Immune Checkpoint Inhibitor Nivolumab in People With Select Rare CNS Cancers

Background:

- There are more than 130 identified primary tumors of the central nervous system (CNS).
Most have an annual incidence of less than 1000 in the United States.

- Given the rarity of each of the tumors listed above, there is a paucity of proven
therapies. Most of these neoplasms are treated with maximum surgical resection followed
by treatment with external beam radiotherapy. With few exceptions (medulloblastoma,
adult ependymoma), there are no effective systemic regimens and even in chemotherapy
sensitive disease, most patients with recurrence eventually have no remaining salvage
treatments available.

- In the setting of this unmet need, we propose to create a basket protocol that will
evaluate the efficacy of the PD-1 inhibitor, nivolumab, in patients with refractory rare
central nervous system neoplasms.

- This study seeks to establish effective therapies at recurrence in patients with rare
CNS tumors. We hypothesize that this therapy will improve progression free survival
and/or objective responses.

- It will be important to determine whether any determined survival benefit is associated
with improvements in symptoms or does a worsening of symptoms offset the increase in
survival. Precedence exists for measuring non-therapeutic endpoints in oncology
research, and specifically in studies evaluating therapeutic benefit in patients with
CNS tumors. There have been efforts in neuro-oncology to evaluate secondary endpoints
using validated instruments as an additional indicator of benefit. The M.D. Anderson
Symptom Inventory-Brain Tumor Module (MDASI-BT) and Spine Tumor Module (MDASI-SP) allow
for the self-reporting of symptom severity and interference with daily activities for
patients with either brain or spinal cord tumors. The availability of validated
instruments provides an opportunity to prospectively assess the impact of treatment,
both positive and negative, on patients.

Objective:

Determine the efficacy of nivolumab in a variety of recurrent, refractory primary central
nervous system tumors as measured by either objective imaging response or 6-month progression
free survival rate.

Eligibility:

- Documented recurrent or progressive disease that corresponds to one of the tumors
eligible for testing.

- Age greater than or equal to 18 years of age.

- Karnofsky Performance greater than or equal to 70%.

- Tumor tissue available for review to confirm morphologic diagnosis

- Tumor tissue or slides available for molecular and immune profiling

Design:

- This is an open label phase II clinical trial. Patients will be treated with the immune
checkpoint inhibitor, nivolumab, at a standard dose of 240 mg intravenously every 2
weeks (+/- 3 days) for cycles 1 through 4, then doses of 480 mg every 4 weeks for a
total of 12 additional doses (cycles). A maximum of 20 treatments will be given (64
weeks).

- A cycle will be defined as 4 weeks and patients will undergo efficacy assessments using
MR imaging every 2 cycles. Toxicity assessments will occur before the initiation of each
cycle and patient outcomes measures (PROs) will be completed at the time of each imaging
study (every 2 cycles) but prior to the patient being informed of the imaging results.

- After completion of the planned treatment course or if treatment was stopped because of
toxicity, patients will undergo imaging evaluations and PRO measurements every 8 weeks
(or 2 months) for one year, then every 3 months for the next year, then every 4 months
for the next year and then every 6 months while the patient remains on the protocol.
Patients off treatment because of disease progression will not undergo future imaging or
PRO assessments on this protocol.

- Bayesian multi-stage, multi-cohort design will be used to conduct this phase II trial in
patients with Ependymoma, Medulloblastoma, Pineoblastoma/Pineocytoma, Choroid Plexus
Carcinoma or Papilloma, Chordoma, Gliomatosis Cerebri, Brainstem Glioma, Midline Glioma,
Atypical Teratoid Rhabdoid Tumor (ATRT), Malignant or Atypical Meningioma or Gliosarcoma
or Primary Brain Sarcoma.

- Due the low prevalence of some diseases, the study will be comprised of 3 single disease
cohorts (ependymoma, malignant or atypical meningioma, chordoma) for which accrual is
likely to be robust and a fourth cohort for the remaining 8 diseases which are very rare
and this trial will look for a preliminary signal. Each cohort will be evaluated
independently for efficacy.

- INCLUSION CRITERIA:

- Histopathologically proven diagnosis of Ependymoma, Medulloblastoma,
Pineoblastoma/Pineocytoma, Choroid Plexus Carcinoma/Papilloma, Chordoma, Gliomatosis,
Brainstem Glioma, Midline Glioma, ATRT, Atypical/Malignant Meningioma, Gliosarcoma or
Primary Brain Sarcoma prior to registration as confirmed by NCI Laboratory of
Pathology

- The tumor tissue (e.g. block or 15 unstained slides) must be available to be sent for
immunophenotyping.

