BOLERO-1: Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer
Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00876395
Collaborator
(none)
719
142
2
97.4
5.1
0.1
Study Details
Study Description
Brief Summary
The purpose of this Phase III study was to confirm the value of adding everolimus to weekly paclitaxel and trastuzumab as treatment of HER2-overexpressing metastatic breast cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
719 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination With Trastuzumab and Paclitaxel, as First Line Therapy in Women With HER2 Positive Locally Advanced or Metastatic Breast Cancer
Actual Study Start Date
:
Sep 10, 2009
Actual Primary Completion Date
:
May 30, 2014
Actual Study Completion Date
:
Oct 23, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Everolimus + Paclitaxel + Trastuzumab Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
Drug: Everolimus
Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
Other Names:
Drug: Trastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.
Drug: Paclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.
|
| Placebo Comparator: Placebo + Paclitaxel + Trastuzumab Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
Drug: Placebo
Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
Drug: Trastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.
Drug: Paclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.
|
Outcome Measures
Primary Outcome Measures
- Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population [date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months]
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population.
- Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population [date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months]
PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population.
Secondary Outcome Measures
- Overall Survival (OS) - Full Population [up to about 76 months]
OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population.
- Overall Survival (OS) - HR-negative Population [up to about 76 months]
OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population.
- Overall Response Rate (ORR) - Full Population [up to about 23 months]
ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Overall Response Rate (ORR) - HR-negative Population [up to about 23 months]
ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population [up to about 23 months]
CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population [up to about 23 months]
CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Time to Overall Response Based on Investigator - Full Population [up to about 23 months]
Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Time to Overall Response Based on Investigator - HR-negative Population [up to about 23 months]
Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Overall Response (OR) - Full Population [up to about 23 months]
OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Overall Response (OR) - HR-negative Population [up to about 23 months]
OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.
- Everolimus Blood Level Concentrations at Steady States for Everolimus [predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22]
Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days
- Paclitaxel Plasma Concentrations [Cycle 2/Day 15 (Pre-infusion and end of infusion)]
Blood levels at steady states for everolimus/placebo
- Trastuzumab Serum Concentrations [Cycle 4/Day 1 (Pre-infusion and end of infusion)]
Blood levels at steady states for everolimus/placebo
- Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population [up to about 56 months]
Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
- Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population [up to about 56 months]
Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Adult Women (≥ 18 years old).
-
Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease.
-
Must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease.
-
HER2+ patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
-
Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is allowed but should be discontinued > 12 months prior to randomization.
-
Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment.
-
Documentation of negative pregnancy test.
-
Organ functions at time of inclusion.
Exclusion Criteria:
-
Prior mTOR inhibitors for the treatment of cancer.
-
Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy.
-
Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc).
-
Radiotherapy to ≥ 25% of the bone marrow within 4 weeks prior to randomization
-
History of central nervous system metastasis.
-
Impairment of gastrointestinal (GI) function or GI disease or active ulceration of the upper gastrointestinal tract.
-
Serious peripheral neuropathy.
-
Cardiac disease or dysfunction.
-
Uncontrolled hypertension.
-
HIV.
-
Pregnant,
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst. | Mobile | Alabama | United States | 36688 |
| 2 | Ironwood Cancer and Research Centers | Chandler | Arizona | United States | 85224 |
| 3 | Highlands Oncology Group | Fayetteville | Arkansas | United States | 72703 |
| 4 | Comprehensive Blood and Cancer Center Dept. of CBCC (2) | Bakersfield | California | United States | 93309 |
| 5 | St. Jude Heritage Medical Group Virginia Crosson Cancer Center | Fullerton | California | United States | 92835 |
| 6 | University of California at Los Angeles Dept. of UCLA | Los Angeles | California | United States | 90095 |
