Everolimus for Children With Recurrent or Progressive Ependymoma
Condition: Recurrent Childhood Ependymoma
MeSH terms: Ependymoma; Recurrence
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to evaluate the anti-tumor activity of Everolimus among children
      with recurrent or progressive ependymoma. Recurrent or progressive ependymoma is incurable
      and has very limited treatment options. The rationale for this study is based upon both
      pre-clinical and clinical considerations: Immunohistochemistry studies have demonstrated that
      20 out of 23 (87%) pediatric ependymomas are immunoreactive for phosphorylated S6, a
      biomarker that often predicts response to mTOR pathway-targeted therapy. Furthermore,
      children with with multiply recurrent ependymomas have had objective and durable responses to
      the mTOR inhibitor, Sirolimus (Rapamune, Pfizer). As a result of this pre-clinical and
      clinical data, this study will further investigate the activity of an mTOR pathway inhibitor,
      Everolimus, against children with recurrent or progressive ependymomas. In this study,
      Everolimus will be administered at a dose and schedule that have previously been demonstrated
      as safe and effective in children. Children may take Everolimus for up to 2 years on this
      study, until tumor progression or unacceptable toxicity.
    

Detailed description: 
      Ependymoma is the third most common central nervous system neoplasm in children, accounting
      for approximately 10% of childhood brain tumors. Although the prognosis for children with
      newly-diagnosed completely resected ependymomas is often good, children with incompletely
      resected tumors often suffer repeated episodes of tumor progression and die as a result of
      their tumor. The prognosis for children with recurrent or progressive ependymomas is
      especially dismal and the majority of children with recurrent or progressive ependymomas will
      eventually succumb to their tumor within 8.7 to 24 months. At the time of tumor recurrence,
      therapeutic options are limited. A recent report by Merchant and co-workers described several
      long-term survivors after tumor recurrence when treated with a second course of radiation
      therapy.

      Unfortunately, although chemotherapy occasionally demonstrates anti-tumor activity against
      recurrent ependymoma, but responses are rarely durable.12 Indeed, a recent review by Bouffet
      and co-workers concluded that the frequency of durable responses of recurrent ependymomas to
      chemotherapy was disappointing and encouraged a re-evaluation of the current chemotherapeutic
      approach to intracranial ependymoma and that studies are needed to identify new biological
      targets to inform future clinical trials.

      Everolimus is a novel derivative of rapamycin. It has been in clinical development since 1996
      as an immunosuppressant in solid organ transplantation. Everolimus is approved in Europe and
      other global markets (trade name: Certican®) for cardiac and renal transplantation, and in
      the United States (trade name: Zortress®) for the prevention of organ rejection of kidney
      transplantation. Everolimus was developed in oncology as Afinitor® and was approved for
      advanced renal cell carcinoma (RCC) in 2009. In 2010, Afinitor® received United States (US)
      approval for patients with subependymal giant cell astrocytoma (SEGA) associated with
      tuberous sclerosis (TS). Everolimus is also available as Votubia® in the European Union (EU)
      for patients with SEGA associated with TS. Afinitor® was approved for "progressive pancreatic
      neuroendocrine tumor (PNET) in patients with unresectable, locally advanced, or metastatic
      disease" in 2011 in various countries, including the US and Europe. In 2012, Afinitor®
      received approval for the treatment of postmenopausal women with advanced hormone
      receptor-positive, HER2- negative breast cancer in combination with exemestane, after failure
      of treatment with letrozole or anastrozole. Furthermore in 2012, Afinitor® received approval
      for the treatment of adult patients with TSC who have renal angiomyolipoma not requiring
      immediate surgery.

      At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. It
      selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which
      regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via
      the phosphatidylinositol 3-kinase (PI3-Kinase) pathway through AKT/PKB and the tuberous
      sclerosis complex (TSC1/2). Mutations in these components or in PTEN, a negative regulator of
      PI3-kinase, may result in their dysregulation. Abnormal functioning of various components of
      the signaling pathways contributes to the pathophysiology of numerous human cancers. Various
      preclinical models have confirmed the role of this pathway in tumor development.

      The main known functions of mTOR include the following:

        -  mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels;

        -  Facilitating cell-cycle progression from G1-S phase in appropriate growth conditions;

        -  The PI3K/mTOR pathway itself is frequently dysregulated in many human cancers, and
           oncogenic transformation may sensitize tumor cells to mTOR inhibitors;

        -  PI3-kinase mutations have been reported in the primary tumor in 10-20% of human
           colorectal cancers;16,17

        -  The loss of PTEN protein, either through gene deletion or functional silencing (promoter
           hypermethylation), is reported in approximately 60% of primary human colorectal cancers;

        -  The mTOR pathway is involved in the production of pro-angiogenic factors (i.e., VEGF)
           and inhibition of endothelial cell growth and proliferation;

        -  Through inactivating eukaryotic initiation factor 4E binding proteins and activating the
           40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates protein translation, including
           the HIF-1 proteins. Inhibition of mTOR is expected to lead to decreased expression of
           HIF-1.

      Everolimus inhibits the proliferation of a range of human tumor cell lines in vitro including
      lines originating from lung, breast, prostate, colon, melanoma and glioblastoma. IC50s range
      from sub/low nM to µM. Everolimus also inhibits the proliferation of human umbilical vein
      endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced
      proliferation suggesting that Everolimus may also act as an anti-angiogenic agent. The
      anti-angiogenic activity of Everolimus was confirmed in vivo. Everolimus selectively
      inhibited VEGF-dependent angiogenic response at well tolerated doses. Mice with primary and
      metastatic tumors treated with Everolimus showed a significant reduction in blood vessel
      density when compared to controls.

