Modified Measles Virus (MV-NIS) for Children and Young Adults With Recurrent Medulloblastoma or Recurrent ATRT

This is an open label, multi-center, Phase I study to assess the safety of administering
MV-NIS directly into the tumor bed (for locally recurrent medulloblastoma or ATRT patients)
or into the subarachnoid space (for disseminated recurrent medulloblastoma or ATRT patients).

For locally recurrent patients, MV-NIS will be directly administered into the tumor bed
following a standard of care surgical resection. For patients with disseminated recurrence,
MV-NIS will be injected via lumbar puncture (LP). This is a one-time administration for
either locally or disseminated recurrence.

Patients will be closely monitored for 30 days after injection, and then followed for
evaluation of 6 month progressive free survival and overall response rate.

Inclusion Criteria:

- For stratum A, patients must have local recurrent disease (defined as negative spine
MRI and negative cytology within 21 days prior to study registration) and undergo
resection of local recurrence as part of their standard of care. Children must have
undergone what is considered the standard of care as upfront therapy including either
surgery followed by high dose chemotherapy with stem cell rescue or multi-modality
therapy of surgery, radiation and chemotherapy.

- For stratum B, patients must have disseminated recurrent disease (defined as
multifocal disease, positive spine MRI including leptomeningeal disease and/or
positive cytology within 21 days prior to study registration) and have adequate
cerebrospinal fluid (CSF) flow based on spine MRI with no evidence of bulky disease or
if bulky disease is present based on a CSF flow study per institutional guidelines.
Children must have undergone what is considered the standard of care as upfront
therapy including either surgery followed by high dose chemotherapy with stem cell
rescue or multi-modality therapy of surgery, radiation and chemotherapy.

Prior Therapy:

- The patient must have failed at least one prior therapy - surgery followed by high
dose chemotherapy with stem cell rescue or multi-modality therapy of surgery,
radiation and chemotherapy - prior to study registration. Patients must have fully
recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study.

o Myelosuppressive chemotherapy: Patients must have received their last dose of known
myelosuppressive anticancer chemotherapy at least three weeks prior to study
registration or at least six weeks prior if nitrosourea.

- Biologic agent: Patient must have recovered from any toxicity potentially related
to the agent and received their last dose of the biologic agent ≥ 7 days prior to
study registration.

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended to beyond the time during which adverse
events are known to occur. The duration of this interval should be discussed with the
study chair.

- For biologic agents that have a prolonged half-life, the appropriate interval since
last treatment should be discussed with the Study Chair prior to registration.

o Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
registration. Such patients should be discussed with the study chair prior to
registration. For bevacizumab, patients must have received last dose ≥ 32 days prior
to study registration.

o Bone Marrow Transplant: Patient must be:

- ≥ 6 months since allogeneic bone marrow transplant prior to registration

- ≥ 3 months since autologous bone marrow/stem cell prior to registration

- Radiation:

Patients must have:

- Had their last fraction of local irradiation to primary tumor ≥12 weeks prior to
registration

- Had their last fraction of craniospinal irradiation or total body irradiation ≥ 12
weeks prior to registration

• Age ≥ 12 months to less than or equal to 39 years of age

• Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16
years of age (See Appendix A). Patients who are unable to walk because of paralysis,
but who are up in a wheelchair, will be considered ambulatory for the purpose of
assessing the performance score. Patients with pre-existing neurological deficits need
to be stable prior to surgery or LP as determined by the investigator.

- Anti-measles virus immunity as demonstrated by immunoglobulin G (IgG)
anti-measles antibody per institutional guidelines (within 21 days prior to study
registration).

- Organ Function Requirements (within 7 days prior to study registration)

- Adequate Bone Marrow Function Defined as:

- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and

- Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment).

- Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) greater
than or equal to 70 milliliters (mL)/min/1.73 m2 or

- A serum creatinine based on age/gender as follows:

Age

Maximum Serum

Creatinine (mg/dL)

Male Female

1. - 2 years 0.6 0.6

2. to < 6 years 0.8 0.8

6 to < 10 years 1 1

10 to < 13 years 1.2 1.2

13 to < 16 years 1.5 1.4

- 16 years 1.7 1.4 The threshold creatinine values in this table were derived from the
Schwartz formula for estimating GFR utilizing child length and stature data published
by the Centers for Disease Control and Prevention (CDC).

- Adequate Liver Function Defined as:

- Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 x upper
limit of normal (ULN) for age and

- serum glutamic-pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) less
than or equal to 110 U/L. and

- Serum albumin less than or equal to 2 g/dL.

• The effects of MV-NIS on the developing human fetus are unknown. For this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry, for the duration of study participation and 4 months after
completion of MV-NIS administration. Should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent
document.

-Exclusion Criteria

-Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks
earlier

-Patients who are receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to measles virus vaccination

-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

-Female patients of childbearing potential must not be pregnant or
breast-feeding.

-Female patients of childbearing potential must have a negative serum or urine
pregnancy test (within 7 days prior to study registration)

-HIV-positive patients

- Patients with very low cluster of differentiation 4 (CD4) counts (<200/µL or
14% of total lymphocyte count)

- Patients with inability to return for follow-up visits or obtain follow-up
studies required to assess toxicity to therapy

- Exposure to household contact with known immunodeficiency

- Allergy to measles vaccine or history of severe reaction to prior measles
vaccination

- History of chronic hepatitis B or C infection

- History of organ transplantation

- Patients with evidence of extraneural disease

- Patients on chronic steroid use or other immunosuppressive agents