Clinical Trial 18916

Cancer Type: Cutaneous
Interventions:748645 (Ibrutinib); Ibrutinib (Imbruvica); PCI-32765 (Ibrutinib)

Study Type: Treatment
Phase of Study: Phase II


    Study Title

    A Phase 2 Study of Ibrutinib (PCI-32765) in Refractory Distant Metastatic Cutaneous Melanoma: Correlation of Biomarkers with Response and Resistance


    The purpose of this study is to test any good and/or bad effects of the study drug call ibrutinib. Ibrutinib could shrink the participant's cancer but it could also cause side effects. Researchers hope to learn if the study drug will shrink the cancer by at least one-quarter compared to its present size. Ibrutinib has already been FDA-approved to treat three cancer types: mantle-cell lymphoma, chronic lymphocytic leukemia and Waldenstrom's Macroglobulinemia. However, it is considered investigational for the treatment of metastatic melanoma. Researchers also want to perform studies on participants' tumor tissue and blood samples to see how ibrutinib affects the immune system and how their genes may affect the response to ibrutinib. There will be up to 32 people taking part in this study.


    Primary Objective: - Estimate rate of objective response [OR: complete response (CR) + partial response (PR)] to ibrutinib administered as single agent in patients with immune checkpoint inhibitor-refractory and MAPK inhibitor-refractory (if BRAFV600-mutant) distant metastatic cutaneous melanoma. Secondary Objectives: - Estimate progression-free survival (PFS) after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory and MAPK inhibitor-refractory (if BRAFV600-mutant) distant metastatic cutaneous melanoma. - Estimate overall survival (OS) after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory and MAPK inhibitor-refractory (if BRAFV600-mutant) distant metastatic cutaneous melanoma. - Explore the association of ITK protein expression with OR and PFS. The ITK protein expression in melanoma cells (pretreatment) is assessed by 2-color immunofluorescence (IF) in representative tissue sections obtained from archival formalin-fixed embedded blocks or in representative tissue sections/slides obtained from fresh biopsies from enrolled patients. Exploratory Objectives: - Explore association between other putative targets of ibrutinib (e.g., Tec, ErbB4, Hck, Yes, BTK) in melanoma cells, as assessed by 2-color IF in representative tissue sections obtained from pretreatment archived FFPE tumor blocks or FFPE blocks obtained from fresh tissue biopsy from enrolled patients, with OR and PFS. - Explore ibrutinib-mediated effect(s) on immune cell subsets associated with immunomodulation by performing multiparameter flow cytometric analysis in PBMC obtained prior to treatment, on day 29 (i.e., predose day 1 of cycle 2) following initiation of treatment with ibrutinib, and at the time of disease progression (3 time points).

    Inclusion Criteria

  • Histologically confirmed melanoma of cutaneous primary; metastatic melanoma from unknown primary are allowed
  • Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Stage IV disease
  • If BRAFV600-mutant, documented refractory disease to at least one MAPK inhibitor-based treatment (dabrafenib, vemurafenib) and/or a MEK inhibitor (trametinib or combimetinim)), defined as progression of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 during treatment
  • Documented disease refractory to at least one anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and at least one programmed cell death protein-1 (PD1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint inhibitor, defined as disease progression following at least 2 infusions of the same drug.
  • Prior treatment-related toxicity resolved to equal to or less than grade 1 or baseline with the exception of alopecia
  • Prior radiation allowed (no restriction on amount); measurable lesion(s) may not have been previously irradiated
  • Eastern Cooperative Oncology Group (ECOG) performance status equal to or less than 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count (ANC) > 1,000/uL
  • Platelets > 70,000/uL
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) equal to or less than 2 x upper limit of normal (ULN); equal to or less than 5 x ULN, if liver metastasis
  • Total bilirubin equal to or less than 1.5 x ULN unless Gilbert's syndrome of disease infiltration of the liver is present
  • Creatinine clearance estimated glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (Cockcroft-Gault)
  • Patients with brain metastases are allowed provided that: No leptomeningeal disease is present; Intracranial disease is controlled by local therapies (craniotomy, stereotactic radiosurgery, whole brain irradiation), as evidenced by brain MRI 4 weeks post treatment indicating no new intracranial disease; Stable or decreasing dose of steroids provided patient on less than 20 mg of prednisone or its equivalent daily.
  • Ibrutinib must be discontinued 7 days before (when possible) until 7 days after major surgery, and 3 days before (when possible) until 3 days after minor surgery
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; men treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib administration
  • Negative serum pregnancy test within 7 days of treatment initiation with ibrutinib in women of childbearing potential (WOCBP)
  • Ability to swallow oral medications
  • Willing to consent to allow access to known archival tumor tissue
  • Ability to understand and the willingness to sign a written informed consent document

  • Exclusion Criteria

  • Melanoma of mucosal or ocular primary
  • Have had chemotherapy or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to entering the study or have not recovered from adverse events to equal to or less than grade 1 or baseline, other than alopecia, due to agents administered > 4 weeks earlier
  • Receiving any other biologic, cytotoxic or investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib
  • Uncontrolled intercurrent illness including (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
  • Women who are pregnant or breastfeeding; breastfeeding should be discontinued if the mother is treated with ibrutinib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are eligible; unless cluster of differentiation (CD)4+ count is below the institutional lower limit of normal
  • Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP) resulting in/evidenced by declining platelet or hemoglobin (Hgb) levels within 4 weeks prior to 1st dose of study drug
  • Presence of transfusion-dependent thrombocytopenia
  • Need for daily corticosteroids at high doses (prednisone >= 20 mg daily, or equivalent) is prohibited from 7 days prior to 1st dose and during treatment with ibrutinib
  • Prior exposure to ibrutinib or other ITK inhibitors
  • History of prior malignancy, with exceptions: Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix; Prostate cancer not under active systemic treatment other than hormonal therapy and with documented undetectable PSA; CLL/SLL provided patient has isolated lymphocytosis, and does not require systemic treatment [for 'B' symptoms, Richter's transformation, lymphocyte doubling time (less than 6 months), lymphadenopathy or hepatosplenomegaly]; Lymphoma or any type or hairy-cell leukemia provided patient is not on active systemic treatment and in complete remission for => 3 months; History of malignancy provided patient has completed therapy and is free of disease for ≥ 2 years. If patient had other malignancy within the last 2 years from which he may have been completely cured by surgery alone, may be considered if meets specific conditions.
  • Currently active clinically significant cardiovascular disease or history of myocardial infarction within 6 months prior to 1st dose with study drug
  • Unable to swallow capsules, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of portions of small bowel larger than 3 feet, or poorly controlled inflammatory bowel disease affecting the small intestine
  • Known serologic status reflecting active hepatitis B or C infection; if hepatitis B core antibody positive, but antigen negative, will need a negative polymerase chain reaction (PCR) prior to enrollment (NOTE: hepatitis B antigen or PCR positive patients will be excluded)
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Current life-threatening illness, medical condition, or organ system dysfunction, which, in investigator's opinion, could compromise the patient's safety, or put the study at risk
  • Received anticoagulation therapy with warfarin, or equivalent vitamin K antagonists, within last 28 days prior to day 1 of ibrutinib; patients with familial coagulopathic diseases (e.g. hemophilia, von Willebrand's disease) are also excluded