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INCB024360 and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Incyte Corporation
University of Virginia
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01961115
First received: October 8, 2013
Last updated: November 5, 2014
Last verified: November 2014
  Purpose

This pilot phase II trial studies how well INCB024360 (indoleamine 2,3-dioxygenase 1 [IDO1] inhibitor INCB024360) and vaccine therapy work in treating patients with stage III-IV melanoma. IDO1 inhibitor INCB024360 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 IDO1 inhibitor INCB024360 with vaccine therapy may be an effective treatment for advanced melanoma.


Condition Intervention Phase
Mucosal Melanoma
Recurrent Intraocular Melanoma
Recurrent Melanoma
Stage IIIA Intraocular Melanoma
Stage IIIA Melanoma
Stage IIIB Intraocular Melanoma
Stage IIIB Melanoma
Stage IIIC Intraocular Melanoma
Stage IIIC Melanoma
Stage IV Intraocular Melanoma
Stage IV Melanoma
Drug: IDO1 inhibitor INCB024360
Biological: MELITAC 12.1 peptide vaccine
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Changes in the concentration and number of CD8+ cells infiltrating tumor by IHC [ Time Frame: Baseline to up to 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in the level or character of the vaccine-induced CD8+ and CD4+ specific T-cell immune responses by IFN-gamma ELISPOT [ Time Frame: Baseline to up to 16 weeks ] [ Designated as safety issue: No ]
    Assessment of immunologic response will be based on a fold-increase measure from baseline as well as using a positivity threshold.

  • Change in the number and character of PBMC populations, including T and NK cells, as evaluated by multiparameter flow cytometry [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]
  • Change in PBMC transcriptome [ Time Frame: Baseline to up to 16 weeks ] [ Designated as safety issue: No ]
    Analysis of PBMC gene signature. This may be compared to immunologic response, tumor biopsy data and clinical response.

  • Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
  • Overall response rate using the Response Evaluation Criteria In Solid Tumors (RECIST) or Immune-Related Response Criteria (irRC) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Time to tumor progression using RECIST or irRC [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From the time measurement criteria are met for complete response or partial response until the first date that recurrent and progressive disease is objectively documented, assessed up to 1 year ] [ Designated as safety issue: No ]
  • Changes in expression of IDO1 protein by IHC in tumor or tumor-infiltrating cells [ Time Frame: Baseline up to 16 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: September 2013
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (INCB024360, MELITAC 12.1)
Patients receive IDO1 inhibitor INCB024360 PO BID on days 1-98 and receive MELITAC 12.1 peptide vaccine ID/SC on days 21, 28, 35, 56, 77, and 98 in the absence of disease progression or unacceptable toxicity.
Drug: IDO1 inhibitor INCB024360
Given PO
Other Names:
  • INCB024360
  • indoleamine-2,3-dioxygenase inhibitor INCB024360
Biological: MELITAC 12.1 peptide vaccine
Given ID/SC
Other Name: MELITAC 12.1
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the extent to which a regimen of INCB024360 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 IDO1 inhibitor INCB024360 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 in the absence of disease progression or unacceptable toxicity.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have malignant melanoma validated by histology or cytology; patients may have had primary cutaneous, mucosal, or ocular melanoma or metastasis from an unknown primary site

    • NOTE: patients must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional chest x-ray or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Unresectable stage III or IV validated by clinical criteria (including recurrent melanoma), or patients with multiple skin/soft tissue metastases that may be resectable but are judged to have a future recurrence risk exceeding 90% (e.g., multiple in-transit melanoma metastases); tumor deemed amenable to biopsy (excisional, incisional, or core, with at least 100 mm^3 tumor volume per biopsy date) and fine-needle aspiration (FNA) biopsy

