Patient case: 57-year-old male with melanoma; genetic feature: BRAF (V600E), PTEN loss of function

Clinical trial: Study of Concurrent Intravenous and Intrathecal Nivolumab for Patients With Leptomeningeal Disease (LMD)

Summary: This clinical research study consists of 2 phases: dose escalation (Phase 1) and dose expansion (Phase 2).
  The goal of Phase 1 of this research study is to find the highest tolerable dose level of nivolumab that can be given both by intravenous (IV) infusion and intrathecal (IT) injection to patients with leptomeningeal disease (LMD). IV infusions are given by vein, while IT injections are given directly into the cerebrospinal fluid (CSF).
  The goal of Phase 2 of this research study is to learn if the highest tolerable dose level combination found during Phase 1 can help to control the disease.
  The safety of the drug combination will also be studied in both phases.

Detailed description: Study Groups:
  If participant is found to be eligible to take part in this study, they will be assigned to a study group based on when they join this study. Up to 18 participants will be enrolled in Phase 1 of the study, and up to 12 participants will be enrolled in Phase 2.
  If participant is enrolled in Phase 1, the dose level of IT nivolumab they receive will depend on when they join this study. The first group of 6 participants will receive the lowest dose level of IT nivolumab. Each new group will receive a higher dose of IT nivolumab than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of IT nivolumab is found.
  If participant is enrolled in Phase 2, they will receive IT nivolumab at the highest dose that was tolerated in Phase 1.
  All participants in both phases will receive the same dose level of IV nivolumab.
  Study Drug Administration:
  Each study cycle is 14 days.
  Participant will receive IT nivolumab as an injection directly into your CSF through their Ommaya reservoir on Day 1 of each cycle. The injection should take about 5 minutes. Participant will need to remain in the hospital for 24 hours so that they can be checked for side effects.
  Starting with Cycle 2, participant will receive IV nivolumab by vein over about 30 minutes on Day 2 of every cycle.
  Length of Study:
  Participant may continue taking the study drugs for as long as the doctor thinks it is in their best interest. Participant will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if they are unable to follow study directions.
  Participation in this study will be over after the follow-up.
  Study Visits:
  On Day 1 of Cycles 1 and 2:
  -  Participant will have a physical exam.
  -  Blood (about 1 ½ tablespoons) will be drawn for routine testing, to test how well participant's blood clots, and to check their liver function.
  -  Blood (about 4 ½ tablespoons each time) will be drawn for immune system testing before participant's IT nivolumab dose and then 4 hours after their dose.
  -  CSF will be collected for immune system testing before participant's IT nivolumab dose and then 2 more times over the next 24 hours after participant's dose.
  On Day 2 and 8 of Cycles 1-3 blood (about 4½ tablespoons) and CSF will be collected for immune system testing.
  On Day 3 of Cycle 2, blood (about 4½ tablespoons) and CSF will be collected for immune system testing.
  On Day 1 of Cycle 3:
  -  Participant will have a physical, neurological, and neurocognitive exam.
  -  Blood (about 1½ tablespoons) will be drawn for routine testing and to check participant's liver function.
  -  Participant will have an MRI to check the status of the disease.
  -  Blood (about 4½ tablespoons) and CSF will be collected for immune system testing.
  On Days 1 and 2 of Cycle 4 and beyond:
  -  Blood (about 4½ tablespoons) will be drawn for immune system testing.
  On Day 1 of Cycle 5 and then every 4 cycles after that (Cycles 9, 13, 17, and so on):
  -  Participant will have a physical, neurological, and neurocognitive exam.
  -  Blood (about 1½ tablespoons) will be drawn for routine testing, to see how well participant's blood clots, and to check their liver function.
  -  Participant will have an MRI and either a CT or PET-CT scan to check the status of the disease.
  -  If participant can become pregnant, blood (about 1 tablespoon) or urine will be collected for a pregnancy test.
  Treatment Beyond Progression:
  Sometimes the disease appears to get worse when the study drug is actually working. If the disease appears to be getting worse or the tumors appear to be getting larger, participant may still be able to receive the study drug if they and their doctor decide it is in their best interest.
  However, there are risks of continuing to receive the study drug because the disease may actually be getting worse. Participant is still at risk for side effects due to the study drug. This could also delay starting other treatments. The disease may get worse to the point that participant is no longer able to receive other treatments.
  If participant chooses to receive the study drug after the disease gets worse, they will continue to have study visits as described above.The study doctor will discuss this option with participant.