| 7 | Ventura County Hematology and Oncology | Oxnard | California | United States | 93030 |
| 8 | Cancer Care Associates Medical Group Dept. of CCA | Redondo Beach | California | United States | 90277 |
| 9 | Santa Barbara Hematolgy Oncology Medical Group Dept.ofSantaBarbaraHem/Onc | Santa Barbara | California | United States | 93105 |
| 10 | Central Coast Medical Oncology Corporation Onc Dept | Santa Maria | California | United States | 93454 |
| 11 | Rocky Mountain Cancer Centers RMCC - Denver-Midtown (3) | Greenwood Village | Colorado | United States | |
| 12 | Florida Cancer Specialists Dept.of FloridaCancerSpec. (2) | Fort Myers | Florida | United States | 33901 |
| 13 | Florida Cancer Specialists | West Palm Beach | Florida | United States | 33401 |
| 14 | Central Indiana Cancer Centers CICC - East (3) | Indianapolis | Indiana | United States | 46227 |
| 15 | Kansas City Cancer Center Dept. of KCCC | Overland Park | Kansas | United States | 66210 |
| 16 | University of Nebraska Medical Center Unv Nebraska Med Ctr (2) | Omaha | Nebraska | United States | 68198 |
| 17 | New York Oncology Hematology NYOH Amsterdam | Albany | New York | United States | 12208 |
| 18 | Beth Israel Medical Center Dept.ofBeth Israel Med. Ctr(2) | New York | New York | United States | 10003 |
| 19 | Northwest Cancer Specialists Vancouver Cancer Center (3) | Portland | Oregon | United States | 97210 |
| 20 | Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(5) | Nashville | Tennessee | United States | 37203 |
| 21 | Texas Oncology Charles A. Sammons Cancer Ctr | Dallas | Texas | United States | 75246 |
| 22 | Texas Oncology P A SC-Austin | Dallas | Texas | United States | 75251 |
| 23 | Tyler Cancer Center Dept.ofTylerCancerCtr. (2) | Tyler | Texas | United States | 75702 |
| 24 | Virginia Oncology Associates SC | Norfolk | Virginia | United States | 23502 |
| 25 | Virginia Cancer Institute VCI (3) | Richmond | Virginia | United States | 23230 |
| 26 | Novartis Investigative Site | Caba | Buenos Aires | Argentina | C1050AAK |
| 27 | Novartis Investigative Site | Mar del Plata | Buenos Aires | Argentina | B7600CTO |
| 28 | Novartis Investigative Site | Posadas | Misiones | Argentina | |
| 29 | Novartis Investigative Site | Rosario | Sante Fe | Argentina | S200KZE |
| 30 | Novartis Investigative Site | Rio Negro | Viedma | Argentina | 8500 |
| 31 | Novartis Investigative Site | Capital Federal | Argentina | 1417 | |
| 32 | Novartis Investigative Site | Cordoba | Argentina | X5004BAL | |
| 33 | Novartis Investigative Site | Southport | Queensland | Australia | 4215 |
| 34 | Novartis Investigative Site | East Bentleigh | Victoria | Australia | 3165 |
| 35 | Novartis Investigative Site | Charleroi | Belgium | 6000 | |
| 36 | Novartis Investigative Site | Hasselt | Belgium | 3500 | |
| 37 | Novartis Investigative Site | Verviers | Belgium | 4800 | |
| 38 | Novartis Investigative Site | Wilrijk | Belgium | 2610 | |
| 39 | Novartis Investigative Site | Yvoir | Belgium | 5530 | |
| 40 | Novartis Investigative Site | Belo Horizonte | MG | Brazil | 30130-100 |
| 41 | Novartis Investigative Site | Belo Horizonte | MG | Brazil | 30380-490 |
| 42 | Novartis Investigative Site | Rio de Janeiro | RJ | Brazil | 20230-130 |
| 43 | Novartis Investigative Site | Sao Paulo | SP | Brazil | 01246 000 |
| 44 | Novartis Investigative Site | São Paulo | SP | Brazil | 04038-001 |
| 45 | Novartis Investigative Site | Montreal | Quebec | Canada | H2W 1S6 |
| 46 | Novartis Investigative Site | Montreal | Quebec | Canada | H4J 1C5 |
| 47 | Novartis Investigative Site | St-Jerome | Quebec | Canada | J7Z 5T3 |
| 48 | Novartis Investigative Site | Guangzhou | Guangdong | China | 51000 |
| 49 | Novartis Investigative Site | Harbin | Heilongjiang | China | 150081 |
| 50 | Novartis Investigative Site | Nanjing | Jiangsu | China | 210002 |
| 51 | Novartis Investigative Site | Nanjing | Jiangsu | China | 210009 |
| 52 | Novartis Investigative Site | Shanghai | Shanghai | China | 200032 |
| 53 | Novartis Investigative Site | Hangzhou | Zhejiang | China | 310022 |
| 54 | Novartis Investigative Site | Beijing | China | 100021 | |
| 55 | Novartis Investigative Site | Beijing | China | 100039 | |
| 56 | Novartis Investigative Site | Guangzhou | China | 510060 | |
| 57 | Novartis Investigative Site | Shanghai | China | 200025 | |
| 58 | Novartis Investigative Site | Bogota | Cundinamarca | Colombia | 0000 |
| 59 | Novartis Investigative Site | Bogota | Colombia | ||
| 60 | Novartis Investigative Site | Florida Blanca | Colombia | ||
| 61 | Novartis Investigative Site | Monteria | Colombia | ||
| 62 | Novartis Investigative Site | Alexandria | Egypt | ||
| 63 | Novartis Investigative Site | Cairo | Egypt | ||
| 64 | Novartis Investigative Site | Limoges | France | 87000 | |
| 65 | Novartis Investigative Site | Rouen | France | 76000 | |
| 66 | Novartis Investigative Site | Saint-Herblain Cédex | France | 44805 | |
| 67 | Novartis Investigative Site | Strasbourg Cedex | France | F 67098 | |
| 68 | Novartis Investigative Site | Thonon-les-Bains Cedex | France | 74203 | |
| 69 | Novartis Investigative Site | Toulouse Cedex 9 | France | 31059 | |
| 70 | Novartis Investigative Site | Villejuif Cedex | France | 94805 | |
| 71 | Novartis Investigative Site | Berlin | Germany | 10098 | |
| 72 | Novartis Investigative Site | Chemnitz | Germany | 09113 | |
| 73 | Novartis Investigative Site | Esslingen | Germany | 73730 | |
| 74 | Novartis Investigative Site | Kiel | Germany | 24105 | |
| 75 | Novartis Investigative Site | Muenster | Germany | 48149 | |
