Alisertib for Rhabdoid Tumors

(SJATRT Trial)

Recruiting at 8 trial locations

Overseen By Tabatha E. Doyle, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 35

Duration: Up to 105 weeks

125 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like enzyme-inducing antiepileptic drugs or St. John's wort within 7 days before starting alisertib. It's best to discuss your current medications with the study team.

What makes the drug Alisertib unique for treating rhabdoid tumors?

Alisertib is unique because it specifically targets and inhibits Aurora Kinase A, a protein that is highly active in rhabdoid tumors due to the loss of a tumor suppressor gene. This targeted approach is different from other treatments that may not specifically address this protein's role in tumor growth. ^{1 2 3 4 5}

Research Team

Amar Gajjar, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for patients under 22 years old with rhabdoid tumors, including AT/RT or MRT. They must have a confirmed diagnosis and measurable disease or tumor cells in CSF. Participants need proper organ function, no prior alisertib treatment, and a life expectancy over 8 weeks. Females of childbearing age must test negative for pregnancy and agree to birth control use.

Inclusion Criteria

My tumor lacks INI1 or BRG1, confirmed by tests.

My neurological condition is stable, and I've been on a consistent dose of corticosteroids for over a week.

I have been recently diagnosed with AT/RT.

Exclusion Criteria

Other severe acute or chronic medical or psychiatric condition that would make the patient inappropriate for enrollment in this study

Clinically significant medical disorders that could compromise the ability to tolerate protocol therapy or that would interfere with the study procedures or results history

I am not pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Alisertib is administered as a single agent or in combination with chemotherapy and radiation therapy, depending on the stratum. For recurrent patients, alisertib is given on days 1-7 of each 21-day cycle.

Up to 105 weeks

35 cycles of 3 weeks each

Follow-up

Participants are monitored for safety and effectiveness after treatment, with progression-free survival and overall survival being key measures.

Up to 5 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if they show sustained response or stabilization.

Long-term

Treatment Details

Interventions

• Alisertib

Trial Overview The study tests alisertib's effectiveness on pediatric patients with recurrent or newly diagnosed rhabdoid tumors. It will be given alone or with chemotherapy/radiation depending on the patient's condition and age. The trial aims to measure response rates, progression-free survival (PFS), overall survival (OS), drug toxicity, local/distant failure patterns, and pharmacokinetics.

Participant Groups

Group I: (C) Alisertib, chemotherapy, radiation therapy Experimental Treatment 6 Interventions

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.

Group II: (B) Alisertib, chemotherapy, radiation therapy Experimental Treatment 10 Interventions

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.

Group III: (A) Alisertib alone Experimental Treatment 2 Interventions

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.

Alisertib is already approved in United States, European Union for the following indications:

Approved in United States as Alisertib for:

• Acute myeloid leukemia (AML)

Approved in European Union as Alisertib for:

• None approved; under investigation for various cancers

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Takeda Pharmaceuticals U.S.A., Inc.

Collaborator

Trials

1

Recruited

130+

Millennium Pharmaceuticals, Inc.

Industry Sponsor

Trials

406

Recruited

46,900+

Dr. Christophe Bianchi

Millennium Pharmaceuticals, Inc.

Chief Medical Officer since 2006

MD from University of Geneva

Dr. Deborah Dunsire

Millennium Pharmaceuticals, Inc.

Chief Executive Officer since 2005

MD from University of Witwatersrand

Findings from Research

In a phase I trial involving 10 postmenopausal patients with endocrine-resistant ER+ metastatic breast cancer, the combination of alisertib and fulvestrant was well tolerated, with no severe toxicities reported during the first treatment cycle.

The treatment showed promising antitumor activity, with a median progression-free survival of 12.4 months and a 6-month clinical benefit rate of 77.8%, indicating potential effectiveness even in patients who had previously progressed on fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer. Haddad, TC., D'Assoro, A., Suman, V., et al.[2023]

In a phase I study involving 45 patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, the combination of alisertib with rituximab was found to be well tolerated, with a recommended phase II dose of 50 mg b.i.d. for alisertib alone and 40 mg b.i.d. when combined with vincristine.

The treatment showed promising efficacy, particularly in non-germinal center diffuse large B-cell lymphoma, with 45% of patients responding at the recommended dose, including complete and partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Kelly, KR., Friedberg, JW., Park, SI., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. [2020]