    • NOTE: patients with unresectable advanced stage III or IV melanoma (including recurrent melanoma) are only eligible if they have failed at least one other first-line systemic therapy (other than adjuvant therapy); exceptions to this requirement are those patients who have refused and/or are ineligible for other systemic therapies
    • NOTE: v-raf murine sarcoma viral oncogene homolog B (BRAF)i should be considered for all 'unresectable" or metastatic melanoma with BRAFV600E mutation; for low burden in-transit disease patients may enter trial without prior systemic therapy

      • Stage IV no evidence of disease (NED) is excluded by this criterion
  • Patients may have had prior systemic therapy without constraint on the number of prior treatment regimens except:

    • Patients may not have had > 450 mg/m^2 doxorubicin
    • Patients may not have had > 3000 centigray (cGy) to fields encompassing the entire pelvis
  • Patients must not be on any other systemic therapy within the following intervals before study enrollment:

    • 1 week after stereotactic radiosurgery of the brain or comparable technology
    • 4 weeks after cytotoxic chemotherapy or external beam radiation therapy
    • 6 weeks after chemotherapy regimens including BCNU (carmustine) or mitomycin C
    • 12 weeks after ipilimumab, programmed cell death 1 (PD-1) antibody, or other immunologically active antibody
    • NOTE: patients receiving prior cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD1 antibody or other immunologic therapy must show evidence of normal pituitary function at baseline
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)
  • Life expectancy of at least 6 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 75,000/mcL
  • Hemoglobin > 9 g/dL
  • Total bilirubin < 1.5 x institutional upper limit of normal (bilirubin < 3 × institutional upper limit of normal for Gilbert's syndrome)
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) must be less than institutional upper limit of normal (liver function tests [LFT's] must be within normal limits)
  • Creatinine < 1.5 x × institutional upper limit of normal OR
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Prothrombin time (PT), international normalized ratio (INR) =< 1.5 x institutional upper limit of normal (ULN)
  • Thyroid-stimulating hormone (TSH) within normal limits
  • Thyroxine (T4) within normal limits
  • Patients must express human leukocyte antigen (HLA) -A1+, -A2+, or -A3+ (80% of patients)
  • Lactate dehydrogenase (LDH) < 3 × upper limits of normal

    • [NOTE: these criteria will select against patients with bulky disease and will select for patients with less disease and earlier disease]
  • Participants must not have had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement; participants must not have an active or inactive autoimmune disorders (e.g., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who are receiving therapy for an autoimmune or inflammatory disease requiring these therapies are also excluded
  • The following will not be exclusionary:

    • Resolved ipilimumab associated inflammatory disease
    • The presence of laboratory evidence of autoimmune disease (e.g., positive antinuclear antibody [ANA] titer) without associated symptoms
    • Subjects with vitiligo, thyroiditis, or atopic dermatitis, but otherwise not meeting this criterion may be enrolled; individual cases can be discussed with the sponsor
  • Not believed curable with surgery alone
  • Not currently receiving therapy
  • Females of childbearing potential must have a negative pregnancy test within 48 hours before initiating protocol therapy

    • NOTE: women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) before study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception before the study, for the duration of study participation, and 4 months after completing INCB024360 and MELITAC 12.1 administration
    • NOTE: subjects are considered not of child bearing potential if they are surgically sterile, have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy, or are postmenopausal; menopause is the age associated with complete cessation of menstrual cycles and menses, and implies the loss of reproductive potential; by a practical definition, the term assumes menopause after 1 year without menses with an appropriate clinical profile at the appropriate age
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had cytotoxic chemotherapy, radiotherapy, interferon (IFN), immunosuppressive therapy, or steroids within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier
  • Ipilimumab, anti-PD1, anti-programmed cell death 1 ligand 1 (PDL1) or other immunologically active therapy within 12 weeks
  • Active immunosuppressive therapy, including concurrent systemic immunosuppressive therapy or steroid therapy with more than 7 consecutive days of steroids within the prior 4 weeks

