11.1.1 Definitions Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first treatment with INCB024360 followed by MELITAC 12.1 vaccine. Evaluable for objective response. Only those pa tients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re- evaluated will be considered evaluable for res ponse. These patients will have their response classified according to the definitions stated below. (NOTE: Patients who exhibit objective disease progression before the end of cycle 1 will also be considered evaluable.) Evaluable Non-target Disease Response. Patients who have lesions pres ent at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their diseas e re-evaluated will be considered evaluable for non-target disease. The response assessmen t is based on the presence, absence, or unequivocal progression of the lesions. 11.1.2 Disease Parameters Measurable disease. Measurable lesions ar e defined as those that can be accurately measured in at least one dimension (l ongest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or cal ipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). NOTE: Tumor lesions that are situated in a prev iously irradiated area might or might not be considered measurable Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when asse ssed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 67 Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesi ons (neither measurable nor nonmeasurable) since they are, by definition, simple cysts. ‘Cystic lesions’ thought to repr esent cystic metastases can be considered as measurable lesions, if they meet the definition of m easurability described above. However, if non- cystic lesions are present in the same patient , these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of al l involved organs, shoul d be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions w ith the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstan ce the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal le sions) for all target lesions wi ll be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regres sion in the measurable dimension of the disease. Non-target lesions. All other le sions (or sites of disease) in cluding any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 11.1.3 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at ba seline and during follow-up. Imaging-based evaluation is preferre d to evaluation by clin ical examination unless the lesion(s) being followed cannot be imaged but ar e assessable by clinical exam. Clinical lesions Clinical lesions will onl y be considered measurable when they are NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 68 superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules ). In the case of skin le sions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e .g., for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, sp atial, and temporal resolution; however, there are many image ac quisition variables involved in MRI, which greatly impact image quality, lesion conspicu ity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used sh ould be optimized for the evaluation of the type and site of disease. Furt hermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the le sions should be measured /assessed on the same pulse sequence. It is beyond th e scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acqui sition protocol should be followed as closely as possible to prior scans. Body scans shoul d be performed with breath-hold scanning techniques, if possible. PET-CT At present, the low dose or attenuation correction CT portion of a combined PET- CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and or al contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accu rately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not r outinely or serially performed. Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, b ecause they are operator dependent, it cannot be guaranteed that the same technique a nd measurements will be taken from one assessment to the next. If new lesions are id entified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy The utilization of thes e techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm co mplete pathological response when biopsies are obtained or to de termine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 69 Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guide lines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurr ent prostate cancer) have been published [Bubley 1999; Rustin 2004; Scher 2008 ]. In addition, the Gyneco logic Cancer Intergroup has developed CA-125 progression criteria which are to be in tegrated with objective tumor assessment for use in first-line trials in ovarian cancer [ Vergote 2000 ]. Cytology, Histology These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria fo r response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatm ent) and progressive disease. FDG-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-P ET scanning to complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: a. Negative FDG-PET at baseline, with a posit ive FDG-PET at follow-up is a sign of PD based on a new lesion. b. No FDG-PET at baseline and a positive F DG-PET at follow-up: If the positive FDG- PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not c onfirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG- PET scan). If the positive FDG-PET at follow- up corresponds to a pre-existing site of disease on CT that is not progressing on the ba sis of the anatomic images, this is not PD. c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to repr esent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-sp ecific medical literat ure for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. NOTE: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surroundi ng tissue on the attenuation corrected image. 11.1.4 Response Criteria 11.1.4.1 Evaluation of Target Lesions by RECIST Complete Response (CR): Disappearance of a ll target lesions. Any pathological lymph nodes (whether target or no-nt arget) must have reduction in short axis to <10 mm. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 70 Partial Response (PR): At least a 30% decreas e in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% incr ease in the sum of the diameters of target lesions, taking as reference the smallest su m on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (NOTE : the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient sh rinkage to qualify for PR nor sufficient increase to qualify for PD, taking as refe rence the smallest sum diameters while on study. 11.1.4.2 Evaluation of Non-targ et Lesions by RECIST Complete Response (CR): Disappearance of a ll non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). NOTE: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be consider ed in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion stat us. It must be representati ve of overall disease status change, not a single lesion increase. Although a clear progressi on of “non-target” lesions only is exceptional, the opinion of the treating physician should pr evail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Prin cipal Investigator). 11.1.4.3 Evaluation of Target Lesions by irRC Complete Response (irCR): Complete disappear ance of all lesions (whether measurable or not, and no new lesions) confirmati on by a repeat, consecu tive assessment no less than 4 weeks from the date first documented. Partial Response (irPR): A ≥50% decrease in tumor burden compared with baseline in 2 observations at least 4 weeks apart. (NOTE: For irRC, index and measurable lesions are taken into account. At the baseline tumor assessment, the sum of the products of the 2 largest perpendicular diameters (SPD) of a ll index lesions (5 lesions per organ, up to 10 visceral lesions and 5 cuta neous index lesions) is calcul ated. At each subsequent tumor assessment, the SPD of the index lesi ons and of the new, measurable lesions ( ≥5 × 5mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 71 are added together to provide the total tumor burden: Tumor Burden = SPD index lesions + SPD new, measurable lesions Progressive Disease (irPD): At least 25% increase in tumor burden compared with nadir (at any single time point) in 2 consecuti ve observations at least 4 weeks apart. (NOTE: The appearance of 1 or more new lesi ons does not define progression but does preclude irCR). Stable Disease (irSD): A 50% decrease in tumor burden compared with baseline cannot be established, nor can a 25% in crease compared with nadir. 11.1.4.4 Evaluation of Best Overall Response (RECIST) The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since th e treatment started). The patient’s best response assignment will depend on the achievement of both measurement and confirmation criteria. For Patients with Measurable Disease ( i.e., Target Disease) Target Lesions Nontarget Lesions New LesionsOverall ResponseBest Overall Response when Confirmation is Required* CR CR No CR ≥4 wks. Confirmation** CR Non-CR/Non-PD No PR ≥4 wks. Confirmation** CR Not evaluated No PR PR Non-CR/Non-PD/not evaluated No PR SD Non-CR/Non-PD/not evaluated No SD Documented at least once ≥4 wks. from baseline** PD Any Yes or No PD no prior SD, PR or CR Any PD*** Yes or No PD Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** Only for nonrandomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progr ession in nontarget lesions may be accepted as disease progression. NOTE : Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment. For Patients with Non-measurable Disease ( i.e., Non-target Disease) Nontarget Lesions New Lesions Overall Response CR No CR Non-CR/non-PD No Non-CR/non-PD* Not all evaluated No not evaluated NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 72 Unequivocal PD Yes or No PD Any Yes PD  “Non-CR/non-PD” is preferred over “stable disease” for nontarget disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 11.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whi chever is first recorded) until the first date that recurrent or progressive disease is obj ectively documented (taking as reference for progressive disease the smallest measuremen ts recorded since the treatment started). The duration of overall CR is measured from th e time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as re ference the smallest measurements recorded since the treatment started, includ ing the baseline measurements. 11.1.6 Progression-Free Survival – N/A 11.1.7 Response Review No review of response rate is contemplate d. Investigator determined responses will be chronicled. 11.2 Antitumor Effect – Hematologic Tumors - N/A 11.3 Other Response Parameters 11.3.1 Circulating Tumor Cells Circulating tumor cells will be en umerated by the approved CELLSEARCH ® assay (Veridex LLC, Raritan, NJ) as exploratory analysis. 12. DATA REPORTING/REGULATORY REQUIREMENTS Adverse event lists, guidelines, and instru ctions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements). NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 73 12.1 Data Reporting 12.1.1 Method This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. Reports are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web site: (http://ctep.cancer.gov /reporting/cdus.html) Note: This study has been assigned to CDUS-A bbreviated reporting. No adverse event reporting (routine or expedited) is required to be reported via CDUS. 12.1.2 Responsibility for Data Submission The CITN COSC is responsible for compiling and submitting CDUS data for all participants. The Coordinating Center will submit the data quarterly. The date for submission to the CITN will be set by them. When setting the dates, allow time for Coordinating Center compilati on, Principal Investigator revi ew, and timely submission to CTEP by the quarterly deadlines (see Section 12.1.1). The CITN COSC is responsible for compiling and submitting CDUS data to CTEP for all participants and for providing the data to the Principal Investigator for review. 12.2 CTEP Multicenter Guidelines This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. The specific responsibilities of th e Principal Investigator and the Coordinating Center (Study Coordinator) and the pro cedures for auditing are presented in Appendix B .  