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
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT02131064
Collaborator
(none)
444
79
2
47.1
5.6
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
444 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date
:
Jun 25, 2014
Actual Primary Completion Date
:
Dec 31, 2015
Actual Study Completion Date
:
May 29, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Trastuzumab (TCH) + Pertuzumab Participants will receive pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion followed by trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion followed by docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). |
Drug: Carboplatin
Carboplatin IV infusion at a dose to achieve an AUC of 6 mg*min/mL q3w
Drug: Docetaxel
Docetaxel 75 mg/m^2 IV infusion q3w
Drug: Pertuzumab
Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w
Other Names:
Drug: Trastuzumab
Trastuzumab 8 mg/kg (loading dose); and 6 mg/kg (maintenance dose) IV infusion q3w
Other Names:
|
| Experimental: Trastuzumab Emtansine (T-DM1) + Pertuzumab Participants will receive pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
Drug: Pertuzumab
Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w
Other Names:
Drug: Trastuzumab Emtansine
Trastuzumab Emtansine 3.6 mg/kg IV infusion q3w
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples [Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)]
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.
Secondary Outcome Measures
- Overall Survival [From randomization until death (up to approximately 47 months)]
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.
- Percentage of Participants Who Received Breast-Conserving Surgery (BCS) [Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)]
BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer.
- Event-Free Survival [From randomization up to disease progression or recurrence or death (up to approximately 47 months)]
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.
- Invasive Disease-free Survival (IDFS) [From surgery to the first documented occurrence of IDFC event (up to approximately 47 months)]
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.
- Percentage of Participants by Response for Neuropathy Single Item [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)]
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.
- Percentage of Participants by Response for Skin Problem Single Items [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)]
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.
- Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score [From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period]
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.
- Time to Clinically Meaningful Deterioration in GHS/QoL Score [From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period]
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.
- Time to Clinically Meaningful Deterioration in Function Subscale [From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period]
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.
- Maximum Observed Serum Concentration (Cmax) of Trastuzumab [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]
Only participants who received trastuzumab were to be analyzed for this outcome.
- Cmax of Trastuzumab Emtansine and Total Trastuzumab [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.]
Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
- Minimum Observed Serum Concentration (Cmin) of Trastuzumab [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]
Only participants who received trastuzumab were to be analyzed for this outcome.
- Cmin of Trastuzumab Emtansine and Total Trastuzumab [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]
Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
- Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations [15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period]
DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
- 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]
- 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]
- Percentage of Participants by Response for Hair Loss Single Item [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)]
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.
- Percentage of Participants With Selected Adverse Events (AEs) [Baseline to end of study (approximately 47 months)]
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.
- Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales [From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period]
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.
- Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1 [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]
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.
- Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales [From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | St. Jude Heritage Healthcare; Virgiia K.Crosson Can Ctr | Fullerton | California | United States | 92835 |
| 2 | Cancer Care Assoc Med Group | Los Angeles | California | United States | 90095-1772 |
| 3 | Coastal Integrative Cancer Care | San Luis Obispo | California | United States | 93401 |
| 4 | Central Coast Medical Oncology | Santa Maria | California | United States | 93454 |
| 5 | UCLA Hematology/Oncology | Santa Monica | California | United States | 90404 |
| 6 | Memorial Cancer Institute | Hollywood | Florida | United States | 33021 |
| 7 | Md Anderson Cancer Center Orlando | Orlando | Florida | United States | 32806 |
| 8 | New England Cancer Specialists | Scarborough | Maine | United States | 04074 |
| 9 | Comprehensive Cancer Centers of Nevada - Henderson | Henderson | Nevada | United States | 89052 |
| 10 | Montefiore Medical Center | Bronx | New York | United States | 10467 |
| 11 | ProHEALTH Care Associates LLP | Lake Success | New York | United States | 11042 |
| 12 | Hope A Women's Cancer Center | Asheville | North Carolina | United States | 28806 |
| 13 | Levine Cancer Institute | Charlotte | North Carolina | United States | 28204 |
| 14 | Roper Bon Secours St. Francis Cancer Center | Charleston | South Carolina | United States | 29414 |
| 15 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
| 16 | MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 17 | UZ Antwerpen | Edegem | Belgium | 2650 | |
| 18 | UZ Leuven Gasthuisberg | Leuven | Belgium | 3000 | |
| 19 | Clinique Saint-Joseph | Liège | Belgium | 4000 | |
| 20 | Clinique Ste-Elisabeth, Pharmacie | Namur | Belgium | 5000 | |
| 21 | Sint Augustinus Wilrijk | Wilrijk | Belgium | 2610 | |
| 22 | Cross Cancer Institute ; Dept of Medical Oncology | Edmonton | Alberta | Canada | T6G 1Z2 |
| 23 | Sunnybrook Health Sciences Centre | Toronto | Ontario | Canada | M4N 3M5 |
| 24 | St. Michael'S Hospital | Toronto | Ontario | Canada | M5B 1W8 |
| 25 | Chum Hospital Notre Dame | Montreal | Quebec | Canada | H2L 4M1 |
| 26 | McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology | Montreal | Quebec | Canada | H3T 1E2 |
| 27 | CHU de Québec - Hôpital du Saint-Sacrement / ONCOLOGY | Quebec | Canada | G1S 4L8 | |
| 28 | Ico - Paul Papin | Angers | France | 49000 | |
| 29 | HOPITAL JEAN MINJOZ; Oncologie | Besancon | France | 25030 | |
| 30 | Hopital Morvan | Brest | France | 29200 | |
| 31 | CHD Les Oudairies | La Roche Sur Yon | France | 85925 | |
| 32 | Centre Oscar Lambret | Lille | France | 59020 | |
| 33 | Institut Paoli Calmettes | Marseille | France | 13009 | |
| 34 | Centre Catherine De Sienne | Nantes | France | 44202 | |
| 35 | Centre Rene Gauducheau | Saint Herblain | France | 44805 | |
| 36 | Nouvel Hopital Civil - CHU Strasbourg | Strasbourg | France | 67091 | |
| 37 | Klinikum Sindelfingen-Böblingen; Frauenklinik | Böblingen | Germany | 71032 | |
| 38 | Luisenkrankenhaus GmbH, Brustzentrum | Düsseldorf | Germany | 40235 | |
| 39 | Universitätsklinikum Erlangen; Frauenklinik | Erlangen | Germany | 91054 | |
| 40 | Universitätsklinikum Mainz | Mainz | Germany | 55131 | |
| 41 | Interdisziplinäres Onkologisches Zentrum | München | Germany | 80336 | |
| 42 | National Cancer Center | Gyeonggi-do | Korea, Republic of | 10408 | |
| 43 | Seoul National University Bundang Hospital | Gyeonggi-do | Korea, Republic of | 13620 | |
| 44 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 | |
| 45 | Severance Hospital | Seoul | Korea, Republic of | 03722 | |
| 46 | Asan Medical Center - Oncology | Seoul | Korea, Republic of | 05505 | |
| 47 | Samsung Medical Center | Seoul | Korea, Republic of | 6351 | |
| 48 | Moscow City Oncology Hospital #62 | Moscovskaya Oblast | Moskovskaja Oblast | Russian Federation | 143423 |
| 49 | Regional Oncology Hospital Of Kursk; Chemotherapy | Kislino, Kursk Region | Russian Federation | 305524 | |
| 50 | S.I. Russian Oncological Research Center n.a. N.N. Blokhin | Moscow | Russian Federation | 115478 | |
| 51 | State Inst. Of Healthcare Orenburg Regional Clinical Oncology Dis | Orenburg | Russian Federation | 460021 | |
| 52 | Railway Clinical Hospital on Saratov - 2 Station Oao "Rzhd" | Saratov | Russian Federation | 410004 | |
| 53 | Saint-Petersburg City Clinical Oncology Dispensary | St Petersburg | Russian Federation | 197022 | |
| 54 | Corporacio Sanitaria Parc Tauli; Servicio de Oncologia | Sabadell | Barcelona | Spain | 08208 |
| 55 | IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de Oncologia | San Sebastian | Guipuzcoa | Spain | 20014 |
| 56 | Hospital Universitari de Lleida Arnau de Vilanova | Lleida | Lerida | Spain | 25198 |
| 57 | Hospital Nuestra Señora de Sonsoles; servicio de Oncologia | Avila | Spain | 05071 | |
| 58 | Hospital del Mar; Servicio de Oncologia | Barcelona | Spain | 08003 | |
| 59 | Fundacio Santa Creu I Sant Pau | Barcelona | Spain | 08006 | |
| 60 | Complejo Hospitalario de Jaen | Jaen | Spain | 23007 | |
| 61 | Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología | La Coruña | Spain | 15006 | |
| 62 | Hospital General Universitario Gregorio Marañon; Servicio de Oncologia | Madrid | Spain | 28007 | |
| 63 | Hospital Universitario Clínico San Carlos; Servicio de Oncologia | Madrid | Spain | 28040 | |
| 64 | Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica | Madrid | Spain | 28050 | |
| 65 | Hospital Quiron de Madrid; Servicio de Oncologia | Madrid | Spain | 28223 | |
| 66 | Hospital Universitario Virgen de la Victoria | Malaga | Spain | 29010 | |
| 67 | Hospital Universitario Virgen del Rocio | Sevilla | Spain | 41013 | |
| 68 | Hospital Clinico Universitario de Valencia | Valencia | Spain | 46010 | |
| 69 | Hospital Universitario Miguel Servet; Servicio Oncologia | Zaragoza | Spain | 50009 | |
| 70 | Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery | Kaohsiung | Taiwan | 807 | |
| 71 | National Taiwan Uni Hospital | Taipei City | Taiwan | 10041 | |
| 72 | Taipei Veterans General Hospital | Taipei City | Taiwan | 112 | |
| 73 | Mackay Memorial Hospital; Dept of Surgery | Taipei | Taiwan | 104 | |
| 74 | Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology | Taipei | Taiwan | 112 | |
| 75 | Tri-Service General Hospital | Taipei | Taiwan | 11490 | |
| 76 | Cherkassy Regional Oncological Hospital | Cherkassy | Ukraine | 18009 | |
| 77 | State Medical Academy; Oncology | Dnipropetrovsk | Ukraine | 43102 | |
| 78 | Karkiv Regional Oncology Center | Kharkiv | Ukraine | 61070 | |
| 79 | Lvov State Regional Center | Lvov | Ukraine | 79031 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02131064
Other Study ID Numbers:
- BO28408
- TRIO021
- 2012-004879-38
First Posted:
May 6, 2014
