1 . Montanide ISA-51 VG The adjuvant Montanide ISA-51 VG has been us ed in a number of clinical trials with little toxicity observed. The possible side effects of receiving Montanide ISA-51 VG adjuvant include local vaccine-site skin reacti on. In addition, a theoretical risk exists for anaphylaxis in response to one of the i ngredients in Montanide ISA-51 VG. Such a NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 46 reaction might include hives, rash, ge neralized swelling of the body, hypotension, dyspnea, and abdominal pain, and possibly death. 7.1.4 CAEPRs for Commercial Agent: N/A 7.1.5 Adverse Event List(s) for CIP (e.g., Study-Sp ecific) Commercial Imaging Agents: N/A 7.2 Adverse Event Characteristics  CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Termi nology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of th e CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electroni c_applications/ctc.htm .  For expedited reporting purposes only: - AEs for the agent that are bold and italicized in the CAEPR ( i.e., those listed in the SPEER column, Section 7.1.1) should be reported thr ough CTEP-AERS only if the grade is above the grade provided in the SPEER. - Other AEs for the protocol that do not re quire expedited reporting are outlined in Section 7.3.4 .  Attribution of the AE: - Definite – The AE is clearly related to the study treatment. - Probable – The AE is likely related to the study treatment. - Possible – The AE may be related to the study treatment. - Unlikely – The AE is doubtfully related to the study treatment. - Unrelated – The AE is clearly NOT related to the study treatment. 7.3 Expedited Adverse Event Reporting 7.3.1 Expedited AE reporting for this study mu st use CTEP-AERS (CTEP Adverse Event Reporting System), accessed vi a the CTEP Web site ( http://ctep.cancer.gov ). The reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting Re quirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP Web site (http://ctep.cancer.gov ). These requirements are briefl y outlined in the tables below (Section 7.3.3). In the rare occurrence when In ternet connectivity is lost, a 24-hour notification is to be made to CTEP by telephone at 301-897-7497. On ce Internet connectivity is restored, the 24-hour notification phoned in must be ente red electronically into CTEP-AERS by the original submitter at the site. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 47 7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local treating physician. CTEP-AERS provides a copy feature for other e-mail recipients. 7.3.3 Expedited Reporting Guidelines Use the NCI protocol number and the protocol -specific patient ID assigned during trial registration on all reports. Note: A death on study requires both rout ine and expedited reporting regardless of causality, unless as noted below. Attribution to treatment or other cause must be provided. Death due to progressive dis ease should be reported as Grade 5 “Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system organ class (SOC) of the same name. Evidence that the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: clinical dete rioration associated with a disease process) should be submitted. Early Phase 2 Studies: Expedited Reporting Re quirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2 FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are considered related to the investi gational agent(s)/intervention (21 CFR 312.64) An adverse event is considered serious if it results in ANY of the following outcomes: 1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospita lization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacit y or substantial disruption of the abi lity to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life th reatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervent ion to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312 .32; ICH E2A and ICH E6). ALL SERIOUS adverse events that meet the abov e criteria MUST be immediatel y reported to the NCI via CTEP- AERS within the timeframes detailed in the table below. Hospitalization Grade 1 and Grade 2 Timeframes Grade 3–5 Timeframes Resulting in Hospitalization ≥ 24 hrs 10 Calendar Days 24-Hour 5 Calendar Days Not resulting in Hospitalization ≥ 24 hrs Not required NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 48 NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Expedited AE reporting timelines are defined as: o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE. 1Serious adverse events that occur more than 30 days after the last administr ation of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for:  All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:  Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last adminis tered. Footnote “1” above applies after this reporting period. Effective Date: May 5, 2011 7.3.4 Additional Protocol-Specific Expedite d Adverse Event Reporting Exclusions : N/A 7.4 Routine Adverse Event Reporting All Adverse Events must be reported in routine study data submissions. AEs reported through CTEP-AERS must also be reporte d in routine study data submissions. 