Trial Outcomes & Findings for SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors (NCT NCT01661283)
NCT ID: NCT01661283
Last Updated: 2019-03-06
Results Overview
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.
COMPLETED
PHASE2
25 participants
Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days
2019-03-06
Participant Flow
Participant milestones
| Measure |
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.
|
|---|---|
|
Overall Study
STARTED
|
25
|
|
Overall Study
COMPLETED
|
25
|
|
Overall Study
NOT COMPLETED
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
Baseline characteristics by cohort
| Measure |
Treatment
n=25 Participants
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.
|
|---|---|
|
Age, Continuous
All
|
37 years
n=25 Participants • 17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
|
|
Age, Continuous
NF1
|
28 years
n=17 Participants • 17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
|
|
Age, Continuous
Sporadic
|
61 years
n=8 Participants • 17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
|
|
Sex: Female, Male
Female
|
15 Participants
n=25 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=25 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
0 Participants
n=25 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
25 Participants
n=25 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=25 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=25 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=25 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=25 Participants
|
|
Race (NIH/OMB)
Black or African American
|
8 Participants
n=25 Participants
|
|
Race (NIH/OMB)
White
|
16 Participants
n=25 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=25 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=25 Participants
|
|
Was the primary tumor resected
No
|
5 Participants
n=25 Participants
|
|
Was the primary tumor resected
Yes
|
20 Participants
n=25 Participants
|
|
Patient had prior chemotherapy
No
|
2 Participants
n=25 Participants
|
|
Patient had prior chemotherapy
Yes
|
23 Participants
n=25 Participants
|
|
Patient had prior radiation
No
|
4 Participants
n=25 Participants
|
|
Patient had prior radiation
Yes
|
21 Participants
n=25 Participants
|
|
ECOG performance score at baseline
0
|
12 Participants
n=25 Participants
|
|
ECOG performance score at baseline
1
|
11 Participants
n=25 Participants
|
|
ECOG performance score at baseline
2
|
2 Participants
n=25 Participants
|
|
Margins of surgical resection
Unknown
|
2 Participants
n=20 Participants • 20 subjects had the primary tumor resected out of the 25 total subjects.
|
|
Margins of surgical resection
R0- All Margins Pathologically Negative
|
9 Participants
n=20 Participants • 20 subjects had the primary tumor resected out of the 25 total subjects.
|
|
Margins of surgical resection
R1- Microscopically Positive Margins
|
4 Participants
n=20 Participants • 20 subjects had the primary tumor resected out of the 25 total subjects.
|
|
Margins of surgical resection
R2- Macroscopically Positive Margins
|
5 Participants
n=20 Participants • 20 subjects had the primary tumor resected out of the 25 total subjects.
|
PRIMARY outcome
Timeframe: Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 daysEvaluate 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.
Outcome measures
| Measure |
Treatment
n=25 Participants
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.
|
|---|---|
|
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 outcome
Timeframe: greater than or equal to 4 monthsPopulation: NF1 germline mutations were not analyzed.
To evaluate the spectrum of germline NF1 mutations in individuals with NF1 associated MPNSTs
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 daysPopulation: The rows are broken up by patients with NF1 associated MPNST (n=17) and sporadic MPNST (n=8)
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.
Outcome measures
| Measure |
Treatment
n=25 Participants
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.
|
|---|---|
|
Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST
NF1 associated MPNST
|
2 Participants
|
|
Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST
Sporadic MPNST
|
1 Participants
|
SECONDARY outcome
Timeframe: greater than or equal to 4 monthsPopulation: Tumor samples were not analyzed for NF1 mutations.
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
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Baseline, Pre-Cycle 3, Pre-Cycle 5Population: Paired samples for analysis were collected for 14 patients at baseline and time of first restaging and 8 patients at time of second restaging.
To assess changes in Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels in peripheral blood specimens during treatment.
Outcome measures
| Measure |
Treatment
n=14 Participants
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.
|
|---|---|
|
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
Interval 31.2 to 593.61
|
|
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
Interval 55.82 to 334.49
|
|
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
Interval 138.51 to 262.94
|
|
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
Interval 1043.25 to 2109.18
|
|
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
Interval 658.63 to 1815.49
|
|
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
Interval 500.85 to 1678.16
|
SECONDARY outcome
Timeframe: greater than or equal to 4 monthsPopulation: 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.
