Summary

This phase II trial studies how well alisertib alone or in combination with chemotherapy and radiation therapy works in treating younger patients with central nervous system (CNS) atypical teratoid rhabdoid tumors that are newly diagnosed; have returned; or are growing, spreading, or getting worse or extra-CNS malignant rhabdoid tumors that have returned or are growing, spreading, or getting worse. Alisertib may stop the growth of cancer cells by blocking a protein called aurora kinase A that is needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses x-rays to kill tumor cells. Giving alisertib alone or with chemotherapy and radiation therapy may be effective in treating patients with rhabdoid tumors.

Objectives

PRIMARY OBJECTIVES:
I. To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive AT/RT (atypical teratoid/rhabdoid tumor) (Stratum A1) treated with alisertib and to determine if the response is sufficient to merit continued investigation of alisertib in this population.
II. To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive extra-CNS MRT (malignant rhabdoid tumor outside the CNS) (Stratum A2) treated with alisertib and determine if the response is sufficient to merit continued investigation of alisertib in this population.
III. To estimate the 3-year progression-free survival (PFS) rate of patients with newly diagnosed AT/RT who are younger than 36 months of age at diagnosis with no metastatic disease (Stratum B1) treated with alisertib in sequence with induction and consolidation chemotherapy and radiation therapy (depending on age) and to determine if the rates are sufficient to merit continued investigation of alisertib in this population.
IV. To estimate the 1-year PFS rate of patients with newly diagnosed AT/RT who are younger than 36 months of age at diagnosis, with metastatic disease (Stratum B2) treated with alisertib in sequence with induction and consolidation chemotherapy and to determine if the rates are sufficient to merit continued investigation of alisertib in this population.
V. To estimate the 3-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or older at diagnosis with no metastatic disease and gross- or near-total resection (Stratum C1) treated with alisertib in sequence with radiation therapy and consolidation chemotherapy, and to determine if the rates are sufficient to merit continued investigation of alisertib in this population.
VI. To estimate the 1-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or older at diagnosis with metastatic or residual disease (Stratum C2) treated with alisertib in sequence with radiation therapy and consolidation chemotherapy, and to determine if the rates are sufficient to merit continued investigation of alisertib in this population.
VII. To characterize the pharmacokinetics and pharmacodynamics of alisertib in pediatric patients and to relate drug disposition to toxicity.

SECONDARY OBJECTIVES:
I. To estimate the duration of objective response and PFS in patients with recurrent or progressive AT/RT and MRT (Strata A1 and A2).
II. To estimate PFS and overall survival (OS) distributions in patients with newly diagnosed AT/RT (Strata B1, B2, B3, C1 and C2).
III. To describe toxicities experienced by patients treated on this trial, specifically any toxicities of alisertib when administered as a single agent or in combination with other therapy over multiple courses, and toxicities related to proton or photon radiation therapy.
IV. To describe the patterns of local and distant failure in newly diagnosed patients (Strata B1, B2, B3, C1 and C2). Local control relative to primary-site radiation therapy, with criteria for infield, marginal, or distant failure will also be reported descriptively.

