Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors

NCT02114229 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: ATRTNCI-2014-00901
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 9

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. 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.

Conditions

Atypical Teratoid Rhabdoid Tumor; Malignant Rhabdoid Tumor

Keywords

Alisertib; MLN8237; AT/RT; MRT

Outcome Measures

Primary Outcomes (7)

• Sustained response rate of pediatric participants with recurrent or refractory AT/RT treated with alisertib (stratum A1)

  Efficacy endpoint: Objective responses (partial response + complete response) that occur within the first 10 courses (approximately 30 weeks) of treatment which are sustained for an additional 2 courses (approximately 6 weeks) and/or 12-week disease stabilization as confirmed by MRI are considered a success in the statistical analysis of the efficacy endpoint.

  Within 30 weeks after start of alisertib therapy

• Sustained response rate of pediatric participants with recurrent or refractory MRT treated with alisertib (stratum A2)

  Efficacy endpoint: Objective responses (partial response + complete response) that occur within the first 10 courses (approximately 30 weeks) of treatment which are sustained for an additional 2 courses (approximately 6 weeks) and/or 12-week disease stabilization as confirmed by MRI are considered a success in the statistical analysis of the efficacy endpoint.

  Within 30 weeks after start of alisertib therapy

• 3-year progression free survival rate (stratum B1)

  Participants with AT/RT who are younger than 36 months of age at diagnosis with no metastatic disease treated with alisertib in sequence with induction and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.

  Up to 3 years after the last enrolled patient starts therapy

• 1-year progression free survival rate (stratum B2)

  Participants with AT/RT who are younger than 36 months of age at diagnosis with metastatic disease treated with alisertib in sequence with induction and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.

  Up to 1 year after the last enrolled patient starts therapy

• 3-year progression free survival rate (stratum C1)

  Participants with AT/RT who are 3 years of age or older at diagnosis with no metastatic disease and gross total resection or near total resection treated with alisertib in sequence with radiation therapy and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.

  Up to 3 years after the last enrolled patient starts therapy

• 1-year progression free survival rate (stratum C2)

  Participants with AT/RT who are 3 years of age or older at diagnosis with metastatic or residual disease treated with alisertib in sequence with radiation therapy and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up

  Up to 1-year after the last enrolled patient starts therapy

• Single dose and steady state pharmacokinetics and pharmacodynamics of alisertib

  Single dose pharmacokinetic studies will be performed on cycle 1 day 1 and serial plasma samples will be collected at: pre-dose and 0.5, 1, 1.5, 4, 6 (± 0.5), 24 (± 4), and 48 (± 6) hours after the first dose. Steady-state pharmacokinetic studies will be performed on cycle 1 day 7 and serial plasma samples will be collected at: pre-dose, and 1.5, 4, and 24 (±4) hours after the dose. The analysis for the pharmacokinetic primary objective of this study will be conducted using compartmental and noncompartmental approaches. The noncompartmental analysis will provide an estimate of the maximum concentration (Cmax), minimum concentration (Cmin), area under the concentration time curve (AUC), and apparent oral clearance (CL/F). Compartmental analysis will be performed using nonlinear mixed effects modeling and estimated pharmacokinetic parameters may include absorption rate constant (ka), apparent oral clearance (CL/F), and apparent volume of distribution (Vd/F).

  Treatment Cycle 1 on days 1 and 7

Secondary Outcomes (5)

• Duration of objective response by stratum A1 and A2

  At the time of tumor assessment (up to 5 years)

• 1-year progression-free survival (PFS) by stratum A1 and A2

  Up to 5 years after the last enrolled patient starts treatment.

• 5-year Progression-free survival (PFS) rate in patients with newly diagnosed AT/RT (strata B1, B2, B3, C1, C2)

  Up to 5 years after the last enrolled patient starts treatment.

