Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Vemurafenib, Cetuximab, and Irinotecan in Advanced Solid Cancers

Summary: The goal of this clinical research study is to find the highest tolerable dose of vemurafenib that can be given in combination with cetuximab and irinotecan to patients with advanced cancer. The safety of this drug combination will also be studied.
  Vemurafenib is designed to block BRAFV600 inside the cancer cells, which is involved in cancer cell growth.
  Cetuximab is designed to block proteins inside the cancer cell, which may prevent or slow the growth of cancer cells and leads to cell death.
  Irinotecan is designed to stop cancer cells from making new DNA (the genetic material of cells). If the cancer cells cannot make DNA, they cannot divide into new cells and may die.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, your doctor will decide which dose level of vemurafenib you will receive. All participants will receive the standard dose of cetuximab and irinotecan.
  Dose Escalation Group:
  Up to 3 dose levels of vemurafenib will be tested in combination with cetuximab and irinotecan. Up to 6 participants will be enrolled at each dose level.
  The dose of any of the study drug combinations that you receive may be lowered if you have intolerable side effects.
  Dose Expansion Group:
  After the highest tolerable dose of vemurafenib is found, additional participants will be enrolled in the expansion group and will receive the study drug combination at that dose. This group will have up to 15 participants with BRAF mutant, KRAS wild type colorectal cancer.
  Study Drug Administration:
  You will take vemurafenib by mouth 2 times a day. If the doctor thinks it is needed, you may take it less often. Vemurafenib can be taken with or without food. Always take it with food or always take on an empty stomach. Take with full glass of water.
  You will receive cetuximab and irinotecan by vein over 90 minutes on Day 1 of each cycle. You will be monitored for at least 1 hour after the end of drug infusion.
  Study Visits:
  During Week 1 of Cycles 2 and beyond:
  -  You will have a physical exam and your skin will be checked.
  -  Your medical history will be recorded.
  -  Blood (about 4 teaspoons) will be collected for routine tests.
  -  You will be asked about any drugs you may be taking and side effects you may be having.
  At Week 1 of Cycles 1-2, if you are in a certain group on study, blood (about 2 teaspoons each time) will be drawn before your dose of irinotecan and 8 more times over the next 24 hours for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body at different time points.
  If you are enrolled in the colorectal cancer dose expansion group, you will have a biopsy for biomarker testing on Day 14 of Cycle 2.
  Beginning at Week 1 of Cycle 3, you will have EKG every other cycle (once monthly) for 3 months, and then once every 3 months until the end of the study.
  Beginning at Week 1 of Cycle 3, blood (about 2 teaspoons) will be drawn for biomarker testing every other cycle (once monthly).
  Beginning at Week 1 of Cycle 3, women who are able to become pregnant will have a blood (about 2 teaspoons) or urine pregnancy test every other cycle.
  At Week 1 of Cycle 3 and Cycle 5, urine will be collected for routine tests.
  At Week 1 of Cycle 3, if you are in a certain group on study, blood (about 2 teaspoons) will be drawn for PD testing.
  Every 3 Cycles, you will have imaging to check the status of the disease. These tests can include some or all of the following: a CT scan, MRI scan, PET scan, and/or bone scan. You will also have a chest x-ray.
  You will have an additional head and neck exam every 12 weeks while on study.
  All patients will have a chest CT 6 months after their last dose of vemurafenib. SCC patients will have additional chest CTs at screening and every 6 months while on study.
  Length of Study:
  You may continue taking the study drugs for as long as your doctor thinks it is in your best interest. You will be taken off study early if the disease gets worse, if you continue to have intolerable side effects, or if you are unable to follow study directions.
  Your participation on the study will be over once you have completed the end-of-study visit.
  End-of-Study Visit:
  Within 30 days after your last dose of study drugs, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed:
  -  Your medical history will be recorded.
  -  You will have a physical exam, including measurement of your vital signs and weight. °Your skin will be checked. You will also have a head and neck exam.
  -  You will be asked about any drugs you may be taking and side effects you may be having.
  -  Your performance status will be recorded.
  -  Blood (about 4 teaspoons) will be collected for routine tests.
  -  If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn to measure tumor markers.
  -  If you are in a certain group on study, blood (about 2 teaspoons) will be drawn for PK testing.
  -  You will have imaging to check the status of the disease. These tests can include some or all of the following: a chest x-ray, CT scan, MRI scan, PET scan, and/or bone scan.
  This is an investigational study. Vemurafenib is FDA approved and commercially available for the treatment of certain types of melanoma in patients with BRAF mutation.
  Cetuximab is FDA approved and commercially available for the treatment of KRAS wild type, EGFR expressing metastatic colorectal cancer and squamous cell carcinoma of the head and neck.
  Irinotecan is FDA approved and commercially available for the treatment of metastatic colorectal cancer.
  The use of these drugs together in advanced cancer is investigational.
  Up to 33 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients must have histologically confirmed malignancy that is metastatic or unresectable
  2. Cancers with positive BRAF V600 mutation detected by a CLIA-certified laboratory
  3. Age 18 years or older
  4. ECOG performance status of 0 to 2
  5. Life expectancy of greater than 3 months
  6. Patients must have measurable disease per RECIST 1.1 criteria
  7. Patients must have a K-RAS WT tumor
  8. Patients must have normal organ and marrow function as defined below, within 14 days: • Absolute neutrophils count >,=1500/mcl • Platelets >,=100000/mcl • Hb >,=9 mg/dl • Total bilirubin =,<1.5 mg/dl • AST/ALT =,<5x upper limit of normal if liver metastases present; otherwise, then =,< 2.5x upper limit • Estimated creatinine clearance by Cockcroft-Gault equation > 30 mL/min
  9. Current treatment may cause harm to the developing human fetus. For this reason women of child-bearing age must have a negative pregnancy test at screening and both women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 6 months after last dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  10. Signed informed consent approved by the Institutional Review Board prior to patient entry
  11. Expansion cohort: We propose a final expansion cohort for this study in a subset of interest utilizing the recommended dosing of combination. This cohort will include patients harboring characteristics that may predict response of combination or with clinical features that proved to derive most benefit of the study combination during preclinical studies. Cancers with positive BRAF (V600) mutation detected by a CLIA-certified laboratory.
  Exclusion Criteria:
  1. Patient receiving any concurrent chemotherapy
  2. Concurrent severe and/or uncontrolled medical disease including, but not limited to, ongoing or active infection requiring intravenous antibiotics, bowel obstruction
  3. Symptomatic congestive heart failure (NYHA Class III or IV), or unstable angina pectoris
  4. Patients who have had a myocardial infarction, transient ischemic attack, unstable angina, or CVS within 6 months before treatment
  5. Presence of symptomatic pleural and/or pericardial effusion not appropriately treated
  6. Prolonged QTc interval (>,=450 msec) as calculated by Bazett's formula, or patients with a history of congenital long QT syndrome or uncorrectable electrolyte abnormalities
  7. Medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk
  8. Known anaphylactic or severe hypersensitivity to the study drugs or their analogs
  9. Patient has failed to recover from any prior surgery within 4 weeks of study entry
  10. Patient is pregnant, lactating, or breastfeeding
  11. Patient has had any treatment specific for tumor control within 3 weeks of dosing with investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of biological targeted agents with half-lives and pharmacodynamic effects lasting less than 5 days
  12. Patient is not able to swallow oral medication
  13. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 complex are ineligible
  14. Patients with known K-RAS mutant (codon 12 or 13) detected by an FDA-approved test in a CLIA-certified laboratory
  15. Patients with BRAF WT cancers

Relevance to patient case: not relevant