A Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

Breast Neoplasms Clinical Trial

Official title:

A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02131064
• Other study ID #: BO28408
• Secondary ID: TRIO0212012-0048
• Status: Completed
• Phase: Phase 3
• Start date: June 25, 2014
• Est. completion date: May 29, 2018

Study information

• Verified date: June 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, multicenter, open-label, two-arm study in treatment-naive participants with operable, locally advanced, or inflammatory, centrally-assessed HER2-positive early breast cancer (EBC) whose primary tumors were greater than or equal to (>/=) 2 centimeters (cm). The study was designed to evaluate the efficacy and safety of trastuzumab emtansine + pertuzumab (experimental arm; T-DM1 + P) versus chemotherapy, trastuzumab + pertuzumab (control arm; TCH + P). The study comprised a neoadjuvant treatment period, followed by surgery, and an adjuvant treatment period.

Treatment can be stopped due to disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 444
• Est. completion date: May 29, 2018
• Est. primary completion date: December 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed invasive breast cancer with a primary tumor size of greater than (>) 2 cm

• HER2-positive breast cancer

• Participants with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as HER2 positive

• Stage at presentation: cT2-cT4, cN0-cN3, cM0, according to American Joint Committee on Cancer (AJCC) staging system

• Known hormone receptor status of the primary tumor

• Participant agreement to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Baseline Left Ventricular Ejection Fraction (LVEF) >/= 55 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)

• Effective contraception as defined by protocol

Exclusion Criteria:

• Stage IV (metastatic) breast cancer

• Participants who have received prior anti-cancer therapy for breast cancer except those participants with a history of breast lobular carcinoma in situ (LCIS) that was surgically managed or ductal carcinoma in situ (DCIS) treated exclusively with mastectomy. In case of prior history of LCIS/DCIS, >5 years must have passed from surgery until diagnosis of current breast cancer

• Participants with multicentric (multiple tumors involving more than 1 quadrant) or bilateral breast cancer

• Participants who have undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes

• Axillary lymph node dissection or positive sentinel lymph node prior to start of neoadjuvant therapy

• History of concurrent or previously non-breast malignancies except for appropriately treated (1) non-melanoma skin cancer and (2) in situ carcinomas, including cervix, colon, and skin. A participant with previous invasive non-breast cancer is eligible provided he/she has been disease-free >/= 5 years

• Treatment with any investigational drug within 28 days prior to randomization

• Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0

• Any significant concurrent medical or surgical conditions or findings that would jeopardize the participant's safety or ability to complete the study

• Current pregnancy or breastfeeding

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• Carboplatin
Carboplatin IV infusion at a dose to achieve an AUC of 6 mg*min/mL q3w
• Docetaxel
Docetaxel 75 mg/m^2 IV infusion q3w
• Pertuzumab
Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w
• Trastuzumab
Trastuzumab 8 mg/kg (loading dose); and 6 mg/kg (maintenance dose) IV infusion q3w
• Trastuzumab Emtansine
Trastuzumab Emtansine 3.6 mg/kg IV infusion q3w

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	Clinique Saint-Joseph	Liège
Belgium	Clinique Ste-Elisabeth, Pharmacie	Namur
Belgium	Sint Augustinus Wilrijk	Wilrijk
Canada	Cross Cancer Institute ; Dept of Medical Oncology	Edmonton	Alberta
Canada	Chum Hospital Notre Dame	Montreal	Quebec
Canada	McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology	Montreal	Quebec
Canada	CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY	Quebec
Canada	St. Michael'S Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
France	Ico - Paul Papin	Angers
France	HOPITAL JEAN MINJOZ; Oncologie	Besancon
France	Hopital Morvan	Brest
France	CHD Les Oudairies	La Roche Sur Yon
France	Centre Oscar Lambret	Lille
France	Institut Paoli Calmettes	Marseille
France	Centre Catherine De Sienne	Nantes
France	Centre Rene Gauducheau	Saint Herblain
France	Nouvel Hopital Civil - CHU Strasbourg	Strasbourg
Germany	Klinikum Sindelfingen-Böblingen; Frauenklinik	Böblingen
Germany	Luisenkrankenhaus GmbH, Brustzentrum	Düsseldorf
Germany	Universitätsklinikum Erlangen; Frauenklinik	Erlangen
Germany	Universitätsklinikum Mainz	Mainz
Germany	Interdisziplinäres Onkologisches Zentrum	München
Korea, Republic of	National Cancer Center	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Gyeonggi-do
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Russian Federation	Regional Oncology Hospital Of Kursk; Chemotherapy	Kislino, Kursk Region
Russian Federation	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast
Russian Federation	S.I. Russian Oncological Research Center n.a. N.N. Blokhin	Moscow
Russian Federation	State Inst. Of Healthcare Orenburg Regional Clinical Oncology Dis	Orenburg
Russian Federation	Railway Clinical Hospital on Saratov - 2 Station Oao "Rzhd"	Saratov
Russian Federation	Saint-Petersburg City Clinical Oncology Dispensary	St Petersburg
Spain	Hospital Nuestra Señora de Sonsoles; servicio de Oncologia	Avila
Spain	Fundacio Santa Creu I Sant Pau	Barcelona
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología	La Coruña
Spain	Hospital Universitari de Lleida Arnau de Vilanova	Lleida	Lerida
Spain	Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica	Madrid
Spain	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid
Spain	Hospital Quiron de Madrid; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Clínico San Carlos; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Malaga
Spain	Corporacio Sanitaria Parc Tauli; Servicio de Oncologia	Sabadell	Barcelona
Spain	IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia	San Sebastian	Guipuzcoa
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
Taiwan	Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery	Kaohsiung
Taiwan	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei
Taiwan	Mackay Memorial Hospital; Dept of Surgery	Taipei
Taiwan	Tri-Service General Hospital	Taipei
Taiwan	National Taiwan Uni Hospital	Taipei City
Taiwan	Taipei Veterans General Hospital	Taipei City
Ukraine	Cherkassy Regional Oncological Hospital	Cherkassy
Ukraine	State Medical Academy; Oncology	Dnipropetrovsk
Ukraine	Karkiv Regional Oncology Center	Kharkiv
Ukraine	Lvov State Regional Center	Lvov
United States	Hope A Women's Cancer Center	Asheville	North Carolina
United States	Montefiore Medical Center	Bronx	New York
United States	Roper Bon Secours St. Francis Cancer Center	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	St. Jude Heritage Healthcare; Virgiia K.Crosson Can Ctr	Fullerton	California
United States	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada
United States	Memorial Cancer Institute	Hollywood	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	ProHEALTH Care Associates LLP	Lake Success	New York
United States	Cancer Care Assoc Med Group	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Md Anderson Cancer Center Orlando	Orlando	Florida
United States	Coastal Integrative Cancer Care	San Luis Obispo	California
United States	Central Coast Medical Oncology	Santa Maria	California
United States	UCLA Hematology/Oncology	Santa Monica	California
United States	New England Cancer Specialists	Scarborough	Maine

