Patient case: 73-year-old male with melanoma; genetic feature: tumor cells negative for PD-L1 expression

Clinical trial: Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma

Summary: The goal of this clinical research study is to learn if giving nivolumab alone or in combination with ipilimumab before and after surgery can help to control metastatic melanoma. The safety of these drugs will also be studied.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one study group is better, the same, or worse than the other group. You will have an equal (1 in 2) chance of being assigned to either of the groups:
  -  If you are in Group A, you will receive nivolumab every 2 weeks (+/- 7 days) for a total of 4 doses and then you will have surgery. After that, you will receive nivolumab for an additional 6 months.
  -  If you are in Group B, you will receive nivolumab (+/- 7 days) and ipilimumab every 3 weeks for 3 doses and then you will have surgery. After that, you will receive nivolumab alone for 6 months.
  You and the study staff will know to which group you have been assigned.
  Study Drug Administration:
  If you are in Group A, you will receive nivolumab by vein over about 1 hour on Days 1, 15, 29, and 43. You will then have surgery. After surgery, you will receive nivolumab by vein every 2 weeks (+/- 7 days) for 6 months (13 doses).
  If you are in Group B, you will receive nivolumab by vein over about 1 hour and ipilimumab by vein over about 90 minutes on Days 1, 22, and 43. You will then have surgery. After surgery, you will receive nivolumab by vein every 2 weeks (+/- 7 days) for 6 months (13 doses).
  If treatment needs to be delayed more than two weeks because of safety reasons, the next dose(s) can be skipped. However, once you are able to begin treatment again and the disease appears to be responding, you can remain on the study and can proceed with surgery as planned.
  Study Visits:
  Group A Before Surgery:
  On Day 1:
  -  You will have a physical exam.
  -  Blood (about 3 ½ tablespoons) will be drawn for routine tests
  On Days 15 and 29:
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the immune system.
  -  You will have a tumor biopsy for biomarker testing on Day 15. Biomarkers are found in blood and tissue and may be related to your reaction to the study drug.
  On Day 43:
  -  You will have a physical exam.
  -  Blood (about 3 ½ tablespoons) will be drawn for routine tests
  On Day 57:
  -  You will have an EKG.
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and tests of the immune system.
  -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease. If the doctor thinks the disease can still be removed through surgery, you will then have surgery in the following week. If the disease is no longer able to be treated with surgery, you will be taken off study. Your doctor will discuss other treatment options with you.
  -  If you can become pregnant, blood (about 1/2 teaspoon) or urine will be collected for pregnancy test.
  Group B Before Surgery:
  On Day 1:
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the immune system.
  On Days 22 and 43:
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the immune system.
  -  You will have a tumor biopsy for biomarker testing on Day 22.
  On Day 57:
  -  You will have an EKG.
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the immune system.
  -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease. If the doctor thinks the disease can still be removed through surgery, you will then have surgery in the following week. If the disease is no longer able to be treated with surgery, you will be taken off study. Your doctor will discuss other treatment options with you.
  -  If you can become pregnant, blood (about 1/2 teaspoon) or urine will be collected for pregnancy test.
  Surgery (All Participants):
  On Day 57 you will have surgery to remove the disease. You will sign a surgery consent form that describes the procedure and its risks. Tissue will be collected at time of surgery for research to test for any remaining melanoma cells and to check the status of the disease.
  Study Visits After Surgery for All Participants:
  Every 2 weeks after you recover from surgery (every time you receive nivolumab):
  -  You will have a physical exam.
  -  Blood (about 3 ½ tablespoons) will be drawn for routine tests.
  At the following visits additional tests and procedures will be performed:
  -  At Weeks 10, 22, and 34 after surgery, blood (about 3 tablespoons) will also be drawn for tests of the immune system.
  -  At Weeks 22 and 34 after surgery, you will have a CT scan, PET-CT scan, or MRI to check the status of the disease.
  Length of Treatment:
  You may receive up to 13 doses of nivolumab after you have surgery. You will no longer be able to take the study drug(s) if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Your participation on the study will be over after the follow-up visits.
  End-of-Treatment Visit:
  When you stop receiving nivolumab, or if you have an intolerable side effect, you will have an end-of-treatment visit. The following tests and procedures will be performed:
  -  You will have a physical exam.
  -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and tests of the immune system.
  -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease.
  Follow-Up Visits:
  Every 12 weeks after your last dose of drug(s):
  -  You will have a physical exam.
