Ipilimumab and Nivolumab in Leptomeningeal Metastases

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

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