Working... Menu

Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03025256
Recruitment Status : Recruiting
First Posted : January 19, 2017
Last Update Posted : March 20, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Acral Lentiginous Melanoma Central Nervous System Melanoma Clinical Stage IV Cutaneous Melanoma AJCC v8 Leptomeningeal Neoplasm Melanocytoma Metastatic Melanoma Metastatic Uveal Melanoma Mucosal Melanoma Pathologic Stage IV Cutaneous Melanoma AJCC v8 Biological: Nivolumab Phase 1

Detailed Description:


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


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


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. Beginning in course 2, patients also receive nivolumab intravenously (IV) over 30 minutes on day 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Ib Study of Concurrent Intravenous and Intrathecal Nivolumab for Patients With Leptomeningeal Disease (LMD)
Actual Study Start Date : May 2, 2018
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : April 30, 2020

Arm Intervention/treatment
Experimental: Treatment (nivolumab)
Patients receive nivolumab IT over 5 minutes on day 1. Beginning in course 2, patients also receive nivolumab IV over 30 minutes on day 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Biological: Nivolumab
Given IV or IT
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Safety and tolerability of treatment will be assessed by vital signs, laboratory assessments, adverse events, and serious adverse events for the safety population. Adverse events will be graded by the Common Terminology Criteria for Adverse Events version 4.0. Categorical measures will be summarized using frequencies and percentages while continuous variables will be summarized using mean, standard deviation, median, minimum, and maximum.

  2. Recommended dose of combined intrathecal (IT) and intravenous (IV) nivolumab defined as the highest dose for which the posterior probability of toxicity is closest to 30% (dose escalation part) [ Time Frame: Up to 28 days ]
    The Bayesian modified toxicity probability interval method will be used to find the recommended dose.

  3. Overall survival (OS) in patients treated with IT and IV nivolumab (dose expansion part) [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :
  1. OS [ Time Frame: Up to 2 years ]
    The Kaplan-Meier method will be used to estimate the distribution of OS from the start of study treatment, and Cox proportional hazard regression will be used to assess the relationship between OS and various covariates of interest, including but not limited to patient demographics, tumor characteristics, disease characteristics, and the expression of biomarkers.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have radiographic and/or CSF cytological evidence of LMD
  • Must have a confirmed diagnosis of primary central nervous system (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
  • 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
  • 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 >= 7 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
    • Patients who have been treated with an approved targeted therapy (BRAF inhibitor and/or MEK inhibitor) must have received their last treatment >= 7 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 >= 14 days prior to the start of treatment
  • 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 a-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
  • 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 plus ipilimumab 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 (eg, infectious disease) illness

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03025256

Layout table for location contacts
Contact: Isabella C. Glitza 713-792-2921

Layout table for location information
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Isabella C. Glitza    713-792-2921      
Principal Investigator: Isabella C. Glitza         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Layout table for investigator information
Principal Investigator: Isabella Glitza M.D. Anderson Cancer Center

Additional Information:
Layout table for additonal information
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03025256     History of Changes
Other Study ID Numbers: 2016-0567
NCI-2018-01211 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0567 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: January 19, 2017    Key Record Dates
Last Update Posted: March 20, 2019
Last Verified: March 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Skin Neoplasms
Meningeal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Central Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents