Ibrutinib in Treating Patients With Refractory Metastatic Cutaneous Melanoma
Condition: Metastatic Melanoma; Recurrent Cutaneous Melanoma; Stage IV Cutaneous Melanoma AJCC v6 and v7
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Ibrutinib; Laboratory Biomarker Analysis; Pharmacogenomic Study; Pharmacological Study
Intervention description: Given PO; Correlative studies; Correlative studies; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well ibrutinib works in treating patients with stage IV
      melanoma of the skin that has not responded to previous treatment. Ibrutinib may stop the
      growth of tumor cells by blocking some of the enzymes needed for cell growth.
    

Eligibility criteria:

        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 BRAF inhibitor
             (dabrafenib or vemurafenib) and/or a MEK inhibitor (trametinib or cobimetinib),
             defined as progression of measurable disease as per Response Evaluation Criteria in
             Solid Tumors (RECIST) criteria while on treatment; subjects with MAPK
             inhibitor-intolerance are eligible if they meet criteria

          -  Documented disease refractory to at least one PD1/PD-L1 inhibitor, defined as disease
             progression following at least 2 infusions of the same drug; radiographic disease
             progression will be documented by the institutional radiologist based on any
             radiographic evidence (magnetic resonance imaging [MRI], computed tomography [CT],
             positron emission tomography [PET], or other modalities, etc.) of disease progression
             on two separate radiographic scans assessment obtained at least 4 weeks apart; this
             minimum 4-week interval is required to define PD-1 inhibitor resistance based on
             imaging; alternatively, clinical disease progression may be documented on examination
             by the treating investigator

          -  Prior treatment-related toxicity resolved to =< grade 1 or baseline with the exception
             of alopecia and permanent grade =< 2 toxicities related to prior immune checkpoint
             inhibitor treatment (e.g. PD-1/PD-L1, CTLA-4, CD40, LAG3) treatment with the review
             and approval by the lead principal investigator (PI)

          -  Prior radiation allowed (no restriction on amount); measurable lesion(s) may not have
             been previously irradiated

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 3 months

          -  Hemoglobin >= 9.0 g/dL

          -  Absolute neutrophil count (ANC) > 1,500/uL

          -  Platelets > 100,000/uL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2 x upper limit of normal (ULN); =< 5 x ULN, if liver metastasis

          -  Total bilirubin =< 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 prior 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 =< 20 mg of prednisone
                  or its equivalent daily

          -  Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon
             the type of surgery and risk of bleeding

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation and for 90 days after completion of ibrutinib
             administration; 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 prior to the study, for the duration of study participation, and 90 days
             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

          -  Patients with autoimmune disease requiring systemic corticosteroid treatment (and
             previously ineligible to receive systemic immunotherapies for melanoma) are allowed on
             condition that they do not receive more than 20 mg of daily dose methylprednisolone,
             prednisone, or its equivalent; this does not include autoimmune diseases caused by
             previous immunotherapy treatments for melanoma that require ongoing treatment with
             corticosteroids (e.g. autoimmune colitis or autoimmune hepatitis receiving
             corticosteroids)

          -  Willing to consent to allow access to known archival tumor tissue (NOTE: designated
             pathologist from participating site OR lead principal investigator must sign-off to
             ensure "sufficient" tumor should be available for support of tumor imaging studies
             [multi-color immunofluorescence])

          -  If archival tumor tissue from a metastatic melanoma lesion is unavailable OR
             designated pathologist from participating site cannot sign-off to ensure that
             "sufficient" tumor is available from existing archival tumor block for support of
             tumor imaging studies, patients must be willing to consent to undergo a biopsy to
             collect metastatic tumor tissue; collection of fresh biopsy tissue does not guarantee
             enrollment, unless the pathologist from the participating site signs-off that
             "sufficient" tumor has been collected

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Subjects who are unable to tolerate BRAF inhibitor and/or MEK inhibitor therapy due to
             grade >= 2 toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version
             [v]4.0) from these agents, irrespective of antitumor response, are eligible on
             condition that: (a) toxicities persisted despite change from doublet to singlet
             therapy (i.e. from concurrent BRAF inhibition plus MEK inhibition to BRAF inhibition
             alone), (b) toxicities are attributed to a class effect, and therefore switch from one
             drug to another is expected to induce the same type of toxicity (e.g. ocular
             toxicities or cardiac dysfunction from MEK inhibitor), (c) drug-specific toxicities
             that do not resolve with switch from one BRAF inhibitor to another (i.e. dabrafenib to
             vemurafenib, or vice versa), will be eligible for enrollment in 9922; in other words,
             patients will be allowed to enroll into the NCI9922 study despite lack of progression
             to MAPK inhibitor treatments, on condition that grade 2 or higher toxicities
             attributed to MAPK inhibitors resolve to grade 1, or less, at the time of study
             enrollment

        Exclusion Criteria:

          -  Patients with melanoma of mucosal or ocular primary

          -  Patients who have had chemotherapy or immunotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to cycle 1 day 1;
             patients who have had tyrosine kinase inhibitors (such as Braf or MEK inhibitors)
             within 15 days of cycle 1 day 1

          -  Patients who are receiving any other biologic, cytotoxic or investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ibrutinib (difficulty breathing, lip swelling, itching or rash)

          -  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

          -  Pregnant and breastfeeding women are excluded from this study; breastfeeding should be
             discontinued if the mother is treated with ibrutinib

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are eligible; unless the patient's 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 (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within
             the 4 weeks prior to first dose of study drug

          -  Presence of transfusion-dependent thrombocytopenia

          -  Need for daily corticosteroids at high doses (prednisone >= 20 mg daily, or an
             equivalent) is prohibited from 28 days prior to first dose and during treatment with
             ibrutinib; brief (up to 7 days) and episodic use of systemic corticosteroids for other
             general conditions (e.g. pre-medication for radiographic imaging due to intravenous
             [IV] contrast allergy, chronic obstructive pulmonary disease [COPD] exacerbation,
             poison ivy, etc.) is allowed

          -  Prior exposure to ibrutinib or other ITK inhibitors

          -  History of prior malignancy, with the exception of the following:

               -  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 prostate-specific antigen (PSA) (< 0.2 ng/mL)

               -  Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) provided
                  patient has isolated lymphocytosis (Rai stage O), and does not require systemic
                  treatment (for "B" symptoms, Richter's transformation, lymphocyte doubling time
                  [< 6 months], lymphadenopathy or hepatosplenomegaly)

               -  Lymphoma of any type of hairy-cell leukemia provided patient is not on active
                  systemic treatment and is in complete remission, as evidenced by PET/CT scans and
                  bone marrow biopsies for at least 3 months

               -  History of malignancy provided that 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, he may be
                  considered to be enrolled on condition that the risk of development of distant
                  metastatic disease based on American Joint Committee on Cancer (AJCC) staging
                  system is less than 30%

          -  Currently active clinically significant cardiovascular disease, such as uncontrolled
             arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease, as defined by
             the New York Heart Association Functional Classification, or history of myocardial
             infarction within 6 months prior to first 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; patients that are
             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 the 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 the last 28 days prior to day 1 of ibrutinib; patients with familial
             coagulopathic diseases (e.g. hemophilia, von Willebrand disease) are also excluded; if
             applicable, subjects must discontinue fish oil and vitamin E supplements within 7 days
             prior to initiating ibrutinib therapy

          -  Subjects with known hepatic insufficiency (i.e. Child-Pugh score A [mild], Child-Pugh
             score B [moderate] or Child-Pugh score C [severe]) according to Child-Pugh criteria

          -  Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
             to the first dose of ibrutinib or subjects who require continuous treatment with a
             strong CYP 450 3A inhibitor