Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer

NCT00876395 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: CRAD001J23012008-006556-21
• Study Type: interventional
• Target: 719
• Locations: 28 countries
• Sites: 140

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.

Conditions

Breast Cancer

Keywords

Breast Cancer; HER2+; mTOR; everolimus; RAD001; first line; metastatic; locally advanced; Trastuzumab; Paclitaxel; First Line Therapy; HER2 Positive; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population

  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.

  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

• Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population

  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.

  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

Secondary Outcomes (15)

• Overall Survival (OS) - Full Population

  up to about 76 months

• Overall Survival (OS) - HR-negative Population

  up to about 76 months

• Overall Response Rate (ORR) - Full Population

  up to about 23 months

• Overall Response Rate (ORR) - HR-negative Population

  up to about 23 months

• Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population

  up to about 23 months

Study Arms (2)

Everolimus + Paclitaxel + Trastuzumab

EXPERIMENTAL

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; Drug: Trastuzumab; Drug: Paclitaxel

Placebo + Paclitaxel + Trastuzumab

PLACEBO COMPARATOR

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; Drug: Trastuzumab; Drug: Paclitaxel

Interventions

Everolimus DRUG

Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).

Also known as: RAD001

Everolimus + Paclitaxel + Trastuzumab

Placebo DRUG

Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).

Placebo + Paclitaxel + Trastuzumab

Trastuzumab DRUG

Trastuzumab, 2 mg/kg weekly was used intravenously.

Everolimus + Paclitaxel + Trastuzumab; Placebo + Paclitaxel + Trastuzumab

Paclitaxel DRUG

Paclitaxel, 80 mg/m2 weekly was used intravenously.

Everolimus + Paclitaxel + Trastuzumab; Placebo + Paclitaxel + Trastuzumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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,

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (140)

University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.

Mobile, Alabama, 36688, United States

Location

Ironwood Cancer and Research Centers

Chandler, Arizona, 85224, United States

Location

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

Comprehensive Blood and Cancer Center Dept. of CBCC (2)

Bakersfield, California, 93309, United States

Location

St. Jude Heritage Medical Group Virginia Crosson Cancer Center

Fullerton, California, 92835, United States

Location

University of California at Los Angeles Dept. of UCLA

Los Angeles, California, 90095, United States

Location

Ventura County Hematology and Oncology

Oxnard, California, 93030, United States

Location

Cancer Care Associates Medical Group Dept. of CCA

Redondo Beach, California, 90277, United States

Location

Santa Barbara Hematolgy Oncology Medical Group Dept.ofSantaBarbaraHem/Onc

Santa Barbara, California, 93105, United States

Location

Central Coast Medical Oncology Corporation Onc Dept

Santa Maria, California, 93454, United States

Location

Rocky Mountain Cancer Centers RMCC - Denver-Midtown (3)

Greenwood Village, Colorado, United States

Location

Florida Cancer Specialists Dept.of FloridaCancerSpec. (2)

Fort Myers, Florida, 33901, United States

Location

Florida Cancer Specialists

West Palm Beach, Florida, 33401, United States

Location

Central Indiana Cancer Centers CICC - East (3)

Indianapolis, Indiana, 46227, United States

Location

Kansas City Cancer Center Dept. of KCCC

Overland Park, Kansas, 66210, United States

Location

University of Nebraska Medical Center Unv Nebraska Med Ctr (2)

Omaha, Nebraska, 68198, United States

Location

New York Oncology Hematology NYOH Amsterdam

Albany, New York, 12208, United States

Location

Beth Israel Medical Center Dept.ofBeth Israel Med. Ctr(2)

New York, New York, 10003, United States

Location

Northwest Cancer Specialists Vancouver Cancer Center (3)

Portland, Oregon, 97210, United States

Location

Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(5)

Nashville, Tennessee, 37203, United States

Location

Texas Oncology Charles A. Sammons Cancer Ctr

Dallas, Texas, 75246, United States

Location

Texas Oncology P A SC-Austin

Dallas, Texas, 75251, United States

Location

Tyler Cancer Center Dept.ofTylerCancerCtr. (2)

Tyler, Texas, 75702, United States

Location

Virginia Oncology Associates SC

Norfolk, Virginia, 23502, United States

Location

Virginia Cancer Institute VCI (3)

Richmond, Virginia, 23230, United States

Location

Novartis Investigative Site

CABA, Buenos Aires, C1050AAK, Argentina

Location

Novartis Investigative Site

Mar del Plata, Buenos Aires, B7600CTO, Argentina

Location

Novartis Investigative Site

Posadas, Misiones Province, Argentina

Location

Novartis Investigative Site

Rosario, Sante Fe, S200KZE, Argentina

Location

Novartis Investigative Site

Rio Negro, Viedma, 8500, Argentina

Location

Novartis Investigative Site

Capital Federal, 1417, Argentina

Location

Novartis Investigative Site

Córdoba, X5004BAL, Argentina

Location

Novartis Investigative Site

Southport, Queensland, 4215, Australia

Location

Novartis Investigative Site

East Bentleigh, Victoria, 3165, Australia

Location

Novartis Investigative Site

Charleroi, 6000, Belgium

Location

Novartis Investigative Site

Hasselt, 3500, Belgium

Location

Novartis Investigative Site

Verviers, 4800, Belgium

Location

Novartis Investigative Site

Wilrijk, 2610, Belgium

Location

Novartis Investigative Site

Yvoir, 5530, Belgium

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30130-100, Brazil

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30380-490, Brazil

Location

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 20230-130, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01246 000, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 04038-001, Brazil

Location

Novartis Investigative Site

Montreal, Quebec, H2W 1S6, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H4J 1C5, Canada

Location

Novartis Investigative Site

Saint-Jérôme, Quebec, J7Z 5T3, Canada

Location

Novartis Investigative Site

Guangzhou, Guangdong, 51000, China

Location

Novartis Investigative Site

Harbin, Heilongjiang, 150081, China

Location

Novartis Investigative Site

Nanjing, Jiangsu, 210002, China

Location

Novartis Investigative Site

Nanjing, Jiangsu, 210009, China

Location

Novartis Investigative Site

Shanghai, Shanghai Municipality, 200032, China

Location

Novartis Investigative Site

Hangzhou, Zhejiang, 310022, China

Location

Novartis Investigative Site

Beijing, 100021, China

Location

Novartis Investigative Site

Beijing, 100039, China

Location

Novartis Investigative Site

Guangzhou, 510060, China

Location

Novartis Investigative Site

Shanghai, 200025, China

Location

Novartis Investigative Site

Bogota, Cundinamarca, 0000, Colombia

Location

Novartis Investigative Site

Bogotá, Colombia

Location

Novartis Investigative Site

Florida Blanca, Colombia

Location

Novartis Investigative Site

Montería, Colombia

Location

Novartis Investigative Site

Alexandria, Egypt

Location

Novartis Investigative Site

Cairo, Egypt

Location

Novartis Investigative Site

Limoges, 87000, France

Location

Novartis Investigative Site

Rouen, 76000, France

Location

Novartis Investigative Site

Saint-Herblain Cédex, 44805, France

Location

Novartis Investigative Site

Strasbourg, F 67098, France

Location

Novartis Investigative Site

Thonon-les-Bains, 74203, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Berlin, 10098, Germany

Location

Novartis Investigative Site

Chemnitz, 09113, Germany

Location

Novartis Investigative Site

Esslingen am Neckar, 73730, Germany

Location

Novartis Investigative Site

Kiel, 24105, Germany

Location

Novartis Investigative Site

Münster, 48149, Germany

Location

Novartis Investigative Site

Heraklion Crete, Greece, 711 10, Greece

Location

Novartis Investigative Site

Athens, GR, 151 23, Greece

Location

Novartis Investigative Site

Thessaloniki, GR, 564 03, Greece

Location

Novartis Investigative Site

Athens, 115 28, Greece

Location

Novartis Investigative Site

Athens, 18547, Greece

Location

Novartis Investigative Site

Shatin, New Territories, Hong Kong, Hong Kong

Location

Novartis Investigative Site

Hong Kong SAR, Hong Kong

Location

Novartis Investigative Site

Tuenmen, Hong Kong

Location

Novartis Investigative Site

Wilton, Cork, Ireland

Location

Novartis Investigative Site

Dublin, Ireland

Location

Novartis Investigative Site

Monza, MB, 20900, Italy

Location

Novartis Investigative Site

Modena, MO, 41124, Italy

Location

Novartis Investigative Site

Camposampiero, PD, 35012, Italy

Location

Novartis Investigative Site

Roma, RM, 00128, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Nagoya, Aichi-ken, 464-8681, Japan

