                     | Human Data Sharing Plan ...........................................................................................................54                 |                                                                                                            |
| 6.2.2                                                                                                                     | Genomic Data Sharing Plan.......................................................................................................54                    |                                                                                                            |
| Response Criteria                                                                                                         |                                                                                                                                                       |                                                                                                            |
| 6.3                                                                                                                       | Definitions .......................................................................................................................................54 |                                                                                                            |
| 6.3.1                                                                                                                     |                                                                                                                                                       |                                                                                                            |
| 6.3.2                                                                                                                     | Disease Parameters .                                                                                                                                  |                                                                                                            |  
S  
| Version Date: 04/28/21                                                                                                                                  |                                                                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 6.3.3                                                                                                                                                   | Methods for Evaluation of Measurable Disease ...................................................................56                                      |
| 6.3.4                                                                                                                                                   | Response Criteria                                                                                                                                       |
| D DURATION OF RESPONSE                                                                                                                                  |                                                                                                                                                         |
| 6.3.5                                                                                                                                                   |                                                                                                                                                         |
| 6.4                                                                                                                                                     | Modified immune-related response criteria (irRC) ................................................................60                                     |
| Toxicity Criteria                                                                                                                                       |                                                                                                                                                         |
| 6.5                                                                                                                                                     |                                                                                                                                                         |
| 7                                                                                                                                                       | NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....60                                                                                       |
| 7.1                                                                                                                                                     | DEFINITIONS                                                                                                                                             |
| 7.2                                                                                                                                                     | OHSRP Office of Compliance and Training / IRB Reporting.............................................61                                                  |
| 7.2.1                                                                                                                                                   | Expedited Reporting .................................................................................................................61                 |
| 7.2.2                                                                                                                                                   | IRB Requirements for PI Reporting at Continuing Review .........................................61                                                      |
| 7.3                                                                                                                                                     | NCI Clinical Director Reporting ..................................................................................................61                    |
| NIH Required Data and Safety Monitoring Plan ......................................................................61                                   |                                                                                                                                                         |
| 7.4                                                                                                                                                     | Principal Investigator/Research Team ................................................................................61                                 |
| 7.4.1                                                                                                                                                   |                                                                                                                                                         |
| 8                                                                                                                                                       | SPONSOR protocol/SAFETY REPORTING ..................................................................................61                                  |
| Definitions                                                                                                                                             |                                                                                                                                                         |
| 8.1                                                                                                                                                     | Adverse Event...........................................................................................................................61              |
| 8.1.1                                                                                                                                                   |                                                                                                                                                         |
| 8.1.2                                                                                                                                                   | Serious Adverse Event (SAE) ..............................................................................................62                            |
| 8.1.3                                                                                                                                                   | Life-threatening ........................................................................................................................62             |
| Severity ............................................................................................................................................62 |                                                                                                                                                         |
| 8.1.4                                                                                                                                                   |                                                                                                                                                         |
| 8.1.5                                                                                                                                                   | Relationship to Study Product ..............................................................................................62                          |
| 8.1.6                                                                                                                                                   | Adverse Events of Special Interest (AESI) ...................................................................63                                         |
| 8.2                                                                                                                                                     | Assessment of Safety Events .........................................................................................................63                 |
| 8.3                                                                                                                                                     | Reporting of Serious Adverse Events .......................................................................................63                           |
| 8.4                                                                                                                                                     | Waiver of Expedited Reporting to CCR ...................................................................................63                              |
| 8.5                                                                                                                                                     | Reporting Criteria to the Pharmaceutical Collaborators .......................................................64                                        |
| 8.5.1                                                                                                                                                   | Expedited Adverse Event Reporting Criteria to the IND Manufacturer ................64                                                                   |
| 8.5.2                                                                                                                                                   | Other events requiring reporting .............................................................................................65                        |
| 8.6                                                                                                                                                     | Reporting Pregnancy ..............................................................................................................................65    |
| 8.6.1                                                                                                                                                   | Maternal exposure ..........................................................................................................................66          |
| Paternal exposure.                                                                                                                                      |                                                                                                                                                         |
| 8.6.2                                                                                                                                                   |                                                                                                                                                         |
| 8.7                                                                                                                                                     | Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................66                                                                 |
| 9                                                                                                                                                       | CLINICAL MONITORING .................................................................................................................................66 |  
| Version Date: 04/28/21                                                                                                                    |                                                                                                                                                |                                                                                               |
|-------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------|
| 10                                                                                                                                        | STATISTICAL CONSIDERATIONS ...............................................................................................67                   |                                                                                               |
| COLLABORATIVE AGREEMENTS ......................................................................................................68         |                                                                                                                                                |                                                                                               |
| 11                                                                                                                                        | 1.1                                                                                                                                            | Cooperative Research and Development Agreement (CRADA) ....................................68 |
| 1.2                                                                                                                                       | Material Transfer Agreements (MTA) .................................................................................68                         |                                                                                               |
| HUMAN SUBJECTS PROTECTIONS ................................................................................................68             |                                                                                                                                                |                                                                                               |
| 12                                                                                                                                        | Ethical Conduct of the Study                                                                                                                   |                                                                                               |
| 12.1                                                                                                                                      |                                                                                                                                                |                                                                                               |
| 12.2                                                                                                                                      | Rationale For Subject Selection .................................................................................................68            |                                                                                               |
| 12.3                                                                                                                                      | Participation of Children .........................................................................................................68          |                                                                                               |
| PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ......................68                                                                 |                                                                                                                                                |                                                                                               |
| 12.4                                                                                                                                      |                                                                                                                                                |                                                                                               |
| 12.5                                                                                                                                      | Evaluation of Benefits and Risks/Discomforts for all participants ...............................69                                            |                                                                                               |
| 12.5.1                                                                                                                                    | Known potential risks .........................................................................................................69              |                                                                                               |
| Known potential benefits..............................................................................................................73  |                                                                                                                                                |                                                                                               |