• 5-year Overall survival (OS) rate in patients with newly diagnosed AT/RT (strata B1, B2, B3, C1, C2)

  Up to 5-years after the last patient starts protocol treatment

• Proportion of local and distant failure in strata B1, B2, B3, C1 and C2

  Up to 5 years after the last patient starts therapy

Study Arms (3)

(A) Alisertib alone

EXPERIMENTAL

Stratum A: Patients with recurrent/progressive AT/RT or extra-CNS malignant rhabdoid tumors (MRT). Interventions: alisertib, 35 cycles of 3 weeks each (up to 105 weeks). Surgical resection, if indicated.

Drug: alisertib; Procedure: Surgical resection

(B) Alisertib, chemotherapy, radiation therapy

EXPERIMENTAL

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. Interventions: * B1 or D1: Induction chemotherapy using methotrexate, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by focal radiation therapy; followed by induction therapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by maintenance alisertib. Those \<12 months who are not ready for focal radiation therapy will receive consolidation chemotherapy using alisertib, cyclophosphamide, carboplatin and etoposide while RT is delayed. Surgical resection, if indicated. * B2, B3, D2 or D3: Induction chemotherapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by consolidation with topotecan and cyclophosphamide or optional craniospinal irradiation; followed by maintenance alisertib. Surgical resection, if indicated.

Drug: alisertib; Drug: methotrexate; Drug: cisplatin; Drug: carboplatin; Drug: cyclophosphamide; Drug: etoposide; Drug: topotecan; Drug: vincristine; Procedure: Surgical resection; Radiation: Radiation therapy

(C) Alisertib, chemotherapy, radiation therapy

EXPERIMENTAL

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. Interventions: Craniospinal radiation therapy; followed by consolidation chemotherapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by maintenance alisertib, surgical resection, if indicated.

Drug: alisertib; Drug: cisplatin; Drug: cyclophosphamide; Drug: vincristine; Procedure: Surgical resection; Radiation: Radiation therapy

Interventions

alisertib DRUG

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.

(A) Alisertib alone; (B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

methotrexate DRUG

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.

Also known as: MTX

(B) Alisertib, chemotherapy, radiation therapy

cisplatin DRUG

Cisplatin will be given intravenously (IV): 75 mg/m\^2 IV infusion.

Also known as: Platinol-AQ

(B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

carboplatin DRUG

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.

Also known as: paraplatin

(B) Alisertib, chemotherapy, radiation therapy

cyclophosphamide DRUG

Cyclophosphamide will be given 1.5 g/m\^2 IV infusion during induction and consolidation.

Also known as: cytoxan

(B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

etoposide DRUG

Etoposide will be given 100 mg/m\^2 IV infusion. In case of etoposide reactions, etoposide phosphate will be given 40 mg/kg/day.

Also known as: VP-16, Vepesid, Etoposide phosphate (Etopophos)

(B) Alisertib, chemotherapy, radiation therapy

topotecan DRUG

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.

Also known as: Hycamtin

(B) Alisertib, chemotherapy, radiation therapy

vincristine DRUG

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.

Also known as: Oncovin

(B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

Surgical resection PROCEDURE

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.

Also known as: surgical management

(A) Alisertib alone; (B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

Radiation therapy RADIATION

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.

Also known as: Craniospinal irradiation (CSI), Radiotherapy

(B) Alisertib, chemotherapy, radiation therapy; (C) Alisertib, chemotherapy, radiation therapy

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Takeda Pharmaceuticals U.S.A., Inc.: collaborator

Study Sites (9)

Lucille Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Rady Children's Hospital

San Diego, California, 92123, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

UF Cancer Center at Orlando Health

Orlando, Florida, 32806, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Children's Hospital and Clinics of Minnesota

Minneapolis, Minnesota, 55102, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Rhabdoid Tumor

Interventions

MLN 8237; Methotrexate; Cisplatin; Carboplatin; Cyclophosphamide; Etoposide; etoposide phosphate; Topotecan; Vincristine; Radiotherapy; Craniospinal Irradiation

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Camptothecin; Alkaloids; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indoles; Indolizidines; Indolizines; Therapeutics

Study Officials

• Amar Gajjar, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2014
• First Posted: April 15, 2014
• Study Start: May 14, 2014
• Primary Completion: September 1, 2025
• Study Completion (Estimated): September 1, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-03

Locations

US (9)