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

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ClinicalTrials.gov Identifier: NCT01661283
Recruitment Status : Completed
First Posted : August 9, 2012
Results First Posted : March 6, 2019
Last Update Posted : March 6, 2019
Sponsor:
Collaborators:
Novartis Pharmaceuticals
Genentech, Inc.
United States Department of Defense
Information provided by (Responsible Party):
Sarcoma Alliance for Research through Collaboration

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Malignant Peripheral Nerve Sheath Tumors
MPNST
Sarcoma
Interventions Drug: everolimus
Drug: bevacizumab
Enrollment 25
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Treatment
Hide Arm/Group Description

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.

Period Title: Overall Study
Started 25 [1]
Completed 25
Not Completed 0
[1]
15 patients enrolled in the first stage; 10 patients enrolled in the second stage
Arm/Group Title Treatment
Hide Arm/Group Description

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 Number of Baseline Participants 25
Hide Baseline Analysis Population Description
17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
Age, Continuous   [1] 
Median (Full Range)
Unit of measure:  Years
All Number Analyzed 25 participants
37
(19 to 81)
NF1 Number Analyzed 17 participants
28
(19 to 63)
Sporadic Number Analyzed 8 participants
61
(19 to 81)
[1]
Measure Analysis Population Description: 17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Female
15
  60.0%
Male
10
  40.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
25
 100.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   4.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
8
  32.0%
White
16
  64.0%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Was the primary tumor resected  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
No
5
  20.0%
Yes
20
  80.0%
Patient had prior chemotherapy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
No
2
   8.0%
Yes
23
  92.0%
Patient had prior radiation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
No
4
  16.0%
Yes
21
  84.0%
ECOG performance score at baseline   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
0
12
  48.0%
1
11
  44.0%
2
2
   8.0%
[1]
Measure Description:

Eastern Cooperative Oncology Group (ECOG) Performance Status Scale:

Grade 0: Normal activity. Fully active, able to carry on all pre-disease performance without restriction.

Grade 1: Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature.

Grade 2: In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.

Margins of surgical resection   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants
Unknown
2
  10.0%
R0- All Margins Pathologically Negative
9
  45.0%
R1- Microscopically Positive Margins
4
  20.0%
R2- Macroscopically Positive Margins
5
  25.0%
[1]
Measure Analysis Population Description: 20 subjects had the primary tumor resected out of the 25 total subjects.
1.Primary Outcome
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 25
Measure Type: Count of Participants
Unit of Measure: Participants
3
  12.0%
2.Secondary Outcome
Title Spectrum of Germline NF1 Mutations in Individuals With NF1 Associated MPNSTs
Hide Description To evaluate the spectrum of germline NF1 mutations in individuals with NF1 associated MPNSTs
Time Frame greater than or equal to 4 months
Hide Outcome Measure Data
Hide Analysis Population Description
NF1 germline mutations were not analyzed.
Arm/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
3.Secondary Outcome
Title Number of Participants With Response Stratified by Individuals With Sporadic or NF1 Associated MPNST
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The rows are broken up by patients with NF1 associated MPNST (n=17) and sporadic MPNST (n=8)
Arm/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 25
Measure Type: Count of Participants
Unit of Measure: Participants
NF1 associated MPNST Number Analyzed 17 participants
2
  11.8%
Sporadic MPNST Number Analyzed 8 participants
1
  12.5%
4.Secondary Outcome
Title Relationship Between Response to Everolimus in Combination With Bevacizumab and the Presence of NF1 Mutations or NF1 Inactivation in MPNST Tumor Samples
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Tumor samples were not analyzed for NF1 mutations.
Arm/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Levels at Baseline and Pre-Cycles 3 and 5
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 14
Median (Full Range)
Unit of Measure: pg/mL
VEGF- Baseline Number Analyzed 14 participants
103.58
(31.20 to 593.61)
VEGF- Pre Cycle 3 Number Analyzed 14 participants
184.24
(55.82 to 334.49)
VEGF- Pre Cycle 5 Number Analyzed 8 participants
192.49
(138.51 to 262.94)
VEGFR2- Baseline Number Analyzed 14 participants
1363.76
(1043.25 to 2109.18)
VEGFR2 Pre Cycle 3 Number Analyzed 14 participants
911.89
(658.63 to 1815.49)
VEGFR2 Pre Cycle 5 Number Analyzed 8 participants
863.85
(500.85 to 1678.16)
6.Secondary Outcome
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Treatment
Hide Arm/Group Description:

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 Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame ~4 years
Adverse Event Reporting Description CTCAE version 4.0
 
Arm/Group Title Treatment
Hide Arm/Group Description

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.

All-Cause Mortality
Treatment
Affected / at Risk (%)
Total   3/25 (12.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Treatment
Affected / at Risk (%) # Events
Total   11/25 (44.00%)    
Cardiac disorders   
Pericardial effusion   1/25 (4.00%)  1
Gastrointestinal disorders   
Abdominal pain   1/25 (4.00%)  1
Diarrhea   1/25 (4.00%)  1
Gastrointestinal disorders - Other, specify   1/25 (4.00%)  1
Intra-abdominal hemorrhage   1/25 (4.00%)  1
Mucositis oral   2/25 (8.00%)  2
Nausea   1/25 (4.00%)  1
Upper gastrointestinal hemorrhage   1/25 (4.00%)  1
Vomiting   1/25 (4.00%)  1
General disorders   
Death NOS   1/25 (4.00%)  1
General disorders and administration site conditions - Other, specify   1/25 (4.00%)  2
Pain   1/25 (4.00%)  1
Investigations   
Alanine aminotransferase increased   1/25 (4.00%)  2
Metabolism and nutrition disorders   
Dehydration   1/25 (4.00%)  1
Musculoskeletal and connective tissue disorders   
Flank pain   1/25 (4.00%)  1
Nervous system disorders   
Dizziness   1/25 (4.00%)  1
Headache   1/25 (4.00%)  1
Renal and urinary disorders   
Renal and urinary disorders - Other, specify   1/25 (4.00%)  1
Urinary tract infection   1/25 (4.00%)  1
Respiratory, thoracic and mediastinal disorders   
Pleural effusion   1/25 (4.00%)  1
Vascular disorders   
Hypertension   1/25 (4.00%)  1
Thromboembolic event   1/25 (4.00%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4%
Treatment
Affected / at Risk (%) # Events
Total   23/25 (92.00%)    
Blood and lymphatic system disorders   
Anemia   3/25 (12.00%)  5
Platelet count decreased   4/25 (16.00%)  6
White blood cell decreased   3/25 (12.00%)  3
Gastrointestinal disorders   
Constipation   5/25 (20.00%)  5
Diarrhea   3/25 (12.00%)  4
Dyspepsia   2/25 (8.00%)  2
Mucositis oral   12/25 (48.00%)  20
Oral pain   2/25 (8.00%)  4
Nausea   7/25 (28.00%)  8
Vomiting   5/25 (20.00%)  6
General disorders   
Fever   2/25 (8.00%)  2
Fatigue   11/25 (44.00%)  14
Pain (neck, back, chest wall, ear, flank)   5/25 (20.00%)  7
Investigations   
Alanine aminotransferase increased   2/25 (8.00%)  2
Creatinine increased   3/25 (12.00%)  3
Weight loss   8/25 (32.00%)  9
Metabolism and nutrition disorders   
Anorexia   7/25 (28.00%)  8
Cholesterol high   4/25 (16.00%)  4
Dehydration   3/25 (12.00%)  3
Hypertriglyceridemia   3/25 (12.00%)  4
Hypokalemia   3/25 (12.00%)  3
Hyponatremia   2/25 (8.00%)  2
Hypophosphatemia   5/25 (20.00%)  10
Musculoskeletal and connective tissue disorders   
Muscle weakness (lower limb, upper limb)   1/25 (4.00%)  2
Nervous system disorders   
Headache   2/25 (8.00%)  2
Psychiatric disorders   
Insomnia   2/25 (8.00%)  2
Renal and urinary disorders   
Proteinuria   4/25 (16.00%)  6
Respiratory, thoracic and mediastinal disorders   
Cough   2/25 (8.00%)  2
Epistaxis   3/25 (12.00%)  3
Nasal congestion   2/25 (8.00%)  2
Dyspnea   4/25 (16.00%)  5
Sore throat   3/25 (12.00%)  4
Skin and subcutaneous tissue disorders   
Dry skin   2/25 (8.00%)  2
Vascular disorders   
Hypertension   5/25 (20.00%)  7
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: SARC
Organization: SARC
Phone: (734) 930-7600
EMail: sarc@sarctrials.org
Layout table for additonal information
Responsible Party: Sarcoma Alliance for Research through Collaboration
ClinicalTrials.gov Identifier: NCT01661283     History of Changes
Other Study ID Numbers: SARC016
First Submitted: August 7, 2012
First Posted: August 9, 2012
Results First Submitted: January 21, 2019
Results First Posted: March 6, 2019
Last Update Posted: March 6, 2019