Malignant Peripheral Nerve Sheath Tumors, MPNST, Sarcoma
Conditions
Keywords
MPNST, malignant peripheral nerve sheath tumors, RAD001, Everolimus, Bevacizumab, Sarcoma, Avastin, mTOR inhibitor
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
Interventions
DRUGeverolimus
10 mg tablet once daily
DRUGbevacizumab
10 mg/kg dose every 14 days
Sponsors
Novartis Pharmaceuticals
Genentech, Inc.
United States Department of Defense
Sarcoma Alliance for Research through Collaboration
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Spectrum of Germline NF1 Mutations in Individuals With NF1 Associated MPNSTs | greater than or equal to 4 months | 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 | Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days | 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 | greater than or equal to 4 months | 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 | Baseline, Pre-Cycle 3, Pre-Cycle 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 | greater than or equal to 4 months | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Everolimus (2.5, 5, and 10 mg tablets) was administered at 10 mg per dose once daily at the same time on a continuous dosing schedule.
Bevacizumab (400 mg vials) was administered at 10 mg/kg as intravenous infusion over 30-90 minutes every 2 weeks (days 1 and 15).
One treatment cycle was 28 days. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Treatment |
|---|---|
| Age, Continuous All | 37 years |
| Age, Continuous NF1 | 28 years |
| Age, Continuous Sporadic | 61 years |
| ECOG performance score at baseline 0 | 12 Participants |
| ECOG performance score at baseline 1 | 11 Participants |
| ECOG performance score at baseline 2 | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Margins of surgical resection R0- All Margins Pathologically Negative | 9 Participants |
| Margins of surgical resection R1- Microscopically Positive Margins | 4 Participants |
| Margins of surgical resection R2- Macroscopically Positive Margins | 5 Participants |
| Margins of surgical resection Unknown | 2 Participants |
| Patient had prior chemotherapy No | 2 Participants |
| Patient had prior chemotherapy Yes | 23 Participants |
| Patient had prior radiation No | 4 Participants |
| Patient had prior radiation Yes | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 10 Participants |
| Was the primary tumor resected No | 5 Participants |
| Was the primary tumor resected Yes | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 25 |
| other Total, other adverse events | 23 / 25 |
| serious Total, serious adverse events | 11 / 25 |
Outcome results
Primary
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.
Time frame: Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | 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 | 3 Participants |
Secondary
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.
Time frame: Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days
Population: The rows are broken up by patients with NF1 associated MPNST (n=17) and sporadic MPNST (n=8)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST | NF1 associated MPNST | 2 Participants |
| Treatment | Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST | Sporadic MPNST | 1 Participants |
Secondary
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
Time frame: greater than or equal to 4 months
Population: Tumor samples were not analyzed for NF1 mutations.
Secondary
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
Time frame: greater than or equal to 4 months
Population: NF1 germline mutations were not analyzed.
Secondary
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
Time frame: greater than or equal to 4 months
Population: Imaging studies of sufficient quality to analyze tumors were not collected. Therefore, unable to analyze volumes and compare 3-D to 1-D and 2-D measurements.
Secondary
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.
Time frame: Baseline, Pre-Cycle 3, Pre-Cycle 5
Population: Paired samples for analysis were collected for 14 patients at baseline and time of first restaging and 8 patients at time of second restaging.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGF- Baseline | 103.58 pg/mL |
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGF- Pre Cycle 3 | 184.24 pg/mL |
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGF- Pre Cycle 5 | 192.49 pg/mL |
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGFR2- Baseline | 1363.76 pg/mL |
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGFR2 Pre Cycle 3 | 911.89 pg/mL |
| Treatment | Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5 | VEGFR2 Pre Cycle 5 | 863.85 pg/mL |