| 12.5.2                                                                                                                                    | Risks/Benefits Analysis ................................................................................................................73     |                                                                                               |
| 12.5.3                                                                                                                                    |                                                                                                                                                |                                                                                               |
| 12.6                                                                                                                                      | Consent Process and Documentation ........................................................................................74                   |                                                                                               |
| Consent Process for Adults Who Lack Capacity to Consent to Research                                                                       |                                                                                                                                                |                                                                                               |
| 12.6.1                                                                                                                                    |                                                                                                                                                |                                                                                               |
| Participation                                                                                                                             |                                                                                                                                                |                                                                                               |
| 13                                                                                                                                        | REGULATORY AND OPERATIONAL CONSIDERATIONS ..................................................74                                                 |                                                                                               |
| Study Discontinuation and Closure ................................................................................................74      |                                                                                                                                                |                                                                                               |
| 13.1                                                                                                                                      |                                                                                                                                                |                                                                                               |
| 13.2                                                                                                                                      | Quality Assurance and Quality Control .....................................................................................75                  |                                                                                               |
| 13.3                                                                                                                                      | Conflict of Interest Policy ................................................................................................................75 |                                                                                               |
| 13.4                                                                                                                                      | Confidentiality and Privacy ...............................................................................................................75  |                                                                                               |
| PHARMACEUTICAL INFORMATION ..............................................................................................76               |                                                                                                                                                |                                                                                               |
| 14                                                                                                                                        | 14.1                                                                                                                                           | T Tremelimumab                                                                                |
| 14.1.1                                                                                                                                    | SOURCE .                                                                                                                                       |                                                                                               |
| 14.1.2                                                                                                                                    | Formulation and Preparation ...................................................................................................76              |                                                                                               |
| Administration Procedures .............................................................................................................77 |                                                                                                                                                |                                                                                               |
| 14.1.3                                                                                                                                    |                                                                                                                                                |                                                                                               |
| 14.1.4                                                                                                                                    | Dose Calculation                                                                                                                               |                                                                                               |
| 14.1.5                                                                                                                                    | Investigational Product Inspection .....................................................................................78                     |                                                                                               |
| 14.1.6                                                                                                                                    | Dose Preparation Steps ...............................................................................................................78       |                                                                                               |
| 14.1.7                                                                                                                                    | Investigational Product Accountability ...............................................................................78                       |                                                                                               |
| 14.1.8                                                                                                                                    | Reporting Product Complaints ................................................................................................79                |                                                                                               |
| D DURVALUMAB                                                                                                                              |                                                                                                                                                |                                                                                               |
| 14.2                                                                                                                                      |                                                                                                                                                |                                                                                               |  
| 14.2.1                                                                                                                                                             | SOURCE .                                                                                                                                                           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Formulation and Preparation .....................................................................................................79                                |                                                                                                                                                                    |
| 14.2.2                                                                                                                                                             |                                                                                                                                                                    |
| 14.2.3                                                                                                                                                             | Stability                                                                                                                                                          |
| 14.2.4                                                                                                                                                             | Dose Calculation                                                                                                                                                   |
| Investigational Product Preparation Steps ..............................................................................81                                         |                                                                                                                                                                    |
| 14.2.5                                                                                                                                                             | Investigational Product Inspection .......................................................................................81                                       |
| 14.2.6                                                                                                                                                             |                                                                                                                                                                    |
| 14.2.7                                                                                                                                                             | Investigational Product Accountability ...............................................................................82                                           |
| Reporting Product Complaints .................................................................................................82                                   |                                                                                                                                                                    |
| 14.2.8                                                                                                                                                             |                                                                                                                                                                    |
| REFERENCES .....................................................................................................................................................84 |                                                                                                                                                                    |
| 15                                                                                                                                                                 |                                                                                                                                                                    |
| 16                                                                                                                                                                 | APPENDICES .....................................................................................................................................................87 |
| 16.1                                                                                                                                                               | Appendix A -Performance Status Criteria                                                                                                                            |
| Appendix B - Child-Pugh Classification System ...............................................................87                                                    |                                                                                                                                                                    |
| 16.2                                                                                                                                                               | Appendix C: Modified Immune-Related Response Criteria (irRC)                                                                                                       |
| 16.3                                                                                                                                                               |                                                                                                                                                                    |
| 16.4                                                                                                                                                               | Appendix D - MedImmune Sample Preparation Procedures .........................................91                                                                   |
| Appendix E - Data Collection Elements Required by Manufacturer ..........................92                                                                        |                                                                                                                                                                    |
| 16.5                                                                                                                                                               | Appendix F: DOSING MODIFICATION AND TOXICITY MANAGEMENT                                                                                                            |
| 16.6                                                                                                                                                               |                                                                                                                                                                    |
| GUIDELINES (TMG) FOR IMMUNE-MEDIATED, INFUSION-RELATED, AND NON-                                                                                                   |                                                                                                                                                                    |
| IMMUNE–MEDIATED REACTIONS (DURVALUMAB MONOTHERAPY OR IN                                                                                                            |                                                                                                                                                                    |
| COMBINATION WITH OTHER PRODUCTS) 14 OCTOBER 2020 .....................................94                                                                           |                                                                                                                                                                    |
| 16.7                                                                                                                                                               | Appendix G: Frequency of ADRs for Durvalumab Monotherapy From Pooled Data                                                                                          |  
Across Multiple Tumour Types (N=3006)
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N:BB3750 interventions and their indications - is outlined below. The approach to management has traditionally comprised loco-regional strategies: surgery (partial resection or transplantation) or interventional radiologic procedures, such as chemoembolization or ablative techniques.  
Recently, sorafenib has been added to this paradigm and it is the only systemic drug therapy which has demonstrated a survival benefit in modern randomized studies.  
Table 1: Therapeutic paradigm for HCC  
| Table 1: Therapeutic paradigm for HCC   |                                |                      |
|-----------------------------------------|--------------------------------|----------------------|
| Intervention                            | Indication                     | Potentially curative |
| Partial Hepatectomy                     | Limited liver disease with     | Yes                  |
| god reserve                             |                                |                      |
| Transplantation                         | 1 lesion <5cm or 3 < 3cm       | Yes                  |
| RFA                                     | Lesion to be ablated at least  | Yes                  |
| 1cm and not greater than 5cm.           |                                |                      |
| TACE                                    | Liver confined; no portal vein | No                   |
| thrombosis                              |                                |                      |
| Sorafenib                               | Metastatic disease             | No                   |  
The most widely used staging system in HCC is the Barcelona Clinic Liver Cancer (BCLC) Staging system, the major advantage of which is that in addition to staging patients it also directs management[ 2 ]. The BCLC staging system is shown in Figure 1 below.  
  
  
For the proposed study, we will not include patients for whom surgical resection or transplantation is a possibility. We will also exclude patients with isolated lesions for whom RFA alone is possible, given the curative potential of that intervention. The target population will be those with advanced disease for whom the only available interventions are TACE or sorafenib.
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1.2.2

Recent advances in immune-based approaches in solid tumor malignancies The past few years have seen progress for immune-based approaches in solid tumor malignancies, with FDA approvals for these approaches in prostate cancer and lung cancer in addition to renal cell carcinoma and melanoma[ 3 -5 ]. In melanoma, anti-CTLA4 therapy has been shown to demonstrate a median survival benefit in two separate phases 3 studies, both of which were associated with long-term disease control in approximately one-fifth of patients. More recently, anti-PD1 therapy has demonstrated a similar degree of clinical activity not only in melanoma and kidney cancer but also in lung cancer, a disease type previously thought to be refractory to an immune approach. Appreciation of the role in developing tumors of immuneevasion has also been evidenced by its inclusion as one of the (updated) hallmarks of cancer[ 6 ].  
Both anti-PD1 and anti-CTLA4 therapy enhance anti-tumor immunity by blocking tumor induced immune suppression of cytotoxic T cells and therefore exaggerating the immune activation that must first occur of its own accord and is thought to be the result of tumor neoantigens formed as a tumor progresses. The role of CTLA4 in inhibiting T-cell activation is represented in the schematic in Figure 2 below. CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)-mediated signaling. After the TCR
is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR.  
  
Whilst these studies demonstrate the potential for anti-CTLA4 (or anti PD1) therapy to enhance the anti-tumor immune response already in process, it clearly does not work in the majority of patients. The question is whether the initial immune activation stage can be enhanced. The potential for this was intriguingly demonstrated in a recent publication by Postow et al who reported a case of the so-called abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy[ 8 ]. Temporal associations were noted between tumor shrinkage and antibody responses to the cancer-testis antigen NY-ESO-1 in addition to changes in peripheralblood immune cells and increases in antibody responses to other antigens after a patient being treated with anti-CTLA4 was then treated with external beam radiotherapy. The enhanced effect from anti-CTLA4 seen after radiation appears to have been due to a boost effect of tumor cell death and immune stimulation following deliverance of a tumor antigen load. It is this enhanced effect we wish to study in the context of interventional procedures for HCC.
untitled h1
1.2.3 immune response to interventional

