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

Primary Purpose

Malignant Peripheral Nerve Sheath Tumors, MPNST, Sarcoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
everolimus
bevacizumab
Sponsored by
Sarcoma Alliance for Research through Collaboration
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Peripheral Nerve Sheath Tumors focused on measuring MPNST, malignant peripheral nerve sheath tumors, RAD001, Everolimus, Bevacizumab, Sarcoma, Avastin, mTOR inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • Children's National Medical Center
  • Ann and Robert Lurie Children's Hospital of Chicago
  • University of Iowa
  • Johns Hopkins
  • National Cancer Institute
  • Massachusetts General Hospital
  • University of Michigan
  • Washington University in St. Louis
  • Cincinnati Children's Hospital Medical Center
  • Children's Hospital of Philadelphia
  • Pennsylvania Oncology Hematology Associates

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm A

Arm Description

All patients with MPNST will continue everolimus 10 mg daily and bevacizumab 10 mg/kg dose every 14 days

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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.
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
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.
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

Full Information

First Posted
August 7, 2012
Last Updated
February 13, 2019
Sponsor
Sarcoma Alliance for Research through Collaboration
Collaborators
Novartis Pharmaceuticals, Genentech, Inc., United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT01661283
Brief Title
SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
September 2012 (undefined)
Primary Completion Date
June 2017 (Actual)
Study Completion Date
December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sarcoma Alliance for Research through Collaboration
Collaborators
Novartis Pharmaceuticals, Genentech, Inc., United States Department of Defense

4. Oversight

5. Study Description

Brief Summary
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Peripheral Nerve Sheath Tumors, MPNST, Sarcoma
Keywords
MPNST, malignant peripheral nerve sheath tumors, RAD001, Everolimus, Bevacizumab, Sarcoma, Avastin, mTOR inhibitor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A
Arm Type
Experimental
Arm Description
All patients with MPNST will continue everolimus 10 mg daily and bevacizumab 10 mg/kg dose every 14 days
Intervention Type
Drug
Intervention Name(s)
everolimus
Other Intervention Name(s)
Afinitor, everolimus
Intervention Description
10 mg tablet once daily
Intervention Type
Drug
Intervention Name(s)
bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
10 mg/kg dose every 14 days
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days
Secondary Outcome Measure Information:
Title
Spectrum of Germline NF1 Mutations in Individuals With NF1 Associated MPNSTs
Description
To evaluate the spectrum of germline NF1 mutations in individuals with NF1 associated MPNSTs
Time Frame
greater than or equal to 4 months
Title
Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST
Description
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.
Time Frame
Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days
Title
Relationship Between Response to Everolimus in Combination With Bevacizumab and the Presence of NF1 Mutations or NF1 Inactivation in MPNST Tumor Samples
Description
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
Time Frame
greater than or equal to 4 months
Title
Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5
Description
To assess changes in Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels in peripheral blood specimens during treatment.
Time Frame
Baseline, Pre-Cycle 3, Pre-Cycle 5
Title
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
Description
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
Time Frame
greater than or equal to 4 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brigitte C. Widemann, MD
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-0024
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Ann and Robert Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21218
Country
United States
Facility Name
National Cancer Institute
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-1101
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington University in St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Pennsylvania Oncology Hematology Associates
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19106
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.sarctrials.org
Description
SARC Website

Learn more about this trial

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

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