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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

Spots Global Cancer Trial Database for melitac 12.1 peptide vaccine