Alisertib Alone or in Combination with Chemotherapy and Radiation Therapy in Treating Younger Patients with Recurrent, Progressive, or Newly Diagnosed Central Nervous System Atypical Teratoid Rhabdoid Tumors or Extra-Central Nervous System Malignant Rhabdoid Tumors

Summary

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.