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Melanoma

Melanoma, Cutaneous Malignant

Uveal Neoplasms

Skin Neoplasms

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Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Eye Neoplasms

Uveal Diseases

Intraocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Vaccines

Patients receive epacadostat PO BID on days 1-98 and receive MELITAC 12.1 peptide vaccine ID/SC on days 21, 28, 35, 56, 77, and 98 for up to 3 additional courses in the absence of disease progression or unacceptable toxicity.

Epacadostat

MELITAC 12.1 Peptide Vaccine

Craig Slingluff

This pilot phase II trial studies how well epacadostat and vaccine therapy work in treating patients with stage III-IV melanoma. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vaccines made from peptides and antigens may help the body build an effective immune response to kill tumor cells. Giving epacadostat with vaccine therapy may be an effective treatment for advanced melanoma.

PRIMARY OBJECTIVES:

I. To determine the extent to which a regimen of INCB024360 (epacadostat) that normalizes serum kynurenine (Kyn)/ tryptophan (Trp) ratios alters the tumor microenvironment of melanoma, including determining the number and character of tumor-infiltrating lymphocytes as determined by examination of serial biopsies with immunohistochemistry (IHC) and gene signatures.

II. To determine the extent to which continued INCB024360 treatment plus the addition of the multipeptide melanoma vaccine, MELITAC 12.1 (MELITAC 12.1 peptide vaccine), further alters the tumor microenvironment of melanoma, including determining the number and character of tumor-infiltrating lymphocytes as determined by serial biopsies evaluating IHC and gene signatures.

SECONDARY OBJECTIVES:

I. 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 clusters of differentiation (CD) 8+ and CD4+ T-cell immune responses as measured in peripheral blood, as compared to prior published experience.

II. To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the number and character of peripheral blood mononuclear cell (PBMC) populations, including T and natural killer (NK) cells, as evaluated by multiparameter flow cytometry.

III. To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the PBMC transcriptome.

IV. To assess the safety and tolerability of INCB024360 plus MELITAC 12.1 vaccine.

V. To obtain preliminary data on the tumor response rate of INCB024360 plus MELITAC 12.1 vaccine by objective response rate (ORR), time to tumor progression, and overall survival.

VI. To associate any observed changes with the expression of IDO1 protein by IHC in tumor or tumor-infiltrating cells.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) on days 1-98 and receive MELITAC 12.1 peptide vaccine intradermally (ID)/subcutaneously (SC) on days 21, 28, 35, 56, 77, and 98. Treatment with epacadostat may repeat every 98 days for up to 3 additional courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

A Phase II Pilot Trial of an Indoleamine 2,3, Dioxygenase-1 (IDO1) Inhibitor (INCB024360) Plus a Multipeptide Melanoma Vaccine (MELITAC 12.1) in Patients With Advanced Melanoma

Immunohistochemistry: Tumors were assessed by IHC for pattern of T-cell distribution and infiltration of cells expressing CD3 and CD8.

Immunohistochemistry: Tumors (day 21 \& day 42) were assessed by IHC for pattern of T-cell distribution and infiltration of cells expressing CD3 and CD8.

Analysis of PBMC gene signature. This may be compared to immunologic response, tumor biopsy data and clinical response

Assessment of immunologic response will be based on a fold-increase measure from baseline as well as using a positivity threshold

Incyte Corporation

National Cancer Institute (NCI)

University of Virginia

Fred Hutchinson Cancer Center

Principal Investigator

Pts. enrolled \>6 wks after failing anti-PD-1/PDL-1

Cohort A

Pts. enrolled 2-6 wks after failing anti-PD-1/PDL-1

Cohort B

Pts. enrolled who have not been treated with check point inhibition

* 100 mg INCB024360 po bid continuous for 98 days
* MELITAC 12.1 intradermal/subcutaneous on days 21, 28, 35, 56, 77, 98

