Avelumab With Radiotherapy in Patients With Leptomeningeal Disease

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of melanoma, lung cancer, or
breast cancer

- Leptomeningeal disease and a histologic diagnosis of melanoma, lung cancer, or breast
cancer.

- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance scale
of ≤ 2

- An interval of at least 2 weeks after the end of prior radiation therapy to the brain.

- An interval of at least 4 weeks following any surgical resection of brain lesions
prior to treatment

- An interval of at least 4 weeks after the last administration of any investigational
agent, bevacizumab, immunotherapy, or prior cytotoxic agents

- 18 years of age or older on the day of signing consent

- Demonstrate adequate organ function.

- Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest

- Participants must have recovered from the toxic effects of prior therapies (≤ Grade 1)

- Provision of signed and dated informed consent form

- Life expectancy of ≥ 8 weeks

- Pregnancy test: negative serum or urine pregnancy test at screening for women of
childbearing potential. Must be repeated once-monthly during treatment with Avelumab,
at the end of study study treatment, at 30 ±3, 60 ±3, and 90 ±3 days follow-up and
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is
otherwise suspected."

- Contraception: Highly effective contraception for both male and female subjects
throughout the study and for at least 30 days after last Avelumab treatment
administration, if the risk of conception exists.

Exclusion Criteria:

- - Participants receiving other treatments specifically administered to treat LMDz.
However, Participants receiving concomitant non-cytotoxic therapy (hormonal or
cytostatic therapy) to control systemic disease or bulk CNS disease will be eligible,
provided the therapy is not a phase I agent, an agent which significantly penetrates
the CSF (e.g., high-dose methotrexate, thiotepa, or high-dose ara-C), or an agent
known to have serious unpredictable CNS side effects. Careful documentation of
concurrently administered systemic drugs is required.

- Clinical evidence of obstructive hydrocephalus or compartmentalization of the CSF flow

- Participants with a ventriculoperitoneal or ventriculoatrial shunt must have an on/off
device in their shunt systems to be eligible for the study. Participants must be able
to tolerate shunt closure for ~4 hours without development of clinical signs of
increased intracranial pressure.

- Unable or unwilling to have a contrast-enhanced brain MRI.

- Currently participating in or having participated in a study of an investigational
agent or device ≤ 4 weeks prior to the first dose of study treatment.

- Currently participating in or having participated in a study of an investigational
agent or use of an investigational device within 4 weeks of the first dose of
treatment.

- Diagnosis of immunodeficiency or receipt of systemic immunosuppressive therapy within
7 days prior to the first dose of trial treatment. Physiologic doses of steroid
therapy (< 10 mg/day prednisone equivalents) are allowed.

- Prior chemotherapy, targeted small molecule therapy, or monoclonal antibody within 4
weeks prior to study Day 1 or nonrecovery (i.e., < Grade 1 or at baseline) from
adverse events (AEs) due to agents administered > 4 weeks earlier.

- Known additional malignancy that is progressing or requires active treatment. Some
exceptions apply.

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Some exceptions apply.

- Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Had major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to day 1 of treatment on study.

- Requires escalating or chronic supraphysiologic doses of corticosteroids (> 10 mg/day
prednisone equivalents).

- Has a history of current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- 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 received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (cTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1, 2 antibodies).

- Any test for hepatitis B (HBV) or hepatitis C virus (HCV) indicating acute or chronic
infection.

- Has received a live vaccine within 30 days prior to the first dose of trial treatment.

- Prior administration of WBRT.

- Known symptomatic brain metastases requiring steroids.

- Known severe hypersensitivity reactions to monoclonal antibodies or any known history
of anaphylaxis.

- Ongoing cardiac dysrhythmias

- ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell
transplantation.

- CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular disease

- OTHER PERSISTING TOXICITIES: "Persisting toxicity related to prior therapy (NCI CTCAE
v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤
2 not constituting a safety risk based on investigator's judgment are acceptable.

- Other severe acute or chronic medical conditions that may increase the risk associated
with study participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.