  -  Blood (about 6 tablespoons) will be drawn for routine tests and for tests of the immune system.
  -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease.
  The study staff will contact you for follow-up, for up to 2 years after surgery. You will be asked about your health status, any anti-cancer therapy you receive (including radiation), and how the disease may be responding to therapy. If you need to stop receiving treatment early, the study staff will contact you to check you health status every 3 months until you start a new treatment for melanoma. This follow-up contact may be done in-person, if you continue treatment at MD Anderson. If not you will be contacted by phone, email or letter.
  This is an investigational study. Ipilimumab and nivolumab are FDA approved and commercially available to treat metastatic melanoma. It is investigational to give the drugs in combination before and after surgery. The study doctor can explain how the study drugs are designed to work.
  Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  2. Patients must have histologically or cytologically confirmed Stage IIIB/C or Stage IV oligometastatic melanoma. Oligometastatic melanoma is defined as three or fewer areas of resectable disease excluding central nervous system and bone involvement. Patients with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for enrollment. For patients with stage IV disease with distant lymph nodes (stage M1a), a maximum of three separate lymph node sites fit the definition of oligometastatic disease. Resectable tumors are defined as having no significant vascular, neural or bony involvement. Only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable.
  3. Patients will have at least one melanoma deposit that can undergo serial biopsy (at least 2 time points) during the neoadjuvant phase of the protocol. Patients must be willing to provide tumor samples at the time points specified in the Study Procedure Tables.
  4. All patients must undergo a baseline tumor biopsy for PD-L1 testing (PD-L1 positivity is determined by greater than or equal to 1% of cells staining in the membrane by immunohistochemistry). For patients with stage IV disease, site of tumor biopsy will preferably be from non-lymph node disease site. For PD-L1 testing, the biopsy should contain sufficient tumor content (>/=100 tumor cells/4-micron tissue section). If a sample contains insufficient tumor content, a re-biopsy will be required to obtain a sample with sufficient tumor content prior to treatment.
  5. Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team
  6. Patients who have been previously been treated in the adjuvant setting for melanoma (including use of prior interferon alpha, pegylated interferon or vaccine on clinical trial) will be eligible for treatment after a 28 day wash-out period
  7. Patients must have measurable disease, defined by RECIST 1.1
  8. Age >/= 18 years
  9. ECOG performance status 0-1
  10. Patients must have organ and marrow function as defined below: Hematologic Absolute neutrophil count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.5 g/dL Platelets >/= 100 X 10^9/L PT/INR and PTT </= 1.5 X ULN. Hepatic Total bilirubin </= 1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) AST and ALT Albumin </= 2.5 X ULN 1 >/=2.5 g/dL Renal Creatinine OR Calculated creatinine clearance OR 24-hour urine creatinine clearance </=1.5 X ULN 2 >/= 50 mL/min >/= 50 mL/min
  11. Women are eligible to participate if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT.
  12. 11b) The individual methods of contraception and duration should be determined in consultation with the investigator. Women of childbearing potential (WOCBP) must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
  13. Women must not be breastfeeding
  14. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year The investigator shall review contraception methods and the time period that contraception must be followed. Men who are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Therefore, men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
  15. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile and azoospermic men do not require contraception.
  Exclusion Criteria:
  1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
  2. Any major surgery within the last 3 weeks
  3. Brain metastases, leptomeningeal disease or bone metastases
  4. Pregnant or lactating female
  5. Unwillingness or inability to follow the procedures required in the protocol
  6. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels
  7. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
  8. Prior malignancy active within the previous 2 years except for patient's prior diagnosis of melanoma and locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation).
  9. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  10. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  11. Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody
  12. Any positive test result for hepatitis B or C virus indicating acute or chronic infection
  13. Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome
  14. History of severe hypersensitivity reaction to any monoclonal antibody
  15. Prisoners or subjects who are involuntarily incarcerated
  16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (infection disease) illness

Relevance to patient case: not relevant