| 76 | Novartis Investigative Site | Athens | GR | Greece | 151 23 |
| 77 | Novartis Investigative Site | Thessaloniki | GR | Greece | 564 03 |
| 78 | Novartis Investigative Site | Athens | Greece | 115 28 | |
| 79 | Novartis Investigative Site | Athens | Greece | 18547 | |
| 80 | Novartis Investigative Site | Heraklion Crete | Greece | 711 10 | |
| 81 | Novartis Investigative Site | Hong Kong SAR | Hong Kong | ||
| 82 | Novartis Investigative Site | Shatin, New Territories | Hong Kong | ||
| 83 | Novartis Investigative Site | Tuen Mun | Hong Kong | ||
| 84 | Novartis Investigative Site | Wilton | Cork | Ireland | |
| 85 | Novartis Investigative Site | Dublin 4 | Ireland | ||
| 86 | Novartis Investigative Site | Dublin 8 | Ireland | ||
| 87 | Novartis Investigative Site | Dublin 9 | Ireland | ||
| 88 | Novartis Investigative Site | Monza | MB | Italy | 20900 |
| 89 | Novartis Investigative Site | Modena | MO | Italy | 41124 |
| 90 | Novartis Investigative Site | Camposampiero | PD | Italy | 35012 |
| 91 | Novartis Investigative Site | Roma | RM | Italy | 00128 |
| 92 | Novartis Investigative Site | Napoli | Italy | 80131 | |
| 93 | Novartis Investigative Site | Nagoya | Aichi | Japan | 464-8681 |
| 94 | Novartis Investigative Site | Kashiwa | Chiba | Japan | 277-8577 |
| 95 | Novartis Investigative Site | Fukuoka-city | Fukuoka | Japan | 811-1395 |
| 96 | Novartis Investigative Site | Kitakyushu | Fukuoka | Japan | 802-0077 |
| 97 | Novartis Investigative Site | Maebashi city | Gunma | Japan | 371 8511 |
| 98 | Novartis Investigative Site | Sapporo city | Hokkaido | Japan | 060 8648 |
| 99 | Novartis Investigative Site | Isehara-city | Kanagawa | Japan | 259-1193 |
| 100 | Novartis Investigative Site | Kumamoto City | Kumamoto | Japan | 860-8556 |
| 101 | Novartis Investigative Site | Sakyo-ku | Kyoto | Japan | 606 8507 |
| 102 | Novartis Investigative Site | Osaka-city | Osaka | Japan | 540-0006 |
| 103 | Novartis Investigative Site | Suita-city | Osaka | Japan | 565 0871 |
| 104 | Novartis Investigative Site | Kitaadachi-gun | Saitama | Japan | 362-0806 |
| 105 | Novartis Investigative Site | Bunkyo-ku | Tokyo | Japan | 113-8677 |
| 106 | Novartis Investigative Site | Chuo-ku | Tokyo | Japan | 104-8560 |
| 107 | Novartis Investigative Site | Osaka | Japan | 537-8511 | |
| 108 | Novartis Investigative Site | Gyeonggi-do | Korea | Korea, Republic of | 10408 |
| 109 | Novartis Investigative Site | Seoul | Korea | Korea, Republic of | 06351 |
| 110 | Novartis Investigative Site | Seoul | Korea, Republic of | 02841 | |
| 111 | Novartis Investigative Site | Seoul | Korea, Republic of | 03722 | |
| 112 | Novartis Investigative Site | Ashrafieh | Lebanon | 166830 | |
| 113 | Novartis Investigative Site | Beirut | Lebanon | 1107 2020 | |
| 114 | Novartis Investigative Site | Ciudad De Mexico | Distrito Federal | Mexico | 04980 |
| 115 | Novartis Investigative Site | Zaragoza | Veracruz | Mexico | 91910 |
| 116 | Novartis Investigative Site | San Borja | Lima | Peru | 41 |
| 117 | Novartis Investigative Site | Surquillo | Lima | Peru | 34 |
| 118 | San Juan VA Hospital San Juan Hospital | San Juan | Puerto Rico | 00921 | |
| 119 | Novartis Investigative Site | Kazan | Tatarstan Republic | Russian Federation | 420029 |
| 120 | Novartis Investigative Site | Moscow | Russian Federation | 115478 | |
| 121 | Novartis Investigative Site | Moscow | Russian Federation | 129128 | |
| 122 | Novartis Investigative Site | Moscow | Russian Federation | 143423 | |
| 123 | Novartis Investigative Site | St Petersburg | Russian Federation | 197758 | |
| 124 | Novartis Investigative Site | St. Petersburg | Russian Federation | 198255 | |
| 125 | Novartis Investigative Site | Bloemfontein | South Africa | 9301 | |
| 126 | Novartis Investigative Site | Durban | South Africa | 4091 | |
| 127 | Novartis Investigative Site | Pretoria | South Africa | 0002 | |
| 128 | Novartis Investigative Site | Genève | Switzerland | 1211 | |
| 129 | Novartis Investigative Site | Zuerich | Switzerland | 8038 | |
| 130 | Novartis Investigative Site | Taipei | Taiwan, ROC | Taiwan | 11217 |
| 131 | Novartis Investigative Site | Kaohsiung | Taiwan | 80756 | |
| 132 | Novartis Investigative Site | Taichung | Taiwan | 40447 | |
| 133 | Novartis Investigative Site | Taipei | Taiwan | 10002 | |
| 134 | Novartis Investigative Site | Taoyuan | Taiwan | 33305 | |
| 135 | Novartis Investigative Site | Altunizade | Turkey | 34662 | |
| 136 | Novartis Investigative Site | Ankara | Turkey | 06100 | |
| 137 | Novartis Investigative Site | Izmir | Turkey | 35040 | |
| 138 | Novartis Investigative Site | Izmir | Turkey | 35340 | |
| 139 | Novartis Investigative Site | Truro | Cornwall | United Kingdom | TR1 3LJ |
| 140 | Novartis Investigative Site | London | United Kingdom | SW3 6JJ | |
| 141 | Novartis Investigative Site | Sutton | United Kingdom | SM2 5PT | |
| 142 | Novartis Investigative Site | Valencia | Estado Carabobo | Venezuela | 2001 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00876395
Other Study ID Numbers:
- CRAD001J2301
- 2008-006556-21
First Posted:
Apr 6, 2009
Last Update Posted:
Dec 19, 2018
Last Verified:
Dec 1, 2018
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 717 patients were planned to be randomized. A total of 719 patients were randomized between 10-Sep-2009 and 16-Dec-2012. Not completed reasons = primary reasons for end of treatment |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Period Title: Overall Study | ||
| STARTED | 480 | 239 |
