- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02155920
Everolimus for Children With Recurrent or Progressive Ependymoma
Phase II Study of Everolimus (RAD001, Afinitor®) for Children With Recurrent or Progressive Ependymoma
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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California
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Stanford, California, United States, 94305
- Lucile Packard Children's Hospital Stanford University
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New York
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New York, New York, United States, 10016
- New York University Stephen D. Hassenfeld Children's Center for Cancer & Blood Disorders
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Texas
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Dallas, Texas, United States, 75390
- UT Southwestern Medical Center / Children's Medical Center
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Houston, Texas, United States, 77030
- Baylor College of Medicine / Texas Children's Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Diagnosis and Age: Ependymoma (WHO grade II) or Anaplastic Ependymoma (WHO grade III) that has relapsed or become refractory to standard therapy. Patients must have had histologic verification of their malignancy at original diagnosis or time of recurrence. Age must be ≥ 2 years and ≤ 21 years of age at study entry.
- Tumor tissue must be available (from either time of initial diagnosis or relapse) and submitted for central pathology review and correlative biological studies.
- Performance status: Lansky ≥ 50% for patients ≤ 10 years of age or Karnofsky ≥ 50% for patients > 10 years of age.
- Adequate bone marrow, liver and renal function.
- Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x the upper limit of normal. 6. Patients must have measurable residual disease, defined as tumor that is measurable in two diameters on MRI. Diffuse leptomeningeal disease is not considered measurable.
- Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy prior to participating in this trial. No prior myelosuppressive chemotherapy for 28 days prior to study enrollment. Must not have received craniospinal radiation therapy within 24 weeks prior to study entry and no involved field radiation therapy for 12 weeks prior to study enrollment. If patients received prior monoclonal antibody treatment, at least three half-lives must be elapsed by the time of treatment initiation. No investigational drugs for 4 weeks prior to study enrollment.
- MRI of the brain and the complete spine: All patients must have an MRI of the brain and spine that has measurable tumor (not only diffuse leptomeningeal tumor) within two weeks prior to study enrollment.
Exclusion Criteria:
- Prior treatment with Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus).
- Concommitant use of medications known to have inhibition or induction of CYP3A enzymes. Systemic corticosteroids (e.g., dexamethasone is a CYP3A inducer) are not allowed. Inhaled corticosteroids are allowed.
- Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus.
- Uncontrolled diabetes mellitus as defined by HbA1c > 8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Everolimus
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.
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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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Objective Response Rate (Complete Response Rate and Partial Response Rate) following treatment with everolimus for children with recurrent or progressive ependymomas.
Time Frame: 2 years
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2 years
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Duration of response following treatment with everolimus for children with recurrent or progressive ependymomas.
Time Frame: 2 years
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2 years
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Progression free survival (PRS) following treatment with everolimus for children with recurrent or progressive ependymomas.
Time Frame: 2 years
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2 years
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Event free survival (EFS) following treatment with everolimus for children with recurrent or progressive ependymomas.
Time Frame: 2 years
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2 years
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Number of Participants with Adverse Events as a Measure of Safety and Tolerability.
Time Frame: 2 years
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2 years
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Correlation of tumor Objective Response Rate to established immunohistochemical biomarkers of mTOR pathway activation, including pS6, p4EBP1, pPRAS40, pp70S6K and PTEN.
