Ipilimumab and Imatinib Mesylate in Advanced Cancer
Ipilimumab and Imatinib Mesylate in Advanced Cancer
This phase I trial studies the side effects and best dose of ipilimumab and imatinib mesylate
 in treating patients with solid tumors that have spread to other places in the body or cannot
 be removed by surgery. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help
 the body's immune system attack the cancer, and may interfere with the ability of tumor cells
 to grow and spread. Imatinib mesylate may stop the growth of tumor cells by blocking some of
 the enzymes needed for cell growth. Giving ipilimumab and imatinib mesylate may work better
 in treating patients with solid tumors.
PRIMARY OBJECTIVES:

 I. To evaluate the safety and toxicity profile of intravenous ipilimumab (Yervoy)
 administered in combination with oral imatinib mesylate (GLEEVEC) for patients with advanced
 malignancies that are refractory to standard therapy, relapsed after standard therapy, or
 have no available standard therapy.

 II. To determine the maximum toxic dose (MTD) and dose limiting toxicities (DLT) of
 ipilimumab and imatinib mesylate combination therapy.

 SECONDARY OBJECTIVES:

 I. To determine antitumor activity of ipilimumab and imatinib mesylate combination therapy.

 II. To determine antitumor activity of ipilimumab and imatinib mesylate combination therapy
 in KIT confirmed solid tumors.

 III. To evaluate the potential predictive role of tumor-associated immune biomarkers for
 therapy effectiveness.

 IV. To evaluate the potential predictive role of therapy associated toxicities with antitumor
 activity.

 OUTLINE: This is a dose-escalation study.

 Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1 and imatinib
 mesylated orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the
 absence of disease progression or unacceptable toxicity.
Inclusion Criteria:

 -  For dose escalation study, patients must have histological confirmation of solid
 tumors that is metastatic or unresectable. For expansion cohorts, patients must have
 metastatic or unresectable gastrointestinal stromal tumor (GIST), melanoma, or
 uncategorized tumors with tumor biopsies that are positive for c-KIT mutations by
 polymerase chain reaction (PCR) or immunohistochemistry (IHC). For patients enrolled
 in the melanoma expansion cohort, only select KIT mutations will be eligible. Patients
 with mutations in exon 13 V654X, 14 T6701, 17 D816X and all exon 18 mutations will not
 be eligible for enrollment.

 -  Patients who have completed previous therapies 4-weeks prior to (or within 5 drug half
 lives) enrollment on study. Radiation therapy wash out period will be 2 weeks. This
 includes an exception of patients with metastatic GIST tumors who are taking
 maintenance imatinib mesylate therapy. These patients are allowed to remain on
 imatinib mesylate therapy up to enrollment in this study.

 -  Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%).

 -  Leukocytes > 3,000/mcL

 -  Absolute neutrophil count > 1,500/mcL

 -  Platelets > 100,000/mcL

 -  Total bilirubin < or = 2.0 mg/dL. (Does NOT apply to patients with Gilbert's syndrome)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 < 2.5 X institutional upper limit of normal (patients with liver involvement will be
 allowed < or = 5.0 X institutional upper normal limit)

 -  Serum creatinine < 2.0 mg/dL

 -  Patients MUST have recovered from all treatment related toxicities to grade 1 National
 Center Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version
 [v] 4.0) in severity.

 -  Patients must be willing and able to review, understand, and provide written consent
 before starting therapy.

 -  Patients with histologically proven intracranial glioblastoma, gliosarcoma or
 anaplastic astrocytoma will be eligible. Patients must have shown unequivocal
 radiographic evidence for tumor progression by magnetic resonance imaging (MRI) scan.
 A scan should be performed within 14 days prior to registration and on a steroid dose
 that has been stable for at least 5 days. If the steroid dose is increased between the
 date of imaging and registration, a new baseline MRI is required.

 -  Patients in the expansion cohort must also agree to participate in the biomarker
 study. However, patients in the melanoma KIT positive mutant subgroup, patients must
 agree to participate in the biomarker study and biopsies.

 -  Patients must be willing to stay within 2 hours drive of MD Anderson Cancer Center
 whilst receiving Ipilimumab therapy. Patient must also agree to present to MD Anderson
 emergency center while on Ipilimumab therapy.

 Exclusion Criteria:

 -  Autoimmune disease: Patients with a history of inflammatory bowel disease (including
 Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid
 arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus
 or autoimmune vasculitis [e.g., Wegener's granulomatosis] are excluded from this
 study.

 -  History of acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
 obstruction, abdominal carcinomatosis or other known risk factors for bowel
 perforation.

 -  Any underlying medical or psychiatric condition, which in the opinion of the
 Investigator, will make the administration of study drug hazardous or obscure the
 interpretation of adverse events (AEs): e.g. a condition associated with frequent
 diarrhea or chronic skin conditions, recent surgery or colonic biopsy from which the
 patient has not recovered, or partial endocrine organ deficiencies.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, history of congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements.

 -  Known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.

 -  Any non-oncology live vaccine therapy used for prevention of infectious diseases (for
 up to one month prior to or after any dose of ipilimumab).

 -  Concomitant therapy with any of the following: IL-2, interferon or other non-study
 immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
 investigational therapies; or chronic use of systemic corticosteroids (when used in
 the management of cancers other than intracranial glioblastoma, gliosarcoma or
 anaplastic astrocytoma, or when used to treat non-cancer-related illnesses).

 -  Patients who do not agree to practice appropriate birth control methods while on
 therapy.

 -  Pregnant women are excluded from this study. Women of child-bearing potential and men
 must agree to use contraception prior to study entry and for the duration of study
 participation. Should a woman become pregnant or suspect she is pregnant while
 participating in this study, she should inform her treating physician.