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Ipilimumab and Nivolumab in Leptomeningeal Metastases

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ClinicalTrials.gov Identifier: NCT02939300
Recruitment Status : Active, not recruiting
First Posted : October 20, 2016
Last Update Posted : August 14, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Priscilla Brastianos, Massachusetts General Hospital

Brief Summary:

This research study is studying a combination of two drugs as a possible treatment for Leptomeningeal Metastases.

The names of the study interventions involved in this study are:

  • Ipilimumab
  • Nivolumab

Condition or disease Intervention/treatment Phase
Leptomeningeal Carcinomatosis Drug: Nivolumab Drug: Ipilimumab Phase 2

Detailed Description:

This research study is a Phase II clinical trial.

Researchers hope to study the effects of the combination of Nivolumab and Ipilimumab. Many cancers use specific pathways (such as PD-1/PD-L1 and CTLA-4) to evade the body's immune system. Nivolumab and ipilimumab work by blocking the PD-1/PD-L1 and CTLA-4 pathways and thus releasing the brakes on the immune system so it can stop or slow cancer.

The FDA (the U.S. Food and Drug Administration) has approved Nivolumab and Ipilimumab as a treatment option for melanoma, but has not approved them for use when cancer cells spread to the cerebrospinal fluid


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Ipilimumab and Nivolumab in Leptomeningeal Metastases
Actual Study Start Date : January 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combination Of Nivolumab with Ipilimumab

All patients will be treated with the combination regimen of Nivolumab at pre-determine dose with Ipilimumab at a pre-determine dose.This will be followed by Nivolumab Monotherapy.

Each treatment Cycle will last 6 weeks

Drug: Nivolumab
Other Name: Opdivo

Drug: Ipilimumab
Other Name: Yervoy




Primary Outcome Measures :
  1. Overall Survival Rate [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Intracranial Response Rate [ Time Frame: 2 years ]
    The proportion of patients with intracranial response of intraparenchymal brain metastases (according to RANO)

  2. Extracranial Response Rate [ Time Frame: 2 years ]
    Extracranial response rates according to RECIST

  3. Extracranial Response Rate [ Time Frame: 2 years ]
    Extracranial response rates according to irRC

  4. Leptomeningeal Disease Response Rate [ Time Frame: 2 years ]
    The proportion of patients with leptomeningeal disease response (Complete response or partial response)

  5. Time To The First Occurrence Of Extracranial Disease Progression, Or Death From Any Cause [ Time Frame: 2 years ]
  6. Time To The First Occurrence Of Intracranial Disease Progression, Or Death From Any Cause [ Time Frame: 2 years ]
  7. Toxicity by CTCAE Criteria [ Time Frame: 2 years ]


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
Criteria

Inclusion Criteria:

  • Participants must have histologically or cytologically confirmed disease from any solid tumor
  • Age ≥18 years.
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
  • Life expectancy of greater than 3 weeks
  • Participants must have normal organ and marrow function as defined below, all screening labs should be performed within 10 days of treatment initiation.

Adequate Organ Function Laboratory Values:

  • Hematological

    • Absolute neutrophil count (ANC) ≥1500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
  • Renal
  • Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

    • Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL
    • Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
  • Hepatic

    • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • AST (SGOT) and ALT (SGPT) ≤ 3 ULN OR ≤ 5 X ULN for subjects with liver metastases
    • Albumin ≥ 2.5 mg/dL
  • Coagulation

    • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Creatinine clearance should be calculated per institutional standard.
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab
  • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
  • Ability to understand and the willingness to sign a written informed consent document.
  • Stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment
  • Carcinomatous meningitis, as defined by positive cytology

Exclusion Criteria:

  • Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  • Participants who are receiving any other investigational agents.
  • Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone 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. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  • As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
  • Patients should be excluded if they have had prior systemic treatment with an anti-CTLA4 antibody
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • Has known history of, or any evidence of active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  • History of allergy to study drug components
  • History of severe hypersensitivity reaction to any monoclonal antibody

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 ClinicalTrials.gov identifier (NCT number): NCT02939300


Locations
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United States, Massachusetts
Massachusetts general Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Massachusetts General Hospital
Bristol-Myers Squibb
Investigators
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Principal Investigator: Priscilla Brastianos, MD Massachusetts General Hospital

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Responsible Party: Priscilla Brastianos, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02939300     History of Changes
Other Study ID Numbers: 16-136
First Posted: October 20, 2016    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Priscilla Brastianos, Massachusetts General Hospital:
Leptomeningeal Metastases

Additional relevant MeSH terms:
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Neoplasm Metastasis
Carcinoma
Meningeal Carcinomatosis
Neoplastic Processes
Neoplasms
Pathologic Processes
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents