Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors

We propose a study with 3 primary treatment strata according to participant's previous
treatment, age and presence of extra-CNS disease, with substrata for presence of focal or
metastatic disease:

- STRATUM A - RECURRENT OR PROGRESSIVE DISEASE: Patients < 22 years of age at diagnosis
with recurrent or progressive MRT (either CNS and/or extra-CNS) and measurable disease
as defined in the protocol.

- Stratum A1: patients with AT/RT (CNS MRT).

- Stratum A2: patients with extra-CNS MRT (patients with concurrent progression of
AT/RT and MRT are eligible for therapy, but their data will be analyzed
separately).

- Stratum A3: patients with synchronous AT/RT and extra-CNS MRT

- STRATUM B - NEWLY DIAGNOSED DISEASE IN YOUNG CHILDREN < 36 MONTHS: Patients < 36 months
of age at diagnosis of CNS-AT/RT, no prior therapy:

- Stratum B1: Patients with no metastatic disease (M0).

- Stratum B2: Patients with metastatic disease (M+) regardless of degree of
resection.

- Stratum B3: Patients for whom CSF by lumbar puncture was not obtained for clinical
reasons and have no other evidence of metastatic disease (MX).

- STRATUM C - NEWLY DIAGNOSED DISEASE IN CHILDREN > 3 YEARS: Patients > 3 years (36
months) of age at diagnosis of AT/RT, no prior therapy:

- Stratum C1: Patients with gross total (GTR) or near total resection (NTR) defined
as <1.5 cm2 of residual tumor, and no metastatic disease.

- Stratum C2: Patients with metastatic disease (M+) and/or bulky residual tumor >1.5
cm^2.

STRATUM D - SYNCHRONOUS EXTRANEURAL AT/RT and EXTRA-CNS MRT: Treatment will be based on the
extent of both CNS and extra-CNS disease. CNS-directed therapy will be given according to
Strata B1, B2, C1 or C2 according to age and metastatic status. In addition, patients may
receive irradiation according to best clinical management for local control of extra-CNS
disease.

- Stratum D1: Patients < 36 months at time of diagnosis with synchronous AT/RT and
extra-CNS MRT and no metastatic CNS disease (M0).

- Stratum D2: Patients < 36 months at time of diagnosis with synchronous AT/RT and extra-
CNS MRT and metastatic CNS disease (M+).

- Stratum D3: Patients < 36 months at time of diagnosis with synchronous AT/RT and
extra-CNS MRT for whom CSF by lumbar puncture was not obtained for clinical reasons and
without other evidence of metastatic disease (MX)

- Stratum D4: Patients ≥ 36 months at time of diagnosis with synchronous extra-CNS MRT
with or without metastatic CNS disease regardless of the degree of tumor resection.

Biological parents of participants with ATRT/MRT may consent to and provide a genomic blood
specimen for DNA extraction and analysis.

OVERVIEW OF TREATMENT PLAN: Patients with recurrent disease (Stratum A) will receive
alisertib as a single agent days 1-7 out of 21 days. Newly diagnosed patients (Strata B, C
and D) will receive alisertib in sequence with chemo and radiotherapy. Patients on sub-strata
B1 and D1 will receive focal RT once they are >12 months of age. Patients on sub-strata B2
and D2, with disseminated disease will not receive CNS radiation therapy (RT). Patients on
sub-strata C1/C2/D4 will receive risk-stratified craniospinal irradiation (CSI) and boost to
primary tumor site followed by adjuvant chemotherapy. Patients on sub-strata B3 and D3 will
receive therapy similar to sub-strata B2 and D2 and will be considered for local radiotherapy
depending on their age, response to therapy, and subsequent metastatic staging. Those
patients with concurrent CNS and extra-CNS MRT may undergo irradiation of the extra-CNS MRT
according to best clinical management in addition to CNS directed therapy. Alisertib will be
administered only to eligible patients under the supervision of the investigator or
identified sub-investigator(s).

INCLUSION CRITERIA for Patients on All Strata EXCEPT Stratum P

- Patients must be < 22 years of age at time of diagnosis (e.g., eligible until 22nd
birthday).

- Histologic diagnosis of AT/RT or MRT as documented by the institutional pathologist
with loss of INI1 or BRG1 expression in tumor cells confirmed by immunohistochemistry,
or by molecular confirmation of tumor-specific biallelic SMARCB1/SMARCA4 loss/mutation
if INI1/BRG1 immunohistochemistry is not available. For Stratum A participants,
histologic confirmation of the diagnosis of AT/RT or MRT may be from the original
diagnosis or at the time of recurrence/progression.

- Patients must have adequate organ function (bone marrow, renal, liver), as defined in
the protocol.

- Female patients who are at least 10-years-old or are post-menarchal must have a
negative serum or urine pregnancy test prior to enrollment.

- Patients of childbearing or child fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence during study
treatment and 12 months after the last dose of alisertib.

