The goal of this clinical trial is to learn if the intraventricular injection of Pemetrexed and Nivolumab works to treat refractory non-squamous non-small cell lung cancer with leptomeningeal metastases. The main questions to answer are:
* Is the combination of Pemetrexed and Nivolumab safe to inject? * How effective is the combination in disease control?
Participants will：
* Intrathecal injection of 30 mg pemetrexed via Ommaya reservoir, once every 4 weeks until disease progression; * Intrathecal injection of 40 mg nivolumab via Ommaya reservoir, once every 4 weeks until disease progression; * Before each intrathecal administration, a preliminary intrathecal injection of dexamethasone, 5 mg/2 mL, is given.
Patients who sign the informed consent form and are willing to complete the study according to the protocol;
Patients must have radiographic and/or cerebrospinal fluid cytology evidence of leptomeningeal disease (LMD). The diagnosis of non-small cell lung cancer must be confirmed, based on histological and/or cytological diagnosis.
Patients must have an ECOG performance status score of ≤ 2.
Patients may use steroids to control symptoms related to the central nervous system, but the dose must be ≤ 4 mg of dexamethasone (or equivalent dose) within 24 hours. The patient's neurological symptoms should remain stable for at least 7 days, or they are reducing the dose of steroids. Physiological replacement doses for adrenal insufficiency are allowed.
Patients who require a VP shunt due to increased intracranial pressure.
Patients must not have active autoimmune diseases requiring systemic treatment in the past two years (i.e., using disease-modifying agents, corticosteroids, or immunosuppressive drugs). Alternative therapies (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered forms of systemic treatment.
Subjects who need systemic treatment within 14 days prior to administration of the study drug, including the use of corticosteroids (>4 mg daily dexamethasone equivalent dose) or other immunosuppressive drugs. Inhaled or topical steroids and adrenal replacement therapy at a daily replacement dose >10 mg prednisone equivalent are allowed in the absence of active autoimmune diseases.
Patients who have previously received PD-1 and/or anti-CTLA-4 therapy are eligible, unless they are experiencing > grade 2 side effects from such treatments. Ongoing physiological replacement doses for adrenal and thyroid insufficiency are allowed in the protocol.
Single group
Intraventricular Pemetrexed
DrugIntraventricular injection of 30 mg pemetrexed via Ommaya reservoir, once every 4 weeks until disease progression.
Intraventricular Nivolumab
DrugIntraventricular injection of 40 mg nivolumab via Ommaya reservoir, once every 4 weeks until disease progression.
Intraventricular Dexamethasone
DrugIntraventricular injection of 5mg/2ml pemetrexed via Ommaya reservoir before injection of pemetrexed and nivolumab.
Adverse Event
Per CTCAE version 4.0
objective response rate (ORR)
LM objective response rate (ORR) is defined as the proportion of patients with at least one objective response in LM, using a combined approach taking into account radiographic, neurologic and cytologic assessments based on RANO-LM.
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