SJATRT: Phase II Study of Alisertib Therapy for Rhabdoid Tumors (CLOSED TO ACCRUAL)

Brief Summary

This study incorporates alisertib, the small-molecule inhibitor of Aurora A activity, in the treatment of patients younger than 22 years of age. 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.

Primary Objectives

• To estimate the sustained objective response rate and disease stabilization in pediatric patients with recurrent or progressive ATRT (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 progression-free survival (PFS) rate of patients with newly diagnosed ATRT 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 ATRT 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 ATRT 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 ATRT 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

Trial Outline

• Patients with recurrent disease (Stratum A) will receive alisertib as a single agent days 1 to 7 out of 21 days.
• Newly diagnosed patients (Strata B, C and D) will receive alisertib in sequence with chemotherapy and radiotherapy (RT).
• 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 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 RT depending on their age, response to therapy, and subsequent metastatic staging.
• 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).

Interventions

• Drugs: Alisertib, methotrexate, cisplatin, carboplatin, cyclophosphamide, etoposide, topotecan and vincristine
• Procedure: Surgical resection
• Radiation: Radiation therapy

Study Arms

Experimental: (A) Alisertib alone

Stratum A: Patients with recurrent/progressive AT/RT or extra-CNS malignant rhabdoid tumors (MRT).

Experimental: (B) Alisertib, chemotherapy, radiation therapy

Stratum B: Children < 36 months old with newly diagnosed AT/RT. AT/RT those with synchronous extraneural AT/RT (Stratum D1) may also be treated on this arm.

Experimental: (C) Alisertib, chemotherapy, radiation therapy

• Stratum C: Children ≥36 months old with newly diagnosed AT/RT.
• Participants with synchronous extraneural AT/RT (Stratum D4) will also be treated as those assigned to Stratum C.

Eligibility Criteria

Inclusion Criteria:

• Patients must be <22 years of age at time of diagnosis (ie, 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 loss/mutation or SMARCA4 loss/mutation if INI1/BRG1 immunohistochemistry is not available. Patients with synchronous extraneural AT/RT are eligible.
• 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 postmenarchal 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

Stratum A Participants

• Patients with recurrent or progressive ATRT/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).
  • Karnofsky for patients >16 years
  • Lansky for patients <16 years
• 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
  • 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 ATRT and MRT will be eligible for Stratum A3
  • Patients may not have previously received alisertib
  • Life expectancy >8 weeks
  • Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at least 1 week before study enrollment

Stratum B or C Participants

• Patients with newly diagnosed ATRT
• 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 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes last surgery to resect residual tumor)

Stratum D Participants

• Patients with newly diagnosed ATRT 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 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes repeat surgeries to resect residual tumor)

Stratum P Participants

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

Exclusion Criteria:

• 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)
• 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, or any condition that would modify the absorption of oral medications in the small bowel 

Study Design

• Allocation: Non-Randomized
• Endpoint Classification: Safety/Efficacy Study
• Intervention Model: Parallel Assignment
• Masking: Open Label
• Primary Purpose: Treatment

About this clinical trial

SJATRT is a clinical trial studying more effective treatments for a rare and fast-growing cancerous tumor called malignant rhabdoid tumor (MRT). MRTs are types of tumors that are found in the brain, and/or in other areas of the body, particularly the kidneys, but also liver and other soft tissue sites. When an MRT originates in the brain or spinal cord, it is usually called an atypical teratoid rhabdoid tumor (ATRT).

MRTs and ATRTs can be difficult to cure. Children with MRTs and ATRTs are usually treated with surgery, radiation therapy and chemotherapy drugs.

Treatment on this research study is based on a “risk-adapted” approach. Children taking part in this study will be divided into different risk groups. The risk group your child will be assigned to depends on certain aspects of your child’s tumor, such as age at diagnosis and whether or not the tumor has spread to the spinal fluid and/or other areas of the brain and spine.

Purpose of this clinical trial

The main purpose of SJATRT is to study the effects of an experimental study drug called alisertib in children and young adults with recurrent or progressive ATRTs or MRTs, and those with newly diagnosed ATRT.

Treatment

There are three parts to this study:

• Staging–The first step is to determine how much tumor is present and where it has spread.
• Treatment – Treatment depends on several key factors, including if the tumor is recurrent/progressive or newly diagnosed, your child’s age and clinical risk. All participants enrolled in this study will be treated with alisertib. Some participants may also receive treatment with surgery, chemotherapy and radiation.
• Follow-up – After treatment ends, routine follow-up examinations and medical tests will be done for about five years following treatment.

Eligibility overview

• Has one of the following:
  • Newly diagnosed atypical teratoid rhabdoid tumors (ATRTs) with or without tumors affecting other areas outside the brain and spine
    
  • ATRTs or malignant rhabdoid tumors (MRTs) that have come back after initial treatment (recurrent/progressive disease)
• 21 years of age or younger