Patient case: 62-year-old female with melanoma; genetic feature: KIT (K642E)

Clinical trial: Ipilimumab and Imatinib Mesylate in Advanced Cancer

Summary: The goal of this clinical research study is to find the highest tolerable dose of the combination of ipilimumab and imatinib that can be given to patients with advanced cancer. The safety of this drug combination will also be studied.
  Ipilimumab is designed to increase the immune system's ability to fight cancer.
  Imatinib is designed to bind to certain proteins on the tumor cells, which may prevent the cells from growing.

Detailed description: Study Groups:
  Dose Escalation Group:
  If you are found to be eligible to take part in this study, you will be assigned to a dose level of your study drug combination based on when you joined this study. Up to 4 dose levels of the study drug combination will be tested. Up to 6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the study drug combination is found.
  Dose Expansion Group:
  After the highest tolerable dose level of the study drug combination is found, up to 20 additional participants will be enrolled in the dose expansion group. Patients with metastatic gastrointestinal stromal tumors (GIST), melanoma, or tumors with original tumor biopsies testing positive for KIT mutations (a cancer biomarker) will be eligible to enroll and will receive the highest dose of the study drug combination that was tolerated in the dose escalation group.
  Study Drug Administration:
  If you are in the Dose Escalation Group, the first study cycle is 35 days. Each cycle after that is 21 days.
  If you are in the Dose Expansion Group, all study cycles are 21 days.
  If you are in the Dose Escalation Group, you will start taking imatinib by mouth 1 time each day for 14 days before you receive ipilimumab. On Day 15 of each cycle, you will receive a single dose of ipilimumab by vein over 90 minutes. You will continue to take imatinib by mouth 1 time each day.
  If you are in the Dose Expansion Group, you will receive ipilimumab by vein over 90 minutes on Day 1 of each cycle. You will also take imatinib by mouth 1 time each day of each cycle.
  Study Visits:
  One (1) time each week during Cycle 1:
  -  You will have a physical exam, including measurement of your weight and vital signs.
  -  Blood (about 1 tablespoon) will be collected for routine tests.
  -  Urine will be collected for routine tests.
  -  You will have an EKG.
  Every 3-4 weeks during Cycles 2 and beyond:
  -  You will have a physical exam, including measurement of your weight and vital signs.
  -  Blood (about 1 tablespoon) and urine will be collected for routine tests.
  -  You will have an EKG.
  On Day 15 of Cycles 2 through 4:
  -  You will have a physical exam, including measurement of your weight and vital signs.
  -  Blood (about 1 tablespoon) and urine will be collected for routine tests.
  Starting after Cycle 2:
  -  You will have a CT or MRI scan after every 2 cycles to check the status of the disease.
  -  If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine pregnancy test once a month.
  Length of Study:
  You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  This is an investigational study. Ipilimumab is FDA approved and commercially available for the treatment of unresectable or metastatic melanoma. Imatinib is FDA approved and commercially available for the treatment of advanced or metastatic gastrointestinal stromal tumor (GIST).
  The combination of ipilimumab and imatinib is currently being used for research purposes only.
  Up to 96 participants will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. 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 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.
  2. 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.
  3. Age > or = 15 years
  4. ECOG performance status < 2 (Karnofsky > 60%).
  5. Patients must have normal organ and marrow function as defined below: 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); AST(SGOT)/ALT(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
  6. Patients MUST have recovered from all treatment related toxicities to Grade 1 NCI CTCAE (v 4.0) in severity
  7. Patients must be willing and able to review, understand, and provide written consent before starting therapy
  8. Patients with histologically proven intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma will be eligible. Patients must have shown unequivocal radiographic evidence for tumor progression by 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.
  9. Patients in the expansion cohort must also agree to participate in the immunotherapy platform protocol (PA13-0291).
  10. 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:
  1. 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.
  2. History of acute diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis or other known risk factors for bowel perforation.
  3. 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.
  4. 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.
  5. Known HIV, Hepatitis B, or Hepatitis C.
  6. 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).
  7. 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).
  8. Patients who do not agree to practice appropriate birth control methods while on therapy.
  9. 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.

Relevance to patient case: not relevant