Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title A Phase II Pilot Trial of an Indoleamine2,3, dioxygenase-1 (IDO1) Inhibitor (INCB024360) Plus a Multipeptide Melanoma Vaccine (MELITAC 12.1) in Patients with Advanced Melanoma
IRB FHCC 1615
CC 15-193
Hospital Main Campus
Phase Phase 2
Disease Melanoma
Drug INCB024360 , MELITAC 12.1
Description
Primary Objectives- To determine the extent to which a regimen of INCB024360 that normalizes serum Kyn/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
- To determine the extent to which continued INCB024360 treatment plus the addition of the multipeptide melanoma vaccine, MELITAC 12.1, 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
- 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 CD8+ and CD4+ T-cell immune responses as measured in peripheral blood, as compared to prior published experience
- 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
- To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the PBMC transcriptome
- To assess the safety and tolerability of INCB024360 plus MELITAC 12.1 vaccine
- 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
- To associate any observed changes with the expression of IDO1 protein by IHC in tumor or tumor-infiltrating cells
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 nonnodal 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. See Section 11 for the evaluation of measurable disease.
- Unresectable stage III or IV melanoma 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 90% (e.g., distant skin metastases or multiple in-transit melanoma metastases). Tumor deemed amenable to biopsy (excisional, incisional, or core, with at least 100 mm3 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: 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.
- 3.1.2.1 Stage IV no evidence of disease (NED) is excluded by this criterion
- Prior and concurrent therapy
- Patients may have had prior systemic therapy without constraint on the number of prior treatment regimens except:
- Patients may not have had >450 mg/m2 doxorubicin
- Patients may not have had >3000 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, PD-1 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.
- Patients may have had prior systemic therapy without constraint on the number of prior treatment regimens except:
- Age ≥18 years. [NOTE: Because no dosing or AE data are currently available on the use of INCB024360 in combination with MELITAC 12.1 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.]
- ECOG performance status 0-1 (Karnofsky ≥70%, see Appendix A).
- Life expectancy of at least 6 months
- Patients must have normal organ and marrow function as defined below:
- leukocytes ≥3,000/mcL
- absolute neutrophil count ≥1,500/mcL
- platelets ≥75,000/mcL
- hemoglobin >9g/dL
- total bilirubin <1.5 x institutional upper limit of normal [bilirubin <3 x institutional upper limit of normal for Gilbert's syndrome]
- AST(SGOT)/ALT(SGPT) Up to 2.5 times ULN
- creatinine <1.5 x institutional upper limit of normal OR
- creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- PT, 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.
- TSH, Up to 4 times ULN if 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 HLA-A1+, -A2+, or -A3+ (80% of patients)
- LDH <5 x 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 ipilumumab 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: The effects of INCB024360 and MELITAC 12.1 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to 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, 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 AEs due to agents administered more than 4 weeks earlier
- Ipilimumab, anti-PD1, anti-PDL1 or other immunologically active therapy within 8 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) that has required surgical or percutaneous intervention or documented PVD that requires medical management with medications such as ASA + Clopidogrel. Patients with Diabetes that is not well controlled are excluded from participation. Not well controlled is defined as a 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
- Cirrhosis, chronic hepatitis C virus positivity, or chronic hepatitis B infection. Subjects who may not tolerate immune-mediated hepatitis due to compromised hepatic reserve are also excluded from participation including: 1) Subjects with extensive liver metastasis (as judged by the investigator) 2) Subjects who drink more than two standard alcoholic beverages per day on a regular basis 3) 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., HBsAbpositive and 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 Barre 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 because INCB024360 and MELITAC 12.1 have the potential for teratogenic or abortifacient effects. Because of unknown but potential risks for AEs in nursing infants secondary to treatment of the mother with INCB024360 and MELITAC 12.1, breastfeeding should be discontinued if the mother is treated with INCB024360 and MELITAC 12.1 These potential risks may also apply to other agents used in this study.
- Known HIV or other history of immunodeficiency disorder NOTE: HIV-positive patients taking combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with INCB024360 and MELITAC 12.1. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- 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), (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 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