NCT02114229

Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors

Phase 2 Study of Alisertib as a Single Agent in Recurrent or Progressive Central Nervous System (CNS) Atypical Teratoid Rhabdoid Tumors (AT/RT) and Extra-CNS Malignant Rhabdoid Tumors (MRT) and in Combination Therapy in Newly Diagnosed AT/RT

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 125 (actual)
• Sponsor: St. Jude Children's Research Hospital · Academic / Other
• Sex: All
• Age: 21 Years
• Healthy volunteers: Not accepted

Summary

This study incorporates alisertib, the small-molecule inhibitor of Aurora A activity, in the treatment of patients younger than 22 years of age. Patients with recurrent or refractory AT/RT or MRT will receive alisertib as a single agent. Patients with newly diagnosed AT/RT will receive alisertib as part of age- and risk-adapted chemotherapy. Radiation therapy will be given to children ≥12 months of age. Patients with AT/RT and concurrent extra-CNS MRT are eligible. Alisertib will be administered as a single agent on days 1-7 of each 21-day cycle in all recurrent patients enrolled on Stratum A. For the patients on the newly diagnosed strata (B, C or D), alisertib will be administered in sequence with chemotherapy and radiotherapy. This study has 3 primary strata: (A) children with recurrent/progressive AT/RT or extra-CNS MRT, (B) children \< 36 months-old with newly diagnosed AT/RT, (C) children \> 36 months old with newly diagnosed AT/RT. Children with concurrent MRT will be treated according to age and risk stratification schemes outlined for strata B and C and will have additional treatment for local control. Children with synchronous AT/RT will be treated with age and CNS risk-appropriate therapy, and also receive surgery and/or radiation therapy for local control of the non-CNS tumor. PRIMARY OBJECTIVES * To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive AT/RT (atypical teratoid rhabdoid tumor in the CNS) (Stratum A1) treated with alisertib and to determine if the response is sufficient to merit continued investigation of alisertib in this population. * 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 to determine if the response is sufficient to merit continued investigation of alisertib in this population. * To estimate the 3-year 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. * 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. * To estimate the 3-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or greater at diagnosis with no metastatic disease and gross total resection 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. * To estimate the 1-year PFS rate of patients with newly diagnosed AT/RT who are 3 years of age or greater 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. * To characterize the pharmacokinetics and pharmacodynamics of alisertib in pediatric patients and to relate drug disposition to toxicity. SECONDARY OBJECTIVES * To estimate the duration of objective response and PFS in patients with recurrent/progressive AT/RT and MRT (Strata A1 and A2). * To estimate PFS and OS distributions in patients with newly diagnosed AT/RT (Strata B1, B2, B3, C1 and C2). * 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. * 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.

Detailed description

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 A is Closed to Accrual \* 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 B is Closed to Accrual \* 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. Stratums D1, D2 and D3 are Closed to Accrual 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).

Conditions

• Malignant Rhabdoid Tumor
• Atypical Teratoid Rhabdoid Tumor

Interventions

Type	Name	Description
DRUG	alisertib	Alisertib will be administered orally at 80 mg/m\^2 per day for enteric coated tablet formulation and 60 mg/m\^2 per day for oral solution formulation.
DRUG	methotrexate	Methotrexate will be given at a dose of 5 g/m\^2/dose as an intravenous infusion over 24 hours on day 1 of each induction cycle except in patients ≤ 31 days of age at enrollment. These young infants will receive methotrexate at a reduced dose of 2.5g/m\^2/dose.
DRUG	cisplatin	Cisplatin will be given intravenously (IV): 75 mg/m\^2 IV infusion.
DRUG	carboplatin	Carboplatin may be substituted for cisplatin during induction for patients having Grade 4 ototoxicity or bi-lateral hearing loss after having prior cisplatin dose reduction. Route of administration is IV.
DRUG	cyclophosphamide	Cyclophosphamide will be given 1.5 g/m\^2 IV infusion during induction and consolidation.
DRUG	etoposide	Etoposide will be given 100 mg/m\^2 IV infusion. In case of etoposide reactions, etoposide phosphate will be given 40 mg/kg/day.
DRUG	topotecan	Topotecan will be administered by intravenous infusion over 4 hours on days 1-5 of each consolidation cycle for Stratum B2 and B3 patients not receiving craniospinal irradiation. The initial dose of Topotecan will be based on patient's age with subsequent doses adjusted, if necessary, to achieve a topotecan lactone area under the curve (AUC) of 140 ± 20 ng/mL\*hr.
DRUG	vincristine	Vincristine will be given 1 mg/m\^2 IV via 25 mL normal saline (NS) mini-bag (maximum 2 mg for all patients) or administration per local institutional standards for participating sites.
PROCEDURE	Surgical resection	For patients with localized AT/RT, gross total resection results in a significant survival benefit. Maximal resection that can be achieved without undue risk to the patient should be attempted prior to trial enrollment. Decisions about initial resectability will be at the discretion of the local neurosurgeon. In rare instances, the feasibility of completely resecting residual tumor may change as a result of induction chemotherapy; in these cases a "second-look" operation is encouraged if and may be performed prior to consolidation therapy.
RADIATION	Radiation therapy	The guidelines for this protocol were developed to maximize the curative potential of radiation therapy and minimize the risk of treatment complications for children with newly diagnosed CNS AT/RT. Focal irradiation is indicated for children \< 36 months with no evidence of metastatic disease. Craniospinal irradiation is indicated for children age \> 36 months.

Timeline

• Start date: 2014-05-14
• Primary completion: 2025-09-01
• Completion: 2027-09-01
• First posted: 2014-04-15
• Last updated: 2026-03-17

Locations

9 sites across 1 country: United States

Regulatory

• FDA-regulated drug study