- Patients must have progressive tumor growth after having received established standard
of care treatment for their disease

- Age greater than or equal to 18;

- Karnofsky performance status greater than or equal to 70 within 14 days prior to Step
2 registration;

- Adequate hematologic function based on CBC/differential within 14 days prior to Step 2
registration defined as follows:

- Absolute neutrophil count greater than or equal to 1,500 cells/mm3;

- Platelet count greater than or equal to 100,000 cells/mm3

- Hemoglobin > 9.0 g/dl (may be transfused to achieve this level)

- Adequate renal function within 14 days prior to Step 2 registration defined as
follows:

- BUN less than or equal to 30 mg/dl and

- Serum creatinine less than or equal to 1.7 mg/dl

- Adequate hepatic function within 14 days prior to Step 2 registration defined as
follows:

- Total bilirubin (except patients with Gilbert s Syndrome, who are eligible for
the study but exempt from the total bilirubin eligibility criterion) less than or
equal to 2.0 mg/dl and

- ALT and AST less than or equal to 2.5x ULN

- No active or chronic hepatitis infection. HCV antibody (for Hepatitis C) and
Hepatitis B Surface antigen must be negative. This has been routinely
incorporated into immunotherapy trials with checkpoint inhibitors because of
concerns that the risk of treatment-induced hepatic injury is increased in the
setting of active viral hepatitis.

- The patient must not be on a corticosteroid dose greater than physiologic replacement
dosing defined as 30 mg of cortisone per day or its equivalent.

- The patient must provide study-specific informed consent prior to study entry. No
Durable Power of Attorney or Next of Kin can provide initial consent.

- The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of investigational drug.

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 7 months after the last
dose of investigational product. Women who are not of childbearing potential (i.e., who are
postmenopausal or surgically sterile as well as azoospermic men do not require
contraception.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or
intracavitary or convectional enhanced delivery of therapy

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years

- Severe, active co-morbidity defined as follows:

- Unstable angina within the last 6 months prior to Step 2 registration

- Transmural myocardial infarction within the last 6 months prior to Step 2
registration

- Evidence of recent myocardial infarction or ischemia by the findings of S-T
elevations of greater than or equal to 2 mm using the analysis of an EKG
performed within 14 days prior to Step 2 registration

- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to Step 2 registration

- History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
within 6 months prior to Step 2 registration

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g., aortic aneurysm, history of aortic
dissection) or clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
fistula, gastrointestinal perforation, intra-abdominal abscess major surgical
procedure, open biopsy, or significant traumatic injury within 28 days prior to
Step 2 registration, with the exception of the craniotomy for tumor resection.

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;

- Known acquired immune deficiency syndrome (AIDS) based upon current CDC
definition; note, however, that HIV testing is not required for entry into this
protocol. The need to exclude patients with AIDS is based on the lack of
information regarding the safety of nivolumab in patients with active HIV
infection.

- Active connective tissue disorders, such as lupus or scleroderma, which in the
opinion of the treating physician may put the patient at high risk for
immunologic toxicity.

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded. These include but are not
limited to patients with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or CIDP,
myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue
diseases, scleroderma, inflammatory bowel disease (IBD), Crohn s, ulcerative colitis,
hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the
risk of recurrence or exacerbation of disease.

--Of note, patients with vitiligo, endocrine deficiencies including thyroiditis
managed with replacement hormones including physiologic corticosteroids are eligible.
Patients with rheumatoid arthritis and other arthropathies, Sj(SqrRoot)(Delta)gren s
syndrome and psoriasis controlled with topical medication and patients with positive
serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be
evaluated for the presence of target organ involvement and potential need for systemic
treatment but should otherwise be eligible. However, patients with vitiligo, diabetes
mellitus, and Hashimoto thyroiditis on appropriate replacement therapy may be
enrolled.

- Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol therapy.

- Allergies and Adverse Drug Reaction: History of allergy to study drug components

- Pregnancy or lactating females due to possible adverse effects on the developing fetus
or infant due to study drug. Women of childbearing potential must have a negative
serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to Step 2 registration.

- History of severe hypersensitivity reaction to any monoclonal antibody.