Time Frame: 2 years
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2 years
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Collaborators and Investigators
Investigators
- Principal Investigator: Daniel C Bowers, MD, UT Southwestern Medical Center at Dallas, Dallas, TX
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Disease Attributes
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Recurrence
- Ependymoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Protein Kinase Inhibitors
- MTOR Inhibitors
- Everolimus
Other Study ID Numbers
- STU 052014-038
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Recurrent Childhood Ependymoma
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National Cancer Institute (NCI)CompletedRecurrent Childhood Ependymoma | Childhood Infratentorial Ependymoma | Childhood Supratentorial Ependymoma | Recurrent Childhood Cerebellar Astrocytoma | Recurrent Childhood Cerebral Astrocytoma | Recurrent Childhood Subependymal Giant Cell Astrocytoma | Childhood Mixed Glioma | Childhood Oligodendroglioma and other conditionsUnited States, Canada, Australia
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National Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Recurrent Childhood Anaplastic Astrocytoma | Recurrent Childhood Brain Stem Glioma | Recurrent Childhood Giant Cell Glioblastoma | Recurrent Childhood Glioblastoma | Recurrent Childhood Gliosarcoma | Recurrent Childhood OligodendrogliomaUnited States
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Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Childhood Atypical Teratoid/Rhabdoid Tumor | Ependymoma | Childhood Craniopharyngioma | Childhood Grade I Meningioma | Childhood Grade II Meningioma | Childhood Grade III Meningioma | Childhood Infratentorial Ependymoma | Childhood... and other conditionsUnited States, Canada, Australia, New Zealand, Puerto Rico, Switzerland
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National Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Childhood Atypical Teratoid/Rhabdoid Tumor | Childhood Grade I Meningioma | Childhood Grade II Meningioma | Childhood Grade III Meningioma | Childhood Infratentorial Ependymoma | Childhood Supratentorial Ependymoma | Recurrent Childhood... and other conditionsUnited States
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Sue O'DorisioNational Cancer Institute (NCI); Ride for KidsWithdrawnRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Untreated Childhood Brain Stem Glioma | Untreated Childhood Medulloblastoma | Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor | Adult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma and other conditionsUnited States
-
The Hospital for Sick ChildrenCompletedChildhood Solid Tumor | Recurrent Childhood CNS Tumor | Ependymoma, Recurrent ChildhoodUnited States, Canada, Australia
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National Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Childhood Choroid Plexus Tumor | Childhood Craniopharyngioma | Childhood Ependymoblastoma | Childhood Grade I Meningioma | Childhood Grade II Meningioma | Childhood Grade III Meningioma | Childhood High-grade Cerebellar Astrocytoma | Childhood High-grade Cerebral Astrocytoma and other conditionsUnited States
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National Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Childhood Choroid Plexus Tumor | Childhood Craniopharyngioma | Childhood Ependymoblastoma | Childhood Grade I Meningioma | Childhood Grade II Meningioma | Childhood Grade III Meningioma | Childhood High-grade Cerebellar Astrocytoma | Childhood High-grade Cerebral Astrocytoma and other conditionsUnited States
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Children's Oncology GroupNational Cancer Institute (NCI)CompletedUnspecified Childhood Solid Tumor, Protocol Specific | Recurrent Childhood Medulloblastoma | Recurrent Childhood Ependymoma | Recurrent Neuroblastoma | Recurrent Osteosarcoma | Recurrent Childhood Rhabdomyosarcoma | Previously Treated Childhood Rhabdomyosarcoma | Recurrent Ewing Sarcoma/Peripheral... and other conditionsUnited States
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M.D. Anderson Cancer CenterNational Cancer Institute (NCI)CompletedRecurrent Childhood Medulloblastoma | Recurrent Ependymoma | Recurrent MedulloblastomaUnited States
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-
Novartis PharmaceuticalsCompletedLymphangioleiomyomatosis (LAM) | Tuberous Sclerosis Complex (TSC)United States, United Kingdom, Germany, Italy, Russian Federation, Netherlands, Japan, Canada, Poland, France, Spain
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University of LuebeckTerminatedCoronary Artery DiseaseGermany
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Guangdong Provincial People's HospitalNovartisUnknownNeuroendocrine Tumors | Carcinoid TumorChina
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Leiden University Medical CenterUnknownHead and Neck CancerNetherlands
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Novartis PharmaceuticalsTerminatedCarcinoma, Renal CellAustralia, Korea, Republic of
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Centre Leon BerardSuspended