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

This study is not yet open for participant recruitment.
See Contacts and Locations
Verified July 2017 by M.D. Anderson Cancer Center
Bristol-Myers Squibb
Information provided by (Responsible Party):
M.D. Anderson Cancer Center Identifier:
First received: January 17, 2017
Last updated: July 13, 2017
Last verified: July 2017

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.

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

Study Type: Interventional
Study Design: 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)

Resource links provided by NLM:

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • 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%.

  • 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.

Estimated Enrollment: 30
Anticipated Study Start Date: September 2017
Estimated Study Completion Date: September 2020
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: 10 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 3 mg/kg for all participants.

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

Other Names:
  • BMS-936558
  • Opdivo

  Show Detailed Description


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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.

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. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
  8. 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.
  9. History of allergy to study drug components.
  10. History of severe hypersensitivity reaction to any monoclonal antibody.
  11. Prisoners or subjects who are involuntarily incarcerated.
  12. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: 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 Not yet 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
  More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT03025256     History of Changes
Other Study ID Numbers: 2016-0567
Study First Received: January 17, 2017
Last Updated: July 13, 2017

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 processed this record on September 21, 2017