Pembrolizumab and Ibrutinib in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) in patients with advanced melanoma receiving
ibrutinib and pembrolizumab.

SECONDARY OBJECTIVES:

I. To assess the safety and adverse-event profiles of combination of ibrutinib with
pembrolizumab in patients with advanced melanoma.

II. To evaluate the progression-free-survival (PFS) in patients advanced melanoma receiving
ibrutinib and pembrolizumab.

III. To evaluate the duration of response, overall survival (OS) in patients with advanced
melanoma receiving ibrutinib and pembrolizumab.

IV. To assess the effect of treatment with ibrutinib and pembrolizumab on Th1/Th2 immune
polarity.

TERTIARY OBJECTIVES:

I. To assess the CD8 T cell response to multiple melanoma-associated antigens, and to
correlate CD8 T cell responses with changes in Th1/Th2 immune polarity.

II. To assess changes in plasma cytokines induced by treatment with ibrutinib and
pembrolizumab.

III. To assess the change in potential biomarkers, such as tumor-bound and soluble PD-L1
levels and tumor-infiltrating lymphocytes, that may correlate with treatment responses.

OUTLINE:

Patients receive ibrutinib orally (PO) daily on days 1-28 of course 1 and days 1-21 of course
2 and subsequent courses. Patients also receive pembrolizumab intravenously (IV) over 30
minutes on day 8 of course 1 and day 1 of course 2 and subsequent courses. Course 1 continues
for 28 days and subsequent courses repeat every 21 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Inclusion Criteria:

- PRE-REGISTRATION- INCLUSION CRITERIA

- Diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to
local therapy

- At least one non-nodal lesion considered measurable by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria (that is, a lesion whose longest diameter can be
accurately measured as >= 1.0 cm with computed tomography [CT] scan, CT component of a
positron emission tomography [PET]/CT, or magnetic resonance imaging [MRI]) or at
least one malignant lymph node is considered measurable by RECIST criteria (that is,
its short axis is >= 1.5 cm when assessed by CT scan)

- NOTE: tumor lesions in a previously irradiated area are not considered measurable
disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- Provide informed written consent

- Patient is willing to undergo treatment and monitoring at the enrolling institution

- Willing to provide tissue and blood samples for correlative research purposes

- REGISTRATION- INCLUSION CRITERIA

- Histologic or cytologic confirmation of unresectable stage III or metastatic melanoma
(stage IV) not amenable to local therapy

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 75,000/mm^3

- Criteria must be met without a transfusion within four weeks of registration

- Hemoglobin >= 9.0 g/dL

- Total bilirubin =< 1.5 X upper limit of normal (ULN); if total bilirubin > 1.5 X ULN
then direct bilirubin =< ULN

- Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x ULN OR =< 5 X ULN
for patients with liver metastases

- Creatinine =< 1.5 X ULN and creatinine clearance (CrCL) >= 30 ml/min per Cockcroft
Gault formula

- Female patients of childbearing potential, negative urine pregnancy test done =< 7
days prior to study registration

Exclusion Criteria:

- PRE-REGISTRATION EXCLUSION CRITERIA

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception within the projected duration of the study, starting with the
screening visit through 120 days after the last dose of study medication;
adequate contraception is defined as 2 methods of birth control (e.g., hormonal
contraceptives, intrauterine device, diaphragm with spermicide, cervical cap with
spermicide, male condoms, or female condom with spermicide) or prior surgical
sterilization, or abstinence from heterosexual activity

- Prior treatment with ibrutinib or an anti-PD-1, or PD-L1 or PD-L2 agent or ipilimumab
in the metastatic setting

- Current use of warfarin or other vitamin K antagonists

- Current use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor or inducer

- Currently participating or has participated in a study of an investigational cancer
therapy agent or using an investigational device within 28 days prior to study
registration

- Live vaccines within 28 days prior to study pre-registration

- Invasive surgical procedure within 28 days prior to study pre-registration

- History of clinically severe (e.g., requires chronic immunosuppressive therapy, [e.g.,
cyclosporine A, tacrolimus]) autoimmune disease (e.g., ulcerative colitis, lupus), or
history of organ transplant

- Known history of human immunodeficiency virus (HIV) infection, active infection with
hepatitis B virus or hepatitis C virus, or any uncontrolled active systemic infection

- Gastrointestinal disease that might inhibit ibrutinib absorption (e.g., malabsorption
syndrome, resection of the stomach or a large portion of small bowel, or
partial/complete bowel obstruction), or unable to swallow capsules

- Active central nervous system metastases and/or carcinomatous meningitis

- Note: Patients with untreated brain metastasis will be excluded; patients with
previously treated brain metastases may participate provided they meet the
following criteria:

- Inactive (without evidence of progression which is documented by CT or MRI
within 90 days prior to registration), AND

- On =< 10 mg/day prednisone or equivalent for at least 28 days prior
pre-registration

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Clinically significant cardiovascular disease such as unstable angina, myocardial
infarction, or acute coronary syndrome within =<180 days prior to registration,
symptomatic or uncontrolled arrhythmia, congestive heart failure, or any class 3 or 4
cardiac disease as defined by the New York Heart Association Functional Classification

- Other active malignancy =< 3 years prior to pre-registration; note: if there is a
history of prior malignancy, the patient must not be receiving other specific
treatment for cancer

- EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart
Association Functional Classification; or a history of myocardial infarction, unstable
angina, or acute coronary syndrome =< 6 months prior to pre-randomization

- Known bleeding disorders (von Wilebrand?s disease or hemophilia)

- History of ischemic stroke or intracranial hemorrhage =< 180 days prior to
pre-registration

- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification

- REGISTRATION- EXCLUSION

- Failure to confirm histologically or cytologically unresectable stage III or
metastatic melanoma (stage IV) not amenable to local therapy

- Prior chemotherapy, immunotherapy, radioactive, or biological cancer therapy
(including monoclonal antibody [mAb]) within 28 days prior to registration