The CITN COSC is responsible for distri buting all IND Action Letters or Safety Reports received from CTEP to all participating institutions for submission to their individual IRBs for action as required.  Agent will be supplied by Incyte Corporation. Agent distribution to a participating site will occur only after all required regul atory documents have been submitted to the appropriate institution at the dire ction of the CITN Coordinating Center. 12.3 Collaborative Agreements Language – N/A NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 74 13. STATISTICAL CONSIDERATIONS 13.1 Study Design/Endpoints The proposed study is a Phase II, open label, multicenter study of the administration of INCB024360, an IDO1 inhibitor, plus a multipeptide melanoma vaccine, MELITAC 12.1, in patients with advanced (i .e., surgically incurable stage III or IV) melanoma having tissue amenable to serial biopsy. The first 3 patients will be administered the INCB024360 in a reduced amount of 300 mg bid and enrolled in a staggered design with a 2-week waiting period between each of the first 3 patients ( Table 5.1 ). This is a safety precaution due to unknown effects of the combination of INCB024360 with the multipeptide melanoma vaccine. Although both agents have excellent safety profiles, unexpect ed toxicities could occu r when used together. Each patient’s tumor(s) will be biopsied befo re therapy and during therapy to assess the effects of INCB024360 and vaccine by IHC and transcriptome analysis ( Table 5.1 ). INCB024360 is expected to normalize serum Ky n/Trp ratios, in turn altering the tumor microenvironment, which includes the number and character of tumor-infiltrating T cells. The addition of MELITAC 12.1, a multipeptid e melanoma vaccine, will be used to compare INCB024360 alone and with the vaccine. Effects of IDO i nhibition on systemic vaccine-induced immunity will be asse ssed by evaluating peripheral blood immune responses to the MELITAC 12.1 vaccine. The co mparator for immune responses will be taken from published experience with simila r patients treated with the same vaccine regimen but without INCB024360 [Slingluff 2011 ; Slingluff 2009 ]. 13.2 Primary Endpoint Published data on immune cell infiltration of melanoma metastases showed that amongst 148 metastases, CD8 T cells ranged from 0 to 592 per mm2. The mean was 137, with standard deviation of 143; median 94 pe r mm2.[ Erdag, Cancer Research 2012] The primary endpoint will be changes in the concentration and number of CD8+ cells infiltrating tumor pre- and post-treatment with each patient serving as their own control so that relative increases within each patient will be assessed. We will use the assessment of total CD3 T cells and total CD45 lymphocytes as confirmatory assays. Twelve patients should enable adequate power to discern large changes (e.g. increases of about 1 SD of the original data set.) 13.3 Sample Size/Accrual Rate The study plans to enroll a total of 12 patients at 3 or 4 clinical research sites. Each patient will act as their own control. Patients without adequate sampling for immune responses will be replaced. Accrual rate of patients is expected to be approximately 3 patients per month. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 75 13.4 Stratification Factors - None 13.5 Analysis of Secondary Endpoints 13.5.1 To determine whether a regimen 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+ specific T-cell immune responses as measured in peripheral blood, as compared to prior publishe d experience. 13.5.2 To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the number and character of PB MC populations, including T and NK cells, as evaluated by multiparameter flow cytometry. 13.5.3 To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the PBMC transcriptome. 13.5.4 To assess the safety and tolerability of INCB024360 plus MELI TAC 12.1 vaccine. 13.5.5 To obtain preliminary data on the tumor response rate of INCB024360 plus MELITAC 12.1 vaccine by ORR, time to tumor progression, and overall survival. 13.5.6 To associate any observed changes with the expr ession of IDO1 protein by IHC in tumor or tumor-infiltrating cells. 13.6 Reporting and Exclusions 13.6.1 Evaluation of Toxicity All patients will be evaluable for toxicity from the time of their first treatment with INCB024360. 13.6.2 Evaluation of Response All patients included in the study will be asse ssed for response to treatment, even if major deviations from protocol treatment occur or if they are ineligible. Each patient will be assigned one of the following categories: (1 ) complete response,( 2) partial response, (3) stable disease, (4) progressive disease, (5 ) early death from maligna nt disease, (6) early death from toxicity, (7) early death because of other cause, or (9) unknown (not assessable, insufficient data). [NOTE: By arbitrary convention, category 9 usua lly designates the “ unknown” status of any type of data in a clinical database.] All of the patients who met the eligibility crite ria (with the possible ex ception of those who received no study medication) will be included in the main analysis of the response rate. Patients in response categories 4–9 will be consid ered to have a treatment failure (i.e., disease progression). Thus, an incorrect trea tment schedule or drug administration does not NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 76 result in exclusion from the an alysis of the response rate. All conclusions will be based on all eligible patients. Subanalyses may then be performed on the basis of a subset of pa tients, excluding those for whom major protocol deviations have been identified (e.g., ear ly death due to other reas ons, early discontinuation of treatment, major protocol violations, etc.). Ho wever, these subanalyses will not serve as the basis for drawing conclusions concerning treat ment efficacy, and the reasons for excluding patients from the analysis will be clearly reported. The 95% confidence intervals will also be provided. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 77 REFERENCES Brinckerhoff, L. H., V.