Last Update Posted:
Jul 2, 2019
Last Verified:
Jun 1, 2019
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 574 participants were screened at 65 sites in 10 countries, of which 444 participants were randomized in two arms: Trastuzumab (TCH) + Pertuzumab (P) (Arm A) and Trastuzumab Emtansine (TDM1) + P (Arm B) |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Period Title: Overall Study | ||
| STARTED | 221 | 223 |
| COMPLETED | 196 | 189 |
| NOT COMPLETED | 25 | 34 |
Baseline Characteristics
| Arm/Group Title | TCH + P | T-DM1 + P | Total |
|---|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). | Total of all reporting groups |
| Overall Participants | 221 | 223 | 444 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
49.3
(11.2)
|
50.5
(10.6)
|
49.9
(10.9)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
221
100%
|
222
99.6%
|
443
99.8%
|
| Male |
0
0%
|
1
0.4%
|
1
0.2%
|
Outcome Measures
| Title | Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples |
|---|---|
| Description | 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. |
| Time Frame | Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Intent-to-treat (ITT) Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Number (95% Confidence Interval) [Percentage of Participants] |
56.1
25.4%
|
44.4
19.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | 95% CI for the difference in tPCR rates between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0126 |
| Comments | Threshold for significance at 5% | |
| Method | Cochran-Mantel-Haenszel Chi-Square | |
| Comments | The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation. | |
| Method of Estimation | Estimation Parameter | Difference in tpCR rate |
| Estimated Value | -11.71 | |
| Confidence Interval |
(2-Sided) 95% -20.95 to -2.48 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival |
|---|---|
| Description | 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. |
| Time Frame | From randomization until death (up to approximately 47 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Number (95% Confidence Interval) [Probability] |
97.6
|
97.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7557 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel Chi-Square Test | |
| Comments | The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.21 | |
| Confidence Interval |
(2-Sided) 95% 0.37 to 3.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants Who Received Breast-Conserving Surgery (BCS) |
|---|---|
| Description | BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer. |
| Time Frame | Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 213 | 218 |
| Number (95% Confidence Interval) [Percentage of Participants] |
52.6
(45.65)
23.8%
|
41.7
(35.12)
18.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | 95% CI for the difference in BCS rate between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0228 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel Chi-Square | |
| Comments | The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation. | |
| Method of Estimation | Estimation Parameter | Difference in BCS rate |
| Estimated Value | -10.84 | |
| Confidence Interval |
(2-Sided) 95% -20.21 to -1.47 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Event-Free Survival |
|---|---|
| Description | 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. |
| Time Frame | From randomization up to disease progression or recurrence or death (up to approximately 47 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Number (95% Confidence Interval) [Probability] |
94.21
|
85.28
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0027 |
| Comments | ||
| Method | Log Rank | |
| Comments | The Log Rank was used and stratified by local hormone receptor status and clinical stage at presentation. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 2.61 | |