    • The use of prednisone or equivalent < 0.125 mg/kg/day (absolute maximum of 10 mg/day) as replacement therapy is permitted
    • Inhaled corticosteroids are permitted
  • Cardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction or acute coronary syndrome (within the last 6 months)
  • History of peripheral vascular disease (PVD) or extensive diabetes
  • Current or history of systemic autoimmune disease requiring systemic therapy, including significant autoimmunity associated with prior ipilimumab therapy
  • Cirrhosis, chronic hepatitis C virus positivity, or chronic hepatitis B infection; subjects who may not tolerate immune-mediated hepatitis due to compromised hepatic reserve also excluded from participation including: subjects with extensive liver metastasis (as judged by the investigator); subjects who drink more than two standard alcoholic beverages per day on a regular basis; subjects who consume more than 2 grams of acetaminophen per day on a regular basis

    • A positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antibody [HBsAb]-positive and hepatitis B core antibody [HBcAb]-negative), or a fully resolved acute hepatitis B infection is not an exclusion criterion
  • Patients who are receiving any other investigational agents for melanoma
  • Patients who have had a grade one or grade two gastrointestinal adverse event during or after receiving anti-CTLA-4, anti-PD1 or anti-PD, without a colonoscopy verifying complete resolution of the adverse event
  • Patients who have experienced bowel perforation, neurologic involvement, Guillain Barré syndrome, Myasthenia Gravis, Steven Johnson syndrome and other intractable events or grade 4 non-laboratory toxicity
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnancy, nursing, or unwilling to take adequate birth control during therapy

    • NOTE: pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with INCB024360 and MELITAC 12.1
  • Known human immunodeficiency virus (HIV) or other history of immunodeficiency disorder

    • NOTE: HIV-positive patients taking combination antiretroviral therapy are ineligible
  • Extensive active brain disease, including symptomatic brain metastases or the presence of leptomeningeal disease

    • Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for > 4 weeks, are eligible
  • Any malignancy that has not been in complete remission for at least 3 years

    • NOTE: patients with cured basal or squamous cell skin cancer are not excluded
  • Monoamine oxidase (MAO) inhibitor use within the past 3 weeks or prior evidence of serotonin syndrome
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to INCB024360, MELITAC 12.1, or other vaccine components
  • Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in place
  • Medical or psychiatric illness that would, in the opinion of the investigator, preclude participation in the study or the ability of patients to provide informed consent for themselves
  • History of pulmonary disease such as emphysema or chronic obstructive pulmonary disease (COPD), (forced expiratory volume in one second [FEV1] > 60% of predicted for height and age); pulmonary function tests (PFTs) are required in patients with prolonged smoking history or symptoms of respiratory dysfunction
  • Subjects who are currently receiving therapy with a potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer or inhibitor; subjects may enter screening when therapy with the potent inhibitor or inducer is completed
  • Use of any UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor including: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid from screening through follow-up period
  • Low-dose Coumadin (1 mg) is acceptable; however, doses that increase INR are not permitted; if an alternative to Coumadin-based anticoagulants cannot be used, the INR should be monitored weekly after initiation of therapy and upon discontinuation of INCB024360, until INR normalization
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01961115

Locations
United States, Georgia
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Keith A. Delman    404-778-3303      
Principal Investigator: Keith A. Delman         
United States, New Hampshire
Dartmouth Hitchcock Medical Center Withdrawn
Lebanon, New Hampshire, United States, 03756
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Douglas S. Tyler    919-684-6858      
Principal Investigator: Douglas S. Tyler         
United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Craig L. Slingluff    434-243-6143      
Principal Investigator: Craig L. Slingluff         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Incyte Corporation
University of Virginia
Investigators
Principal Investigator: Craig Slingluff Cancer Immunotherapy Trials Network
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01961115     History of Changes
Other Study ID Numbers: CITN-04, NCI-2013-01605, CITN-04, CITN-04, U01CA154967
Study First Received: October 8, 2013
Last Updated: November 5, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Uveal Neoplasms
Eye Diseases
Eye Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Uveal Diseases

ClinicalTrials.gov processed this record on November 20, 2014