51 8.4 Montanide ISA-51 VG .......................................................................................................54 8.5 Commerical Agent: N/A ....................................................................................................55 NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 6 9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................55 9.1 Biomarker Studies ............................................................................................................. .55 9.2 Laboratory Correlative Studies ..........................................................................................56 9.3 Special Studies: Cytokine and INCB024360 Blood Levels ..............................................61 10. STUDY CALENDAR .......................................................................................................62 11. MEASUREMENT OF EFFECT........................................................................................65 11.1 Antitumor Effect – Solid Tumors ......................................................................................66 11.2 Antitumor Effect – Hematologic Tumors - N/A ................................................................72 11.3 Other Response Parameters ...............................................................................................72 12. DATA REPORTING/REGULATORY REQUIREMENTS .............................................72 12.1 Data Reporting ...................................................................................................................73 12.2 CTEP Multicenter Guidelines ............................................................................................73 12.3 Collaborative Agreements Language – N/A ......................................................................73 13. STATISTICAL CONSIDERATIONS...............................................................................74 13.1 Study Design/Endpoints.....................................................................................................74 13.2 Primary Endpoint .............................................................................................................. .74 13.3 Sample Size/Accrual Rate ..................................................................................................74 13.4 Stratification Factors - None ..............................................................................................75 13.5 Analysis of Secondary Endpoints ......................................................................................75 13.6 Reporting and Exclusions ..................................................................................................75 REFERENCES ……………………………………………………………………………77 APPENDIX A PERFORMANCE STATUS CRITERIA ..................................................81 APPENDIX B CTEP MULTICENTER GUIDELINES ....................................................82 APPENDIX C INFORMATION ON POSSIB LE DRUG INTERACTIONS ...................84 APPENDIX D BIOASSAY TEMPLATES .......................................................................87 APPENDIX E VACCINE PREPARATION .....................................................................88 APPENDIX F PATIENT MEDICATION DIARY ...........................................................91 NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 7 1. OBJECTIVES INCB024360 is an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor w ith the capacity to normalize serum kynurenine/tryptophan (Kyn/Trp) rati os. The goal of this trial is to determine alterations in the tumor microenvironment of melanoma, first using a regimen of INCB024360 that normalizes serum Kyn/Trp ratios and then by adding a multiple peptide melanoma vaccine to INCB024360 treatment. The primary endpoint will be changes in the concentration and number of CD8+ cells, as CD8+ T cell number has been shown to have the best correlation with survival [ Erdag 2012], with each patient serving as their own control. If substantial changes at sites of tumor are detected (i.e., changes in CD8+ T cell infiltration) in response to INCB024360 alone or in combination with the vaccine, subs equent iterative trials will be developed to determine the individual contributions of each agent. 1.1 Primary Objectives Objective 1: To determine the extent to which a regimen of INCB024360 that normalizes serum Kyn/Trp ratios alters the tumor microenvironment of melanoma, including determining the number and character of tumo r-infiltrating lymphocytes as determined by examination of serial biopsies with immunohi stochemistry (IHC) and gene signatures Objective 2: To determine the extent to which continued INCB024360 treatment plus the addition of the multipeptide melanoma vacci ne, MELITAC 12.1, further alters the tumor microenvironment of melanoma, including de termining the number and character of tumor-infiltrating lymphocytes as determined by serial biopsies evaluating IHC and gene signatures 1.2 Secondary Objectives Objective 3: To determine whether a regi men of INCB024360 that normalizes serum Kyn/Trp ratios plus MELITAC 12.1 vaccine changes the level or character of the vaccine-induced CD8+ and CD4+ T-cell immu ne responses as measured in peripheral blood, as compared to prio r published experience Objective 4: To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the number and character of peripheral blo od mononuclear cell (PBMC) populations, including T and natural killer (NK) cells, as evaluated by multiparameter flow cytometry Objective 5: To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the PBMC transcriptome Objective 6: To assess the safety and to lerability of INCB024 360 plus MELITAC 12.1 vaccine NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 8 Objective 7: To obtain preliminary data on the tumor response ra te of INCB024360 plus MELITAC 12.1 vaccine by objective response ra te (ORR), time to tumor progression, and overall survival Objective 8: To associate any observed cha nges with the expression of IDO1 protein by IHC in tumor or tumor-infiltrating cells 2. BACKGROUND 2.1 Study Disease(s) Melanoma represents only 6% of all skin cancer diagnoses, however, it accounts for about 85% of all skin cancer–related deaths [ NCI 2012 ].