SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors

Study Overview
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Brief Summary
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To determine the clinical response rate of everolimus in combination with bevacizumab for patients with chemotherapy refractory sporadic or neurofibromatosis type 1 (NF1) associated malignant peripheral nerve sheath tumor (MPNST). To evaluate the toxicity and safety of everolimus in combination with bevacizumab in individuals with MPNST

Official Title
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Phase 2 Study of the mTOR Inhibitor Everolimus in Combination With Bevacizumab in Patients With Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors

Conditions
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Malignant Peripheral Nerve Sheath Tumors, MPNST, Sarcoma

Intervention / Treatment
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* Drug: everolimus
* Drug: bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 or older Unresectable or metastatic sporadic or NF1 associated high-grade MPNST Experienced progression after one or more prior regimens of cytotoxic chemotherapy Patients must be able to swallow tablets Patients must have measurable disease, defined as at least one tumor that is measurable Patients who develop a recurrence or progression (WHO criteria) of an MPNST in a previously radiated field may be enrolled if it has been at least 4 weeks since the last dose of radiation therapy Patients must have recovered from the toxic effects of all prior therapy before entering this study Adequate organ function Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Patents who received an anthracycline prior to enrollment must have an ejection fraction ≥ 50% Subjects of childbearing potential requires acceptable form of birth control Informed consent Exclusion Criteria: Patients currently receiving anticancer therapies or who have received anticancer therapies within 3 weeks of the start of study drug or patients receiving prior treatment with investigational drugs 4 weeks of the start of study drug Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry Prior radiotherapy within 4 weeks of the start of study drug Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, Patients who have not recovered from the side effects of any major surgery Patients that may require major surgery during the course of the study Less than 7 days have passed from core biopsies or other minor surgical procedures excluding placement of a vascular access device Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent(Topical or inhaled corticosteroids are allowed) Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Female patients who are pregnant or breast feeding Patients who have received prior treatment with an mTOR inhibitor or bevacizumab Patients with known hypersensitivity to rapamycins concurrent use of anti-coagulant drugs Patients using Seville orange, star fruit, grapefruit and their juices, and St. John's Wort Patients taking enzyme inducing anticonvulsants

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>All patients with MPNST will continue everolimus 10 mg daily and bevacizumab 10 mg/kg dose every 14 days | Drug: everolimus<br>* 10 mg tablet once daily<br>* Other names: Afinitor, everolimus;Drug: bevacizumab<br>* 10 mg/kg dose every 14 days<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Complete Response, Partial Response, and Stable Disease at ≥ 4 Months Using World Health Organization (WHO) Criteria) of Everolimus in Combination With Bevacizumab | Evaluate if the combination of the mTOR inhibitor everolimus combined with the angiogenesis inhibitor bevacizumab would result in a modest clinical benefit rate, which included confirmed partial and complete responses and disease stability for four or more treatment cycles based on WHO Response Criteria. Per WHO for target lesions: Complete Response (CR): Disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart. Partial Response (PR): A > 50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive. Stable Disease (SD): A 50% decrease in total tumor area cannot be established nor has a 25% increase in the size of one or more measurable lesions been demonstrated. | Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spectrum of Germline NF1 Mutations in Individuals With NF1 Associated MPNSTs | To evaluate the spectrum of germline NF1 mutations in individuals with NF1 associated MPNSTs | greater than or equal to 4 months | 
| Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST | To explore differences in the response rate to everolimus in combination with bevacizumab in individuals with sporadic and NF1 associated MPNST. Responses include confirmed partial and complete responses and disease stability for four or more treatment cycles based on WHO Response Criteria. Per WHO for target lesions: Complete Response (CR): Disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart. Partial Response (PR): A > 50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive. Stable Disease (SD): A 50% decrease in total tumor area cannot be established nor has a 25% increase in the size of one or more measurable lesions been demonstrated. | Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days | 
| Relationship Between Response to Everolimus in Combination With Bevacizumab and the Presence of NF1 Mutations or NF1 Inactivation in MPNST Tumor Samples | To explore the relationship between response to everolimus in combination with bevacizumab and the presence of NF1 mutations or NF1 inactivation in MPNST tumor samples | greater than or equal to 4 months | 
| Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | To assess changes in Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels in peripheral blood specimens during treatment. | Baseline, Pre-Cycle 3, Pre-Cycle 5 | 
| Utility of 3-D MRI Analysis in Comparison to 1-D and 2-D Measurements to More Sensitively Monitor Response to Everolimus in Combination With Bevacizumab | To evaluate the utility of 3-D MRI analysis in comparison to 1-D and 2-D measurements to more sensitively monitor response to everolimus in combination with bevacizumab | greater than or equal to 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoma, MPNST, malignant peripheral nerve sheath tumors, RAD001, Everolimus, Bevacizumab, Avastin, mTOR inhibitor