Location

Novartis Investigative Site

Kashiwa, Chiba, 277-8577, Japan

Location

Novartis Investigative Site

Fukuoka, Fukuoka, 811-1395, Japan

Location

Novartis Investigative Site

Kitakyushu, Fukuoka, 802-0077, Japan

Location

Novartis Investigative Site

Maebashi, Gunma, 371 8511, Japan

Location

Novartis Investigative Site

Sapporo, Hokkaido, 060 8648, Japan

Location

Novartis Investigative Site

Isehara, Kanagawa, 259-1193, Japan

Location

Novartis Investigative Site

Kumamoto, Kumamoto, 860-8556, Japan

Location

Novartis Investigative Site

Sakyo-ku, Kyoto, 606 8507, Japan

Location

Novartis Investigative Site

Osaka, Osaka, 540-0006, Japan

Location

Novartis Investigative Site

Suita, Osaka, 565 0871, Japan

Location

Novartis Investigative Site

Kitaadachi-gun, Saitama, 362-0806, Japan

Location

Novartis Investigative Site

Bunkyo-ku, Tokyo, 113-8677, Japan

Location

Novartis Investigative Site

Chuo-ku, Tokyo, 104-8560, Japan

Location

Novartis Investigative Site

Osaka, 537-8511, Japan

Location

Novartis Investigative Site

Beirut, 1107 2020, Lebanon

Location

Novartis Investigative Site

El Achrafiyé, 166830, Lebanon

Location

Novartis Investigative Site

Mexico City, Mexico City, 04980, Mexico

Location

Novartis Investigative Site

Zaragoza, Veracruz, 91910, Mexico

Location

Novartis Investigative Site

San Borja, Lima region, 41, Peru

Location

Novartis Investigative Site

Surquillo, Lima region, 34, Peru

Location

San Juan VA Hospital San Juan Hospital

San Juan, 00921, Puerto Rico

Location

Novartis Investigative Site

Kazan', Tatarstan Republic, 420029, Russia

Location

Novartis Investigative Site

Moscow, 115478, Russia

Location

Novartis Investigative Site

Moscow, 129128, Russia

Location

Novartis Investigative Site

Moscow, 143423, Russia

Location

Novartis Investigative Site

Saint Petersburg, 197758, Russia

Location

Novartis Investigative Site

Saint Petersburg, 198255, Russia

Location

Novartis Investigative Site

Bloemfontein, 9301, South Africa

Location

Novartis Investigative Site

Durban, 4091, South Africa

Location

Novartis Investigative Site

Pretoria, 0002, South Africa

Location

Novartis Investigative Site

Gyeonggi-do, Korea, 10408, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 06351, South Korea

Location

Novartis Investigative Site

Seoul, 02841, South Korea

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Geneva, 1211, Switzerland

Location

Novartis Investigative Site

Zurich, 8038, Switzerland

Location

Novartis Investigative Site

Taipei, Taiwan, ROC, 11217, Taiwan

Location

Novartis Investigative Site

Kaohsiung City, 80756, Taiwan

Location

Novartis Investigative Site

Taichung, 40447, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Taoyuan District, 33305, Taiwan

Location

Novartis Investigative Site

Altunizade, 34662, Turkey (Türkiye)

Location

Novartis Investigative Site

Ankara, 06100, Turkey (Türkiye)

Location

Novartis Investigative Site

Izmir, 35040, Turkey (Türkiye)

Location

Novartis Investigative Site

Izmir, 35340, Turkey (Türkiye)

Location

Novartis Investigative Site

Truro, Cornwall, TR1 3LJ, United Kingdom

Location

Novartis Investigative Site

London, SW3 6JJ, United Kingdom

Location

Novartis Investigative Site

Sutton, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

Valencia, Carabobo, 2001, Venezuela

Location

Related Publications (3)

• Toi M, Shao Z, Hurvitz S, Tseng LM, Zhang Q, Shen K, Liu D, Feng J, Xu B, Wang X, Lee KS, Ng TY, Ridolfi A, Noel-Baron F, Ringeisen F, Jiang Z. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1. Breast Cancer Res. 2017 Apr 11;19(1):47. doi: 10.1186/s13058-017-0839-0.

  PMID: 28399902 DERIVED

• Buyse M, Hurvitz SA, Andre F, Jiang Z, Burris HA, Toi M, Eiermann W, Lindsay MA, Slamon D. Statistical controversies in clinical research: statistical significance-too much of a good thing .... Ann Oncol. 2016 May;27(5):760-2. doi: 10.1093/annonc/mdw047. Epub 2016 Feb 9.

  PMID: 26861602 DERIVED

• Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. doi: 10.1016/S1470-2045(15)00051-0. Epub 2015 Jun 16.

  PMID: 26092818 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

Everolimus; Trastuzumab; Paclitaxel

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Limitations and 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.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2009
• First Posted: April 6, 2009
• Study Start: September 10, 2009
• Primary Completion: May 30, 2014
• Study Completion: October 23, 2017
• Last Updated: December 19, 2018
• Results First Posted: December 19, 2018

Record last verified: 2018-12

Locations

PE (2); BE (5); CH (2); BR (5); ME (2); HK (3); TU (4); AR (7); DE (5); EG (2); CA (3); RU (6); KR (4); VE (1); AU (2); CO (4); GR (5); JP (15); IT (5); ZA (3); PR (1); TW (5); FR (7); IE (2); CN (10); LE (2); GB (3); US (25)