Skip to main content

Intravenous and Intrathecal Nivolumab in Treating Patients with Leptomeningeal Disease

Trial Status: Active

This phase I / Ib trial studies the side effects and best dose of intrathecal nivolumab, and how well it works in combination with intravenous nivolumab in treating patients with leptomeningeal disease. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Patients must have radiographic and/or CSF cytological evidence of LMD. For patient with melanoma: Must have a confirmed diagnosis of primary CNS melanoma, melanocytomas or metastatic melanoma (cutaneous, acral-lentiginous, uveal and mucosal in origin), based on histological analysis of metastatic tissue and/or cancer cells, archival tissue permitted. For patients with lung cancer: non small cell lung cancer, based on histological analysis of metastatic tissue and/or cancer cells, archival tissue permitted
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of =< 2
  • 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
  • Patients who have received radiation to brain and/or spine, including whole brain radiation, stereotactic radiosurgery, or stereotactic body radiation therapy (SBRT), are eligible, but must have completed radiation treatment at least 7 days prior to the start of treatment
  • Patients who have been treated with an approved targeted therapy (BRAF inhibitor and/or MEK inhibitor) will be allowed to remain on concurrent approved targeted therapy. 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 >= 7 days prior to the start of treatment * Patients who have received systemic chemotherapy must have received their last treatment >= 14 days prior to the start of treatment * Patients who have received an approved systemic biologic therapy (e.g. anti-PD-1, anti-CTLA4, IL2, interferon) must have received their last treatment >= 2 weeks prior to the start of treatment * Patients who have received any other investigational agents must have received their last treatment >= 14 days prior to the start of treatment
  • For patients with lung cancer: * For chemotherapy: patients do not require a washout period, and can continue with chemotherapy during treatment with IT/IV nivolumab * Patients who have received an approved systemic biologic therapy (e.g. anti-PD-1, anti-CTLA4, IL2, interferon) must have received their last treatment >= 2 weeks prior to the start of treatment * Patients who have received any other investigational agents must have received their last treatment >= 14 days prior to the start of treatment * No other concomitant intrathecal therapy with another agent will be allowed
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Absolute neutrophil count (ANC) >= 1.5 X 10^9/L
  • Hemoglobin >= 9.0 g/dL
  • Platelets >= 75 X 10^9/L
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 X upper limit of normal (ULN)
  • Total bilirubin: =< 1.5 X ULN (isolated bilirubin > 1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN
  • Albumin >= 2.5 g/dL
  • Creatinine OR =< 2 x ULN; calculated creatinine clearance OR >= 50 mL/min; 24-hour urine creatinine clearance >= 50 mL/min
  • Absence of contraindication for Ommaya reservoir

Exclusion Criteria

  • 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
  • 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
  • Patients who have previously received alpha-PD-1 and/or anti-CTLA-4 will be eligible, unless they have ongoing > grade 2 adverse event (AE) side effects of such therapy. Ongoing physiologic replacement doses for adrenal and thyroid insufficiency are allowed on protocol
  • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug (concurrent treatment with approved targeted therapies is allowed.)
  • Pregnant or lactating female
  • 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
  • Patients with a history of pneumonitis
  • Evidence of active infections =< 7 days prior to initiation of study drug therapy (does not apply to viral infections that are presumed to be associated with the underlying tumor type required for study entry)
  • Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to study drug
  • Any positive test for hepatitis B virus or hepatitis C virus indicating acute or 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 (ART)—due to the unknown effects of HIV on the immune response to combined nivolumab or the unique toxicity spectrum of these drugs in patients with HIV
  • History of allergy to study drug components
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Prisoners or subjects who are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Isabella Claudia Glitza
Phone: 713-792-2921

PRIMARY OBJECTIVE:

I. To determine the safety and/or recommended dose of intrathecal (IT) nivolumab in combination with systemic nivolumab treatment in patients in melanoma and lung cancer patients with leptomeningeal disease (LMD).

SECONDARY OBJECTIVE:

I. To assess overall survival with combined intrathecal and systemic administration of nivolumab in this patient population.

EXPLORATORY OBJECTIVES:

I. Compare the immunological effects of this treatment on immune cells in the cerebrospinal fluid (CSF) to those observed in the peripheral blood and in non-LMD tumors.

II. Evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety of this regimen.

III. To assess the effect of nivolumab on subsequent treatment.

IV. To compare levels of nivolumab in the CSF and peripheral blood.

OUTLINE: This is a phase I, dose-escalation study followed by a phase Ib study.

Patients receive nivolumab IT over 5 minutes on day 1 of every cycle. Beginning in cycle 2, patients also receive nivolumab intravenously (IV) over 30 minutes on day 1 (4 hours after the IT dose). Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 4 weeks and then every 12 weeks thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Isabella Claudia Glitza

  • Primary ID 2016-0567
  • Secondary IDs NCI-2018-01211
  • Clinicaltrials.gov ID NCT03025256