The aim of our proposed study is to enhance the antitumor immune response which has been shown to occur following interventional radiological treatments. The attractive aspect of this approach - especially in a disease as prevalent as HCC - is that it has the potential for enhancing the effect of treatments (both RFA and TACE) which have already been approved, have demonstrated survival benefit in randomized studies and are commonly performed throughout the community. Following RFA and TACE necrotic tumor results in the release of tumor antigens which are taken up by antigen-presenting cells (mainly dendritic cells) and which activate a tumor-specific immune response[ 9 ]. Ablated tumor tissue has been shown to promote dendritic cell maturation (and resultant T-cell stimulatory properties)[ 10 , 11 ]. This antigen release is potentially significant because, although ablative procedures are very effective in eradicating visible lesions, a tumor-specific immune response may prevent recurrent disease in addition to treating distant metastases. In other words, RFA and TACE have the potential to turn a patient's tumor into an endogenous vaccine.  
Several studies have documented an increase in peripheral antitumor immunity following interventional radiological procedures, predominantly RFA[ 10 , 12-15 ]. This has been demonstrated both in animal models and in human studies[ 12 , 14 , 15 ]. Ayaru et al. evaluated the immune response in HCC patients (N=10) undergoing TACE[ 16 ]. They found that AFP-specific CD4-T cell responses were significantly expanded during ( p < 0.0001) and after embolization ( p
< 0.002). The development of higher frequencies of AFP-specific CD4 T cells after treatment were significantly associated with the induction of >50% necrosis of tumor and an improved clinical outcome ( p < 0.007). Mizukoshi et al. measured cytotoxic T cell response to tumor associated antigens (TAA) in HCC patients undergoing treatment[ 17 ]. They measured the frequency of TAA-specific T cells before and after HCC treatment by ELISPOT assay in 12 cases who received TACE, RFA or chemotherapy. The frequency of TAA-specific T cells was found to be increased in all patients. Furthermore, incubation of T cells with CTLA-4 antibodies resulted in an increase of the number of TAA-specific T cells. Dromi et al. evaluated the influence of subtotal RFA on tumor-specific immune response in a murine urothelial carcinoma
(MB49) tumor model[ 18 ]. RFA resulted in enhanced systemic antitumor T-cell immune responses and tumor regression that was associated with increased dendritic cell infiltration into the remaining viable, non-ablated tumor. Hansler et al. assessed the specific cytotoxic T cell response in patients with malignant liver tumors (both metastatic colon cancer and HCC) which were treated with RFA. Significant tumor-specific cytotoxic T-cell stimulation was seen, with a dramatically increased tumor specific cytolytic activity of CD8(+) T cells against autologous liver and tumor lysate after RFA[ 12 ]. Hiroishi et al. analyzed tumor-specific CD8(+) T-cell responses in twenty patients with HCC undergoing loco-regional therapy (either RFA or TACE)[ 13 ]. They found that the CD8(+)
T-cell response was increased and, on multivariate analysis, the magnitude of the immune response was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, P = 0.022).  
Despite this, only a few cases of spontaneous remission of metastases following RFA - the socalled abscopal effect - have been reported, presumably because this immune response by itself is too weak to be clinically significant[ 19-21 ]. A number of studies have tried to boost this antitumor immune response following ablation by combining with an immunomodulatory agent:
Waitz et al. provided preclinical proof-of-concept for this in a mouse model of prostate cancer using CTLA-4 blockade to augment the immune response from cryoablation[ 22 ]. The combination therapy resulted in >80% of intratumoral CD8+ T cells being antigen-specific. The effect on secondary responses was assessed by injection of the secondary tumor on the opposite flank of the mouse on Day 2 following ablation. The growth of secondary tumors was found to be unaffected by cryoablation alone, but the combination treatment (anti-CTLA4 + RFA) was sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly infiltrated by CD4+ T cells and CD8+ T cells, and there was a significant increase in the ratio of intratumoral T effector cells to T regulatory cells, compared with either RFA or anti-CTLA4 alone. Johnson et al. sought to enhance the antitumor effect of RFA by combining it with huKS-
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The combination therapy (dual targeting of PD-L1 and CTLA-4) has been shown in preclinical studies with a mouse model to cause tumor regression of colorectal cancer. To date, 2 clinical trials employing durvalumab as combination therapy with tremelimumab in adults with advanced non-small cell lung cancer (NSCLC) and advanced solid tumors was initiated with preliminary efficacy data for combination still pending. Nivolumab plus ipilimumab clinical data: Results of Nivolumab administered in combination with ipilimumab for stage III or IV measurable, unresectable melanoma have recently been reported. At the maximum tolerated combination dose—1mg/kg anti-PD1 plus 3 mg/kg ipilimumab every three weeks administered concurrently, 5% of patients had an objective response, all with tumor reduction of 80% or more. Adverse effects occurred in 53% of patients and were similar in quality and intensity to those observed with ipilimumab monotherapy. Sequential administration resulted in a lower response rate and lower toxicity rate. With regard to biomarkers previously associated with responses to anti¬
CTLA4 or anti-PD1, investigators evaluated PD-L1 expression in tumors and absolute lymphocyte counts and looked for relationships with response. In patients treated concurrently, 6/13 patients with PD-L1+ tumors responded whereas 9/22 patients with PD-L1- tumors responded (P>0.99 by Fisher's exact). Interestingly however, in the sequential group, 4/8 patients whose tumors were PD-L1+ responded whereas only 1/13 who had PD-L1- tumors responded.  
Absolute lymphocyte counts at weeks 5-7 were not associated with response in this study.  
