Ipilimumab and Nivolumab in Leptomeningeal Metastases
Condition: Leptomeningeal Carcinomatosis
MeSH terms: Neoplasm Metastasis; Carcinoma; Meningeal Carcinomatosis
Intervention: Nivolumab; Ipilimumab
Intervention description: Melanoma:
- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle.
Non-small Cell Lung Cancer / Head and Neck Cancer:
- Combination therapy with Nivolumab 3 mg/kg
Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:
- Combination therapy with Nivolumab 1 mg/kg for 4 doses followed by monotherapy Nivolumab 240 mg per cycle.
Renal Cell Carcinoma / Other Solid Tumors (not listed above):
Combination therapy with Nivolumab 3 mg/kg for 4 doses followed by monotherapy Nivolumab 480 mg per cycle.; Non-small Cell Lung Cancer / Head and Neck Cancer:
- Combination therapy with Ipilimumab 1 mg/kg
Small Cell Lung Cancer / Breast Cancer / Bladder Cancer:
- Combination therapy with Ipilimumab 3 mg/kg for 4 doses
Renal Cell Carcinoma / Other Solid Tumors (not listed above):
Combination therapy with Ipilimumab 3 mg/kg for 4 doses
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Leptomeningeal Metastases

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
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed disease from any
             solid tumor

          -  Age ≥18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%)

          -  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:

        Unit key: mcL = microliter, ULN = upper limit normal

          -  Hematological

               -  Absolute neutrophil count (ANC) ≥1500 /mcL

               -  Platelets ≥100,000 / mcL

               -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or Erythropoietin (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

               -  Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 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