Inclusion Criteria for Stratum A Participants:

- Patients with recurrent or progressive AT/RT/MRT (either CNS and/or extra-CNS) with
radiographically measurable disease as defined by at least 1 lesion that can be
measured in 2 dimensions or with tumor cells present in the CSF taken within 2 weeks
prior to enrollment.

- Performance status defined by Karnofsky or Lansky > 60 (except for patients with
posterior fossa syndrome). Use Karnofsky for patients > 16 years and Lansky for
patients < 16 years. Note: Patients who are unable to walk because of paralysis, but
who are up in a wheelchair, will be considered to be ambulatory for the purpose of
assessing the performance score.

- Patient has fully recovered from the acute toxic effects of chemotherapy,
immunotherapy, or radiation therapy prior to entering this study:

- Myelosuppressive chemotherapy: Patient has not received myelosuppressive
chemotherapy within 3 weeks of enrollment onto this study (4 and 6 weeks if prior
temozolomide and nitrosourea, respectively).

- Hematopoietic growth factors: At least 7 days must have elapsed since the
completion of therapy with a growth factor. At least 14 days must have elapsed
after receiving pegfilgrastim.

- Biologic (anti-neoplastic agent): At least 7 days must have elapsed since
completion of therapy with a biologic agent. For agents that have known adverse
events occurring beyond 7 days after administration, this period prior to
enrollment must be extended beyond the time during which adverse events are known
to occur.

- Monoclonal antibodies: At least 3 half-lives must have elapsed since prior
therapy that included a monoclonal antibody (see Appendix I).

- Radiation therapy: at least 3 months must have elapsed since any irradiation
unless measurable disease progression occurs at a site separate from the
irradiated area and the patient has recovered from toxicities associated with
radiation therapy.

- Patients with progressive synchronous/metachronous AT/RT and MRT will be eligible for
stratum A3.

- Patients may not have previously received alisertib.

- Live expectancy >8 weeks.

- Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at
least 1 week before study enrollment.

Inclusion Criteria for Strata B or C Participants:

- Patients with newly diagnosed AT/RT.

- Performance status defined by Karnofsky or Lansky > 30 (except for patients with
posterior fossa syndrome). Other requirements of performance evaluation are the same
as for Stratum A participants.

- No previous anticancer therapy (radiation therapy or chemotherapy) other than the use
of corticosteroids.

- Patients must begin treatment as outlined in the protocol within 42 days of definitive
surgery (day of surgery is day 0; definitive surgery includes last surgery to resect
residual tumor).

Inclusion Criteria for Stratum D Participants:

- Patients with newly diagnosed AT/RT and synchronous extra-CNS MRT.

- Performance status defined by Karnofsky or Lansky > 30 (except for patients with
posterior fossa syndrome). Other requirements of performance evaluation are the same
as for Stratum A participants.

- No previous anticancer therapy (radiation therapy or chemotherapy) other than the use
of corticosteroids.

- Patients must begin treatment within 42 days of definitive surgery (day of surgery is
day 0; definitive surgery includes repeat surgeries to resect residual tumor).

Inclusion Criteria for Stratum P Participants:

- Biological parent of patient enrolling on the protocol (SJATRT) will be assigned to
Stratum P.

EXCLUSION CRITERIA for All Strata Except Stratum P:

- Clinically significant medical disorders that could compromise the ability to tolerate
protocol therapy or that would interfere with the study procedures or results history.

- Presence of an active, uncontrolled infection.

- Known history of uncontrolled sleep apnea syndrome or other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease or a requirement for supplemental oxygen.

- Requirement for constant administration of proton-pump inhibitor, H2 antagonist, or
pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed while
patients are on dexamethasone as described in the protocol.

- Inability to comply with the safety monitoring requirements of the study, as judged by
the investigator.

- Female participants of childbearing potential cannot be pregnant or breast-feeding.

- Patients who are receiving other investigational drugs 14 or fewer days before
enrollment.

- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or with rifampin,
rifabutin, rifapentine, or St. John's wort within 7 days prior to initiation of
alisertib.

- Known gastrointestinal disease or procedures that could interfere with the oral
absorption or tolerance of alisertib. Examples include, but are not limited to partial
gastrectomy, history of small intestine surgery, and celiac disease.

- Myocardial infarction within 6 months prior to enrollment or New York Heart
Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities. If for some reason an electrocardiogram is obtained
before study enrollment, any abnormalities detected should be documented as clinically
irrelevant.

- Other severe acute or chronic medical or psychiatric condition, including uncontrolled
diabetes, malabsorption, resection of the pancreas or upper small-bowel, or
requirement for pancreatic enzymes, any condition that would modify the absorption of
oral medications in the small bowel or any laboratory abnormality that may increase
the risk associated with study participation or investigational product administration
or that may interfere with the interpretation of study results and, in the judgment of
the investigator, would make the patient inappropriate for enrollment in this study.