| Untreated | 8 | 1 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 480 | 239 |
Baseline Characteristics
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab | Total |
|---|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Total of all reporting groups |
| Overall Participants | 480 | 239 | 719 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
53.4
(11.46)
|
52.1
(11.63)
|
53.0
(11.53)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
480
100%
|
239
100%
|
719
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Caucasian |
214
44.6%
|
97
40.6%
|
311
43.3%
|
| Black |
26
5.4%
|
12
5%
|
38
5.3%
|
| Asian |
198
41.3%
|
105
43.9%
|
303
42.1%
|
| Native American |
3
0.6%
|
0
0%
|
3
0.4%
|
| Other |
39
8.1%
|
25
10.5%
|
64
8.9%
|
Outcome Measures
| Title | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population |
|---|---|
| Description | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population. |
| Time Frame | date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Median (95% Confidence Interval) [months] |
14.95
|
14.49
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1166 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.89 | |
| Confidence Interval |
(2-Sided) 95% 0.73 to 1.08 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population |
|---|---|
| Description | PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population. |
| Time Frame | date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 56 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Median (95% Confidence Interval) [Months] |
20.27
|
13.08
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0049 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.66 | |
| Confidence Interval |
(2-Sided) 95% 0.48 to 0.91 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival (OS) - Full Population |
|---|---|
| Description | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population. |
| Time Frame | up to about 76 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. Due to the exploratory nature of the OS analysis, OS was not statistically tested |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Median (95% Confidence Interval) [Months] |
48.56
|
49.97
|
| Title | Overall Survival (OS) - HR-negative Population |
|---|---|
| Description | OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population. |
| Time Frame | up to about 76 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline. Due to the exploratory nature of the OS analysis, OS was not statistically tested. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Median (95% Confidence Interval) [Months] |
56.97
|
41.63
|
| Title | Overall Response Rate (ORR) - Full Population |
|---|---|
| Description | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Number (95% Confidence Interval) [Percentage of participants] |
67.1
14%
|
69.0
28.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7276 |
| Comments | ||
| Method | Exact Cochran-Mantel-Haenzel chi-square | |
| Comments | ||
| Title | Overall Response Rate (ORR) - HR-negative Population |
|---|---|
| Description | ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Number (95% Confidence Interval) [Percentage of participants] |
73.1
15.2%
|
70.9
29.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4085 |
| Comments | ||
| Method | Exact Cochran-Mantel-Haenzel chi-square | |
| Comments | ||
| Title | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population |
|---|---|
| Description | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Number (95% Confidence Interval) [Percentage of participants] |
75.8
15.8%
|
81.2
34%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.9573 |
| Comments | ||
| Method | Exact Cochran-Mantel-Haenzel chi-square | |
| Comments | ||
| Title | Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population |
|---|---|
| Description | CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Number (95% Confidence Interval) [Percentage of participants] |
78.8
16.4%
|
79.6
33.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Everolimus + Paclitaxel + Trastuzumab, Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6382 |
| Comments | ||
| Method | Exact Cochran-Mantel-Haenzel chi-square | |
| Comments | ||
| Title | Time to Overall Response Based on Investigator - Full Population |
|---|---|
| Description | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Median (95% Confidence Interval) [months] |
2.10
|
2.00
|
| Title | Time to Overall Response Based on Investigator - HR-negative Population |
|---|---|
| Description | Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Median (95% Confidence Interval) [months] |
1.94
|
1.97
|
| Title | Overall Response (OR) - Full Population |
|---|---|
| Description | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Complete Response (CR) |
5.6
1.2%
|
5.9
2.5%
|
| Partial Response (PR) |
61.5
12.8%
|
63.2
26.4%
|
| Title | Overall Response (OR) - HR-negative Population |
|---|---|
| Description | OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit. |
| Time Frame | up to about 23 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Complete Response (CR) |
7.7
1.6%
|
2.9
1.2%
|
| Partial Response (PR) |
65.4
13.6%
|
68.0
28.5%
|
| Title | Everolimus Blood Level Concentrations at Steady States for Everolimus |
|---|---|
| Description | Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days |
| Time Frame | predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set: consists of all patients who received at least 1 dose of study treatment & have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment. |
| Arm/Group Title | Everolimus 10 mg/Day | Everolimus 5 mg/Day |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily | Everolimus 5 mg daily |
| Measure Participants | 60 | 21 |
| Pre-dose (Cmin) @ C2D1 |
14.380
(10.0169)
|
7.959
(8.1546)
|
| 2 hrs post administration (C2h) @ C2D1 |
44.485
(22.1986)
|
23.449
(10.4112)
|
| Pre-dose (Cmin) @ C2D15 |
13.206
(9.9821)
|
5.473
(3.9690)
|
| 2 hrs post administration (C2h) @ C2D15 |
43.494
(21.5940)
|
20.329
(7.9518)
|
| Pre-dose (Cmin) @ C2D22 |
13.432
(13.2782)
|
7.494
(5.8503)
|
| 2 hrs post administration (C2h) @ C2D22 |
43.947
(28.0107)
|
22.192
(10.9277)
|
| Title | Paclitaxel Plasma Concentrations |
|---|---|
| Description | Blood levels at steady states for everolimus/placebo |
| Time Frame | Cycle 2/Day 15 (Pre-infusion and end of infusion) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set: consists of all patients who received at least 1 dose of study treatment & have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment. |
| Arm/Group Title | Everolimus | Everolimus Placebo |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg/day | Placebo of everolimus 10 mg daily |
| Measure Participants | 91 | 43 |
| Pre-infusion (Cmin) @ C2D15 |
1.424
(5.8645)
|
0
(0)
|
| End of infusion (Cmax) @ C2D15 |
5159.338
(15473.636)
|
4296.697
(7431.0799)
|
| Title | Trastuzumab Serum Concentrations |
|---|---|
| Description | Blood levels at steady states for everolimus/placebo |
| Time Frame | Cycle 4/Day 1 (Pre-infusion and end of infusion) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Set: consists of all patients who received at least 1 dose of study treatment & have at least 1 valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received. If patient took at least 1 dose of treatment to which he/she was randomized then the treatment actually received was the rand. treatment. |
| Arm/Group Title | Everolimus + Trastuzumab | Everolimus Placebo |
|---|---|---|
| Arm/Group Description | Everolimus plus trastuzumab | Placebo of everolimus 10 mg daily |
| Measure Participants | 98 | 54 |
| Pre-infusion (Cmin) @ C4D1 |
26.606
(9.6548)
|
29.180
(12.1252)
|
| End of infusion (Cmax) @ C4D1 |
64.296
(23.4635)
|
67.643
(20.8852)
|
| Title | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population |
|---|---|
| Description | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. |
| Time Frame | up to about 56 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Full Analysis Set (FAS) consists of all randomized patients. Following the intent-to-treat principle patients will be analyzed according to the treatment and stratum they were assigned to at randomization. |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 480 | 239 |
| Median (95% Confidence Interval) [months] |
39.20
|
NA
|
| Title | Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population |
|---|---|
| Description | Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. |
| Time Frame | up to about 56 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| HR-negative Full Analysis Set (HR-negative FAS) consists of subset of patients from the FAS population with HR-negative status at Baseline |
| Arm/Group Title | Everolimus + Paclitaxel + Trastuzumab | Placebo + Paclitaxel + Trastuzumab |
|---|---|---|
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 |
| Measure Participants | 208 | 103 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
Adverse Events
| Time Frame | Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until 30 days after Last Patient Last Visit. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Everolimus+ Paclitaxel+ Trastuzumab | Placebo+ Paclitaxel+ Trastuzumab | ||
| Arm/Group Description | Everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | Placebo of everolimus 10 mg daily in combination with paclitaxel 80mg/m2 weekly on days 1, 8, 15 and trastuzumab 2mg/kg weekly on days 1, 8, 15, 22 | ||
All Cause Mortality |
||||
| Everolimus+ Paclitaxel+ Trastuzumab | Placebo+ Paclitaxel+ Trastuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 23/472 (4.9%) | 2/238 (0.8%) | ||
Serious Adverse Events |
||||
| Everolimus+ Paclitaxel+ Trastuzumab | Placebo+ Paclitaxel+ Trastuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 173/472 (36.7%) | 40/238 (16.8%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 6/472 (1.3%) | 0/238 (0%) | ||
| Febrile neutropenia | 4/472 (0.8%) | 1/238 (0.4%) | ||
| Iron deficiency anaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Leukopenia | 2/472 (0.4%) | 0/238 (0%) | ||
| Neutropenia | 2/472 (0.4%) | 2/238 (0.8%) | ||
| Thrombocytopenia | 4/472 (0.8%) | 0/238 (0%) | ||
| Cardiac disorders | ||||
| Acute myocardial infarction | 1/472 (0.2%) | 0/238 (0%) | ||
| Aortic valve incompetence | 0/472 (0%) | 1/238 (0.4%) | ||
| Atrial fibrillation | 2/472 (0.4%) | 0/238 (0%) | ||
| Cardiac arrest | 1/472 (0.2%) | 0/238 (0%) | ||
| Cardiac failure | 1/472 (0.2%) | 0/238 (0%) | ||
| Cardiac failure congestive | 2/472 (0.4%) | 0/238 (0%) | ||
| Cardio-respiratory arrest | 1/472 (0.2%) | 0/238 (0%) | ||
| Cardiomyopathy | 1/472 (0.2%) | 0/238 (0%) | ||
| Left ventricular dysfunction | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Pericardial effusion | 1/472 (0.2%) | 0/238 (0%) | ||
| Sinus tachycardia | 1/472 (0.2%) | 0/238 (0%) | ||
| Supraventricular tachycardia | 1/472 (0.2%) | 0/238 (0%) | ||
| Tachycardia | 2/472 (0.4%) | 0/238 (0%) | ||
| Ventricular tachycardia | 1/472 (0.2%) | 0/238 (0%) | ||
| Ear and labyrinth disorders | ||||
| Vertigo | 2/472 (0.4%) | 0/238 (0%) | ||