  End-of-Study Visit:
  Within 4 weeks after participant's last dose of study drug, the following tests and procedures will be performed:
  -  Participant will have a physical exam.
  -  Blood (about 1 ½ tablespoons) will be drawn for routine tests.
  -  CSF will be collected for immune system testing.
  Long-Term Follow-Up:
  Every 12 weeks after participant's last dose of study drug, the following tests and procedures will be performed:
  -  Participant will have a physical exam.
  -  Blood (about 1 ½ tablespoons) will be drawn for routine tests.
  -  CSF will be collected for immune system testing.
  -  Participant will have an MRI and either a CT scan or PET-CT scan to check the status of the disease.
  Every 12 weeks, participant will also be contacted by a member of the study staff to ask how they are doing and about any new anti-cancer therapy they may be receiving. This contact will take place at a regular clinic visit, or participant may be contacted by phone, email, or mail. If participant is contacted by phone, the call should last about 15 minutes.
  This is an investigational study. Nivolumab is FDA approved and commercially available for the treatment of several types of cancer. Its use in LMD is considered investigational. The method of injecting nivolumab into the CSF is investigational. The study doctor can explain how the study drug is designed to work.
  Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Patients must have radiographic and/or CSF cytological evidence of LMD.
  2. Must have a confirmed diagnosis of metastatic melanoma (cutaneous, acral-lentiginous, uveal and mucosal in origin), based on histological analysis of metastatic tissue and/or cancer cells, archival tissue permitted.
  3. Patients must have an ECOG PS of </= 2.
  4. Patients may receive steroids to control symptoms related to CNS involvement, but the dose must be </= 4 mg per 24 hours of dexamethasone (or the equivalent). Patient's symptoms should experience stability of neurological symptoms for at least 7 days, or on tapering dose of steroids. Physiologic replacement doses for adrenal insufficiency is allowed on this protocol.
  5. Patients who have received radiation to brain and/or spine, including whole brain radiation, stereotactic radiosurgery, or SBRT, are eligible, but must have completed radiation treatment at least 7 days prior to the start of treatment.
  6. Concurrent treatment with other anti-cancer systemic therapies is not allowed. No other concomitant intrathecal therapy with another agent will be allowed. For patients that have received other systemic therapies, the minimum wash out period is as follows:
  -  Patients that received previous IT therapy must have received their last treatment >/= 14 days prior to the start of treatment
  -  Patients who have received systemic chemotherapy must have received their last treatment >/= 21 days prior to the start of treatment
  -  Patients who have received an approved biologic therapy (e.g. anti-PD-1, anti-CTLA4, IL2, interferon) must have received their last treatment>/= 4 weeks prior to the start of treatment
  7. contd from #7:
  -  Patients who have been treated with an approved targeted therapy (BRAF inhibitor and/or MEK inhibitor) must have received their last treatment >/= 28 days or 5 half-lives (whichever is shorter) prior to the start of treatment
  -  Patients who have received any other investigational agents must have received their last treatment >/= 28 days or 5 half-lives (whichever is shorter) prior to the start of treatment
  8. Age >/= 18 years
  9. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  10. Patients must have organ and marrow function: Hematologic: Absolute neutrophil count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.0 g/dL; Platelets >/= 75 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; </= 2.5 X ULN Albumin>/= 2.5 g/dL; Renal: Creatinine OR </= 1.5x ULN; Calculated creatinine clearance OR >/= 50 mL/min; 24-hour urine creatinine clearance >/= 50 mL/min.
  Exclusion Criteria:
  1. Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  2. Subjects with a condition requiring systemic treatment with either corticosteroids (> 4 mg daily dexamethasone 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.
  3. Patients who have previously received a-PD-1 and/or anti-CTLA-4 will be eligible, unless they have ongoing >Grade 2 AE side effects of such therapy. Ongoing physiologic replacement doses for adrenal and thyroid insufficiency are allowed on protocol.
  4. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
  5. Pregnant or lactating female
  6. Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled.
  7. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
  8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART—due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV.
  9. History of allergy to study drug components.
  10. History of severe hypersensitivity reaction to any monoclonal antibody.
  11. Prisoners or subjects who are involuntarily incarcerated.
  12. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Relevance to patient case: not relevant