| Confidence Interval |
(2-Sided) 95% 1.36 to 4.98 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Invasive Disease-free Survival (IDFS) |
|---|---|
| Description | 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. |
| Time Frame | From surgery to the first documented occurrence of IDFC event (up to approximately 47 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT Population comprised all randomized patients, whether or not they received any study treatment or completed a full course of study treatment. Patients were analyzed according to their randomized treatment. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Number (95% Confidence Interval) [Probability] |
91.99
|
93.04
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 95% 0.52 to 2.40 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants by Response for Neuropathy Single Item |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Not at all: Baseline |
78.7
35.6%
|
81.2
36.4%
|
| A little bit: Baseline |
9.5
4.3%
|
9.4
4.2%
|
| Somewhat: Baseline |
0
0%
|
0
0%
|
| Quite a bit: Baseline |
0.9
0.4%
|
0.9
0.4%
|
| Very much: Baseline |
0.5
0.2%
|
0
0%
|
| Not at all: Neoadjuvant Cycle 3 |
54.3
24.6%
|
59.6
26.7%
|
| A little bit: Neoadjuvant Cycle 3 |
20.8
9.4%
|
19.3
8.7%
|
| Somewhat: Neoadjuvant Cycle 3 |
0
0%
|
0
0%
|
| Quite a bit: Neoadjuvant Cycle 3 |
3.2
1.4%
|
2.7
1.2%
|
| Very much: Neoadjuvant Cycle 3 |
1.8
0.8%
|
0.4
0.2%
|
| Not at all: Neoadjuvant Cycle 5 |
37.1
16.8%
|
54.3
24.3%
|
| A little bit: Neoadjuvant Cycle 5 |
29.9
13.5%
|
21.1
9.5%
|
| Somewhat: Neoadjuvant Cycle 5 |
0
0%
|
0
0%
|
| Quite a bit: Neoadjuvant Cycle 5 |
8.6
3.9%
|
2.7
1.2%
|
| Very much: Neoadjuvant Cycle 5 |
6.8
3.1%
|
1.8
0.8%
|
| Not at all: Pre-Surgery |
22.6
10.2%
|
52.0
23.3%
|
| A little bit: Pre-Surgery |
29.0
13.1%
|
17.9
8%
|
| Somewhat: Pre-Surgery |
0
0%
|
0
0%
|
| Quite a bit: Pre-Surgery |
15.4
7%
|
5.4
2.4%
|
| Very much: Pre-Surgery |
10.0
4.5%
|
1.3
0.6%
|
| Not at all: Adjuvant Cycle 4 |
31.2
14.1%
|
42.6
19.1%
|
| A little bit: Adjuvant Cycle 4 |
31.7
14.3%
|
15.2
6.8%
|
| Somewhat: Adjuvant Cycle 4 |
0
0%
|
0
0%
|
| Quite a bit: Adjuvant Cycle 4 |
9.5
4.3%
|
9.0
4%
|
| Very much: Adjuvant Cycle 4 |
6.3
2.9%
|
2.7
1.2%
|
| Not at all: Adjuvant Cycle 8 |
33.0
14.9%
|
31.8
14.3%
|
| A little bit: Adjuvant Cycle 8 |
28.1
12.7%
|
19.3
8.7%
|
| Somewhat: Adjuvant Cycle 8 |
0
0%
|
0
0%
|
| Quite a bit: Adjuvant Cycle 8 |
10.9
4.9%
|
9.0
4%
|
| Very much: Adjuvant Cycle 8 |
4.1
1.9%
|
4.0
1.8%
|
| Not at all: End of Therapy |
31.2
14.1%
|
31.4
14.1%
|
| A little bit: End of Therapy |
30.8
13.9%
|
23.8
10.7%
|
| Somewhat: End of Therapy |
0
0%
|
0
0%
|
| Quite a bit: End of Therapy |
10.9
4.9%
|
12.1
5.4%
|
| Very much: End of Therapy |
5.0
2.3%
|
6.7
3%
|
| Not at all: Follow-up 2 |
38.0
17.2%
|
32.7
14.7%
|
| A little bit: Follow-up 2 |
19.9
9%
|
19.3
8.7%
|
| Somewhat: Follow-up 2 |
0
0%
|
0
0%
|
| Quite a bit: Follow-up 2 |
5.9
2.7%
|
7.6
3.4%
|
| Very much: Follow-up 2 |
4.1
1.9%
|
1.3
0.6%
|
| Not at all: Follow-up 4 |
39.8
18%
|
32.7
14.7%
|
| A little bit: Follow-up 4 |
15.4
7%
|
17.9
8%
|
| Somewhat: Follow-up 4 |
0
0%
|
0
0%
|
| Quite a bit: Follow-up 4 |
4.1
1.9%
|
3.1
1.4%
|
| Very much: Follow-up 4 |
2.3
1%
|
1.8
0.8%
|
| Title | Percentage of Participants by Response for Skin Problem Single Items |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Q1: Not at all: Baseline |
71.9
32.5%
|
72.6
32.6%
|
| Q1: A little bit: Baseline |
14.9
6.7%
|
16.1
7.2%
|
| Q1: Somewhat: Baseline |
0
0%
|
0
0%
|
| Q1: Quite a bit: Baseline |
2.3
1%
|
2.2
1%
|
| Q1: Very much: Baseline |
0
0%
|
0.4
0.2%
|
| Q1: Not at all: Neoadjuvant Cycle 3 |
35.3
16%
|
48.9
21.9%
|
| Q1: A little bit: Neoadjuvant Cycle 3 |
31.2
14.1%
|
27.4
12.3%
|
| Q1: Somewhat: Neoadjuvant Cycle 3 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Neoadjuvant Cycle 3 |
