Patient case: 40-year-old female with thyroid cancer; genetic feature: BRAF

Clinical trial: Tremelimumab (Anti-CTLA-4) Plus MEDI4736 (Anti-PD-L1) in Resectable Colorectal Cancer Liver Metastases

Summary: The goal of this clinical research study is to learn if tremelimumab in combination with MEDI4736, FOLFOX (fluorouracil, leucovorin, and oxaliplatin), and bevacizumab can help to control colorectal cancer that has spread to the liver. The safety of these drugs will also be studied.

Detailed description: Study Drug Administration:
  If participant is found to be eligible to take part in this study, they will receive FOLFOX and bevacizumab by vein over about 2 days during Weeks 1, 3, 5, and 7.
  Participant will also receive tremelimumab by vein over about 1 hour and MEDI4736 by vein over about 4 hours during Week 11. After Week 11, participant will receive MEDI4736 alone by vein over about 1 hour during Weeks 21, 25, 29, and 33.
  Between Weeks 15 and 17, participant will have their already scheduled liver surgery. This means participant will receive FOLFOX, bevacizumab, and tremelimumab before their surgery and MEDI4736 after their surgery.
  Study Visits:
  During Week 1:
  -  Participant will have a physical exam.
  -  Blood (about 6 tablespoons) will be drawn for routine tests and for testing related to participant's immune system.
  -  If participant can become pregnant, part of the above routine blood sample will be used for a pregnancy test. Urine may also be collected for this test.
  During Weeks 3, 5, and 7:
  -  Blood (about 1 tablespoon) will be drawn for routine tests.
  -  During Week 5, participant will have a physical exam.
  Between Weeks 9 and 11:
  -  Blood (about 4 tablespoons) will be drawn for tests related to the immune system.
  -  Participant will have a CT scan.
  -  Participant will have a liver tumor biopsy to check the status of the disease and for biomarker testing. To perform a tumor tissue biopsy, the affected area is numbed with anesthetic and a small amount of tissue is removed with a small needle. Participant will also receive anesthesia before the procedure. This will be discussed with participant in more detail before the biopsy.
  During Week 11:
  -  Participant will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine tests.
  -  If participant can become pregnant, part of the above routine blood sample will be used for a pregnancy test. Urine may also be collected for this test.
  During Week 15:
  -  Participant will have a physical exam.
  -  Blood (about 5 tablespoons) will be drawn for routine tests and tests related to participant's immune system.
  -  Participant will have a CT scan.
  Between Weeks 15 and 17, participant will have liver surgery as part of their standard care. Participant will sign a separate consent form for this procedure.
  During Weeks 19:
  -  Participant will also have a physical exam.
  -  Blood (about 7 tablespoons) will be drawn for routine tests, to check the status of the disease, and for tests related to participant's immune system.
  During Week 21:
  -  Participant will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine tests.
  -  If participant can become pregnant, part of the above routine blood sample will be used for a pregnancy test. Urine may also be collected for this test.
  During Week 25:
  -  Participant will have a physical exam.
  -  Blood (about 4 teaspoons) will be drawn for routine tests.
  During Weeks 29, 44, and 68:
  -  Participant will have a physical exam.
  -  Blood (about 8 teaspoons) will be drawn for routine tests and to check the status of the disease.
  -  Participant will have a CT scan or MRI.
  During Week 33:
  -  Participant will have a physical exam.
  -  Blood (about 6 tablespoons) will be drawn for routine tests and tests related to participant's immune system.
  During Week 56:
  -  Participant will have a physical exam.
  -  Blood (about 7 tablespoons) will be drawn for routine tests, to check the status of the disease, and for tests related to participant's immune system.
  -  Participant will have a CT scan.
  Length of Study:
  Participant may receive FOLFOX and bevacizumab during Weeks 1, 3, 5, and 7. Participant may receive tremelimumab and MEDI4736 for 1 week and MEDI4736 alone for up to an additional 4 weeks. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if they are unable to follow study directions.
  Patient's participation on this study will be over after follow-up.
  Follow-Up:
  If participant stops treatment for any reason, they will be asked to come to the hospital so their study doctor may check their health and follow up any ongoing side effects or discomfort until they get better.
  If the disease has gotten better or remained the same, participant's doctor will continue to check on the status of the disease as part of their standard of care, which may include imaging scans and/or blood draws for routine tests.
  Follow-up will continue for 1½ years or until participant withdraws from the study.
  This is an investigational study. MEDI4736 and tremelimumab are not FDA approved or commercially available. They are currently being used for research purposes only. FOLFOX and bevacizumab are FDA approved and commercially available for the treatment of colorectal cancer.
  The study doctor can explain how the study drugs are designed to work.
  Up to 35 participants will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients must have histologically or cytologically confirmed colorectal cancer with metastases deemed resectable by a general or liver surgeon (resectability may involve the use of ablative techniques to some but not all liver metastases). Those patients with known disease outside of the liver are not eligible (except for patients with primary lesions in place that are planned for resection or nonspecific lung metastases <1cm).
  2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as =/>10 mm with spiral CT scan.
  3. All lines of prior therapy accepted. Subjects with prior hepatic or extra-hepatic resections of metastatic disease will be included.
  4. Age =/>18 years. Because no dosing or adverse event data are currently available on the use of tremelimumab in combination with MEDI4736 in patients <18 years of age, children are excluded from this study.
  5. Life expectancy of greater than 6 months.
  6. ECOG performance status =/<1 (Karnofsky =/>70%).
  7. Patients must have normal organ and marrow function as defined: a) leukocytes =/>3,000/mcL; b) absolute neutrophil count =/>1,500/mcL; c) platelets =/>100,000/mcL; d) total bilirubin < 1.5 X institutional normal limits (subjects with known Gilbert syndrome are eligible with total bilirubin < 3.0 mg/dL); e) AST(SGOT)/ALT(SGPT) =/< 3 X institutional upper limit of normal; f) creatinine within normal institutional limits OR g) creatinine clearance =/>60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
  8. Known MSI, BRAF, and KRAS status.
  9. The effects of tremelimumab and/or MEDI4736 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because immune checkpoint inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, 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, for the duration of study participation, and 180 days after the last dose of tremelimumab. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  10. Ability to understand and the willingness to sign a written informed consent document.
  Exclusion Criteria:
  1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. An exception to this criterion is if patients are enrolled after the completion of neoadjuvant chemotherapy. If this is the case then 2 weeks must elapse prior to the beginning of immune checkpoint therapy.
  2. Patients may not be receiving any other investigational agents.
  3. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: a) Patients with vitiligo or alopecia; b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; c) Any chronic skin condition that does not require systemic therapy; d) Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
  4. Subjects with a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  5. Prior exposure to T cell checkpoint inhibitor therapies.
  6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  7. Positive test for hepatitis B virus surface antigen or hepatitis C (IgG or RNA test) indicating acute or chronic infection.
  8. Positive test for HIV.
  9. Women who are pregnant, which includes women with a positive pregnancy test at enrollment or prior to the administration of study medication, or breastfeeding are not allowed on study.
  10. Receipt of a live vaccine within 30 days of study entry.

Relevance to patient case: not relevant