EXPLORATORY OBJECTIVES:
I. To describe the PFS rate of patients with newly diagnosed AT/RT younger than 36 months of age at diagnosis with no evidence of metastatic disease by imaging but with unknown cerebrospinal fluid (CSF) status (Stratum B3) treated with alisertib in sequence with induction and consolidation chemotherapy.
II. To evaluate the relationship of genomic and epigenomic variations to outcome and therapeutic response by performing high-resolution genome and/or epigenetic analyses of formalin fixed paraffin-embedded (FFPE) and/or snap-frozen tumor and normal tissues (e.g., by using targeted or complete mutational analysis, targeted or complete transcriptomic analyses, deoxyribonucleic acid [DNA] copy-number variation analyses, or protein and methylome analyses).
III. To examine the relationship between aurora A expression, phosphorylation status, and polymorphic variants in tumor tissue and correlate this relationship with the clinical response to aurora kinase A (AURKA) inhibition by alisertib.
IV. To identify prognostic factors in patients with AT/RT by using new techniques to study patient (e.g., isolation of microvesicles from stored plasma and cerebrospinal fluid) and parental samples.
V. To explore the expression of claudin-6, bone morphogenetic protein-4 (BMP-4), Yes-associated protein 1 (YAP-1), and other potential biomarkers of AURKA pathway activation in tumor tissue.
VI. To explore the feasibility of using circulating tumor deoxyribonucleic acid (DNA) (ctDNA) expression in CSF, and plasma samples at diagnosis, during and after completion of therapy, and at time of tumor recurrence as biomarkers of disease and treatment response.
VII. To explore the relationship between the phosphorylation status of AURKA pathway targets in peripheral blood mononuclear cells and systemic exposure to alisertib.
VIII. To explore the extent of inter-patient variability in the pharmacokinetics of intravenous cyclophosphamide and metabolites in young children with brain tumors, and to explore possible associations between cyclophosphamide pharmacokinetic parameters and patient-specific covariates (e.g., age, sex, race, weight).
IX. To explore the extent of inter-patient variability in the pharmacokinetics of intravenous topotecan in young children with brain tumors, and to explore possible associations between systemic exposure to topotecan (topotecan hydrochloride) and patient-specific covariates (e.g., age, sex, race, weight).
X. To explore inter- and intra-patient pharmacokinetic variability for high-dose methotrexate in young children with brain tumors, assess the ability of various covariates to explain this variability, and to explore the relationship between clinical effects (toxicity and antitumor efficacy) and methotrexate pharmacokinetics.
XI. To explore the inter- and intra-patient pharmacokinetic variability for pegfilgrastim in infants and young children with brain tumors, assess potential covariates that may explain this variability, and to explore the relationship between pegfilgrastim pharmacokinetics and pharmacodynamics (e.g., white blood cell count over time).
XII. To assess the relationship between the pharmacogenetic variation in drug-metabolizing enzymes or drug transporters and the pharmacokinetics of alisertib, methotrexate, cyclophosphamide, and topotecan in young children with brain tumors.
XIII. To compare the neurocognitive function of newly diagnosed patients treated with alisertib (Strata B1, B2, B3, C1, and C2) with historical controls treated on SJYC07 and SJMB03.
XIV. To characterize fatigue and quality of life in newly diagnosed patients treated with alisertib (Strata B1, B2, B3, C1, and C2).
XV. To develop a magnetic resonance imaging (MRI)-based evaluation scheme to characterize the imaging features of AT/RT at initial diagnostic workup (e.g. specific points of origin in supra or infratentorial locations) and to correlate these features with epidemiologic data, clinical and biological phenotypes, and outcomes.
XVI. To describe MRI patterns of metastatic disease in AT/RT and to identify possible imaging predictors of metastatic disease dissemination (e.g., primary tumor location, contrast enhancement, and diffusion-weighted imaging properties of primary tumor).

OUTLINE: Patients are assigned to 1 of 8 treatment strata.

STRATUM A (PATIENTS WITH RECURRENT OR PROGRESSIVE AT/RT or MRT ALL AGES):
Patients receive alisertib orally (PO) once daily (QD) on days 1-7. Treatment repeats every 21 days for 35 courses in the absence of disease progression or unacceptable toxicity.

STRATUM B1 (NEWLY DIAGNOSED PATIENTS WITH AVERAGE RISK CNS-AT/RT < 36 MONTHS):

Methotrexate-Induction Therapy: Patients receive methotrexate intravenously (IV) over 24 hours on day 1, vincristine sulfate IV on days 8 and 15, cisplatin IV over 6 hours on day 8, and cyclophosphamide IV over 1 hour on day 9. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients >= 12 months of age proceed to radiation therapy prior to alisertib induction therapy and consolidation therapy. Patients < 12 months of age proceed to Alisertib-Induction.