10.9
4.9%
|
4.0
1.8%
|
| Q1: Very much: Neoadjuvant Cycle 3 |
2.3
1%
|
1.8
0.8%
|
| Q1: Not at all: Neoadjuvant Cycle 5 |
48.9
22.1%
|
46.2
20.7%
|
| Q1: A little bit: Neoadjuvant Cycle 5 |
23.1
10.5%
|
26.0
11.7%
|
| Q1: Somewhat: Neoadjuvant Cycle 5 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Neoadjuvant Cycle 5 |
7.7
3.5%
|
6.3
2.8%
|
| Q1: Very much: Neoadjuvant Cycle 5 |
2.3
1%
|
1.3
0.6%
|
| Q1: Not at all: Pre-Surgery |
40.3
18.2%
|
48.0
21.5%
|
| Q1: A little bit: Pre-Surgery |
26.7
12.1%
|
21.5
9.6%
|
| Q1: Somewhat: Pre-Surgery |
0
0%
|
0
0%
|
| Q1: Quite a bit: Pre-Surgery |
7.2
3.3%
|
5.8
2.6%
|
| Q1: Very much: Pre-Surgery |
2.7
1.2%
|
1.3
0.6%
|
| Q1: Not at all: Adjuvant Cycle 4 |
38.5
17.4%
|
39.0
17.5%
|
| Q1: A little bit: Adjuvant Cycle 4 |
23.5
10.6%
|
21.5
9.6%
|
| Q1: Somewhat: Adjuvant Cycle 4 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Adjuvant Cycle 4 |
9.5
4.3%
|
6.7
3%
|
| Q1: Very much: Adjuvant Cycle 4 |
6.8
3.1%
|
2.2
1%
|
| Q1: Not at all: Adjuvant Cycle 8 |
34.8
15.7%
|
39.0
17.5%
|
| Q1: A little bit: Adjuvant Cycle 8 |
27.6
12.5%
|
15.7
7%
|
| Q1: Somewhat: Adjuvant Cycle 8 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Adjuvant Cycle 8 |
9.0
4.1%
|
6.3
2.8%
|
| Q1: Very much: Adjuvant Cycle 8 |
4.1
1.9%
|
3.1
1.4%
|
| Q1: Not at all: End of Therapy |
39.4
17.8%
|
42.6
19.1%
|
| Q1: A little bit: End of Therapy |
26.7
12.1%
|
22.9
10.3%
|
| Q1: Somewhat: End of Therapy |
0
0%
|
0
0%
|
| Q1: Quite a bit: End of Therapy |
6.8
3.1%
|
6.7
3%
|
| Q1: Very much: End of Therapy |
4.5
2%
|
1.8
0.8%
|
| Q1: Not at all: Follow-up 2 |
43.9
19.9%
|
39.9
17.9%
|
| Q1: A little bit: Follow-up 2 |
19.0
8.6%
|
14.8
6.6%
|
| Q1: Somewhat: Follow-up 2 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Follow-up 2 |
3.6
1.6%
|
4.0
1.8%
|
| Q1: Very much: Follow-up 2 |
0.9
0.4%
|
2.2
1%
|
| Q1: Not at all: Follow-up 4 |
46.2
20.9%
|
37.7
16.9%
|
| Q1: A little bit: Follow-up 4 |
10.4
4.7%
|
12.1
5.4%
|
| Q1: Somewhat: Follow-up 4 |
0
0%
|
0
0%
|
| Q1: Quite a bit: Follow-up 4 |
3.2
1.4%
|
4.5
2%
|
| Q1: Very much: Follow-up 4 |
1.4
0.6%
|
1.3
0.6%
|
| Q2: Not at all: Baseline |
64.7
29.3%
|
67.3
30.2%
|
| Q2: A little bit: Baseline |
21.3
9.6%
|
17.9
8%
|
| Q2: Somewhat: Baseline |
0
0%
|
0
0%
|
| Q2: Quite a bit: Baseline |
3.2
1.4%
|
5.8
2.6%
|
| Q2: Very much: Baseline |
0.5
0.2%
|
0.4
0.2%
|
| Q2: Not at all: Neoadjuvant Cycle 3 |
14.0
6.3%
|
24.2
10.9%
|
| Q2: A little bit: Neoadjuvant Cycle 3 |
40.7
18.4%
|
38.6
17.3%
|
| Q2: Somewhat: Neoadjuvant Cycle 3 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Neoadjuvant Cycle 3 |
18.6
8.4%
|
14.8
6.6%
|
| Q2: Very much: Neoadjuvant Cycle 3 |
6.8
3.1%
|
4.5
2%
|
| Q2: Not at all: Neoadjuvant Cycle 5 |
21.3
9.6%
|
25.6
11.5%
|
| Q2: A little bit: Neoadjuvant Cycle 5 |
35.7
16.2%
|
37.7
16.9%
|
| Q2: Somewhat: Neoadjuvant Cycle 5 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Neoadjuvant Cycle 5 |
20.4
9.2%
|
12.6
5.7%
|
| Q2: Very much: Neoadjuvant Cycle 5 |
5.0
2.3%
|
4.0
1.8%
|
| Q2: Not at all: Pre-Surgery |
21.3
9.6%
|
27.4
12.3%
|
| Q2: A little bit: Pre-Surgery |
33.9
15.3%
|
37.2
16.7%
|
| Q2: Somewhat: Pre-Surgery |
0
0%
|
0
0%
|
| Q2: Quite a bit: Pre-Surgery |
15.4
7%
|
8.1
3.6%
|
| Q2: Very much: Pre-Surgery |
6.3
2.9%
|
4.0
1.8%
|
| Q2: Not at all: Adjuvant Cycle 4 |
23.5
10.6%
|
24.2
10.9%
|
| Q2: A little bit: Adjuvant Cycle 4 |
33.0
14.9%
|
30.9
13.9%
|
| Q2: Somewhat: Adjuvant Cycle 4 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Adjuvant Cycle 4 |
13.1
5.9%
|
9.4
4.2%
|
| Q2: Very much: Adjuvant Cycle 4 |
9.0
4.1%
|
4.9
2.2%
|
| Q2: Not at all: Adjuvant Cycle 8 |
23.1
10.5%
|
25.6
11.5%
|
| Q2: A little bit: Adjuvant Cycle 8 |
35.7
16.2%
|
24.2
10.9%
|
| Q2: Somewhat: Adjuvant Cycle 8 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Adjuvant Cycle 8 |
12.2
5.5%
