Intrathecal Double Checkpoint Inhibition

Inclusion Criteria:

• Newly diagnosed confirmed or probable leptomeningeal metastases according to EuropeanAssociation of Neuro-Oncology (EANO) - European Society for Medical oncology (ESMO)criteria (Le Rhun et al., 2017).
• Histologically confirmed (from primary tumor or from a metastatic lesion, including inthe brain) non-small cell lung cancer without actionable oncogenic driver mutation ormelanoma. Programmed death-ligand 1 (PD-L1) expression status (from primary tumor orfrom a metastatic lesion, including brain) is optional, but should be documented ifavailable
• Requirements for patients with non-small cell lung cancer: non-small cell lungcancer without a specified targetable oncogenic driver alteration: sensitisingEpidermal Growth Factor Receptor (EGFR) mutation (exon 19-del and 21-L858R),anaplastic lymphoma kinase (ALK) or ROS proto-oncogene-1 (ROS1) rearrangement.
• Clinically eligible for systemic immunotherapy with nivolumab and ipilimumab at thetime of enrolment as judged by the investigator. If already initiated, the systemictreatment must be well tolerated, without common terminology criteria for adverseevents (CTCAE) grade 3 or more toxicity, and there must be no evidence of systemicprogression and no indication for whole brain radiotherapy. Intrathecal immunotherapyalone may be acceptable for exceptional patients after discussion with thecoordinators of the study. Systemic immunotherapy can be started later in thesepatients based on investigator decision.
• Patients previously treated with systemic chemotherapy must have received the lastdose at least 21 days prior to treatment initiation, patients who have receivedanother investigational agent must have received the last treatment at least 14 daysprior to treatment initiation.
• Age of 18 years or older on day of signing informed consent, female or male.
• Karnofsky performance status of 60 or more.
• Life expectancy >8 weeks. Patients with rapidly progressive systemic disease are noteligible.
• Patients may receive steroids to control symptoms related to central nervous systeminvolvement, but the dose must be stable or decreasing and < 4 mg per 24 hours ofdexamethasone (or equivalent) in the last 7 days. Patients should experience stabilityof neurological symptoms for at least 7 days. Physiologic replacement doses ofsteroids are permitted.
• Cerebrospinal MRI criteria (on the baseline MRI, performed within 14 days prior tostudy treatment initiation)
• MRI can be normal or can show leptomeningeal metastases, including nodules <0.5cm diameter largest diameter (or more if stereotactic radiosurgery is planned)
• No evidence of cerebrospinal fluid flow obstruction at the discretion of theinvestigator
• Co-existing asymptomatic brain metastases <2 cm diameter are permitted. Largerasymptomatic or oligosymptomatic brain metastases are permitted if they areplanned to be treated by stereotactic radiosurgery
• Central nervous system radiotherapy criteria:
• Focal brain radiotherapy by stereotactic radiotherapy is allowed for meningealnodules > 5 mm diameter or concomitant brain metastases. The treated lesionscannot be used as a target for the evaluation of the study treatment
• Prior brain focal radiotherapy for central nervous system metastases is permittedif completed at least 14 days prior to enrolment, but the treated lesions cannotbe used as a target for the evaluation of the study treatment
• Planned whole brain radiotherapy is not allowed
• Prior whole brain radiotherapy for brain metastases is permitted if terminated atleast 3 months prior enrolment.
• Planned or prior craniospinal irradiation is not allowed
• Women of childbearing potential, including women who had their last menstruation inthe last 2 years, must have a negative urinary or serum pregnancy test within 24 hoursbefore the first dose of study treatment.
• Ability to understand the requirements of the study, provide written informed consentand authorization of use and disclosure of protected health information, and agree toabide by the study restrictions and return for the required assessments.
• Written informed consent for study participation must be signed and dated by thepatient and the investigator prior to any study-related intervention.

Exclusion Criteria:

• Leptomeningeal metastases related to primary tumors other than non-small cell lungcancer without driver mutation or melanoma.
• Inability to undergo craniospinal MRI evaluation.
• Progressive parenchymal brain metastases thought to require whole brain radiotherapy.
• Contra-indication to lumbar puncture or to implantation of a ventricular device.
• Prior intrathecal chemotherapy, intrathecal immunotherapy or intrathecal targetedtherapy.
• Ventriculo-peritoneal shunt (except if intrathecal therapy is administered via aventricular device with an ON/OFF option).
• Condition requiring systemic treatment with either corticosteroids (> 4 mg dailydexamethasone equivalents) or other immunosuppressive medications within 7 days ofstudy drug administration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmunedisease.
• Patients with a history of pneumonitis or previous non-hematological grade >2 toxicityunder previous immunotherapy treatment.
• Active infection (systemic or central nervous system) within 7 days prior toinitiation of the study drug.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment.
• Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis Cvirus ribonucleic acid (HCV antibody) indicating acute or active chronic infection.
• Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS) even if fully immunocompetent onantiretroviral therapy due to the unknown effects of HIV on the immune response tocombined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs inpatients with HIV infection.
• Use of vaccines containing live virus for prevention of infectious disease within 12weeks prior to study drug.
• History of allergy to study drug components and history of severe hypersensitivityreaction to any monoclonal antibody.
• Concurrent treatment with other systemic cancer-derived pharmacotherapies is notallowed. No other concomitant intrathecal therapy is allowed.
• Any investigational anticancer therapy other than those under investigation in thisstudy.
• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements.
• Intention to become pregnant during the course of the study. Women who are pregnant.
• Women who are breast feeding and who do not agree to discontinue nursing prior to thefirst study treatment and for the period defined in the protocol.
• Sexually active men and women of childbearing potential who are not willing to use aneffective contraceptive method during the study.