1.2.6.1 Updated information for combination of durvalumab and tremelimumab:
Study D4190C0006 is a phase Ib dose-escalation study to establish safety, PK/PDx, and preliminary anti-tumor activity of durvalumab + tremelimumab combination therapy in patients with advanced NSCLC. The dosing schedule utilized is durvalumab every 2 weeks (q2w) or every 4 weeks (q4w) up to Week 50 and 48 (12 months), combined with tremelimumab q4w up to Week 24 for 7 doses then every 12 weeks for 2 additional doses for up to 12 months. The study is ongoing and continues to accrue.  
Study D4190C0006: As of 20Feb2015, durvalumab PK (n = 55) and tremelimumab PK (n =
2) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, and 9) following durvalumab every 4 weeks (Q4W) or Q2W dosing in combination with tremelimumab Q4W regimens. An approximately dose-proportional increase in PK exposure (Cmax and area under the concentration-time curve from 0 to 28 days [AUC0 28]) of both durvalumab and tremelimumab was observed over the dose range of 3 to 15 mg/kg durvalumab Q4W and 1 to 10 mg/kg tremelimumab Q4W. Exposures following multiple doses demonstrated accumulation consistent with PK parameters estimated from the first dose. It is to be noted that steady state PK parameters are based on limited numbers of subjects. The observed PK exposures of durvalumab and tremelimumab following combination were consistent with respective monotherapy data, indicating no PK interaction between these 2 agents.  
As of February 20, 2015, ADA data were available from 60 subjects for durvalumab and 53 subjects for tremelimumab in Study D4190C0006. Four of 60 subjects were ADA positive for anti durvalumab antibodies post treatment. One of 53 subjects were ADA positive for anti tremelimumab antibodies post treatment. There was no clear relationship between ADA and the dose of either durvalumab or tremelimumab, and no obvious association between ADA and safety or efficacy. The durvalumab + tremelimumab doses and regimen selected for this study were 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.  
In order to reduce the dosing frequency of durvalumab to align with the q4w dosing of tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, cohorts were narrowed to 15 and 20 mg/kg durvalumab q4w. PK simulations from the durvalumab monotherapy data indicated that a similar area under the plasma drug concentration-time curve at steady state (AUCss; 4 weeks) was expected following both 10 mg/kg q2w and 20 mg/kg q4w durvalumab. The observed durvalumab PK data from the D4190C0006 study were well in line with the predicted monotherapy PK data developed preclinically. This demonstrates similar exposure of durvalumab 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when durvalumab and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed together. While the median Cmax at steady state (Cmax,ss) is expected to be higher with 20 mg/kg q4w
(approximately 1.5-fold) and median trough concentration at steady state (Ctrough,ss) is expected to be higher with 10 mg/kg q2w (approximately 1.25-fold), this is not expected to impact the overall safety and efficacy profile, based on existing preclinical and clinical data. Monotonic increases in PDx activity were observed with increasing doses of tremelimumab relative to the activity observed in patients treated with durvalumab monotherapy. There was evidence of augmented PDx activity relative to durvalumab monotherapy with combination doses containing 1 mg/kg tremelimumab, inclusive of both the 15 and 20 mg/kg durvalumab plus l mg/kg tremelimumab combinations.  
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs. Between the 10 mg/kg durvalumab + 1 mg/kg tremelimumab and 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of patients reporting any AE, grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab + 3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab + 1 mg/kg tremelimumab cohort. A
similar pattern was noted in the q4w regimens, suggesting that, as the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related events may be anticipated. Further, the SAEs frequently attributed to immunotherapy, pneumonitis and colitis, were more commonly seen in cohorts using either 3 or 10 mg/kg of tremelimumab compared to the 1-mg/kg dose cohorts. Together, these data suggest that a combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity when combined with durvalumab. As a result, all combination doses utilizing either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose selection.  
In contrast, cohorts assessing higher doses of durvalumab with a constant dose of tremelimumab did not show an increase in the rate of AEs. The data suggested that increasing doses of durvalumab may not impact the safety of the combination as much as the tremelimumab dose.  
Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were similar, with no change in safety events with increasing dose of durvalumab.  
In Study D4190C0006, of all treatment cohorts, the cohort of 11 patients treated in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥ 3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This cohort had a lower number of treatment-related Grade ≥ 3 AEs or treatment related SAEs. No dose-limiting toxicities were reported.  
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clinical response rates in melanoma. We would therefore like to open new cohorts which combine anti-PDL1 therapy (durvalumab) with anti-CTLA4 (tremelimumab). The combination of tremelimumab and durvalumab has been tested in a dose-escalation study performed by AstraZeneca employing dose ranges of 1-10mg/kg q4weeks (tremelimumab) and 10-20mg/kg q2-4weeks (durvalumab). Patients treated in the 20 mg/kg durvalumab + 1 mg/kg tremelimumab group had the fewest AEs, Grade ≥ 3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of clinical activity. This cohort had a lower number of treatment-related Grade ≥ 3 AEs or treatment related SAEs. No dose-limiting toxicities were reported. This is the dose level the company is bringing forward. Also, of note, PK analysis indicated only minor impact of body weight (WT) on PK of both agents so to minimize errors and for ease of use the company have moved to a fixed-dose schedule of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W).
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1.2.11 regarding research nature of