Alisertib-Induction Therapy: Patients receive alisertib PO QD on days 1-7, vincristine sulfate IV on day 15 and 22, cisplatin IV over 6 hours on day 15 and cyclophosphamide IV over 1 hour on day 16. Treatment repeats every 35 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Consolidation Therapy (Patients < 12 Months of Age): Patients receive alisertib PO QD on days 1-7, cyclophosphamide IV over 1 hour on day 15, etoposide IV over 1 hour on days 15-16, and carboplatin IV over 1 hour on day 16. Treatment repeats every 35 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients >= 12 months of age after consolidation proceed to radiation therapy prior to maintenance therapy.

Radiation therapy (Patients >=12 Months of Age): Within 6 weeks after the start of the last course of chemotherapy, patients undergo radiation therapy (RT) to the tumor bed QD 5 days a week for 6-8 weeks.

Maintenance Therapy: Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM B2 OR B3 (NEWLY DIAGNOSED PATIENTS WITH HIGH-RISK CNS-AT/RT < 36 MONTHS OLD):

Alisertib-Induction Therapy: Patients receive alisertib, vincristine sulfate, cisplatin, and cyclophosphamide as in Stratum B1. Treatment repeats every 35 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Consolidation Therapy: Patients receive topotecan hydrochloride IV over 4 hours on days 1-5 and cyclophosphamide IV over 1 hour on days 4-5. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy: Patients receive alisertib as Stratum B1. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM C1 (NEWLY DIAGNOSED PATIENTS WITH AVERAGE RISK CNS-AT/RT >= 3 YEARS):

Radiation Therapy: Patients undergo low dose craniospinal radiation therapy QD 5 days a week for 6-8 weeks.

Consolidation Therapy: Patients receive alisertib PO QD on day 1-7, cisplatin IV over 6 hours on day 15 of courses 1-4, cyclophosphamide IV over 1 hour on days 16 and 17 (days 15 and 16 of course 5), and vincristine sulfate on days 15 and 22. Treatment repeats every 35 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy: Patients receive alisertib PO QD on days 1-7. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM C2 (NEWLY DIAGNOSED PATIENTS WITH HIGH-RISK CNS-AT/RT >= 3 YEARS):

Radiation Therapy: Patients undergo high dose craniospinal radiation therapy QD 5 days a week for 6-8 weeks.

Consolidation Therapy: Patients receive alisertib, cisplatin, cyclophosphamide, and vincristine phosphate as in Stratum C1. Treatment repeats every 35 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy: Patients receive alisertib as in Stratum C1. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM D1 (NEWLY DIAGNOSED PATIENTS WITH AVERAGE RISK CONCURRENT CNS AT/RT AND EXTRA-CNS MRT < 36 months):

Methotrexate Induction Therapy: Patients receive methotrexate, vincristine, cisplatin, and cyclophosphamide as in Stratum B1. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Alisertib-Induction Therapy: Patients receive alisertib, vincristine sulfate, cisplatin, and cyclophosphamide as in Stratum B1. Treatment repeats every 35 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Consolidation Therapy (Patients < 12 Months of Age): Patients receive alisertib, cyclophosphamide, etoposide IV, and carboplatin as in Stratum B1. Treatment repeats every 35 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Radiation Therapy (Patients >= 12 Months of Age): Patients undergo RT as in Stratum B1.

Maintenance Therapy: Patients receive alisertib as in Stratum B1. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM D2 or D3 (NEWLY DIAGNOSED PATIENTS WITH HIGH-RISK CONCURRENT CNS-AT/RT AND EXTRA-CNS MRT < 36 MONTHS OLD):

Alisertib-Induction Therapy: Patients receive alisertib, vincristine sulfate, cisplatin, and cyclophosphamide as in Stratum B2. Treatment repeats every 35 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Consolidation Therapy: Patients receive topotecan hydrochloride and cyclophosphamide as in Stratum B2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy: Patients receive alisertib as Stratum B2. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

STRATUM D4 (NEWLY DIAGNOSED PATIENTS WITH CONCURRENT CNS-AT/RT AND EXTRA-CNS MRT >= 3 YEARS):

Induction Therapy: Patients undergo craniospinal radiation therapy based on their metastatic status and/or the amount of residual disease identical to the recommendations for Strata C1 and C2.

