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.
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
IV. To evaluate the potential predictive role of therapy associated toxicities with antitumor
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.
- 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.
- 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
- History of acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
obstruction, abdominal carcinomatosis or other known risk factors for bowel
- 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
- 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
- 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.