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
Outcome measures
Outcome data not reported
Adverse Events
Treatment
Serious adverse events
| Measure |
Treatment
n=25 participants at risk
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.
|
|---|---|
|
Gastrointestinal disorders
Abdominal pain
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Investigations
Alanine aminotransferase increased
|
4.0%
1/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
General disorders
Death NOS
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Dehydration
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Diarrhea
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Nervous system disorders
Dizziness
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Musculoskeletal and connective tissue disorders
Flank pain
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Gastrointestinal disorders - Other, specify
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
General disorders
General disorders and administration site conditions - Other, specify
|
4.0%
1/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Nervous system disorders
Headache
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Vascular disorders
Hypertension
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Intra-abdominal hemorrhage
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Mucositis oral
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Nausea
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
General disorders
Pain
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Cardiac disorders
Pericardial effusion
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Pleural effusion
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Renal and urinary disorders
Renal and urinary disorders - Other, specify
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Vascular disorders
Thromboembolic event
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Upper gastrointestinal hemorrhage
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Renal and urinary disorders
Urinary tract infection
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Vomiting
|
4.0%
1/25 • Number of events 1 • ~4 years
CTCAE version 4.0
|
Other adverse events
| Measure |
Treatment
n=25 participants at risk
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.
|
|---|---|
|
Blood and lymphatic system disorders
Anemia
|
12.0%
3/25 • Number of events 5 • ~4 years
CTCAE version 4.0
|
|
Blood and lymphatic system disorders
Platelet count decreased
|
16.0%
4/25 • Number of events 6 • ~4 years
CTCAE version 4.0
|
|
Blood and lymphatic system disorders
White blood cell decreased
|
12.0%
3/25 • Number of events 3 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Constipation
|
20.0%
5/25 • Number of events 5 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Diarrhea
|
12.0%
3/25 • Number of events 4 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Dyspepsia
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Mucositis oral
|
48.0%
12/25 • Number of events 20 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Oral pain
|
8.0%
2/25 • Number of events 4 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Nausea
|
28.0%
7/25 • Number of events 8 • ~4 years
CTCAE version 4.0
|
|
Gastrointestinal disorders
Vomiting
|
20.0%
5/25 • Number of events 6 • ~4 years
CTCAE version 4.0
|
|
General disorders
Fever
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
General disorders
Fatigue
|
44.0%
11/25 • Number of events 14 • ~4 years
CTCAE version 4.0
|
|
Investigations
Alanine aminotransferase increased
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Investigations
Creatinine increased
|
12.0%
3/25 • Number of events 3 • ~4 years
CTCAE version 4.0
|
|
Investigations
Weight loss
|
32.0%
8/25 • Number of events 9 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Anorexia
|
28.0%
7/25 • Number of events 8 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Cholesterol high
|
16.0%
4/25 • Number of events 4 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Dehydration
|
12.0%
3/25 • Number of events 3 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Hypertriglyceridemia
|
12.0%
3/25 • Number of events 4 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Hypokalemia
|
12.0%
3/25 • Number of events 3 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Hyponatremia
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Metabolism and nutrition disorders
Hypophosphatemia
|
20.0%
5/25 • Number of events 10 • ~4 years
CTCAE version 4.0
|
|
Musculoskeletal and connective tissue disorders
Muscle weakness (lower limb, upper limb)
|
4.0%
1/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Nervous system disorders
Headache
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
General disorders
Pain (neck, back, chest wall, ear, flank)
|
20.0%
5/25 • Number of events 7 • ~4 years
CTCAE version 4.0
|
|
Psychiatric disorders
Insomnia
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Renal and urinary disorders
Proteinuria
|
16.0%
4/25 • Number of events 6 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
12.0%
3/25 • Number of events 3 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Nasal congestion
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnea
|
16.0%
4/25 • Number of events 5 • ~4 years
CTCAE version 4.0
|
|
Respiratory, thoracic and mediastinal disorders
Sore throat
|
12.0%
3/25 • Number of events 4 • ~4 years
CTCAE version 4.0
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
8.0%
2/25 • Number of events 2 • ~4 years
CTCAE version 4.0
|
|
Vascular disorders
Hypertension
|
20.0%
5/25 • Number of events 7 • ~4 years
CTCAE version 4.0
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place