7.5 Secondary Malignancy A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigati onal agent/intervention, radi ation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP -AERS. Three options are available to describe the event:  Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  Myelodysplastic syndrome (MDS)  Treatment-related secondary malignancy Any malignancy possibly related to cancer tr eatment (including AML/MDS) should also be reported via the routine reporting m echanisms outlined in each protocol. 7.6 Second Malignancy A second malignancy is one unrelated to th e treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 49 8. PHARMACEUTICAL INFORMATION A list of the adverse events and potential risks asso ciated with the investigational agent, vaccine and adjuvant administered in this study can be found in Section 7.1 . 8.1 CTEP IND Agent(s): N/A 8.2 INCB024360, Inhibitor of Indoleamin e 2,3-dioxygenase (IDO, NSC # 766086) 8.2.1 Product Description The INCB024360 drug substance is a white to off-white powder. INCB024360 is formulated as an immediate-release tablet in 3 strengths (25 mg, 100 mg, and 300 mg). The tablets contain the active drug (INCB024360) along with commonly used compendial excipients. The chemical name of INCB024360 is ( Z)-N-(3-Bromo-4- fluorophenyl)-N ′-hydroxy-4-(2-(sulfamoylamino) ethylamino)-1,2,5-oxadiazole-3- carboximidamide. INCB024360 has a molecular formula of C11H13BrFN7O4S and a molecular weight of 438.23. The predicted clinical plasma Cmax is ≤10 μM for a pharmacologically active dose of INCB024360. 8.2.2 Storage Conditions The INCB024360 drug product should be stored at ambient conditions (15°–30°C or 59°-86°F). 8.2.3 Stability The INCB024360 drug substance has been shown to be stable for at least 6 months at accelerated ICH conditions of 40°C/75% relati ve humidity and at least 24 months at long-term storage conditions of 25°C/60% relative humidity. INCB 024360 tablets (25 mg and 100 mg) are stable for at least 6 months at accelerated ICH conditions and for at least 12 months at long-term storage conditions. INCB024360 300-mg tablets are stable for at least 1 month at accelerated ICH conditions a nd long-term storage conditions. Stability of INCB024360 drug substance and tablets will be monitored to support ongoing clinical trials. 8.2.4 Route of Administration Administration of INCB024360 is by mouth tw ice daily, taken on an empty stomach at least one hour prior or two hours after a meal. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 50 8.2.5 Overdosage No clinical experience with overdosage of INCB024360 has b een reported. Treatment of overdosage should consist of general supportive measures. 8.2.6 Intended Indications The intended indication for INCB024360 is fo r the treatment of malignant diseases. 8.2.7 Contraindications INCB024360 is contraindicated in subjects with clin ically significant hypersensitivity to any component of its formulation. 8.2.8 Carcinogenesis, Mutagenesis, and Impairment of Fertility Studies INCB024360 was not genotoxic in a non-GLP (good laboratory practice) Salmonella Plate Incorporation Assay. Fert ility studies and carcinogenic ity studies have not been performed. 8.2.9 Usage in Pregnancy INCB024360 should not be used by pregnant wo men. Studies to evaluate the potential for embryo toxicity and teratogenic ity have not been performed. 8.2.10 Nursing Mothers It is not known whether INCB024360 passe s into human milk. INCB024360 should not be taken by nursing mothers. 8.2.11 Availability INCB024360 is an investigationa l agent supplied to investig ators by Incyte Corporation (Wilmington, DE). Incyte Corporation will provide a limited stock supply of INCB024360 to each institution participating in protocol CITN04 prior to the first participant being enrolled. 8.2.12 Potential Drug Interactions: Metabolism of INCB024360 occurs via UGT1A 9 isoenzymes and via glucuronidation. Concomitant use of potent UGT1A9 inducers or inhibitors are prohibited. In vitro data suggests INCB024360 is a substrate and weak in hibitor of P-glycoprotein. Interaction studies have not been performed, but INCB0243 60 is believed to have low potential to cause drug-drug interactions through P-gp interaction. INCB024360 may cause an increase in serotonin levels which has the potential to precipitate serotonin syndrome when administered in combination with monoamine oxidase (MAO) inhibitors or NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 51 serotonergic agents. Concomitant use of MAO inhibitors is prohibited. Use of coumadin is discouraged. Low-dose Coumadin (1 mg) is acceptable; however, doses that increase the INR are discouraged and will require dose modification. If an alternative to coumarin-based anticoagulan ts cannot be used, dose adjustment of the Coumadin may be needed. Based on the observed magnitude of epacadostat (INCB024360)/warfarin PK interaction and PK/P D modeling results, for an epacadostat dose of 300 mg BID, the dose of warfarin s hould be reduced by approximately one-third after initiation of epacados tat (INCB024360) administration based on approximately 30% to 40% reduction in S- and R-warfarin oral clearance values. Close INR monitoring is recommended for patients on a stable dose of warfarin who are starting treatment with epacadostat. Based on PK/PD modeling, recommendations for warfarin dose modifications for subjects receiving other ep acadostat doses, are summarized in the table below based on the INR prior to starting epacadostat. Refer to protocol eligibility criteria for additional information. Stable Baseline INR Epacadostat (INCB024360) Dose < 100 mg BID 200 mg BID 300 mg BID INR < Close INR monitoring Close INR monitoring Reduce warfarin by ~33% and monitor INR INR > Close INR monitoring Reduce warfarin by 20- 25% and monitor INR Reduce warfarin by ~ 33% and monitor INR 8.3 MELITAC 12.1 8.3.1 Product Description The MELITAC 12.1 vaccine has 3 components: 12-MP peptides, Peptide-tet, and Montanide ISA-51 VG vaccine adjuvant, which w ill be prepared together as an emulsion for administration. 12-MP is a multipeptide mixture containing 12 class I MHC-restricted peptides derived from melanocyte differentiation proteins (MDP ) and cancer testis antigens (CTA). The 12 peptides included in the vaccine ar e restricted to HLA-A1, -A2, or -A3 (Table 8.3.1.1). Table 8.3.1.1. 12-MP Peptides Allele Sequence Epitope HLA-A1 DAEKSDICTDEY Tyrosinase 240-251 * SSDYVIPIGTY Tyrosinase 146-56 EADPTGHSY MAGE-A1 161-169 EVDPIGHLY MAGE-A3 168-176 HLA-A2 YMDGTMSQV Tyrosinase 369-377  IMDQVPFSV gp100 209-217 # YLEPGPVTA gp100 280-288 NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 52 GLYDGMEHL MAGE-A10 254-262 HLA-A3 ALLAVGATK gp100 17-25 LIYRRRLMK gp100 614-622 SLFRAVITK MAGE-A1 96-104 ASGPGGGAPR NY-ESO-1 53-62 * (substitution of S for C at residue 244)  (post-translational change of N to D at residue 371) # (209-2M, substitution of M for T at position 210 ) Peptide-tet is a slightly modified form of a 15 residue peptide p2 of tetanus toxoid (QYIKANSKFIGITEL), representi ng amino acid residues 830-844. This peptide binds to HLA-DR1, DRw15(2), DRw18(3), DR4Dw 4, DRw11(5), DRw13(w6), DR7, DRw8, DR9, DRw52a, and DRw52b, which account for 80–90% of the patient population. Because glutamine (Q) at the N-terminus can cy clize, giving rise to a slight change in molecular structure, we have prepared this peptide as a 16-residue species, where an alanine residue (A) has been added to the N- terminus. Thus, the sequence of the tetanus peptide used is AQYIKANSKFIGITEL (Table 8.3.1.2). Table 8.3.1.2. Tetanus Toxoid-derived Helper Peptide Allele Sequence Epitope Binds to multiple class II alleles AQYIKANSKFIGITEL p2 830-844 ** All peptide preparations are l yophilized and stored in steril e vials sealed with a rubber stopper. The peptides are stored at ≤-70oC and protected from light. Each lot of peptide has met the lot release criteria for identity, purity, trifluoroacetic acid (TFA) content, potency, pyrogenicity, general safety, and st erility. Human studies investigating the pharmacokinetics and metabolism of the 12-MP and Peptide-tet vaccines have not been conducted . 8.3.2 Agent Supply 8.3.2.1 12-MP The 12-MP mixture is supplied in sterile si ngle-use vials of lyophilized white powder containing a mixture of the 12 peptides and salts to buffer the solution once reconstituted. Each vial of 12-MP contains 150 μg each of the 12 melanoma pe ptides. All peptides are synthesized under GMP conditions by Multiple Peptide Systems (San Diego, CA). The peptides were vialed under GMP conditions by Clinalfa Line (Merck Biosciences AG, Laufelfingen, Switzerland). These 12-MP vi als are provided by the University of Virginia. The University of Virginia will be the distributor of the agent to the research sites. 8.3.2.2 Peptide-tet Peptide-tet is supplied in sterile single-use vial s of white powder. Each vial of Peptide-tet contains 300 μg of tetanus peptide. The peptide was synthesized under GMP conditions by Multiple Peptide Systems (San Diego, CA). The peptides were vialed under GMP conditions by Clinalfa Line (Merck Bios ciences AG, Laufelfingen, Switzerland). The agent is provided by the University of Virginia. The University of Virginia will be the distributor of the agent to the research sites. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 53 8.3.3 Solution Preparation All vaccines are to be made in a certifie d, sterile laminar flow hood. The emulsion will be prepared as 3-mL quantities: 2 mL of this emulsion will be administered, with 1 mL of emulsion administered at each of 2 vaccine site s. At each site, half of each dose (0.5 mL) will be injected subcutaneously and half (0.5 mL) will be injected intradermally. The remaining 1 mL of the prepared emulsion is to be discarded. The 2-mL dose of each vaccine contains 100 μg each of the 12 peptides listed in Table 1 of Appendix E and 200 μ g of tetanus peptide ( Table 2 of Appendix E ), emulsified in 1 mL of Montanide ISA-51 VG adjuvant. See Appendix E for complete solution preparation instructions. 