Clinical trial NCT02131064: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Neoplasms
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-05-06
Enrollment: 444
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples
timeFrame: Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
Secondary outcomes:
measure: Overall Survival
timeFrame: From randomization until death (up to approximately 47 months)
measure: Percentage of Participants Who Received Breast-Conserving Surgery (BCS)
timeFrame: Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)
measure: Event-Free Survival
timeFrame: From randomization up to disease progression or recurrence or death (up to approximately 47 months)
measure: Invasive Disease-free Survival (IDFS)
timeFrame: From surgery to the first documented occurrence of IDFC event (up to approximately 47 months)
measure: Percentage of Participants by Response for Neuropathy Single Item
timeFrame: 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)
measure: Percentage of Participants by Response for Skin Problem Single Items
timeFrame: 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)
measure: Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score
timeFrame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
measure: Time to Clinically Meaningful Deterioration in GHS/QoL Score
timeFrame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
measure: Time to Clinically Meaningful Deterioration in Function Subscale
timeFrame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
measure: Maximum Observed Serum Concentration (Cmax) of Trastuzumab
timeFrame: 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
measure: Cmax of Trastuzumab Emtansine and Total Trastuzumab
timeFrame: 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.
measure: Minimum Observed Serum Concentration (Cmin) of Trastuzumab
timeFrame: 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
measure: Cmin of Trastuzumab Emtansine and Total Trastuzumab
timeFrame: 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
measure: Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations
timeFrame: 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
measure: Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)
timeFrame: 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
measure: Percentage of Participants With ATA to Trastuzumab
timeFrame: 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
measure: Percentage of Participants by Response for Hair Loss Single Item
timeFrame: 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)
measure: Percentage of Participants With Selected Adverse Events (AEs)
timeFrame: Baseline to end of study (approximately 47 months)
measure: Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales
timeFrame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
measure: Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1
timeFrame: 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
measure: Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales
timeFrame: From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Other outcomes:
Locations:
city: Fullerton
country: United States
facility: St. Jude Heritage Healthcare; Virgiia K.Crosson Can Ctr
state: California
city: Los Angeles
country: United States
facility: Cancer Care Assoc Med Group
state: California
city: San Luis Obispo
country: United States
facility: Coastal Integrative Cancer Care
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology
state: California
city: Hollywood
country: United States
facility: Memorial Cancer Institute
state: Florida
city: Orlando
country: United States
facility: Md Anderson Cancer Center Orlando
state: Florida
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Henderson
country: United States
facility: Comprehensive Cancer Centers of Nevada - Henderson
state: Nevada
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Lake Success
country: United States
facility: ProHEALTH Care Associates LLP
state: New York
city: Asheville
country: United States
facility: Hope A Women's Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charleston
country: United States
facility: Roper Bon Secours St. Francis Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liège
country: Belgium
facility: Clinique Saint-Joseph
city: Namur
country: Belgium
facility: Clinique Ste-Elisabeth, Pharmacie
city: Wilrijk
country: Belgium
facility: Sint Augustinus Wilrijk
city: Edmonton
country: Canada
facility: Cross Cancer Institute ; Dept of Medical Oncology
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael'S Hospital
state: Ontario
city: Montreal
country: Canada
facility: Chum Hospital Notre Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
state: Quebec
city: Quebec
country: Canada
facility: CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY
city: Angers
country: France
facility: Ico - Paul Papin
city: Besancon
country: France
facility: HOPITAL JEAN MINJOZ; Oncologie
city: Brest
country: France
facility: Hopital Morvan
city: La Roche Sur Yon
country: France
facility: CHD Les Oudairies
city: Lille
country: France
facility: Centre Oscar Lambret
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Nantes
country: France
facility: Centre Catherine De Sienne
city: Saint Herblain
country: France
facility: Centre Rene Gauducheau
city: Strasbourg
country: France
facility: Nouvel Hopital Civil - CHU Strasbourg
city: Böblingen
country: Germany
facility: Klinikum Sindelfingen-Böblingen; Frauenklinik
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus GmbH, Brustzentrum
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen; Frauenklinik
city: Mainz
country: Germany
facility: Universitätsklinikum Mainz
city: München
country: Germany
facility: Interdisziplinäres Onkologisches Zentrum
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Moscovskaya Oblast
country: Russian Federation
facility: Moscow City Oncology Hospital #62
state: Moskovskaja Oblast
city: Kislino, Kursk Region
country: Russian Federation
facility: Regional Oncology Hospital Of Kursk; Chemotherapy
city: Moscow
country: Russian Federation
facility: S.I. Russian Oncological Research Center n.a. N.N. Blokhin
city: Orenburg
country: Russian Federation
facility: State Inst. Of Healthcare Orenburg Regional Clinical Oncology Dis
city: Saratov
country: Russian Federation
facility: Railway Clinical Hospital on Saratov - 2 Station Oao "Rzhd"
city: St Petersburg
country: Russian Federation
facility: Saint-Petersburg City Clinical Oncology Dispensary
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli; Servicio de Oncologia
state: Barcelona
city: San Sebastian
country: Spain
facility: IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia
state: Guipuzcoa
city: Lleida
country: Spain
facility: Hospital Universitari de Lleida Arnau de Vilanova
state: Lerida
city: Avila
country: Spain
facility: Hospital Nuestra Señora de Sonsoles; servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Fundacio Santa Creu I Sant Pau
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: La Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos; Servicio de Oncologia
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
city: Madrid
country: Spain
facility: Hospital Quiron de Madrid; Servicio de Oncologia
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet; Servicio Oncologia
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery
city: Taipei City
country: Taiwan
facility: National Taiwan Uni Hospital
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital; Dept of Surgery
city: Taipei
country: Taiwan
facility: Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Cherkassy
country: Ukraine
facility: Cherkassy Regional Oncological Hospital
city: Dnipropetrovsk
country: Ukraine
facility: State Medical Academy; Oncology
city: Kharkiv
country: Ukraine
facility: Karkiv Regional Oncology Center
city: Lvov
country: Ukraine
facility: Lvov State Regional Center
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hurvitz SA, Martin M, Jung KH, Huang CS, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Fasching PA, Afenjar K, Spera G, Lopez-Valverde V, Song C, Trask P, Boulet T, Sparano JA, Symmans WF, Thompson AM, Slamon D. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study. J Clin Oncol. 2019 Sep 1;37(25):2206-2216. doi: 10.1200/JCO.19.00882. Epub 2019 Jun 3.
citation: Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H, Campone M, Boileau JF, Beckmann MW, Afenjar K, Fresco R, Helms HJ, Xu J, Lin YG, Sparano J, Slamon D. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):115-126. doi: 10.1016/S1470-2045(17)30716-7. Epub 2017 Nov 23.