| Eye disorders | ||||
| Cataract | 1/472 (0.2%) | 0/238 (0%) | ||
| Diplopia | 2/472 (0.4%) | 0/238 (0%) | ||
| Ocular surface disease | 1/472 (0.2%) | 0/238 (0%) | ||
| Strabismus | 1/472 (0.2%) | 0/238 (0%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 2/472 (0.4%) | 1/238 (0.4%) | ||
| Anal fissure | 1/472 (0.2%) | 0/238 (0%) | ||
| Ascites | 1/472 (0.2%) | 0/238 (0%) | ||
| Colitis | 1/472 (0.2%) | 0/238 (0%) | ||
| Diarrhoea | 5/472 (1.1%) | 1/238 (0.4%) | ||
| Dysphagia | 1/472 (0.2%) | 0/238 (0%) | ||
| Enteritis | 0/472 (0%) | 1/238 (0.4%) | ||
| Gastric haemorrhage | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Gastritis | 2/472 (0.4%) | 0/238 (0%) | ||
| Gastritis erosive | 1/472 (0.2%) | 0/238 (0%) | ||
| Gastrointestinal haemorrhage | 1/472 (0.2%) | 0/238 (0%) | ||
| Gastrointestinal toxicity | 1/472 (0.2%) | 0/238 (0%) | ||
| Haemorrhoids | 2/472 (0.4%) | 0/238 (0%) | ||
| Intestinal obstruction | 0/472 (0%) | 1/238 (0.4%) | ||
| Intussusception | 1/472 (0.2%) | 0/238 (0%) | ||
| Large intestine perforation | 1/472 (0.2%) | 0/238 (0%) | ||
| Melaena | 1/472 (0.2%) | 0/238 (0%) | ||
| Oesophageal perforation | 1/472 (0.2%) | 0/238 (0%) | ||
| Oesophageal stenosis | 1/472 (0.2%) | 0/238 (0%) | ||
| Peritoneal haemorrhage | 1/472 (0.2%) | 0/238 (0%) | ||
| Rectal haemorrhage | 2/472 (0.4%) | 0/238 (0%) | ||
| Stomatitis | 10/472 (2.1%) | 0/238 (0%) | ||
| Upper gastrointestinal haemorrhage | 1/472 (0.2%) | 0/238 (0%) | ||
| Vomiting | 2/472 (0.4%) | 1/238 (0.4%) | ||
| General disorders | ||||
| Asthenia | 1/472 (0.2%) | 0/238 (0%) | ||
| Calcinosis | 0/472 (0%) | 1/238 (0.4%) | ||
| Catheter site related reaction | 1/472 (0.2%) | 0/238 (0%) | ||
| Chest discomfort | 1/472 (0.2%) | 0/238 (0%) | ||
| Chills | 1/472 (0.2%) | 0/238 (0%) | ||
| Fatigue | 2/472 (0.4%) | 0/238 (0%) | ||
| General physical health deterioration | 1/472 (0.2%) | 0/238 (0%) | ||
| Generalised oedema | 1/472 (0.2%) | 0/238 (0%) | ||
| Incarcerated hernia | 0/472 (0%) | 1/238 (0.4%) | ||
| Influenza like illness | 1/472 (0.2%) | 0/238 (0%) | ||
| Multiple organ dysfunction syndrome | 1/472 (0.2%) | 0/238 (0%) | ||
| Oedema peripheral | 0/472 (0%) | 1/238 (0.4%) | ||
| Peripheral swelling | 1/472 (0.2%) | 0/238 (0%) | ||
| Pyrexia | 12/472 (2.5%) | 2/238 (0.8%) | ||
| Hepatobiliary disorders | ||||
| Cholecystitis | 0/472 (0%) | 1/238 (0.4%) | ||
| Cholecystitis acute | 1/472 (0.2%) | 0/238 (0%) | ||
| Drug-induced liver injury | 1/472 (0.2%) | 0/238 (0%) | ||
| Hepatic failure | 1/472 (0.2%) | 0/238 (0%) | ||
| Hepatic function abnormal | 3/472 (0.6%) | 0/238 (0%) | ||
| Hepatitis acute | 1/472 (0.2%) | 0/238 (0%) | ||
| Immune system disorders | ||||
| Anaphylactic shock | 1/472 (0.2%) | 0/238 (0%) | ||
| Drug hypersensitivity | 1/472 (0.2%) | 0/238 (0%) | ||
| Infections and infestations | ||||
| Acute sinusitis | 1/472 (0.2%) | 0/238 (0%) | ||
| Appendicitis | 1/472 (0.2%) | 0/238 (0%) | ||
| Breast abscess | 1/472 (0.2%) | 0/238 (0%) | ||
| Bronchitis | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Cellulitis | 5/472 (1.1%) | 4/238 (1.7%) | ||
| Clostridium colitis | 1/472 (0.2%) | 0/238 (0%) | ||
| Device related infection | 10/472 (2.1%) | 2/238 (0.8%) | ||
| Fungal infection | 1/472 (0.2%) | 0/238 (0%) | ||
| Furuncle | 1/472 (0.2%) | 0/238 (0%) | ||
| Gastroenteritis | 1/472 (0.2%) | 0/238 (0%) | ||
| Herpes zoster | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Klebsiella infection | 0/472 (0%) | 1/238 (0.4%) | ||
| Lower respiratory tract infection | 1/472 (0.2%) | 0/238 (0%) | ||
| Lower respiratory tract infection fungal | 1/472 (0.2%) | 0/238 (0%) | ||
| Lung infection pseudomonal | 1/472 (0.2%) | 0/238 (0%) | ||
| Lymphangitis | 2/472 (0.4%) | 0/238 (0%) | ||
| Mastitis | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Neutropenic sepsis | 1/472 (0.2%) | 0/238 (0%) | ||
| Peritonitis | 1/472 (0.2%) | 0/238 (0%) | ||
| Peritonitis bacterial | 1/472 (0.2%) | 0/238 (0%) | ||
| Pneumocystis jirovecii pneumonia | 3/472 (0.6%) | 0/238 (0%) | ||
| Pneumonia | 22/472 (4.7%) | 0/238 (0%) | ||
| Pneumonia klebsiella | 2/472 (0.4%) | 0/238 (0%) | ||
| Pneumonia pneumococcal | 1/472 (0.2%) | 0/238 (0%) | ||
| Pneumonia streptococcal | 1/472 (0.2%) | 0/238 (0%) | ||
| Post procedural infection | 0/472 (0%) | 1/238 (0.4%) | ||
| Pulmonary tuberculoma | 1/472 (0.2%) | 0/238 (0%) | ||
| Pyelonephritis | 1/472 (0.2%) | 0/238 (0%) | ||
| Rash pustular | 1/472 (0.2%) | 0/238 (0%) | ||
| Respiratory tract infection | 2/472 (0.4%) | 0/238 (0%) | ||
| Salmonellosis | 0/472 (0%) | 1/238 (0.4%) | ||
| Sepsis | 5/472 (1.1%) | 1/238 (0.4%) | ||
| Septic shock | 1/472 (0.2%) | 1/238 (0.4%) | ||
| Skin infection | 1/472 (0.2%) | 0/238 (0%) | ||
| Subdiaphragmatic abscess | 0/472 (0%) | 1/238 (0.4%) | ||
| Upper respiratory tract infection | 4/472 (0.8%) | 1/238 (0.4%) | ||
| Urinary tract infection | 7/472 (1.5%) | 0/238 (0%) | ||
| Urosepsis | 2/472 (0.4%) | 0/238 (0%) | ||
| Wound infection | 1/472 (0.2%) | 0/238 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Fall | 1/472 (0.2%) | 0/238 (0%) | ||
| Femur fracture | 2/472 (0.4%) | 0/238 (0%) | ||
| Foot fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Forearm fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Fractured ischium | 0/472 (0%) | 1/238 (0.4%) | ||
| Fractured sacrum | 1/472 (0.2%) | 0/238 (0%) | ||
| Hip fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Humerus fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Infusion related reaction | 1/472 (0.2%) | 3/238 (1.3%) | ||
| Injury | 1/472 (0.2%) | 0/238 (0%) | ||
| Muscle rupture | 1/472 (0.2%) | 0/238 (0%) | ||
| Post procedural haemorrhage | 1/472 (0.2%) | 0/238 (0%) | ||
| Spinal fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Subarachnoid haemorrhage | 1/472 (0.2%) | 0/238 (0%) | ||
| Thoracic vertebral fracture | 1/472 (0.2%) | 0/238 (0%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 3/472 (0.6%) | 0/238 (0%) | ||
| Aspartate aminotransferase increased | 3/472 (0.6%) | 0/238 (0%) | ||
| Blood potassium decreased | 1/472 (0.2%) | 0/238 (0%) | ||
| Haemoglobin decreased | 1/472 (0.2%) | 0/238 (0%) | ||
| Weight decreased | 2/472 (0.4%) | 0/238 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Appetite disorder | 1/472 (0.2%) | 0/238 (0%) | ||
| Decreased appetite | 3/472 (0.6%) | 0/238 (0%) | ||
| Dehydration | 7/472 (1.5%) | 0/238 (0%) | ||
| Diabetic ketoacidosis | 1/472 (0.2%) | 0/238 (0%) | ||
| Hyperglycaemia | 6/472 (1.3%) | 0/238 (0%) | ||
| Hyperkalaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypertriglyceridaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypoalbuminaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypocalcaemia | 3/472 (0.6%) | 0/238 (0%) | ||
| Hypokalaemia | 3/472 (0.6%) | 0/238 (0%) | ||
| Hypomagnesaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Hyponatraemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypophosphataemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 2/472 (0.4%) | 1/238 (0.4%) | ||
| Bone pain | 0/472 (0%) | 1/238 (0.4%) | ||
| Hypercreatinaemia | 1/472 (0.2%) | 0/238 (0%) | ||
| Musculoskeletal pain | 1/472 (0.2%) | 0/238 (0%) | ||
| Osteonecrosis of jaw | 0/472 (0%) | 3/238 (1.3%) | ||
| Nervous system disorders | ||||
| Ataxia | 0/472 (0%) | 1/238 (0.4%) | ||
| Cerebral artery embolism | 0/472 (0%) | 1/238 (0.4%) | ||
| Cerebral infarction | 1/472 (0.2%) | 0/238 (0%) | ||
| Cerebrovascular accident | 2/472 (0.4%) | 0/238 (0%) | ||
| Depressed level of consciousness | 1/472 (0.2%) | 0/238 (0%) | ||
| Disturbance in attention | 1/472 (0.2%) | 0/238 (0%) | ||
| Dizziness | 5/472 (1.1%) | 0/238 (0%) | ||
| Encephalopathy | 0/472 (0%) | 1/238 (0.4%) | ||
| Headache | 3/472 (0.6%) | 1/238 (0.4%) | ||
| Hemiparesis | 1/472 (0.2%) | 0/238 (0%) | ||
| Hepatic encephalopathy | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypersomnia | 0/472 (0%) | 1/238 (0.4%) | ||
| Lethargy | 1/472 (0.2%) | 0/238 (0%) | ||
| Loss of consciousness | 1/472 (0.2%) | 0/238 (0%) | ||
| Nervous system disorder | 0/472 (0%) | 1/238 (0.4%) | ||
| Neuralgia | 1/472 (0.2%) | 0/238 (0%) | ||
| Peripheral sensory neuropathy | 1/472 (0.2%) | 0/238 (0%) | ||
| Sciatica | 1/472 (0.2%) | 0/238 (0%) | ||
| Seizure | 2/472 (0.4%) | 2/238 (0.8%) | ||
| Spinal cord compression | 1/472 (0.2%) | 0/238 (0%) | ||
| Syncope | 1/472 (0.2%) | 0/238 (0%) | ||
| Transient ischaemic attack | 0/472 (0%) | 1/238 (0.4%) | ||
| Pregnancy, puerperium and perinatal conditions | ||||
| Abortion spontaneous | 1/472 (0.2%) | 0/238 (0%) | ||
| Product Issues | ||||
| Thrombosis in device | 1/472 (0.2%) | 0/238 (0%) | ||
| Psychiatric disorders | ||||
| Confusional state | 3/472 (0.6%) | 1/238 (0.4%) | ||
| Conversion disorder | 1/472 (0.2%) | 0/238 (0%) | ||
| Depression | 1/472 (0.2%) | 0/238 (0%) | ||
| Panic attack | 1/472 (0.2%) | 0/238 (0%) | ||
| Renal and urinary disorders | ||||
| Acute kidney injury | 4/472 (0.8%) | 1/238 (0.4%) | ||
| Cystitis haemorrhagic | 1/472 (0.2%) | 0/238 (0%) | ||
| Proteinuria | 1/472 (0.2%) | 0/238 (0%) | ||
| Renal impairment | 1/472 (0.2%) | 0/238 (0%) | ||
| Urinary retention | 1/472 (0.2%) | 0/238 (0%) | ||
| Reproductive system and breast disorders | ||||
| Breast pain | 0/472 (0%) | 1/238 (0.4%) | ||
| Breast ulceration | 0/472 (0%) | 1/238 (0.4%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory distress syndrome | 2/472 (0.4%) | 0/238 (0%) | ||
| Acute respiratory failure | 1/472 (0.2%) | 0/238 (0%) | ||
| Bronchiectasis | 1/472 (0.2%) | 0/238 (0%) | ||
| Cough | 0/472 (0%) | 1/238 (0.4%) | ||
| Dyspnoea | 12/472 (2.5%) | 1/238 (0.4%) | ||
| Epistaxis | 1/472 (0.2%) | 0/238 (0%) | ||
| Haemoptysis | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypoxia | 1/472 (0.2%) | 0/238 (0%) | ||
| Interstitial lung disease | 7/472 (1.5%) | 0/238 (0%) | ||
| Lung infiltration | 1/472 (0.2%) | 0/238 (0%) | ||
| Pharyngeal inflammation | 1/472 (0.2%) | 0/238 (0%) | ||
| Pleural effusion | 1/472 (0.2%) | 0/238 (0%) | ||
| Pleuritic pain | 1/472 (0.2%) | 0/238 (0%) | ||
| Pneumonitis | 21/472 (4.4%) | 0/238 (0%) | ||
| Pulmonary artery thrombosis | 0/472 (0%) | 1/238 (0.4%) | ||
| Pulmonary embolism | 2/472 (0.4%) | 0/238 (0%) | ||
| Pulmonary oedema | 3/472 (0.6%) | 0/238 (0%) | ||
| Respiratory arrest | 2/472 (0.4%) | 0/238 (0%) | ||
| Respiratory distress | 1/472 (0.2%) | 0/238 (0%) | ||
| Respiratory failure | 5/472 (1.1%) | 0/238 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Angioedema | 1/472 (0.2%) | 0/238 (0%) | ||
| Diabetic ulcer | 1/472 (0.2%) | 0/238 (0%) | ||
| Vascular disorders | ||||
| Aortic dissection | 0/472 (0%) | 1/238 (0.4%) | ||
| Deep vein thrombosis | 1/472 (0.2%) | 0/238 (0%) | ||
| Hypotension | 2/472 (0.4%) | 0/238 (0%) | ||
| Hypovolaemic shock | 1/472 (0.2%) | 0/238 (0%) | ||
| Jugular vein thrombosis | 1/472 (0.2%) | 0/238 (0%) | ||
| Lymphoedema | 1/472 (0.2%) | 0/238 (0%) | ||
| Shock | 1/472 (0.2%) | 0/238 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Everolimus+ Paclitaxel+ Trastuzumab | Placebo+ Paclitaxel+ Trastuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 466/472 (98.7%) | 236/238 (99.2%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 143/472 (30.3%) | 38/238 (16%) | ||
| Leukopenia | 71/472 (15%) | 24/238 (10.1%) | ||
| Neutropenia | 177/472 (37.5%) | 59/238 (24.8%) | ||
| Thrombocytopenia | 46/472 (9.7%) | 6/238 (2.5%) | ||
| Cardiac disorders | ||||
| Left ventricular dysfunction | 32/472 (6.8%) | 10/238 (4.2%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 71/472 (15%) | 29/238 (12.2%) | ||
| Abdominal pain upper | 55/472 (11.7%) | 26/238 (10.9%) | ||
| Aphthous ulcer | 25/472 (5.3%) | 4/238 (1.7%) | ||
| Constipation | 101/472 (21.4%) | 51/238 (21.4%) | ||
| Diarrhoea | 267/472 (56.6%) | 112/238 (47.1%) | ||
| Dyspepsia | 50/472 (10.6%) | 26/238 (10.9%) | ||
| Haemorrhoids | 32/472 (6.8%) | 7/238 (2.9%) | ||
| Mouth ulceration | 60/472 (12.7%) | 14/238 (5.9%) | ||
| Nausea | 154/472 (32.6%) | 83/238 (34.9%) | ||
| Stomatitis | 315/472 (66.7%) | 77/238 (32.4%) | ||
| Toothache | 35/472 (7.4%) | 21/238 (8.8%) | ||
| Vomiting | 122/472 (25.8%) | 55/238 (23.1%) | ||
| General disorders | ||||
| Asthenia | 94/472 (19.9%) | 41/238 (17.2%) | ||
| Chills | 29/472 (6.1%) | 6/238 (2.5%) | ||
| Fatigue | 168/472 (35.6%) | 87/238 (36.6%) | ||
| Oedema peripheral | 156/472 (33.1%) | 59/238 (24.8%) | ||
| Pain | 28/472 (5.9%) | 12/238 (5%) | ||
| Peripheral swelling | 30/472 (6.4%) | 10/238 (4.2%) | ||
| Pyrexia | 181/472 (38.3%) | 63/238 (26.5%) | ||
| Infections and infestations | ||||
| Cellulitis | 28/472 (5.9%) | 8/238 (3.4%) | ||
| Influenza | 36/472 (7.6%) | 24/238 (10.1%) | ||
| Nasopharyngitis | 90/472 (19.1%) | 47/238 (19.7%) | ||
| Paronychia | 26/472 (5.5%) | 8/238 (3.4%) | ||
| Pharyngitis | 25/472 (5.3%) | 5/238 (2.1%) | ||
| Pneumonia | 33/472 (7%) | 10/238 (4.2%) | ||
| Rhinitis | 30/472 (6.4%) | 14/238 (5.9%) | ||
| Upper respiratory tract infection | 67/472 (14.2%) | 34/238 (14.3%) | ||
| Urinary tract infection | 56/472 (11.9%) | 17/238 (7.1%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 95/472 (20.1%) | 45/238 (18.9%) | ||
| Aspartate aminotransferase increased | 72/472 (15.3%) | 29/238 (12.2%) | ||
| Ejection fraction decreased | 35/472 (7.4%) | 15/238 (6.3%) | ||
| Haemoglobin decreased | 41/472 (8.7%) | 8/238 (3.4%) | ||
| Neutrophil count decreased | 44/472 (9.3%) | 23/238 (9.7%) | ||
| Weight decreased | 99/472 (21%) | 13/238 (5.5%) | ||
| Weight increased | 19/472 (4%) | 26/238 (10.9%) | ||
| White blood cell count decreased | 34/472 (7.2%) | 14/238 (5.9%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 110/472 (23.3%) | 36/238 (15.1%) | ||
| Hypercholesterolaemia | 88/472 (18.6%) | 23/238 (9.7%) | ||
| Hyperglycaemia | 58/472 (12.3%) | 13/238 (5.5%) | ||
| Hypertriglyceridaemia | 68/472 (14.4%) | 17/238 (7.1%) | ||
| Hypocalcaemia | 24/472 (5.1%) | 4/238 (1.7%) | ||
| Hypokalaemia | 68/472 (14.4%) | 9/238 (3.8%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 80/472 (16.9%) | 41/238 (17.2%) | ||
| Back pain | 72/472 (15.3%) | 42/238 (17.6%) | ||
| Bone pain | 30/472 (6.4%) | 14/238 (5.9%) | ||
| Muscle spasms | 33/472 (7%) | 9/238 (3.8%) | ||
| Musculoskeletal pain | 37/472 (7.8%) | 17/238 (7.1%) | ||
| Myalgia | 78/472 (16.5%) | 45/238 (18.9%) | ||
| Pain in extremity | 86/472 (18.2%) | 39/238 (16.4%) | ||
| Nervous system disorders | ||||
| Dizziness | 74/472 (15.7%) | 37/238 (15.5%) | ||
| Dysgeusia | 59/472 (12.5%) | 24/238 (10.1%) | ||
| Headache | 130/472 (27.5%) | 70/238 (29.4%) | ||
| Hypoaesthesia | 61/472 (12.9%) | 36/238 (15.1%) | ||
| Neuropathy peripheral | 136/472 (28.8%) | 58/238 (24.4%) | ||
| Neurotoxicity | 40/472 (8.5%) | 24/238 (10.1%) | ||
| Paraesthesia | 35/472 (7.4%) | 25/238 (10.5%) | ||
| Peripheral sensory neuropathy | 61/472 (12.9%) | 37/238 (15.5%) | ||
| Psychiatric disorders | ||||
| Anxiety | 31/472 (6.6%) | 12/238 (5%) | ||
| Depression | 23/472 (4.9%) | 12/238 (5%) | ||
| Insomnia | 78/472 (16.5%) | 39/238 (16.4%) | ||
| Renal and urinary disorders | ||||
| Dysuria | 40/472 (8.5%) | 9/238 (3.8%) | ||
| Reproductive system and breast disorders | ||||
| Breast pain | 26/472 (5.5%) | 12/238 (5%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 191/472 (40.5%) | 80/238 (33.6%) | ||
| Dysphonia | 22/472 (4.7%) | 14/238 (5.9%) | ||
| Dyspnoea | 110/472 (23.3%) | 24/238 (10.1%) | ||
| Epistaxis | 156/472 (33.1%) | 43/238 (18.1%) | ||
| Oropharyngeal pain | 74/472 (15.7%) | 31/238 (13%) | ||
| Pneumonitis | 66/472 (14%) | 11/238 (4.6%) | ||
| Productive cough | 25/472 (5.3%) | 14/238 (5.9%) | ||
| Rhinorrhoea | 43/472 (9.1%) | 18/238 (7.6%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Acne | 29/472 (6.1%) | 4/238 (1.7%) | ||
| Alopecia | 221/472 (46.8%) | 125/238 (52.5%) | ||
| Dry skin | 37/472 (7.8%) | 20/238 (8.4%) | ||
| Erythema | 49/472 (10.4%) | 16/238 (6.7%) | ||
| Nail disorder | 68/472 (14.4%) | 27/238 (11.3%) | ||
| Pruritus | 64/472 (13.6%) | 24/238 (10.1%) | ||
| Rash | 191/472 (40.5%) | 49/238 (20.6%) | ||
| Vascular disorders | ||||
| Hot flush | 13/472 (2.8%) | 12/238 (5%) | ||
| Hypertension | 74/472 (15.7%) | 27/238 (11.3%) | ||
Limitations/Caveats
Of the 480 patients enrolled in the Everolimus arm, 8 were untreated and in the Placebo arm, of the 239 patients enrolled, 1 was untreated.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis Pharmaceuticals |
| Phone | 862-778-8300 |
| novartis.email@novartis.com |
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT00876395
Other Study ID Numbers:
- CRAD001J2301
- 2008-006556-21
First Posted:
Apr 6, 2009
Last Update Posted:
Dec 19, 2018
Last Verified:
Dec 1, 2018