Inclusion Criteria:
Histologically or cytologically confirmed diagnosis of any cancer except leukemia.
Patients must have the presence of malignant cells in the CSF (CSF+) OR at least 2
of the 3 following features: 1) clinical signs and symptoms of LMDz 2) characteristic
radiographic abnormalities , and 3) "suspicious" CSF (Chamberlain 2017)
Patients must have an Eastern Cooperative Oncology Group performance scale of < 3
OR Karnofsky Performance Status of >50.
An interval of at least 2 weeks after the end of prior radiation therapy to the
brain (e.g., stereotactic radiosurgery or other-WBRT is excluded)
An interval of at least 4 weeks following any surgical resection of brain lesions
prior to treatment.
Be > 18 years of age on the day of signing consent.
Demonstrate adequate organ function as defined in Table 2. All screening labs
should be performed with 14 days of treatment initiation.
Resting baseline O2 saturation by pulse oximetry of > 92% at rest.
Patients 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.
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.
If the disease has progressed on current treatment in the CNS prior to consent,
patients may continue Her 2 directed antibody treatment (trastuzumab and pertuzumab),
aromatase inhibitor or tamoxifen while on the study; patients with triple negative
breast cancer may continue capecitabine, eribulin or paclitaxel while on the study per
PI discretion.
Adequate Organ Function as defined per protocol.
Exclusion Criteria:
Receiving other treatments specifically administered to treat LMDz or antibody
based therapies within the last 4 weeks. However, patients 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
Except as listed in Inclusion Criteria #15 (above). Careful documentation of
concurrently administered systemic drugs is required.
Patients with a ventriculoperitoneal or ventriculoatrial shunt must have an on/off
device in their shunt systems to be eligible for the study. Patients must be able to
tolerate shunt closure for ~4 hours without development of clinical signs of increased
intracranial pressure. Patients unable to tolerate shunt closure for ~4 hours will not
be eligible for the study.
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.
Patients on steroid therapy unless < 2 mg/day dexamethasone equivalents.
Prior chemotherapy or targeted small molecule therapy except as listed in Inclusion
Criteria #15 and Exclusion #1(above) 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.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
Has an active autoimmune disease requiring systemic treatment within the past 3
months (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive agents) or has a diagnosis of immunodeficiency. Subjects with
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study. Subjects with hypothyroidism stable on hormone
replacement or Sjorgen's syndrome will not be excluded from the study. Replacement
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment.
Has evidence of 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. Ommaya placement is allowed.
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 90 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) within 6 months before the beginning of study treatment.
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. Patients with previously
diagnosed brain metastases are eligible if they have completed their treatment and
have recovered from the acute effects of radiation therapy or surgery prior to study
treatment, have discontinued corticosteroid treatment for these metastases for at
least 4 weeks and are neurologically stable. Short courses of corticosteroids are
permitted if these were started for leptomeningeal disease and can be tapered down to
< 2 mg/day of dexamethasone equivalents and patients remain stable for 3 days prior to
study treatment.
Known severe hypersensitivity reactions to monoclonal antibodies (Grade > 3) or
any known history of anaphylaxis.
ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell
transplantation.
CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular
disease: cerebral vascular accident/stroke (< 6 months prior to enrollment),
myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive
heart failure (> New York Heart Association Classification Class II), or serious
cardiac arrhythmia requiring medication.
OTHER PERSISTING TOXICITIES: "Persisting toxicity related to prior therapy (NCI
CTCAE v.5.0 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, including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
conditions including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormalities 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
