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Mucosal MelanomaPhase 2NCT01961115

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

A Phase 2 study testing Epacadostat and MELITAC 12.1 Peptide Vaccine in people with Mucosal Melanoma and Recurrent Melanoma, run by Fred Hutchinson Cancer Center at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Epacadostat and MELITAC 12.1 Peptide Vaccine
Type of treatment
Vaccines
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
4 sitesUnited States
Study dates
13 Sep 2013to 18 May 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 of melanoma that may be resectable but are judged to have a future recurrence risk exceeding 70% (e.g., large adenopathy, distant skin metastases or 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: optimally, patients will have tumor approachable for three serial biopsies during the trial; for patients with only one or two tumors approachable for biopsy, available tumor blocks from prior biopsies can serve as the pretreatment sample, but only if formalin-fixed tumor tissue is available and adequate to provide at least 20 unstained slides with sufficient tumor for analysis
  • 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 inhibitor (BRAFi) 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
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  • 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
  • Patients who experience melanoma progression (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) while on or after treatment with programmed cell death 1 (PD-1) or PD ligand-1 (PDL-1) antibody may enroll on this study
  • NOTE: Patients must be off PD-1/PDL- antibody for at least 2 weeks to assess for delayed toxicity before being enrolled and receiving INCB024360; patients who are enrolled 2 weeks and up to 6 weeks after the last dose of PD-/PDL-1 antibody will enroll in cohort B and receive 100 mg BID of INCB024360; patients enrolled beyond the 6 week period after failing anti-PD-1/PDL-1 will be enrolled in cohort A; cohort A patients will receive 300 mg BID of INCB024360; patients must not have active grade 2 autoimmune toxicities attributed to these antibodies at study entry
  • 8 weeks after ipilimumab, other cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody or other immunologically active antibody
  • NOTE: Patients receiving prior CTLA-4, anti-PD1 antibody or other immunologic therapy must show evidence of normal pituitary function at baseline and must not have active grade 2 autoimmune toxicities attributed to these antibodies at study entry
  • 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]) up to 2.5 times upper limit normal (ULN)
  • 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 ULN unless patient is therapeutically anticoagulated; if on anticoagulants, PT/INR need to be within appropriate anticoagulation limits for the clinical indication; patients who are receiving anticoagulants may participate in the trial if their anticoagulation can be stopped safely for several days at the time of each biopsy
  • Thyroid-stimulating hormone (TSH) up to 4 times ULN if thyroxine (T4) is normal
  • T4 within normal limits; if abnormal and patient is receiving thyroid replacement therapy, the thyroid medication may be adjusted and the T4 may be re-tested
  • Patients must express human leukocyte antigen (HLA) -A1+, -A2+, or -A3+ (80% of patients)
  • Lactate dehydrogenase (LDH) < 5 × 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.); participants 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 likely 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

Who cannot join

  • 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 or other immunologically active therapy within 8 weeks of enrollment; NOTE: patients who experience melanoma progression (by RECIST 1.1 criteria) while on or after treatment with PD-1 or PDL-1 antibody may enroll on this study
  • 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)
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  • History of peripheral vascular disease (PVD) that has required surgical or percutaneous intervention or documented PVD that requires medical management with medications such as acetylsalicylic acid (ASA) + clopidogrel; patients with diabetes that is not well controlled are excluded from participation; not well controlled is defined as a hemoglobin (Hgb) A1C of greater than 7.5%
  • Current or history of systemic autoimmune disease requiring systemic therapy, including significant autoimmunity associated with prior ipilimumab therapy or therapy with antibodies to PD-1 or PD-L1
  • 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; patients with a history of excised in situ cancers, including breast, cervical, colon, superficial bladder, prostate or other body system are not excluded; study entry will be allowed at the discretion of the Principal Investigator
  • NOTE: recurrence of the in situ cancer or tumor at the time of study entry would be exclusionary
  • 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
  • Use of any UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor including: acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, geftinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole, lineoleic acid, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid propofol, quinidine, ritonavir, Sorafenib, sulfinpyrazone, valproic acid and verapamil 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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Emory University/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • University of Virginia Cancer Center

    Charlottesville, Virginia, 22908

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Duke University Medical Center

    Durham, North Carolina, 27710

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  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 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.

  1. 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.

Being tested
Epacadostat, MELITAC 12.1 Peptide Vaccine
Medical subject headings
Melanoma, Uveal Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EpacadostatDrug

    Also called INCB 024360, INCB024360

    Given PO

  • MELITAC 12.1 Peptide VaccineBiological

    Given ID/SC

Study groups in NCT01961115
Study groupRoleWhat they receive
Treatment (epacadostat, MELITAC 12.1)ExperimentalPatients 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.
Receives: Drug: Epacadostat; Biological: MELITAC 12.1 Peptide Vaccine

What is being measured

The primary outcome is the main question the study is designed to answer.

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

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

    Measured: Baseline to up to day 21

  2. 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

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

    Measured: Day 21 up to Day 42

Secondary outcomes (8)

  1. Change in PBMC Transcriptome_v2

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

    Measured: Baseline to up to 16 week

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

    Measured: Baseline to up to 1 year

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

    Measured: Baseline to up to 16 weeks

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

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

    Measured: Baseline to up to 16 weeks

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

    Measured: Up to 1 year

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

    Measured: Up to 1 year

  7. Overall Survival_v2

    Measured: 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

  8. Time to Tumor Progression Using RECIST or irRC_v2

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Oct 2013 (estimated)
  2. Study start13 Sep 2013
  3. Primary completion31 Oct 2016
  4. Study completion18 May 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01961115
Sponsor's protocol ID
CITN-04
Other IDs
NCI-2013-01605, CITN-04, CITN-04, U01CA154967
Status last verified
May 2018
First submitted
8 Oct 2013
Last updated
8 Jun 2018

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Epacadostat and MELITAC 12.1 Peptide Vaccine in people with Mucosal Melanoma and Recurrent Melanoma, run by Fred Hutchinson Cancer Center at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 45 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 7 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in the Concentration and Number of CD8+ Cells Infiltrating Tumor by IHC by Normalization of Kyn/Trp Ratios. (time frame: Baseline to up to day 21). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01961115.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jun 2018.

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