Clinical Trials /

Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors

NCT02114229

Description:

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.

Related Conditions:
  • Rhabdoid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: ATRT
  • SECONDARY ID: NCI-2014-00901
  • NCT ID: NCT02114229

Conditions

  • Malignant Rhabdoid Tumor
  • Atypical Teratoid Rhabdoid Tumor

Interventions

DrugSynonymsArms
alisertib(A) Alisertib alone
methotrexateMTX(B) Alisertib, chemotherapy, radiation therapy
cisplatinPlatinol-AQ(B) Alisertib, chemotherapy, radiation therapy
carboplatinparaplatin(B) Alisertib, chemotherapy, radiation therapy
cyclophosphamidecytoxan(B) Alisertib, chemotherapy, radiation therapy
etoposideVP-16, Vepesid, Etoposide phosphate (Etopophos)(B) Alisertib, chemotherapy, radiation therapy
topotecanHycamtin(B) Alisertib, chemotherapy, radiation therapy
vincristineOncovin(B) Alisertib, chemotherapy, radiation therapy

Purpose

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 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 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.

      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).
    

Trial Arms

NameTypeDescriptionInterventions
(A) Alisertib aloneExperimentalStratum 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
(B) Alisertib, chemotherapy, radiation therapyExperimentalStratum 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.
  • alisertib
  • methotrexate
  • cisplatin
  • carboplatin
  • cyclophosphamide
  • etoposide
  • topotecan
  • vincristine
(C) Alisertib, chemotherapy, radiation therapyExperimentalStratum 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.
  • alisertib
  • cisplatin
  • cyclophosphamide
  • vincristine

Eligibility Criteria

        INCLUSION CRITERIA for Patients on All Strata EXCEPT Stratum P

          -  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.

        Inclusion Criteria for Stratum A Participants:

          -  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.

          -  Live expectancy >8 weeks.

          -  Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at
             least 1 week before study enrollment.

        Inclusion Criteria for Strata B or C Participants:

          -  Patients with newly diagnosed AT/RT.

          -  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 as outlined in the protocol within 42 days of definitive
             surgery (day of surgery is day 0; definitive surgery includes last surgery to resect
             residual tumor).

        Inclusion Criteria for Stratum D Participants:

          -  Patients with newly diagnosed AT/RT 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 42 days of definitive surgery (day of surgery is
             day 0; definitive surgery includes repeat surgeries to resect residual tumor).

        Inclusion Criteria for Stratum P Participants:

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

        EXCLUSION CRITERIA for All Strata Except Stratum P:

          -  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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Sustained response rate of pediatric participants with recurrent or refractory AT/RT treated with alisertib (stratum A1)
Time Frame:Within 30 weeks after start of alisertib therapy
Safety Issue:
Description:Efficacy endpoint: Sustained, objective responses (partial response + complete response) that occur within the first 10 courses (approximately 30 weeks) of treatment. Objective responses must be sustained for an additional 2 courses (approximately 6 weeks) and/or 12-week disease stabilization, as confirmed by MRI in order to be considered a success in the statistical analysis of the efficacy endpoint.

Secondary Outcome Measures

Measure:Duration of objective response by stratum A1 and A2
Time Frame:At the time of tumor assessment (up to 5 years)
Safety Issue:
Description:The duration of objective response will be measured from the initial scan documenting complete or partial response to the earlier of documented progression or death on study. Duration of objective response will be censored at the last tumor assessment date for patients without disease progression.
Measure:1-year progression-free survival (PFS) by stratum A1 and A2
Time Frame:Up to 5 years after the last enrolled patient starts treatment.
Safety Issue:
Description:Progression-free survival (PFS) will be measured from the date of initial treatment to the earliest date of disease progression, second malignancy or death. Duration of PFS will be censored at the last tumor assessment date for patients without disease progression.
Measure:5-year Progression-free survival (PFS) rate in patients with newly diagnosed AT/RT (strata B1, B2, B3, C1, C2)
Time Frame:Up to 5 years after the last enrolled patient starts treatment.
Safety Issue:
Description:PFS 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.
Measure:5-year Overall survival (OS) rate in patients with newly diagnosed AT/RT (strata B1, B2, B3, C1, C2)
Time Frame:Up to 5-years after the last patient starts protocol treatment
Safety Issue:
Description:OS will be measured from the date of diagnosis to the date of death or date of last contact.
Measure:Proportion of local and distant failure in strata B1, B2, B3, C1 and C2
Time Frame:Up to 5 years after the last patient starts therapy
Safety Issue:
Description:Local control relative to primary site radiotherapy, with criteria for infield, marginal or distant failure will be reported descriptively. Patterns of failure and sites of progression of disease will be described separately in each study stratum. Summary statistics of follow-up time and corresponding 95% confidence intervals will be provided. Point estimates of percentages of local and distant failures and exact confidence interval estimates will be constructed as well.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • Alisertib
  • MLN8237
  • AT/RT
  • MRT

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