Clinical Trial: Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 sus

    Detailed Summary:

    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:

      • Stra
        Sponsor: St. Jude Children's Research Hospital

        Current Primary Outcome:

        • 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 ]
          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.
        • Sustained response rate of pediatric participants with recurrent or refractory MRT treated with alisertib (stratum A2) [ Time Frame: Within 30 weeks after start of alisertib therapy ]
          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.
        • 3-year progression free survival rate (stratum B1) [ Time Frame: Up to 3 years after the last enrolled patient starts therapy ]

          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

          Original Primary Outcome:

          • Sustained response rate of pediatric participants with recurrent or refractory ATRT treated with alisertib (stratum A1) [ Time Frame: Within 18 weeks after start of alisertib therapy ]
            Efficacy endpoint: Sustained, objective responses (partial response + complete response) that occur within the first 4 courses (approximately12 weeks) of treatment. Objective responses must be sustained for an additional 2 courses (approximately 6 weeks; total of 18 weeks or 6 cycles of Alisertib) as confirmed by MRI in order to be considered a success in the statistical analysis of the efficacy endpoint. Evaluable participants who begin treatment and fail to have an MRI to confirm an objective response sustained for 6 weeks will be included in the efficacy analysis as a failure.
          • Sustained response rate of pediatric participants with recurrent or refractory MRT treated with alisertib (stratum A2) [ Time Frame: Within 18 weeks after start of alisertib therapy ]
            Efficacy endpoint: Sustained, objective responses (partial response + complete response) that occur within the first 4 courses (approximately12 weeks) of treatment. Objective responses must be sustained for an additional 2 courses (approximately 6 weeks; total of 18 weeks or 6 cycles of Alisertib) as confirmed by MRI in order to be considered a success in the statistical analysis of the efficacy endpoint. Evaluable participants who begin treatment and fail to have an MRI to confirm an objective response sustained for 6 weeks will be included in the efficacy analysis as a failure.
          • 3-year progression free survival rate (stratum B1) [ Time Frame: Up to 3 years after the last enrolled patient starts therapy ]
          • Duration of objective response by stratum A1 and A2 [ Time Frame: At the time of tumor assessment (up to 5 years) ]
            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.
          • 1-year progression-free survival (PFS) by stratum A1 and A2 [ Time Frame: Up to 5 years after the last enrolled patient starts treatment. ]
            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.
          • 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. ]
            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.
          • 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 ]
            OS will be measured from the date of diagnosis to the date of death or date of last contact.
          • 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 ]
            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.


          Original Secondary Outcome:

          • Duration of objective response by stratum A1 and A2 [ Time Frame: At the time of tumor assessment (up to 5 years) ]
            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.
          • 1-year progression-free survival (PFS) by stratum A1 and A2 [ Time Frame: Up to 5 years after the last enrolled patient starts treatment. ]
            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.
          • 5-year Progression-free survival (PFS) rate in patients with newly diagnosed ATRT (strata B1, B2, B3, C1, C2) [ Time Frame: Up to 5 years after the last enrolled patient starts treatment. ]
            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.
          • 5-year Overall survival (OS) rate in patients with newly diagnosed ATRT (strata B1, B2, B3, C1, C2) [ Time Frame: Up to 5-years after the last patient starts protocol treatment ]
            OS will be measured from the date of diagnosis to the date of death or date of last contact.
          • 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 ]
            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.


          Information By: St. Jude Children's Research Hospital

          Dates:
          Date Received: April 11, 2014
          Date Started: May 14, 2014
          Date Completion: May 31, 2027
          Last Updated: May 1, 2017
          Last Verified: November 2016