A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With Human Epidermal Growth Factor-2 (HER2) Positive Locally Advanced or Metastatic Breast Cancer (BC) Who Received Prior Trastuzumab and Taxane Based Therapy
- Conditions
- Metastatic Breast Cancer
- Interventions
- Registration Number
- NCT02924883
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This Phase II, double-blind, randomized, placebo-controlled multicenter study will investigate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with HER2-positive locally advanced or metastatic BC who have received prior trastuzumab and taxane based therapy, either alone or in combination, and/or who have progressed within 6 months after completing adjuvant therapy.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 202
- Archival tumor samples must be obtained from primary and/or metastatic sites
- Able to submit tumor tissue that is evaluable for programmed death- ligand 1 (PD-L1) expression
- HER-2 positive BC as defined by an immunohistochemistry score of 3 or gene amplified by in-situ hybridization as defined by a ratio of greater than or equal to (>=) 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies
- Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic BC
- Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic settings; which must include both, a taxane and trastuzumab (alone or in combination with another agent)
- Progression must have occurred during or after most recent treatment for locally advanced/metastatic BC or within 6 months after completing adjuvant therapy
- Participants must have measurable disease that is evaluable as per RECIST v1.1
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and for women less than 12 months after the onset of menopause
- Use of highly effective method of contraception as defined by the protocol
- Prior treatment with trastuzumab emtansine, cluster of differentiation 137 agonists, anti-programmed death-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
- Receipt of any anti-cancer drug/biologic or investigational treatment within 21 days prior to Cycle 1 Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1 Day 1; recovery of treatment related toxicity consistent with other eligibility criteria
- Radiation therapy within 2 weeks prior to Cycle 1, Day 1
- History of exposure to the cumulative doses of anthracyclines
- History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or participants who have undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to be at low risk for recurrence
- Cardiopulmonary dysfunction, symptomatic pleural effusion, pericardial effusion, or ascites
- Participants with severe infection within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Current severe, uncontrolled systemic disease
- Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
- Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus
- Need for current chronic corticosteroid therapy (>=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids)
- Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for greater than (>) 2 weeks prior to randomization
- Participants with known central nervous system disease
- Leptomeningeal disease
- History of autoimmune disease
- Prior allogeneic stem cell or solid organ transplantation
- Active tuberculosis
- Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
- Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
- Participants who are breastfeeding, or intending to become pregnant during the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Trastuzumab Emtansine + Atezolizumab Placebo Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 29 months) Trastuzumab Emtansine + Placebo Placebo Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 29 months) Trastuzumab Emtansine + Atezolizumab Atezolizumab Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 29 months) Trastuzumab Emtansine + Atezolizumab Trastuzumab emtansine Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 29 months) Trastuzumab Emtansine + Placebo Trastuzumab emtansine Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 29 months)
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Baseline up to approximately 15 months PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.
Percentage of Participants With Adverse Events Baseline up to study completion, approximately 40 months An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Baseline up to study completion or death, whichever occurs first, approximately 40 months OS was defined as the time from randomization to death from any cause.
Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1 Baseline up to approximately 15 months Duration of OR was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.
Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine Pre-infusion (0 hour [h]), 30 minutes (min) after end of infusion (EOI) (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days); at any time during study treatment/early discontinuation visit (approx. 40 months) Average post infusion Trastuzumab Emtansine concentration
Cmax of Total Trastuzumab Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days) Percentage of Participants With Anti-therapeutic Antibodies (ATAs) to Atezolizumab Pre-infusion (0 h) on Day 1 Cycles 1, 2, 3, 4, 8, and every 8 cycles thereafter (each cycle = 21 days) up to 120 days after treatment completion or early discontinuation (approximately 40 months) ATAs are antibodies that inactivate the therapeutic effects of Atezolizumab. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).
Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1 Baseline up to approximately 15 months An OR was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be \< 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.
Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1) Pre-infusion (0 h) on Day 1 Cycle 1 and 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4 (each cycle = 21 days) Average post infusion Deacetyl Mercapto 1-Oxopropyl Maytansine concentration of trastuzumab emtansine infusion
Cmax of Atezolizumab Pre-infusion (0 h), 30 min after EOI (over 60 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycles 2, 3, 8, and every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion/early discontinuation (approx. 40 months) Average post infusion atezolizumab concentration
Percentage of Participants With ATAs to Trastuzumab Emtansine Pre-infusion (0 h) on Day 1 Cycles 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (approximately 40 months) ATAs are antibodies that inactivate the therapeutic effects of Trastuzumab Emtansine. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).
Trial Locations
- Locations (68)
Northside Hospital
🇺🇸Atlanta, Georgia, United States
Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg
🇩🇪Heidelberg, Germany
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
🇨🇳Taipei City, Taiwan
Johns Hopkins Univ Med Center
🇺🇸Baltimore, Maryland, United States
SCRI Tennessee Oncology Chattanooga
🇺🇸Chattanooga, Tennessee, United States
Magee Womens Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Cancer Care Associates of York
🇺🇸York, Pennsylvania, United States
Tennessee Oncology; Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
University of Washington
🇺🇸Seattle, Washington, United States
Lakeridge Health Oshawa; Oncology
🇨🇦Oshawa, Ontario, Canada
Sunnybrook Odette Cancer Centre
🇨🇦Toronto, Ontario, Canada
Hospital Univ Vall d'Hebron; Servicio de Oncologia
🇪🇸Barcelona, Spain
Hospital Universitario Reina Sofia; Servicio de Oncologia
🇪🇸Córdoba, Cordoba, Spain
Studienzentrum Berlin City
🇩🇪Berlin, Germany
Institut für Versorgungsforschung in der Onkologie GbR Koblenz
🇩🇪Koblenz, Germany
University of Colorado
🇺🇸Aurora, Colorado, United States
MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)
🇺🇸Washington, District of Columbia, United States
Breastlink Med Group Inc
🇺🇸Orange, California, United States
SCRI Florida Cancer Specialists South
🇺🇸Fort Myers, Florida, United States
Florida Cancer Specialists; Saint Petersburg
🇺🇸Saint Petersburg, Florida, United States
Ohio State Uni Medical Center
🇺🇸Columbus, Ohio, United States
Laura and ISAAC Perlmutter Cancer Center at NYU Langone.
🇺🇸New York, New York, United States
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Peter MacCallum Cancer Center
🇦🇺East Melbourne, Victoria, Australia
St George Hospital; Cancer Care Centre
🇦🇺Kogarah, New South Wales, Australia
Princess Alexandra Hospital Woolloongabba; Clinical Hematology and Medical Oncology
🇦🇺Woolloongabba, Queensland, Australia
St John of God Hospital; Bendat Cancer Centre
🇦🇺Subiaco, Western Australia, Australia
Sunshine Hospital
🇦🇺St Albans, Victoria, Australia
Peninsula and South Eastern Haematology and Oncology Group
🇦🇺Frankston, Victoria, Australia
McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
🇨🇦Montreal, Quebec, Canada
McGill University; Glen Site; Oncology
🇨🇦Montreal, Quebec, Canada
Hopital du Saint Sacrement
🇨🇦Quebec City, Quebec, Canada
HELIOS Klinikum Berlin-Buch; Klinik für Gynäkologie und Geburtshilfe
🇩🇪Berlin, Germany
IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A
🇮🇹Napoli, Campania, Italy
Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
🇩🇪Essen, Germany
A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
🇮🇹Bologna, Emilia-Romagna, Italy
Praxis für Interdisziplinäre Onkologie und Hämatologie GbR
🇩🇪Freiburg, Germany
Ospedale Regionale Di Parma; Divisione Di Oncologia Medica
🇮🇹Parma, Emilia-Romagna, Italy
Centro Catanese Di Oncologia; Oncologia Medica
🇮🇹Catania, Sicilia, Italy
Centro Di Riferimento Oncologico; SOC Oncologia Medica C
🇮🇹Aviano, Friuli-Venezia Giulia, Italy
Ospedale Santo Stefano, Azienda USL Centro Prato
🇮🇹Prato, Toscana, Italy
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
National Cancer Center
🇰🇷Goyang-si, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología
🇪🇸La Coruña, Spain
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
🇪🇸Valencia, Spain
Hospital Ramon y Cajal; Servicio de Oncologia
🇪🇸Madrid, Spain
China Medical University Hospital; Surgery
🇨🇳Taichung, Taiwan
Hospital Arnau de Vilanova (Valencia) Servicio de Oncologia
🇪🇸Valencia, Spain
Chi-Mei Medical Center
🇨🇳Tainan, Taiwan
Royal United Hospital; Oncology Department
🇬🇧Bath, United Kingdom
Changhua Christian Hospital; Dept of Surgery
🇨🇳Changhua, Taiwan
Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery
🇨🇳Kaohsiung, Taiwan
Chang Gung Memorial Hospital - Linkou
🇨🇳Taoyuan, Taiwan
VETERANS GENERAL HOSPITAL; Department of General Surgery
🇨🇳Taipei, Taiwan
National Taiwan Uni Hospital; General Surgery
🇨🇳Taipei, Taiwan
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
Royal Free Hospital; Dept of Oncology
🇬🇧London, United Kingdom
Christie Hospital; Breast Cancer Research Office
🇬🇧Manchester, United Kingdom
Weston Park Hospital; Cancer Clinical Trials Centre
🇬🇧Sheffield, United Kingdom
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
Royal Marsden Hosp NHS Fnd; Breast Unit
🇬🇧London, United Kingdom
Royal Marsden Hosp NHS Fnd; Medicine - Breast Unit
🇬🇧Sutton, United Kingdom
Singleton Hospital; Pharmacy
🇬🇧Swansea, United Kingdom
The Ottawa Hospital Cancer Centre; Oncology
🇨🇦Ottawa, Ontario, Canada
San Juan Oncology Associates
🇺🇸Farmington, New Mexico, United States
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