Ibrutinib and Nivolumab in Treating Participants With Metastatic Solid Tumors
Ibrutinib and Nivolumab in Treating Participants With Metastatic Solid Tumors
This phase I trial studies how well ibrutinib and nivolumab work in treating participants
 with solid tumors that have spread to other places in the body. Ibrutinib may stop the growth
 of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies,
 such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving
 ibrutinib and nivolumab may work better in treating participants with solid tumors.
PRIMARY OBJECTIVES:

 I. Evaluate the effect of the ibrutinib therapy on circulating levels of myeloid derived
 suppressor cells MDSC.

 SECONDARY OBJECTIVES:

 I. Assess safety of the study combination in study subjects.

 EXPLORATORY OBJECTIVES:

 I. Evaluate the effect of the ibrutinib/nivolumab therapy on circulating levels of MDSC.

 II. Evaluate the effect of the ibrutinib and ibrutinib/nivolumab therapy on the
 immunosuppressive function of circulating MDSC by measuring their ability to inhibit T cell
 proliferation and natural killer cell mediated antibody dependent cell cytotoxicity.

 III. Study the effect of ibrutinib and ibrutinib/nivolumab therapy on levels of circulating
 innate and adaptive immune cells such as natural killer cell and T lymphocyte subsets.

 IV. Study circulating MDSC levels at the time of disease progression. V. Evaluate in a
 preliminary fashion the effect of the regimen on progression-free survival.

 OUTLINE:

 Participants receive ibrutinib orally (PO) daily for 15 days. After 7 days receiving
 ibrutinib, participants receive nivolumab intravenously (IV) over 60 minutes on days 1 and
 15. Courses with nivolumab repeat every 28 days in the absence of disease progression or
 unaccepted toxicity.

 After completion of study treatment, participants are followed up every 3 months.
Inclusion Criteria:

 -  Patients with biopsy-proven metastatic solid tumor and be eligible to receive
 nivolumab per standard of care

 -  Patients will be allowed to have any number of prior lines of therapy for metastatic
 cancer

 -  Patients with measurable and non-measurable disease are allowed to participate

 -  Absolute neutrophil count (ANC) ? 1.5 x 10^3/mm^3

 -  Hemoglobin (Hgb) ? 9 g/dL

 -  Platelet count ? 100 x10^3/mm^3

 -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ? 2.5 x upper limit of
 normal (ULN) or ? 5 x ULN in patients with liver metastases

 -  Prothrombin time ? 1.5 x ULN

 -  Total bilirubin ? 1.5 x ULN (unconjugated bilirubin of < 3 x ULN for patients with
 known Gilbert syndrome)

 -  Creatinine clearance of ? 50 ml/min by Cockcroft-Gault equation

 -  Corrected QT interval of < 480 msec (using either Bazett?s or Fridericia's formula)

 -  Life expectancy of > 12 weeks

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0 ? 2

 -  Sexually active women with child bearing potential must have a negative pregnancy test
 obtained within 14 days prior to initiating study treatment

 -  Sexually active women of child-bearing potential and men must agree to use adequate
 contraception prior to study entry, for the duration of study participation and for 3
 months after completion of study treatment administration; adequate contraception
 includes methods such as oral contraceptives, double barrier method (condom plus
 spermicide or diaphragm), or abstaining from sexual intercourse

 Exclusion Criteria:

 -  History of prior therapy with ibrutinib or nivolumab

 -  Unable to swallow capsules or having disease that is significantly affecting
 gastrointestinal function and/or inhibiting small intestine absorption

 -  Diagnosis of congenital or acquired immunodeficiency with the exception of
 chemotherapy induced immune suppression

 -  Active autoimmune disease requiring systemic treatment within the past 3 months or a
 documented history of clinically severe autoimmune disease, or a syndrome that
 requires systemic steroids of greater than or equal to prednisone 10 mg/day or other
 immunosuppressive agents; patients with history of adequately treated Hashimoto?s
 thyroiditis will be eligible; patients requiring a short course of a high dose
 prednisone burst to treat asthma or common obstructive pulmonary disease will also be
 eligible 5 days following completion of the prednisone treatment

 -  Use of systemic steroids at a dose above 10 mg/day of prednisone or prednisone
 equivalent in cycle 1 of study therapy; systemic steroids must be discontinued at
 least 5 days prior to initiating study therapy; exception will be given to patients
 who develop immune related adverse events that necessitate use of steroids or other
 immune suppressive agents; following cycle 1 of study treatment, the use of systemic
 steroids will be allowed per discretion of the treating physician

 -  Active, non-infectious pneumonitis

 -  Ongoing or active infection requiring systemic therapy

 -  History of being positive for human immunodeficiency virus (HIV)

 -  History of hepatitis B or C

 -  History of receiving live vaccine within 30 days of planned start of study therapy

 -  Central nervous system (CNS) metastases or leptomeningeal carcinomatosis; patients
 with history of adequately treated brain metastases that are stable for > 2 weeks
 prior to the first dose of study regimen are eligible as long they no longer require
 steroids and have no seizures or worsening focal neurologic symptoms; anti-epileptic
 therapy will be allowed

 -  Patients who had prior systemic chemotherapy within 3 weeks (or < 5 half-lives ?
 whichever is longer)

 -  Prior radiation therapy within 2 weeks of study enrollment

 -  Prior investigational therapy within 4 weeks

 -  Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose
 of study drug; port placement will not be considered major or minor surgery

 -  Any inter-current, uncontrolled systemic illness or any medical or psychiatric
 condition that in the opinion of the investigator would make the study therapy unsafe
 to the patient

 -  Unable to understand and sign informed consent form

 -  Uncontrolled, active cardiovascular disease including, but not limited to: symptomatic
 congestive heart failure, any class 3 or 4 cardiac disease as defined by the New York
 Heart Association functional classification, unstable angina pectoris, cardiac
 arrhythmia

 -  Any medications or substances that are strong inhibitors or inducers of CYP 3A4 need
 to be discontinued prior to initiation the study therapy and for the duration of
 ibrutinib treatment; patients can resume these medications 3 days after completion of
 ibrutinib course

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition as ibrutinib or nivolumab