PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of ibrutinib in combination with pembrolizumab in
patients with advanced melanoma. (Phase I) II. To estimate the overall response rate treated
at the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with
advanced melanoma. (Dose expansion cohort)
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 overall response rate (ORR) in patients advanced melanoma receiving
ibrutinib and pembrolizumab.
III. To evaluate the duration of response, progression-free survival (PFS), and 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.
EXPLORATORY 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: This is a dose-escalation study of ibrutinib.
Patients receive ibrutinib orally (PO) daily on days 1-28 of cycle 1 and days 1-21 of cycle 2
and subsequent cycles. Patients also receive pembrolizumab intravenously (IV) over 30 minutes
on day 8 of cycle 1 and day 1 of cycle 2 and subsequent cycles. Cycle 1 continues for 28 days
and subsequent cycles 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
- Only if patient has had previous exposure to anti-PD-1 or anti-PD-L1 therapy:
- Patient had disease progression on or within 6 months after anti-PD-1/anti-PD-L1
therapy in the metastatic setting OR
- Patient had disease progression within 6 months after the last dose of
adjuvant/neoadjuvant anti-PD-1/anti-PD-L1 treatment
- Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
registration)
- Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)
- Criteria must be met without a transfusion =< four weeks prior to registration
- Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
- Total bilirubin =< 1.5 X upper limit of normal (ULN); if total bilirubin > 1.5 X ULN
then direct bilirubin =< ULN (obtained =< 14 days prior to registration)
- Aspartate aminotransferase (aspartate transaminase [AST]) and alanine aminotransferase
(alanine transaminase [ALT]) =< 2.5 x ULN OR =< 5 X ULN for patients with liver
metastases (obtained =< 14 days prior to registration)
- Creatinine =< 1.5 X ULN and creatinine clearance (CrCL) >= 30 ml/min per Cockcroft
Gault formula (obtained =< 14 days prior to registration)
- Patients of childbearing potential only, 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 prior exposure to BTK inhibitors
- Uveal melanoma
- Current use of warfarin or other vitamin K antagonists
- Require continuous treatment with a strong CYP3A inhibitor
- 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 Willebrand'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 A, B or C
according to the Child Pugh classification
- Unresolved toxicities from prior anti-cancer therapy, defined as not resolved to
Common Terminology Criteria for Adverse Events (CTCAE, version [v]4.0) grade 0 or 1,
or to the levels dictated in the inclusion/exclusion criteria with the exceptions of
alopecia and peripheral neuropathy
- 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]) =< 28 days prior to registration
- Received a strong cytochrome P450 (CYP) 3A inhibitor =< 7 days prior to registration
- Concurrent systemic immunosuppressant therapy =< 21 days prior to registration
- Recent infection requiring systemic antibiotic treatment that was completed =< 14
prior to registration
