Study of Concurrent Intravenous and Intrathecal Nivolumab for Patients With Leptomeningeal Disease (LMD)

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 : May 3, 2018
Bristol-Myers Squibb
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

This clinical research study consists of 2 phases: dose escalation (Phase 1) and dose expansion (Phase 2).

The goal of Phase 1 of this research study is to find the highest tolerable dose level of nivolumab that can be given both by intravenous (IV) infusion and intrathecal (IT) injection to patients with leptomeningeal disease (LMD). IV infusions are given by vein, while IT injections are given directly into the cerebrospinal fluid (CSF).

The goal of Phase 2 of this research study is to learn if the highest tolerable dose level combination found during Phase 1 can help to control the disease.

The safety of the drug combination will also be studied in both phases.

This is an investigational study. Nivolumab is FDA approved and commercially available for the treatment of several types of cancer. Its use in LMD is considered investigational. The method of injecting nivolumab into the CSF is investigational. The study doctor can explain how the study drug is designed to work.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Condition or disease Intervention/treatment Phase
Melanoma and Other Malignant Neoplasms of Skin Leptomeningeal Disease Drug: Nivolumab Phase 1

  Show Detailed Description

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 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab

Dose Escalation: Participants receive intrathecal (IT) Nivolumab every 14 days. Cycle 1 consists of IT Nivolumab only, but in subsequent cycles the IT Nivolumab dose is followed by an intervenous dose of Nivolumab.

Intrathecal dose administered by accessing the Ommaya.

Dose Expansion: Maximum tolerated dose from Dose Escalation.

Drug: Nivolumab

Dose Escalation Intrathecal Nivolumab Starting Dose: 5 mg as an injection directly into CSF through Ommaya reservoir on Day 1 of each 14 day cycle for 2 cycles.

No intrasubject dose escalation, and subjects receive the same IT dose level during all subsequent cycles for up to 2 years, given tolerability.

Intravenous dose is 3mg/kg for all participants.

Dose Expansion Intrathecal Nivolumab: Recommended dose from Intrathecal Nivolumab Dose Escalation Phase

Other Names:
  • BMS-936558
  • Opdivo

Primary Outcome Measures :
  1. Recommended Dose of Combined IT and IV Nivolumab [ Time Frame: 28 days ]
    Recommended dose defined as the highest dose for which the posterior probability of toxicity is closest to 30%.

  2. Overall Survival (OS) with Combined IT and IV Nivolumab [ Time Frame: 12 months ]
    Kaplan-Meier method used to estimate the distribution of OS from the start of study treatment.

Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Patients must have radiographic and/or CSF cytological evidence of LMD.
  2. Must have a confirmed diagnosis of metastatic melanoma (cutaneous, acral-lentiginous, uveal and mucosal in origin), based on histological analysis of metastatic tissue and/or cancer cells, archival tissue permitted.
  3. Patients must have an ECOG PS of </= 2.
  4. 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.
  5. Patients who have received radiation to brain and/or spine, including whole brain radiation, stereotactic radiosurgery, or SBRT, are eligible, but must have completed radiation treatment at least 7 days prior to the start of treatment.
  6. 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 >/= 14 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
  7. contd from #7: • Patients who have been treated with an approved targeted therapy (BRAF inhibitor and/or MEK inhibitor) must have received their last treatment >/= 28 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 >/= 28 days or 5 half-lives (whichever is shorter) prior to the start of treatment
  8. Age >/= 18 years
  9. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  10. Patients must have organ and marrow function: Hematologic: Absolute neutrophil count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.0 g/dL; Platelets >/= 75 X 10^9/L; PT/INR and PTT </= 1.5 X ULN; Hepatic: Total bilirubin: </= 1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%); AST and ALT; </= 2.5 X ULN Albumin>/= 2.5 g/dL; Renal: Creatinine OR </= 1.5x ULN; Calculated creatinine clearance OR >/= 50 mL/min; 24-hour urine creatinine clearance >/= 50 mL/min.
  11. Absence of contraindication for Ommaya reservoir

Exclusion Criteria:

  1. 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
  2. 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.
  3. Patients who have previously received a-PD-1 and/or anti-CTLA-4 will be eligible, unless they have ongoing >Grade 2 AE side effects of such therapy. Ongoing physiologic replacement doses for adrenal and thyroid insufficiency are allowed on protocol.
  4. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
  5. Pregnant or lactating female
  6. 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.
  7. Patients with a history of pneumonitis
  8. 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).
  9. Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to study drug.
  10. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
  11. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on 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.
  12. History of allergy to study drug components.
  13. History of severe hypersensitivity reaction to any monoclonal antibody.
  14. Prisoners or subjects who are involuntarily incarcerated.
  15. 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

Contact: Isabella C. Glitza, MD, PHD 713-792-2921
Contact: Clinical Research Operations MD Anderson Cancer Center 713-792-7734

United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bristol-Myers Squibb
Principal Investigator: Isabella C. Glitza, MD, PHD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03025256     History of Changes
Other Study ID Numbers: 2016-0567
First Posted: January 19, 2017    Key Record Dates
Last Update Posted: May 3, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Melanoma and other malignant neoplasms of skin
Leptomeningeal disease

Additional relevant MeSH terms:
Meningeal Neoplasms
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Skin Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs