A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer - Full Text View

Purpose

This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter international clinical trial. Participants who have HER2-positive metastatic breast cancer (MBC) and have not received chemotherapy or biological therapy (including approved or investigational tyrosine kinase/HER inhibitors or vaccines) for their metastatic disease are eligible for study. Participants could have received one prior hormonal treatment for MBC. Participants may have received systemic breast cancer treatment in the neo-adjuvant or adjuvant setting, provided that the participant has experienced a disease-free interval (DFI) of greater than or equal to (>/=) 12 months from completion of adjuvant systemic treatment (excluding hormonal therapy) to metastatic diagnosis. Participants may have received trastuzumab and/or a taxane during the neo-adjuvant or adjuvant treatment.

Condition	Intervention	Phase
Metastatic Breast Cancer	Drug: Pertuzumab Drug: Placebo Drug: Trastuzumab Drug: Docetaxel	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Triple (Participant, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Phase III, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer

Drug Information available for: Docetaxel Trastuzumab Pertuzumab

U.S. FDA Resources

Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:

Progression-free Survival (PFS) Determined by an Independent Review Facility [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]
PFS was defined as the time from randomization to first documented disease progression (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as target lesions.

Secondary Outcome Measures:

Overall Survival [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]
Overall survival was defined as the time from randomization to death from any cause. The median and 95 percent (%) confidence interval (CI) for time to event were estimated using Kaplan-Meier methodology.
Progression-free Survival (PFS) Determined by the Investigator [ Time Frame: Baseline to the third data cut-off (11 February 2014) at 389 deaths (approximately 43 months after enrollment of the last patient, up to 6 years overall) ]
PFS was defined as the time from randomization to first documented disease progression (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as target lesions.
Objective Response Determined by an Independent Review Facility [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]
A patient had an objective response if they had a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
Duration of Objective Response Determined by an Independent Review Facility [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]
Duration of objective response was defined as the time from the initial response to documented disease progression or death from any cause, whichever occurred first.
Time to Symptom Progression [ Time Frame: Baseline to primary data cut-off on 13 May 2011 (up to 3 years, 3 months) ]
Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.


Enrollment:	808
Actual Study Start Date:	February 12, 2008
Estimated Study Completion Date:	March 12, 2022
Primary Completion Date:	May 13, 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pertuzumab, trastuzumab, docetaxel Participants will receive pertuzumab on Day 1 of Cycle 1 followed by trastuzumab and then docetaxel on Day 2 of Cycle 1 (1 Cycle length = 21 days). Participants will continue to receive pertuzumab followed by trastuzumab and then docetaxel every 3 weeks (Q3W) for subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.	Drug: Pertuzumab Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) Q3W on Day 1 of Cycle 1 (1 Cycle length = 21 days), and 420 mg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Other Name: Perjeta; RO4368451 Drug: Trastuzumab Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Other Name: Herceptin Drug: Docetaxel Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Other Name: Taxotere
Placebo Comparator: Placebo, trastuzumab, docetaxel Participants will receive pertuzumab matching placebo on Day 1 of Cycle 1 followed by trastuzumab and then docetaxel on Day 2 of Cycle 1 (1 Cycle length = 21 days). Participants will continue to receive pertuzumab followed by trastuzumab and then docetaxel Q3W for subsequent cycles until nvestigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.	Drug: Placebo Pertuzumab matching placebo will be administered intravenously. Drug: Trastuzumab Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Other Name: Herceptin Drug: Docetaxel Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity. Other Name: Taxotere

Arms

Assigned Interventions

Experimental: Pertuzumab, trastuzumab, docetaxel

Participants will receive pertuzumab on Day 1 of Cycle 1 followed by trastuzumab and then docetaxel on Day 2 of Cycle 1 (1 Cycle length = 21 days). Participants will continue to receive pertuzumab followed by trastuzumab and then docetaxel every 3 weeks (Q3W) for subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Drug: Pertuzumab

Pertuzumab will be administered as an IV loading dose of 840 milligrams (mg) Q3W on Day 1 of Cycle 1 (1 Cycle length = 21 days), and 420 mg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Other Name: Perjeta; RO4368451

Drug: Trastuzumab

Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Other Name: Herceptin

Drug: Docetaxel

Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Other Name: Taxotere

Placebo Comparator: Placebo, trastuzumab, docetaxel

Participants will receive pertuzumab matching placebo on Day 1 of Cycle 1 followed by trastuzumab and then docetaxel on Day 2 of Cycle 1 (1 Cycle length = 21 days). Participants will continue to receive pertuzumab followed by trastuzumab and then docetaxel Q3W for subsequent cycles until nvestigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Drug: Placebo

Pertuzumab matching placebo will be administered intravenously.

Drug: Trastuzumab

Trastuzumab will be administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Other Name: Herceptin

Drug: Docetaxel

Docetaxel will be administered as an IV dose of 75 milligrams per square meter (mg/m^2) Q3W on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) Q3W on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, or unmanageable toxicity.

Other Name: Taxotere

Detailed Description:

Participants will be randomized in 1:1 ratio to receive pertuzumab or placebo along with trastuzumab and docetaxel every 3 weeks (Q3W) in the treatment phase of the study until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. Participants who were on placebo arm will be offered to receive after completion of treatment phase but participants who discontinue from the study, will not receive pertuzumab during open-label phase.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Participants with measurable and non-measurable disease are eligible (locally recurrent disease must not be amenable to resection with curative intent; participants with de novo Stage IV disease are eligible)
HER2-positive MBC
Left ventricular ejection fraction (LVEF) >/=50 percent (%) at baseline (within 42 days of randomization)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
For women of childbearing potential, agreement to use an effective form of contraception and to continue its use for the duration of study treatment and for 6 months after the last dose of study treatment

Exclusion Criteria:

History of anti-cancer therapy for MBC (with the exception of one prior hormonal regimen for MBC)
History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting
History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of less than (<) 12 months
History of persistent Grade >/=2 hematologic toxicity resulting from previous adjuvant therapy
Current peripheral neuropathy of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0, Grade >/=3 at randomization
History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma
Current clinical or radiographic evidence of central nervous system (CNS) metastases
Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is mandatory in cases of clinical suspicion of brain metastases
History of exposure to cumulative doses of anthracyclines
Current uncontrolled hypertension or unstable angina
History of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment
History of myocardial infarction within 6 months of randomization
History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy
Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
Inadequate organ function within 28 days prior to randomization
Current severe, uncontrolled systemic disease
Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
Pregnant or lactating women
History of receiving any investigational treatment within 28 days of randomization
Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
Receipt of IV antibiotics for infection within 14 days of randomization
Current chronic daily treatment with corticosteroids (excluding inhaled steroids)
Known hypersensitivity to any of the study drugs
Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00567190

Show 463 Study Locations

Sponsors and Collaborators

Genentech, Inc.

Hoffmann-La Roche

Investigators


Study Director:	Ru Walker, M.D.	Genentech, Inc.

More Information

Publications:

Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. doi: 10.1056/NEJMoa1113216. Epub 2011 Dec 7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, Kiermaier A, Swain SM, Baselga J, Michiels S, Loi S. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol. 2017 Jan;18(1):52-62. doi: 10.1016/S1470-2045(16)30631-3. Epub 2016 Dec 7.

Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513.

Baselga J, Cortés J, Im SA, Clark E, Ross G, Kiermaier A, Swain SM. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014 Nov 20;32(33):3753-61. doi: 10.1200/JCO.2013.54.5384. Epub 2014 Oct 20.

Swain SM, Baselga J, Miles D, Im YH, Quah C, Lee LF, Cortés J. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol. 2014 Jun;25(6):1116-21. doi: 10.1093/annonc/mdu133. Epub 2014 Mar 31.

Miles D, Baselga J, Amadori D, Sunpaweravong P, Semiglazov V, Knott A, Clark E, Ross G, Swain SM. Treatment of older patients with HER2-positive metastatic breast cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from a randomized, double-blind, placebo-controlled phase III trial (CLEOPATRA). Breast Cancer Res Treat. 2013 Nov;142(1):89-99. doi: 10.1007/s10549-013-2710-z. Epub 2013 Oct 16.

Cortés J, Baselga J, Im YH, Im SA, Pivot X, Ross G, Clark E, Knott A, Swain SM. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013 Oct;24(10):2630-5. doi: 10.1093/annonc/mdt274. Epub 2013 Jul 17.

Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18.

Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer. 2010 Dec 1;10(6):489-91. doi: 10.3816/CBC.2010.n.065.


Responsible Party:	Genentech, Inc.
ClinicalTrials.gov Identifier:	NCT00567190 History of Changes
Other Study ID Numbers:	TOC4129g WO20698 ( Other Identifier: Hoffmann-La Roche ) 2007-002997-72 ( EudraCT Number )
Study First Received:	December 3, 2007
Results First Received:	August 14, 2012
Last Updated:	June 19, 2017


Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Genentech, Inc.:


Herceptin Breast cancer MBC Taxotere HER2	HER2 positive breast cancer HER2 + breast cancer HER2-positive HER2-positive metastatic breast cancer

Additional relevant MeSH terms:


Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Docetaxel Pertuzumab	Trastuzumab Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 18, 2017

A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer (CLEOPATRA)