8.3.4 Storage Requirements Vials of lyophilized peptid es should be stored at ≤-70°C and protected from light. All peptide preparations are lyophi lized and stored in sterile vials sealed with a rubber stopper. Each lot of peptide has met the lot release criteria for identity, purity, TFA content, potency, pyrogenicity, ge neral safety, a nd sterility. Ideally, vials of the 12-MP and Peptide-tet s hould be thawed just before preparing a vaccine (i.e., thawed at room temperatur e for 1–2 minutes before reconstitution). Repeated freeze-thaws should be avoided. Vial s that are frozen and thawed >2 times should not be used. Vials should not be left at room temper ature for more than 24 hours. 8.3.5 Stability All peptide preparations will be assayed for stability at months 3, 6, 12, 24, and 36. High- performance liquid chromatography will be pe rformed to confirm purity and sterility testing will be conducted in accord with FDA guidelines in 21 CFR, part 610.12. In addition, 1 vial of peptide will be submitte d to either the Clinical Microbiology Laboratory at the University of Virginia or Microbiology Research Associates, Inc. (Acton, MA). MELITAC 12.1 vaccine comprises 100 μg each of the 12-MP mixture plus 190 μg of Peptide-tet. Peptides are synthesized under GMP conditions by PolyPeptide Group (formerly Multiple Peptide Systems), reconstituted, mixed, sterile-filtered, and vialed under GMP conditions by Merck. The 12–melanom a peptide mixture and tetanus peptide preparation are made as separate sterile aq ueous solutions to be administered in an emulsion with Montanide ISA-51 VG adjuvant (1 mL), using the 2-syringe method after emulsion stability and quality is verified. After a peptide-based vaccine is mixed, the pr epared vaccine should be refrigerated until just before administration. Ideally, the vacci ne should be administered within 1–2 hours after mixing. The vaccine must be administered within 4 hours of mixing. If the vaccine is not administered within 4 hours of mixing, it should be discarded. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 54 8.3.6 Route of Administration All participants will receive 6 vaccination times over 12 weeks with MELITAC 12.1 (100 μ g of each of 12 Class I MHC restricted melanoma peptides) ( Table 1 of Appendix E ) and 200 μg of a tetanus helper peptide ( Table 2 of Appendix E ) emulsified in Montanide ISA-51 VG adjuvant. In a given patient, half of the vaccine solution will be administered subcutaneously and half intrad ermally, once each week (vaccines 1–3), then once every 3 weeks (vaccines 4–6), in rotating skin locations on extr emities clinically uninvolved with melanoma. For each vaccine, a total of 2 mL of emulsion will be delivered, which will consist of 1 mL of Montanide ISA-51 VG and the MELITAC 12.1 peptides. The vaccine dose will be divided and administered into 2 extremity sites uninvolved with melanoma (typically upper outer arm and/or upper lateral thigh). At each injection site, a single needle punctu re is to be performed, with delivery of 0.5 mL into the dermis and 0.5 mL into the su bcutaneous tissue. This usually will require advancing the needle into the dermis, parallel with the skin surface, to deliver the first 0.5 mL, then pulling the needle ba ck to near the skin puncture site, and advancing it into the subcutaneous tissue for delivery of the remaining 0.5 mL. For the dermal injections, it is acceptable to make several passes of the needle as the emulsion is delivered, where those needle passes are oriented radi ally from the needle puncture site. 8.4 Montanide ISA-51 VG 8.4.1 Product Description The adjuvant Montanide ISA-51 VG has been us ed in a number of clinical trials with little toxicity observed. The possible side effects of receiving Montanide VG adjuvant include anaphylaxis in respons e to one of the ingredients (rare). Such a reaction might include hives, rash, generalized swe lling of the body, hypotension, dyspnea, and abdominal pain, and possibly death. 8.4.2 How Supplied Montanide ISA-51 VG is supplied in a glass co ntainer as a sterile, clear, pale yellow liquid by Seppic, Inc. (Fairfiel d, NJ). It is commercially available from Seppic, Inc., and will be distributed by the University of Virginia. 8.4.3 Solution Preparation The vaccine adjuvant Montanide ISA-51 VG is prepared as a GMP-grade agent, in single-use glass vials or ampules. Refer to Appendix E for complete vaccine preparation instructions. 8.4.4 Storage Conditions Montanide ISA-51 VG should be st ored at room temperature. NCI Protocol #: CITN-04 Version Date: 27 Jan 2016 55 8.4.5 Stability An expiration date for Montanide ISA-51 VG is provided by Seppic, Inc., and the drug should not be used beyond this date. 8.4.6 Route of Administration Refer to Appendix E for complete vaccine preparation instructions.