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

Clinical trial: Sorafenib or Crizotinib and Vemurafenib in Advanced Cancer

Summary: The goal of this clinical research study is to find the highest tolerable dose of the combination of ZelborafTM (vemurafenib) with Nexavar® (sorafenib) or Xalkori® (crizotinib) that can be given to patients with advanced cancer. The safety of these drugs will also be studied.
  Vemurafenib is designed to block a protein called BRAFV600E inside the cancer cells, which is involved in cancer cell growth.
  Sorafenib is designed to block the function of important proteins in and outside of cancer cells. These proteins are involved in cancer cells growth and new blood vessel development.
  Crizotinib is designed to block certain abnormal genes found in cancer cells. This may cause the cancer cells to die.

Detailed description: Study Groups:
  Dose escalation:
  If you are found to be eligible to take part in this study, your doctor will decide if you will receive vemurafenib either with sorafenib or crizotinib. Once it is decided which combination you will receive, you will be assigned to a dose level based on when you join the study.
  Up to 6 dose levels of vemurafenib with sorafenib will be tested. Up to 5 dose levels of vemurafenib with crizotinib 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 vemurafenib either with sorafenib or crizotinib is found.
  Dose expansion:
  Once the highest tolerable dose of vemurafenib either with sorafenib or crizotinib is found, up to 14 more participants may be enrolled. This will be to further study the safety of the combination of drugs at that dose and the level of effectiveness of the study drugs in a certain tumor group.
  Study Drug Administration:
  Each study cycle is 28 days.
  You will take vemurafenib by mouth 2 times a day at the same time every day either with or without food, swallowed whole with a glass of water. Tablets should not be chewed or crushed. If you miss a dose, you can take it up to 4 hours before the next dose. You cannot take both doses at the same time.
  You will take sorafenib by mouth at the same time every day without food (at least 1 hour before or 2 hours after a meal). Depending on which dose level you are enrolled in, you will take sorafenib by mouth either 1 or 2 times a day. The doctor will discuss this with you.
  You will take crizotinib by mouth at the same time every day consistently either with or without food, swallowed whole with a glass of water. Depending on which dose level you are receiving, you will take crizotinib by mouth either 1 or 2 times a day. The doctor will discuss this with you.
  Study Visits:
  At every study visit, you will be asked if you have had any side effects.
  Around Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 and beyond:
  -  Blood (about 2-4 tablespoons) will be drawn for mutation/genetic testing. Mutation/genetic testing looks at whether specific genes are changed (mutated) in the tumor.
  -  Urine will be collected for mutation/genetic testing. You may collect your first urine of the morning, anytime during the day, or you may collect urine for 24 hours. You will be given containers to collect the urine and will be told how to use them.
  If you collect your urine over 24 hours, the study staff will give you a large (3-liter) urine storage container and a small (7-ounce) plastic collection container. You will urinate into the small collection container and then pour the urine into the large urine storage container within 10 minutes after the collection. You should write down the time of the first and last collections in the large storage container and return it to the study staff at the end of the 24-hour period.
  If you collect your first urine of the morning, the study staff will give you 3 plastic collection cups and 3 small tubes filled with a preservative solution. To collect your first morning urine, you will fill the collection cup with urine up to the 100 mL (milliliter) line, add 1 of the small tubes of preservative to the cup within 10 minutes, and then mark on the container that this is your first morning urine. If possible, fill the other 2 collection cups, adding a tube of preservative to each as just described and mark them as part of your first morning urine. You will return the collection cups to the study staff at your next visit.
  If you collect your urine anytime it suits you, the study staff will give you 3 plastic collection cups and 3 small tubes filled with a preservative solution. To collect your urine, you will fill the collection cup with urine up to the 100 mL line, add 1 of the small tubes of preservative to the cup within 10 minutes, and then mark on the container that this is your first morning urine. If possible, fill the other 2 collection cups, adding a tube of preservative to each as just described and mark them so the study doctor will know the time when you collected your urine. You will return the collection cups to the study staff at your next visit. Your study doctor or staff will give you more details, if needed.
  Around Days 15-21 of Cycle 1:
  -  Your medical history will be recorded, including any cancer symptoms.
  -  You will have a physical exam, including measurement of your weight and vital signs.
  -  You will be asked about any health problems you may have and any other drugs or herbal supplements you may be taking.
  -  Your performance status will be recorded.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  Before starting Cycles 2 and beyond:
  -  Your medical history will be recorded, including any cancer symptoms.
  -  You will have a physical exam, including measurement of your weight and vital signs.