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Korea, Republic of,  Russian Federation,  Spain,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples	tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( that is [i.e.], ypT0/is, ypN0 in the American Joint Committee on Cancer [AJCC] staging system, 7th edition). Percentage of participants with tpCR was reported.	Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
Secondary	Overall Survival	Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. 3 years OS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.	From randomization until death (up to approximately 47 months)
Secondary	Percentage of Participants Who Received Breast-Conserving Surgery (BCS)	BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer.	Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)
Secondary	Event-Free Survival	Event-free survival (EFS) is defined as the time from randomization to disease progression or disease recurrence (local, regional, distant, or contralateral, invasive or non-invasive), or death from any cause. 3 years EFS rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.	From randomization up to disease progression or recurrence or death (up to approximately 47 months)
Secondary	Invasive Disease-free Survival (IDFS)	IDFS is defined only for participants who undergo surgery. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence; Ipsilateral local-regional invasive breast cancer recurrence; Distant recurrence; Contralateral invasive breast cancer; and death from any cause. 3 years of IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.	From surgery to the first documented occurrence of IDFC event (up to approximately 47 months)
Secondary	Percentage of Participants by Response for Neuropathy Single Item	Participants answered the question "Did you have tingling hands/feet?", from the Modified Quality of Life Questionnaire Breast Cancer 23 (mQLQ-BR23), on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.	Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)
Secondary	Percentage of Participants by Response for Skin Problem Single Items	Participants answered the Question 1 "Did itching skin bother you?" and Question 2 "Have you had skin problems?", from the mQLQ-BR23, on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.	Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)
Secondary	Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score	Participants rated their quality of life (global health status) on European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ- C30), with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Clinically meaningful deterioration in GHS/QoL was defined as a decrease in score of 10 points in GHS/QoL.	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Secondary	Time to Clinically Meaningful Deterioration in GHS/QoL Score	Participants rated their quality of life (global health status) on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by GHS/QoL. All valid GHS/QoL questionnaires of the neoadjuvant phase including surgery were used. Participants without deterioration were censored at the time of completing the last GHS/QoL plus 1 day. Median time to deterioration was estimated with Kaplan-Meier method. The 95% confidence interval (CI) for the median was computed using the method of Brookmeyer and Crowley.	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Secondary	Time to Clinically Meaningful Deterioration in Function Subscale	Participants rated their function on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by physical function; to first 14-point (or greater) decrease as measured by role function, to first 7-point (or greater) decrease as measured by cognitive function. Median time to deterioration was estimated with Kaplan-Meier method. The 95% CI for the median was computed using the method of Brookmeyer and Crowley.	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Secondary	Maximum Observed Serum Concentration (Cmax) of Trastuzumab	Only participants who received trastuzumab were to be analyzed for this outcome.	15-30 minutes (min) post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period
Secondary	Cmax of Trastuzumab Emtansine and Total Trastuzumab	Only participants who received trastuzumab emtansine were to be analyzed for this outcome.	15-30 min post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant and adjuvant period.
Secondary	Minimum Observed Serum Concentration (Cmin) of Trastuzumab	Only participants who received trastuzumab were to be analyzed for this outcome.	Pre-study treatment infusion (0 hours [hr]) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period
Secondary	Cmin of Trastuzumab Emtansine and Total Trastuzumab	Only participants who received trastuzumab emtansine were to be analyzed for this outcome.	Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant and adjuvant period
Secondary	Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations	DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.	15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
Secondary	Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)		15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
Secondary	Percentage of Participants With ATA to Trastuzumab		Baseline (Pre-trastuzumab [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-trastuzumab infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period
Secondary	Percentage of Participants by Response for Hair Loss Single Item	Participants answered the Question "Have you lost any hair?", from the mQLQ-BR23, on a 5-point scale (1 'Not at all', 2 'A little', 3 'Somewhat', 4 'Quite a bit', 5 'Very much'). Percentage of participants by each response was reported.	Baseline,Cycle(C) 3, C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4(approx 47 months)
Secondary	Percentage of Participants With Selected Adverse Events (AEs)	Selected AEs included hepatotoxicity, pulmonary toxicity, cardiac dysfunction, neutropenia, thrombocytopenia, peripheral neuropathy, hemorrhage, infusion related reaction (IRR)/hypersensitivity, IRR/Hypersensitivity symptoms, rash, diarrhea and mucositis. An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.	Baseline to end of study (approximately 47 months)
Secondary	Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales	Participants rated their function on EORTC QLQ C-30, with total score and single-item (physical, cognitive and role functioning) scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Clinically meaningful deterioration was defined as a decrease in score of 10 points in physical function; decrease of 7 points in cognitive function and decrease of 14 points in role function.	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Secondary	Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1	Participants were considered post-baseline ATA positive if they had ATAs post-baseline that were either treatment-induced or treatment-enhanced. Participants had treatment-induced ATAs if they had a negative or missing ATA result at baseline, and at least one positive ATA result post-baseline. Participants had treatment-enhanced ATAs if they had a positive ATA result at baseline, and at least one positive ATA result post-baseline that was greater than or equal to (>/=) 0.60 titer units higher than the result at baseline.	Baseline (b) (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (pb) (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period
Secondary	Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales	Participants rated their symptoms on EORTC QLQ C-30 and mQLQ-BR23, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates greater degree of symptoms. Clinically meaningful increase in symptoms was defined as an increase in score (deterioration) of 11 points in nausea and vomiting, pain, dyspnea; increase of 9 points in insomnia; increase of 14 points in appetite loss; increase of 15 points in diarrhea, constipation; increase of 10 points in fatigue, systemic therapy side effects, hair loss.	From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period