      The potential of Everolimus as an anti-cancer agent was shown in rodent models. Everolimus is
      orally bioavailable, residing longer in tumor tissue than in plasma in a subcutaneous mouse
      xenograft model, and demonstrating high tumor penetration in a rat pancreatic tumor model.
      The pharmacokinetic profile of Everolimus indicates sufficient tumor penetration, above that
      needed to inhibit the proliferation of endothelial cells and tumor cell lines deemed
      sensitive to Everolimus in vitro.

      Everolimus administered orally daily was a potent inhibitor of tumor growth, at well
      tolerated doses, in 11 different mouse xenograft models (including pancreatic, colon,
      epidermoid, lung and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic
      melanoma). These models included tumor lines considered sensitive and "relatively resistant"
      in vitro. In general, Everolimus was better tolerated in mouse xenograft models than standard
      cytotoxic agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor
      activity. Additionally, activity in a VEGF-impregnated subcutaneous implant model of
      angiogenesis and reduced vascularity (vessel density) of Everolimus-treated tumors (murine
      melanoma) provided evidence of in vivo effects of angiogenesis.

      It is not clear which molecular determinants predict responsiveness of tumor cells to
      Everolimus. Molecular analysis has revealed that relative sensitivity to Everolimus in vitro
      correlates with the degree of phosphorylation (activation) of the AKT/PKB protein kinase and
      the S6 ribosomal protein; in some cases (i.e., glioblastoma) there is also a correlation with
      PTEN status.

      In vivo studies investigating the anti-tumor activity of Everolimus in experimental animal
      tumor models showed that Everolimus monotherapy typically reduced tumor cell growth rates
      rather than produced regressions. These effects occurred within the dose range of 2.5 mg to
      10 mg/kg, orally once a day.

      In preclinical models, the administration of Everolimus is associated with reduction of
      protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 and
      phosphorylated 4EBP1, and occasionally with an increase in phosphorylated AKT, a protein
      upstream of mTOR signaling pathway.

      All significant adverse events observed in toxicology studies with Everolimus in mice, rats,
      monkeys and mini-pigs were consistent with its anticipated pharmacological action as an
      anti-proliferative and immunosuppressant and at least in part reversible after a 2 or 4-week
      recovery period with the exception of the changes in male reproductive organs, most notably
      testes.

      Rationale: The purpose of this study is to evaluate the anti-tumor activity of Everolimus
      among children with recurrent or progressive ependymoma. The rationale for this study is
      based upon both pre-clinical and clinical considerations. Recurrent or progressive ependymoma
      is incurable and has very limited treatment options. In 2011, the investigators group
      published a case report describing a young child with a multiply recurrent ependymoma after 4
      chemotherapy regimens and several courses of radiation therapy and who had an objective and
      long lasting response to sirolimus (Rapamune, Pfizer). This patient, who had been treated
      with various regimens over a span of 20 months without response, subsequently had a near
      complete response to sirolimus of 18 months duration. Subsequently a second child with a
      recurrent ependymoma was treated with sirolimus and oral etoposide and had a near-complete
      response of 18 months duration. Furthermore, immunohistochemistry studies have revealed that
      20 out of 23 (87%) pediatric ependymomas were immunoreactive for phosphorylated S6, a
      biomarker that often predicts response to mTOR pathway-targeted therapy.

      Existing data regarding the anti-tumor activity of mTOR inhibitors among children has
      demonstrated that mTOR inhibitors are well tolerated and have activity against pediatric
      brain tumors. For example, Franz et al. reported five children with tuberous sclerosis
      complex and progressive subependymal giant cell astrocytomas who were treated with sirolimus
      to achieve target trough concentrations between 5 - 15 ng/mL. All tumors demonstrated
      objective responses to sirolimus. One patient who interrupted sirolimus therapy experienced
      tumor progression that responded to resumption of sirolimus therapy. A subsequent phase III
      study of everolimus compared responses of 78 patients treated with everolimus versus 39
      patients treated with placebo. 27 of 78 (35%) patients in the everolimus group had at least
      50% reduction in the volume of subependymal giant cell astrocytomas versus none in the
      placebo group (p<0.0001). Adverse events were mostly grade 1 or 2 and no patients
      discontinued treatment because of adverse events.

      Biomarkers of mTOR pathway activation and sensitivity to mTOR inhibitors, including
      phosphorylated S6235/236, phosphorylated S6240/244, phosphorylated 4EBP1, phosphorylated
      PRAS40 (pT246), phosphorylated P70S6K, and PTEN expression, will be performed. Although these
      biomarkers have, to varying degrees, been correlated with mTOR pathway activation and
      sensitivity to mTOR inhibitors, these studies are considered to be exploratory in the context
      of this clinical trial.
    

Intervention name(s): Everolimus
Intervention type(s): Drug
Intervention description(s): The recommended dose of Everolimus is 4.5 mg/m2/dose, once daily for up to 2 years, until disease progression or unacceptable toxicity occurs.
Other intervention name(s): RAD001, AFINITOR
Intervention MeSH terms: Everolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ependymoma; Anaplastic Ependymoma