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

Phase 2 Study of <span class="go-doc-concept go-doc-intervention">Alisertib</span> Therapy for Rhabdoid Tumors

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

    NCT ID: NCT02114229

    ORG ID: SJATRT

    NCI ID: NCI-2014-00901

    Trial Conditions

    Malignant Rhabdoid Tumor

    Atypical Teratoid Rhabdoid Tumor

    Trial Interventions

    Drug Synonyms Arms
    alisertib (A) Alisertib alone, (B) Alisertib, chemotherapy, radiation therapy, (C) Alisertib, chemotherapy, radiation therapy
    methotrexate MTX (B) Alisertib, chemotherapy, radiation therapy
    cisplatin Platinol-AQ (B) Alisertib, chemotherapy, radiation therapy, (C) Alisertib, chemotherapy, radiation therapy
    carboplatin paraplatin (B) Alisertib, chemotherapy, radiation therapy
    cyclophosphamide cytoxan (B) Alisertib, chemotherapy, radiation therapy, (C) Alisertib, chemotherapy, radiation therapy
    etoposide VP-16, Vepesid, Etoposide phosphate (Etopophos) (B) Alisertib, chemotherapy, radiation therapy
    topotecan Hycamtin (B) Alisertib, chemotherapy, radiation therapy
    vincristine Oncovin (B) Alisertib, chemotherapy, radiation therapy, (C) Alisertib, chemotherapy, radiation therapy

    Trial 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

    Name Type Description Interventions
    (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. alisertib
    (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. alisertib, methotrexate, cisplatin, carboplatin, cyclophosphamide, etoposide, topotecan, vincristine
    (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. alisertib, cisplatin, cyclophosphamide, vincristine

    Eligibility Criteria

    INCLUSION CRITERIA

    - 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 expression in tumor cells confirmed by immunohistochemistry
    demonstrating loss of SMARCB1/BAF47 immunoreactivity in tumor cells, or by molecular
    confirmation of tumor-specific biallelic SMARCB1 loss/mutation if INI1
    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.

    - Performance status defined by Karnofsky or Lansky 30 (except for 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.

    - 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. See Appendix X for further
    guidance for pregnancy prevention for patients receiving alisertib.

    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.

    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).

    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).

    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 14 days prior to dose 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.

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 21 Years

    Eligible Gender: Both

    Primary Outcome Measures

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

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

    3-year progression free survival rate (stratum B1)

    1-year progression free survival rate (stratum B2)

    3-year progression free survival rate (stratum C1)

    1-year progression free survival rate (stratum C2)

    Single dose and steady state pharmacokinetics and pharmacodynamics of alisertib

    Secondary Outcome Measures

    Duration of objective response by stratum A1 and A2

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

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

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

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

    Trial Keywords

    Alisertib

    MLN8237

    AT/RT

    MRT