  -  You will be asked about any health problems you may have and any other drugs or herbal supplements you may be taking.
  -  Your performance status will be recorded.
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  -  If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine pregnancy test.
  Every other cycle (every 8 weeks):
  -  Blood (about 1 tablespoon) will be drawn to check your thyroid gland.
  -  You will have a skin exam by a skin doctor to check for any lesions that might have skin cancer.
  -  You will have an x-ray, CT scan, MRI, and/or PET/CT scan to check the status of the disease. Blood (about 1 tablespoon) will be drawn for tumor marker testing. After at least 6 months of taking the study drugs, you may have CT, MRI, and/or PET/CT scans and blood drawn every 3 cycles (every 12 weeks) if the study doctor thinks it is needed.
  If the study doctor has to change your dose of study drugs, blood (about 1 tablespoon) will be drawn to check for abnormal minerals.
  Anytime during the study if your study doctor thinks it is needed:
  -  You will have an ECG to check your heart function.
  -  Blood (about 1 tablespoon) will be collected for abnormal mineral and digestive enzyme testing.
  -  If you are taking the blood thinner warfarin, blood (about 1 teaspoon) will be drawn to test how well your blood clots.
  Length of Dosing:
  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.
  Follow-up:
  You will have a follow-up-visit within 30 days after your last dose of study drugs. The following tests and procedures will be performed:
  -  You will be asked about any health problems you may have and if you have had any side effects.
  -  If the disease has gotten worse, blood (about 2-4 tablespoons) will be drawn for mutation/genetic testing.
  -  If the disease has gotten worse, urine will be collected for mutation/genetic testing. You may collect your first urine of the morning, anytime during the day, or you may collect urine for 24 hours.
  If your study doctor thinks it is needed, you may have follow-up for a longer period of time.
  You may have a skin exam within 6 months after your last dose of study drugs to check for any new lesions that may have skin cancer if the doctor thinks it is needed.
  This is an investigational study. Vemurafenib is FDA approved and commercially available to treat progressive melanoma with the BRAFV600E mutation. Sorafenib is FDA approved and commercially available to treat progressive hepatocellular carcinoma and renal cell carcinoma. Crizotinib is FDA approved and commercially available to treat locally advanced or metastatic non-small lung cancer. Giving the combination of vemurafenib either with sorafenib or crizotinib to patients with advanced cancer is investigational.
  Up to 183 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients with advanced or metastatic cancers and BRAF mutations that are refractory to standard therapy, relapsed after standard therapy, or who have no standard therapy available that improves survival by at least three months. Patients with BRAF mutation in cell free DNA (tested in CLIA lab) are also eligible.
  2. Patients must be >/= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen, or therapeutic radiation, or major surgery. Patients may have received palliative localized radiation immediately before or during treatment provided that radiation is not delivered to the only site of disease being treated under this protocol. For biologic/targeted agents patients must be >/= 5 half-lives or >/= 3 weeks from the last dose (whichever comes first). Patients previously treated with vemurafenib monotherapy do not have to stop medication before they start on the protocol.
  3. ECOG performance status </= 2
  4. Patients must be >/= 18 years of age.
  5. Patients must have adequate organ and marrow function defined as: absolute neutrophil count (ANC) >/= 1,000/mL, platelets >/=75,000/mL; creatinine </= 2 X ULN; total bilirubin </= 2 X ULN (exceptions may apply to benign non-malignant indirect hyperbilirubinemia such as Gilbert syndrome); ALT (SGPT) and/or AST (SGOT) </= 5 X ULN Exception for patients with liver metastasis: total bilirubin </= 3 x ULN; ALT (SGPT) </= 8 X ULN.
  6. Dermatology evaluation with excision of any suspicious lesions prior to initiation of therapy.
  7. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after the last dose.
  8. Women of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to initiation of therapy.
  9. Life expectancy >12 weeks in the opinion of the Investigator.
  10. Patients must be able to understand and be willing to sign a written informed consent document.
  11. Patient must be able to swallow pills.
  Exclusion Criteria:
  1. Uncontrolled intercurrent illness, including, but not limited to, uncontrolled infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.
  2. Syndrome of congenital QTc prolongation or QTc >500 msec.
  3. Patients with clinically significant cardiovascular disease: history of cerebrovascular accident (CVA) within 6 months, myocardial infarction or unstable angina within 6 months, or unstable angina pectoris.
  4. Pregnant or lactating women.
  5. History of hypersensitivity to vemurafenib.
  6. History of hypersensitivity to sorafenib for vemurafenib/sorafenib arm.
  7. History of hypersensitivity to crizotinib for vemurafenib/crizotinib arm.
  8. History of hypersensitivity to any component of the formulation.
  9. Patients unwilling or unable to sign informed consent document.
  10. Patients using any of the following medications: mesoridazine, dronedarone, thioridazine, ziprasidone, levomethadyl, and saquinavir for vemurafenib/sorafenib arm.

Relevance to patient case: not relevant