Laboratory Biomarker Analysis: Correlative studies

All Other Patients

Pts. enrolled \>6 wks after failing anti-PD-1/PDL-1 INCB024360 - 300 mg po bid continuous for 98 days MELITAC 12.1 - Intradermal/subcutaneous Days 21, 28, 35, 56, 77, 98

Pts.enrolled 2-6 wks after failing anti-PD-1/PDL-1

* INCB024360 - 100 mg po bid continuous for 98 days
* MELITAC 12.1 - Intradermal/subcutaneous Days 21, 28, 35, 56, 77, 98

All advanced melanoma patients not previously treated with anti-PD-1 \& anti-PD-L1 who meet protocol entry criteria INCB024360 - 300 mg po bid continuous for 98 days MELITAC 12.1 - Intradermal/subcutaneous Days 21, 28, 35, 56, 77, 98

Total

Age calculated between time of consent and date of birth.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Martin A. Cheever

Pts.enrolled \>6 wks after failing anti-PD-1/PDL-1

Pts will receive 300mg INCB024360 p.o. bid continuous for 98 days + MELITAC 12.1 vaccine on days 21, 28, 35, 56, 77 \& 98

Pts.enrolled 2-6 wks after failing anti-PD-1/PDL-1

Pts. receive 100 mg po bid INCB024360 continuous for 98 days + MELITAC 12.1 vaccine on days 21, 28, 35, 56, 77 \& 98

All advanced melanoma patients not previously treated with anti-PD-1 \& anti-PD-L1 who meet protocol entry criteria

Pts. will receive 300 mg INCB024360 po bid for 98 days + MELITAC 12. 1 vaccine on days 21, 28, 35, 56, 77 \& 98

For one subject in cohort A day 21 tumor biopsy material was not obtained (For analysis of Cohort A n = 1). For analysis of Cohort "All Other Patients" n = 7 due to day 21 biopsy not being obtained in 2 other subjects. In addition, for one of those subjects there was no baseline tumor biopsy obtained.

Changes in the Concentration and Number of CD8+ Cells Infiltrating Tumor by IHC by Normalization of Kyn/Trp Ratios.

Neither subject in cohort A had day 42 tumor biopsy material available. For analysis of Cohort "All Other Patients" n = 6 due to either a day 21 biopsy missing or a missing day 42 biopsy.

Changes in the Concentration and Number of CD8+ Cells Infiltrating Tumor by IHC by Normalization of Kyn/Trp Ratios in Combination With MELITAC 12.1

Change in PBMC Transcriptome_v2

Change in the Number and Character of PBMC Populations, Including T and NK Cells, as Evaluated by Multiparameter Flow Cytometry_v2

Changes in Expression of IDO1 Protein by IHC in Tumor or Tumor-infiltrating Cells_v2

Changes in the Level or Character of the Vaccine-induced CD8+ and CD4+ Specific T-cell Immune Responses by IFN-gamma ELISPOT_v2

Incidence of Adverse Events Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0_v2

Overall Response Rate Using the RECIST or Immune-Related Response Criteria (irRC)_v2

Overall Survival_v2

Time to Tumor Progression Using RECIST or irRC_v2

Cohort A - Pts. enrolled \>6 wks after failing anti-PD-1/PDL-1 received 300 mg INCB024360 po BID every day for 98 days Cohort B - Pts. enrolled 2-6 weeks after failing anti-PD-1/PDL-1 received 100 mg INCB024360 po BID every day for 98 days All other pts. - received 300 mg po BID

All pts received MELITAC 12.1 intradermal/subcutaneous on days 21, 28, 35, 56, 77, 98

Pts. enrolled 2-6 wks after failing anti-PD-1/PDL-1 received 300 mg INCB024360 po BID every day for 98 days Cohort B - Pts. enrolled 2-6 weeks after failing anti-PD-1/PDL-1 received 100 mg INCB024360 po BID every day for 98 days

Overall Study

Antineoplastic Agents

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Douglas Johnson

This phase II trial studies how well pembrolizumab works in treating patients with uveal melanoma that has spread to other places in the body and usually cannot be cured or controlled with treatment. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.

PRIMARY OBJECTIVES:

I. To evaluate objective response rate (ORR) in patients with advanced uveal melanoma receiving pembrolizumab.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) in patients with advanced uveal melanoma receiving pembrolizumab.

II. To evaluate safety, tolerability and adverse experience profile of pembrolizumab in uveal melanoma.

III. To evaluate overall survival (OS) in patients with advanced uveal melanoma receiving pembrolizumab.

TERTIARY OBJECTIVES:

I. To evaluate objective response rate (ORR; complete response + partial response) in patients with advanced uveal melanoma receiving pembrolizumab as stratified by programmed cell death-ligand 1 (PD-L1) expression and guanine nucleotide-binding protein (GNA)Q/GNA11 mutation status.

II. To evaluate ORR in patients previously treated with ipilimumab or with mitogen-activated protein kinase kinase (MEK) inhibitors.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Pembrolizumab in Treating Patients With Advanced Uveal Melanoma

A Multicenter Phase II Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) in Patients With Advanced Uveal Melanoma

Differences in PFS and OS between subgroups will be assessed by the stratified logrank test. Differences in ORR between subgroups will be assessed by the Pearson chi-square test. No adjustments will be made for multiple comparisons.

Each relevant clinical characteristic will be recorded by the use of tables and/or graphs. The number and percentage of patients treated, and the primary reason for discontinuation will be displayed. Demographic variables (such as age) and baseline characteristics will be summarized by descriptive statistics. Compliance with pembrolizumab administration will be measured by patients: 1) receiving unscheduled study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages of patients and infusion/injection visits with any deviation in these measures will be reported.

Of note, response rates by RECIST 1.1 criteria will also be assessed although irRC will be used for the primary endpoint. The percentage of complete or partial response is calculated and 95% confidence interval is estimated using Wilson method.

PFS will be summarized using the method of Kaplan and Meier. Median PFS time with 95% confidence intervals will be reported. Using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), progression will be defined as ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions, and/or appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.

The Kaplan-Meier method will be used to estimate the overall survival. Median survival and its 95% confidence interval will be estimated and reported.

If sample size permits, response duration will be summarized descriptively using Kaplan-Meier medians and quartiles. Only the subset of patients who show a complete response or partial response will be included in this analysis.

Count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death. This endpoint will be reported descriptively without formal statistical analysis.

Vanderbilt-Ingram Cancer Center

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

Pembrolizumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

Treatment (Pembrolizumab)

Patients received pembrolizumab treatment and evaluated for response.

Objective Response Rate (ORR), Defined as the Percentage of Patients Achieving a Confirmed Complete or Partial Response, as Defined by Immune-related Response Criteria (irRC)

Progression-Free Survival (PFS) Defined as Time From Treatment to Progression Defined by RECIST1.1 Criteria or Death.

Patients received pembrolizumab treatment.

Overall Survival (OS) Defined as Number of Patients Surviving up to 3 Years.

Only 1 participant had a RECIST-defined response, which is ongoing and lasting 23.5 months.

Response Duration

Number of Patients With Each Worst-Grade Toxicity. Incidence of Adverse Events, Using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma	NCT01961115	Mucosal Melanom... Recurrent Melan... Recurrent Uveal... Stage IIIA Skin... Stage IIIA Uvea... Stage IIIB Skin... Stage IIIB Uvea... Stage IIIC Skin... Stage IIIC Uvea... Stage IV Skin M... Stage IV Uveal ...	Epacadostat MELITAC 12.1 Pe...	18 Years -	Fred Hutchinson Cancer Center
Pembrolizumab in Treating Patients With Advanced Uveal Melanoma	NCT02359851	Stage IIIA Uvea... Stage IIIB Uvea... Stage IIIC Uvea... Stage IV Uveal ...	Pembrolizumab Laboratory Biom...	18 Years -	Vanderbilt-Ingram Cancer Center

Spots Global Cancer Trial Database for stage iiib uveal melanoma