While RFA and cryoablation are approved, standard of care procedures for these cancer types, the intent of their use in this protocol is strictly research. The ablative procedure will be performed in a subtotal fashion (per radiologist judgement) in order to stimulate an immune response, rather than complete eradication of the lesion as per standard of care indication. The TACE however will be as per standard of care (BCLC B patients). All procedures will or may be performed under CT guidance.
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inclusion criteria

2.1.1.1 Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or biliary tract carcinoma (BTC) by the Laboratory of Pathology of the NCI prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of HCC (or biliary tract carcinoma). Fibrolamellar variant is also allowed. The term BTC includes intra- or extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.  
2.1.1.2 Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation. HCC patients must have progressed on, been intolerant to, or refused prior sorafenib therapy. Patients with BTC must have received, been intolerant of or refused at least one line of chemotherapy.  
2.1.1.3 Patients must have multiple tumor lesions (at least 2): one for the ablation procedure and another for evaluation located outside the proposal ablation zone.  
2.1.1.4 Disease must be technically amenable to transhepatic arterial chemoembolization
(TACE) (HCC patients only), radiofrequency ablation (RFA), or cryoablation. Each case will be discussed at GI tumor board with interventional radiology. Patients must have evaluable disease.  
2.1.1.5 ECOG performance status 0-2 (see APPENDIX A)
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sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.  
2.1.1.13 Body weight >30kg 2.1.2 Exclusion Criteria
2.1.2.1 Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 2 weeks prior to entering the study. For recent experimental therapies, a 28-day period of time must elapse before treatment.  
2.1.2.2 Patients who have undergone prior liver transplantation are ineligible.
2.1.2.3 Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.  
2.1.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations that would limit compliance with study requirements.  
2.1.2.5 History of chronic autoimmune disease (e.g., Addison's disease, multiple sclerosis, Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.  
2.1.2.6 Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.  
2.1.2.7 Diverticulitis either active or history of within the past 2 years. Note that diverticulosis is  
permitted.
2.1.2.8 Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis.  
2.1.2.9 Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted)  
2.1.2.10 History of sarcoidosis syndrome
2.1.2.11 Patients should not be vaccinated with live attenuated vaccines within 30 days of starting durvalumab or tremelimumab treatment.  
2.1.2.12 Has a known history of Human Immunodeficiency Virus (HIV). HIV-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and tremelimumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events.  
2.1.2.13 History of hypersensitivity reaction to human or mouse antibody products.  
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| 86F@8;?EF 6@B5 789B6;=86 7A6@:6 :66 #1\V                                 |                                                                             |                                                                       |                        |
|--------------------------------------------------------------------------|-----------------------------------------------------------------------------|-----------------------------------------------------------------------|------------------------|
| _`a`bc +`defgch`i                                                        | )jjeik lchjefgchim db`nkoebk                                                | '`lk fkpkf                                                            | +fgiiko .              |
| LM                                                                       | L;G@EB6; IJJO UJqJ [<@F6 J                                                  | r9 @DA@<?G6                                                           | 486C6A?C=C@D "sCF WA@< |
| 789B6;=86                                                                | ;9:6 t!u ;@>: W98 T ;9:6: v=8G@A=C@D MswwCF WA@< ;9:6 t!u ;@>: =E<?A Px[yyy | 2z c`cgf                                                              |                        |
| L!                                                                       | L;G@EB6; IJJO UJqJ [<@F6 U{J                                                | J8>9@DA@<?9E{                                                         | 486C6A?C=C@D "sCF WA@< |
| QRL{4LJP|                                                                | ;9:6 t!u ;@>: W98 T ;9:6: v=8G@A=C@D MswwCF WA@< ;9:6 t!u ;@>: =E<?A Px[||  | #z c`cgf Mw <86C} ;=8 } 4LJP Mw <86C } ;=8 } QRL Mw <86C } ;=8 } B8>9 |                        |
| U                                                                        | ~E<8@{6<8@^ 567@<?B B59A@EF?9B@8B?E 9C@ r€ M:< Mw 7<: r9 @DA@<?G6 789B6;=86 486C6A?C=C@D "sCF WA@< ;9:6 t!u ;@>: W98 T ;9:6: v=8G@A=C@D MswwCF WA@< ;9:6 t!u ;@>: =E<?A Px[||                                                                             | #z c`cgf Mw <86C} ;=8 @A9E6 Mw <86C } ;=8 } QRL Mw <86C } ;=8 } B8>9  |                        |
| QRL{ B8>9@DA@<?9E                                                        |                                                                             |                                                                       |                        |
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3.4.2.5 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 Appendix F.
%&'(
3.4.2.6 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 Appendix F.
%&'(
3.4.2.7 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 Appendix F.
%&'(
3.4.2.8 neurotoxicity

