Inclusion Criteria:
- - Newly diagnosed confirmed or probable leptomeningeal metastases according to European
Association 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 in
the brain) non-small cell lung cancer without actionable oncogenic driver mutation or
melanoma.
Programmed death-ligand 1 (PD-L1) expression status (from primary tumor or
from a metastatic lesion, including brain) is optional, but should be documented if
available.
- - Requirements for patients with non-small cell lung cancer: non-small cell lung
cancer without a specified targetable oncogenic driver alteration: sensitising
Epidermal 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 the
time of enrolment as judged by the investigator.
If already initiated, the systemic
treatment must be well tolerated, without common terminology criteria for adverse
events (CTCAE) grade 3 or more toxicity, and there must be no evidence of systemic
progression and no indication for whole brain radiotherapy. Intrathecal immunotherapy
alone may be acceptable for exceptional patients after discussion with the
coordinators of the study. Systemic immunotherapy can be started later in these
patients based on investigator decision.
- - Patients previously treated with systemic chemotherapy must have received the last
dose at least 21 days prior to treatment initiation, patients who have received
another investigational agent must have received the last treatment at least 14 days
prior 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 not
eligible.
- - Patients may receive steroids to control symptoms related to central nervous system
involvement, but the dose must be stable or decreasing and < 4 mg per 24 hours of
dexamethasone (or equivalent) in the last 7 days.
Patients should experience stability
of neurological symptoms for at least 7 days. Physiologic replacement doses of
steroids are permitted.
- - Cerebrospinal MRI criteria (on the baseline MRI, performed within 14 days prior to
study treatment initiation)
- MRI can be normal or can show leptomeningeal metastases, including nodules <0.5
cm diameter largest diameter (or more if stereotactic radiosurgery is planned)
- No evidence of cerebrospinal fluid flow obstruction at the discretion of the
investigator.
- - Co-existing asymptomatic brain metastases <2 cm diameter are permitted.
Larger
asymptomatic or oligosymptomatic brain metastases are permitted if they are
planned to be treated by stereotactic radiosurgery.
- - Central nervous system radiotherapy criteria:
- Focal brain radiotherapy by stereotactic radiotherapy is allowed for meningeal
nodules > 5 mm diameter or concomitant brain metastases.
The treated lesions
cannot be used as a target for the evaluation of the study treatment.
- - Prior brain focal radiotherapy for central nervous system metastases is permitted
if completed at least 14 days prior to enrolment, but the treated lesions cannot
be 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 at
least 3 months prior enrolment.
- - Planned or prior craniospinal irradiation is not allowed.
- - Women of childbearing potential, including women who had their last menstruation in
the last 2 years, must have a negative urinary or serum pregnancy test within 24 hours
before the first dose of study treatment.
- - Ability to understand the requirements of the study, provide written informed consent
and authorization of use and disclosure of protected health information, and agree to
abide by the study restrictions and return for the required assessments.
- - Written informed consent for study participation must be signed and dated by the
patient and the investigator prior to any study-related intervention.
Exclusion Criteria:
- - Leptomeningeal metastases related to primary tumors other than non-small cell lung
cancer 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 targeted
therapy.
- - Ventriculo-peritoneal shunt (except if intrathecal therapy is administered via a
ventricular device with an ON/OFF option).
- - Condition requiring systemic treatment with either corticosteroids (> 4 mg daily
dexamethasone equivalents) or other immunosuppressive medications within 7 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.
- - Patients with a history of pneumonitis or previous non-hematological grade >2 toxicity
under previous immunotherapy treatment.
- - Active infection (systemic or central nervous system) within 7 days prior to
initiation 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 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.
- - Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
virus ribonucleic acid (HCV antibody) indicating acute or active chronic infection.
- - Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on
antiretroviral therapy 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 infection.
- - Use of vaccines containing live virus for prevention of infectious disease within 12
weeks prior to study drug.
- - History of allergy to study drug components and history of severe hypersensitivity
reaction to any monoclonal antibody.
- - Concurrent treatment with other systemic cancer-derived pharmacotherapies is not
allowed.
No other concomitant intrathecal therapy is allowed.
- - Any investigational anticancer therapy other than those under investigation in this
study.
- - Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
- - 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 the
first study treatment and for the period defined in the protocol.
- - Sexually active men and women of childbearing potential who are not willing to use an
effective contraceptive method during the study.