Consolidation Therapy: Patients receive alisertib, cisplatin, cyclophosphamide, and vincristine phosphate as in Stratum C1. Treatment repeats every 35 days for 5 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy: Patients receive alisertib as in Stratum C1. Treatment repeats every 21-28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Eligibility

1. INCLUSION CRITERIA FOR PATIENTS ON ALL STRATA EXCEPT STRATUM P
2. Patients must be < 22 years of age at time of diagnosis (e.g., eligible until 22nd birthday)
3. Histologic diagnosis of AT/RT or MRT as documented by institutional pathologist with loss of INI1 or BRG1 expression in tumor cells confirmed by immunohistochemistry, or by molecular confirmation of tumor-specific biallelic SMARCB1 loss/mutation or SMARCA4 loss/mutation if INI1/BRG1 immunohistochemistry is not available; patients with synchronous extraneural AT/RT are eligible; 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 * Whereas testing of INI1 expression by immunohistochemistry is widely available, Clinical Laboratory Improvement Amendments (CLIA)-certified sequencing of SMARCB1 in tumor samples is only done in limited institutions; therefore, we expect that the vast majority of patients will have confirmation of their diagnoses by immunohistochemistry only; exceptional cases may require gene sequencing * Of note, occasional patients with histologic diagnosis suggestive of AT/RT or MRT may display immunohistochemical and/or molecular characteristics which are equivocal (e.g., patchy loss of INI1 expression by immunohistochemistry, proof of monoallelic loss of SMARCB1 without confirmation of second hit by sequencing of exons only); these cases may be confirmed unequivocally to represent AT/RT or MRT only by research studies (e.g., whole genome sequencing); therefore, we propose that such patients be candidates for the current study but their outcomes be described separately
4. Hemoglobin concentration > 8 g/dL (with or without support)
5. Absolute neutrophil count (ANC) > 1,000/mm^3
6. Platelet counts > 100,000/mm^3 (without support)
7. Serum creatinine concentration < 3 x the upper limit of normal (ULN) based on the age of the patient
8. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) concentration < 5 x the ULN; patients with metastatic liver disease are eligible if SGPT (ALT) is < 20 x the ULN
9. Total bilirubin concentration < 1.5 x the ULN
10. 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
11. 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
12. INCLUSION CRITERIA FOR PATIENTS TO BE TREATED ON STRATUM A
13. Patients with recurrent or progressive AT/RT or MRT (either CNS and/or extra-CNS) with radiographically measurable disease as defined by at least one lesion that can be measured in two dimensions or with tumor cells present in the CSF taken within 2 weeks prior to enrollment
14. 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
15. 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 three half-lives must have elapsed since prior therapy that included a monoclonal antibody * Radiation therapy: at least 3 months must have elapsed since any previous 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
16. Patients with progressive synchronous/metachronous AT/RT and MRT will be eligible for stratum A3
17. Patients may not have previously received alisertib
18. Life expectancy > 8 weeks
19. Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at least 1 week before study enrollment
20. INCLUSION CRITERIA FOR PATIENTS TO BE TREATED ON STRATA B OR C
21. Patients with newly diagnosed AT/RT
22. Performance status defined by Karnofsky or Lansky >= 30 (except for patients with posterior fossa syndrome); other requirements of performance evaluation are the same as above
23. No previous anticancer therapy (radiation therapy or chemotherapy) other than use of corticosteroids
24. 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)
25. INCLUSION CRITERIA FOR PATIENTS ON STRATUM D
26. Patients with newly diagnosed AT/RT and synchronous extra-CNS MRT
27. Performance status defined by Karnofsky or Lansky >= 30 (except for patients with posterior fossa syndrome); other requirements of performance evaluation are the same as listed above
28. No previous anticancer therapy (radiation therapy or chemotherapy) other than the use of corticosteroids
29. 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)
30. INCLUSION CRITERIA FOR PATIENTS ON STRATUM P
31. Biological parent of patient enrolling on SJATRT will be assigned to Stratum P

Treatment Sites in Georgia