Immune-mediated nervous system events include encephalitis, peripheral motor and sensory neuropathies, Guillain-Barre, and myasthenia gravis. Guidelines for the management of patients with immune-mediated neurotoxic events are provided in Appendix F.
%&'(
3.4.2.9 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 Appendix F.
%&'(
3.4.2.10 autoimmunity

If a subject experience an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, hepatitis, pancreatitis, thrombocytopenia, hypophysitis, diabetes insipidus), the investigator should send a blood sample for appropriate autoimmune antibody testing and should immediately consider endocrinology consultation. If specific auto-antibodies are present, the blood sample taken for storage at baseline can be tested for the presence of auto antibodies.  
Continuation of investigational product in the presence of immune-mediated events should be done by the investigator with consideration to risk-benefit analysis.
%&'(
3.5 specific procedures for tace

Percutaneous procedure is performed under general anesthesia or conscious sedation. Access is obtained from the common femoral artery and selective catheterization of the superior mesenteric and celiac arteries is performed to define anatomy and hepatic arterial supply. Super selective catheterization of hepatic artery branches feeding the tumors is then performed followed by infusion of a chemotherapeutic mixture.  
Trans-arterial chemoembolization will be performed with drug eluding beads (DEB). In this case, 100mg of doxorubicin are loaded into 100-250 micron beads. The DEB are mixed with contrast and infused into the hepatic artery branches supplying the tumor. Patients undergoing trans-arterial chemoembolization are pre-medicated with analgesics, antibiotics and anti-emetics per clinical standards.
%&'(
3.5.2 radiofrequency ablation

Thermal ablation is a minimally invasive image guided procedure performed under general anesthesia or conscious sedation. Radiofrequency or microwave ablations are performed; the ablation zone includes the tumor and a safety margin of surrounding tissue. Thermal ablation therapy will be administered according to the manufacturer's instructions of the device. The probe chosen varies depending on the type of thermal ablation, size of the tumor. The ablation probe will be inserted into the lesion, under image guidance. After confirmation of appropriate positioning, the lesion will be heated typically for 10-15 minutes for RFA and 5-10 minutes for microwave, according to manufacturer's guidelines. The time of ablation will depend on thermal ablation technique (RF vs. microwave) as well as the size of the ablation zone desired. The ablation time might also vary depending on proximity of critical structures, patient-specific anatomy or issues. Depending on ablation zone size, several probes might be required with several heating times to achieve complete coverage of the desired ablation zone. Balloon catheter may be used in cases where the tumor is adjacent to a hepatic vein to avoid "heat sync" where the ablation zone is cooled by the blood inflow. This catheter is typically inserted from the neck vein and is then placed into a hepatic vein. Hydrodissection may also be used in cases where the tumor is adjacent to a critical structure such as the heart or colon. These organs can sustain damage from heating, therefore a catheter is inserted into the space separating them and the tumor and fluid (dextrose 5%) is administered during the ablation.
%&'(
cryoablation 3.5.3

The freeze zone of cryoablation effects depend upon the probe size and configuration as well as the nadir of the freeze cycle (dependent upon the specific cryogen). Two cryoablation systems are commercially available and FDA cleared for human use (Endocare / Healthtronics and Galil). Both use helium and argon gases to induce lethal temperatures locally.  
The systems require argon and helium gases which produce low temperatures upon phase change from gas to liquid. The cryotherapy equipment will be an argon-helium gas system using 1.6mm or 2.4 mm cryoprobes (Endocare, Inc., Irvine, CA) or 0.049 inches = 18 gauge = 1.3 mm cryoprobes (Galil). The ice-ball diameters for these probes may vary according to the tissue and blood supply, but their freeze lengths should be comparable to the RFA system (10-30 mm). Iceball diameters refer to the outer 0°C margin, but cytotoxic temperatures (e.g., < -20 to -40 °C) are known to occur 3-5 mm behind visualized ice margins. A 10-20 minutes' freeze, followed by a 5-10 minutes' thaw, and a 10-20 minute re-freeze produces visible ice and necrosis by rapid and slow mechanisms (dehydration and vascular stasis). The specific times depend upon the temperatures and potentially the temperatures of any remote thermometry used to asse4ss temperature at the margin of a freeze. Rapid intracellular ice formation causes irreversible cell
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+ tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy.  
Non-sterilized male partners of a female patient must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Not engaging in sexual activity for the total duration of the drug treatment and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Female patients should also refrain from breastfeeding throughout this period.  
If a patient becomes pregnant during the course of the study, the study drugs should be discontinued immediately.
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Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy. Not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period.  
Female partners (of childbearing potential) of male patients must also use a highly effective method of contraception throughout this period (Table 2). Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral ophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).  
Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiationinduced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are described in Table 2. Note that some contraception methods are not considered highly effective (e.g. male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; noncopper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).  
Table 2 Highly Effective Methods of Contraception (< 1% failure rate)  
| #$%%&'%()*+%$,+'%&*' -'+./01   | 2/%3/*$4 -'+./01                                                |    |                                                             |
|--------------------------------|-----------------------------------------------------------------|----|-------------------------------------------------------------|
| 5                              | 67889: ; <=>:?@>9:<=9 A9B<C9                                    | 5  | Q>7=7E9F>:9G <J8G?=>FR 9LEL SJ8G?=7= 7: T7:8G?=             |
| 5                              | D9B7=7:E9F>9:9GH:9G9?F<=E <=>:?@>9:<=9 FIF>9J  K9LELM N<:9=?OP? | 5  | S=>:?B?E<=?G A9B<C9R 9LEL 9>U<=IG9F>:?A<7G ?=A 9>7=7E9F>:9G |
| 5                              | N9A:7VI8:7E9F>9:7=9 <=W9C><7=R 9LEL X987H Y:7B9:?               |    |                                                             |
| 5                              | T7:J?G ?=A G7Z A7F9 C7J[<=9A 7:?G C7=>:?C98><B9 8<GG            |    |                                                             |
| 5                              | T7:9GE9F>:7J<=\9>U<=IG9F>:?A<7G >:?=FA9:J?G FIF>9J              |    |                                                             |
| 5                              | 69:?]9>>9 KA9F7E9F>:9GP                                         |    |                                                             |
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| #$%%&'()*+ ,+-)./()&01.2/33 &4 -'$5                 | 63/5+     |
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| =9::<8>                                             |           |
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| YzS MC WUAV                                                                 |        |
| MAEJFAVJEI                                                                  | [{|\X ~YS MC        |
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| ^A>D@ @?DU                                                           | ?B G>DFIBNIA?F JCUAHAFC |                        |                        |                         |
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| GNR?> ZA?=IO                                                         | lT                      | l`T                    | LCC LENUO MD@CFUD> V4W | YDZ?>DE?>O ?B eDEm?@?iO |
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baseline and in response to tremelimumab treatment will be evaluated for any relationship with treatment outcome.  
Plasma-based assays for circulating receptors/ligands e.g. PDL1 5.3.4 Plasma samples are to be collected at the time points listed directly in Study Calendar 3.6 into plastic 6 ml lavender vacutainer tube with EDTA as anticoagulant. 2-3 ml of obtained plasma are to be aliquoted (1 ml each) and frozen. Samples may be analyzed for circulating levels of soluble factors such as CRP, cytokines, and chemokines. They may include but are not limited to soluble CTLA-4, soluble PD-L1, soluble B7.1/B7.2, soluble IL-6R, vascular endothelial growth factor, fibroblast growth factor, IL-1 IL-2, IL-4, IL-6, IL-8, IL-10, cancer biomarkers (alpha fetoprotein, carcinoembryonic antigen, cancer antigen 125, prostate specific antigen, soluble mesothelinrelated protein [SMRP]), granzyme B, IFN, C-X-C motif chemokine 10 (CXCL10), suppressor of cytokine signaling 3 (SOCS3), a proliferation inducing ligand, B-cell activating factor, insulin-like growth factor (IGF)-1, IGF-2, and autoantibodies to host and tumor antigens and explore their association with tremelimumab treatment and clinical outcome.
+4<5
sample storage tracking and disposition

Samples will be ordered in CRIS and tracked through Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All samples will be sent to Dr. Figg's lab for processing and storage until they are distributed to Dr.  
Greten's lab, Dr. Altan-Bonnet's lab or MedImmune for sample analysis as described in the protocol. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required. All samples will be barcoded, with data entered and stored in the secure database Labmatrix.  
These databases create a unique barcode ID for every sample and sample box, which cannot be traced back to patients without database access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.). Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C
according to stability requirements.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in database. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval.  
5.4.1 Samples Managed by Dr. Figg's Blood Processing Core (BPC)
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred).  
For sample pickup, page 102-11964.  
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number) or pager number\# 11964. For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov .  
5.4.2 Dr Greten Lab Contact information Contact information: Sophie Wang Building 10 Rm 3B44 Phone: 240-858-3218 E-mail: sophie.wang@nih.gov Protocol Completion/Sample Destruction 5.4.3 All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described in sections above. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. If the patient withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be done per the requirements of section 7.2.
+4<5
data collection and evaluation 6

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system (C3D) and Labmatrix ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant.  
All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1 of Cycle 1 through 90 days after the subject received the last study drug administration. Beyond 90 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory abnormality is characterized by any of the following:
.  
Results in discontinuation from the study  
.  
Is associated with clinical signs or symptoms
.  
Requires treatment or any other therapeutic intervention
.  
Is associated with death or another serious adverse event, including hospitalization.
.  
Is judged by the Investigator to be of significant clinical impact
.  
If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
Data collection required by MedImmune described in Appendix E End of study procedures: Data will be stored according to HHS, FDA, and NIH Intramural Records Retention Schedule regulations as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section 7.2.1.
+4<5
data sharing plans 6.2 6.2.1

I will share coded, linked human data generated in this research for future research in a NIH- funded or approved public repository (clinicaltrials.gov, dbGaP), in BTRIS, with approved outside collaborators under appropriate agreements, in publication and/or public presentations at the time of publication or shortly thereafter.
+4<5
6.2.2 genomic data sharing plan

Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy
+4<5
response criteria 6.3

For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4-8 weeks following initial documentation of objective response.  
Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline
(version 1.1)[ 37 ]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST
criteria.