|
9.9
4.4%
|
| Q2: Very much: Adjuvant Cycle 8 |
5.0
2.3%
|
4.5
2%
|
| Q2: Not at all: End of Therapy |
27.1
12.3%
|
27.4
12.3%
|
| Q2: A little bit: End of Therapy |
33.9
15.3%
|
30.0
13.5%
|
| Q2: Somewhat: End of Therapy |
0
0%
|
0
0%
|
| Q2: Quite a bit: End of Therapy |
10.0
4.5%
|
13.5
6.1%
|
| Q2: Very much: End of Therapy |
6.8
3.1%
|
3.1
1.4%
|
| Q2: Not at all: Follow-up 2 |
36.2
16.4%
|
27.8
12.5%
|
| Q2: A little bit: Follow-up 2 |
25.8
11.7%
|
25.6
11.5%
|
| Q2: Somewhat: Follow-up 2 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Follow-up 2 |
4.1
1.9%
|
6.3
2.8%
|
| Q2: Very much: Follow-up 2 |
1.8
0.8%
|
1.3
0.6%
|
| Q2: Not at all: Follow-up 4 |
39.8
18%
|
30.0
13.5%
|
| Q2: A little bit: Follow-up 4 |
14.5
6.6%
|
18.8
8.4%
|
| Q2: Somewhat: Follow-up 4 |
0
0%
|
0
0%
|
| Q2: Quite a bit: Follow-up 4 |
4.5
2%
|
4.5
2%
|
| Q2: Very much: Follow-up 4 |
2.7
1.2%
|
2.2
1%
|
| Title | Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score |
|---|---|
| Description | 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. |
| Time Frame | From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 193 | 205 |
| Number [Percentage of Participants] |
69.9
31.6%
|
45.4
20.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | 95% CI for the difference in clinically meaningful deterioration in GHS/QoL score between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Deterioration |
| Estimated Value | -24.58 | |
| Confidence Interval |
(2-Sided) 95% -33.98 to -15.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time to Clinically Meaningful Deterioration in GHS/QoL Score |
|---|---|
| Description | 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. |
| Time Frame | From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 191 | 200 |
| Median (95% Confidence Interval) [months] |
3.02
(2.83)
|
4.63
(4.11)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | Stratified cox proportional hazards regression model was used to estimate Hazard Ratio and CI. Stratification by hormonal receptor status and clinical stage at presentation (stratification factors). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0001 |
| Comments | ||
| Method | Log Rank | |
| Comments | Log Rank was used and stratified by local hormone receptor status and clinical stage at presentation. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.60 | |
| Confidence Interval |
(2-Sided) 95% 0.46 to 0.78 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time to Clinically Meaningful Deterioration in Function Subscale |
|---|---|
| Description | 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. |
| Time Frame | From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients of the ITT population with a baseline assessment and at least one post-treatment assessment was included in this analysis. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 191 | 200 |
| Physical Function |
2.79
|
4.86
|
| Role Function |
2.79
|
4.44
|
| Cognitive Function |
3.42
|
4.44
|
| Title | Maximum Observed Serum Concentration (Cmax) of Trastuzumab |
|---|---|
| Description | Only participants who received trastuzumab were to be analyzed for this outcome. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | TCH + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). |
| Measure Participants | 214 |
| Cycle 1 (neoadjuvant period) |
167
(47.1)
|
| Cycle 6 (neoadjuvant period) |
148
(44.7)
|
| Cycle 1 (adjuvant period) |
159
(36.2)
|
| Cycle 6 (adjuvant period) |
181
(30.7)
|
| Title | Cmax of Trastuzumab Emtansine and Total Trastuzumab |
|---|---|
| Description | Only participants who received trastuzumab emtansine were to be analyzed for this outcome. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 222 |
| Trastuzumab emtansine: C1 (neoadjuvant) |
80.4
(26.5)
|
| Trastuzumab emtansine: C6 (neoadjuvant) |
71.7
(30.2)
|
| Total Trastuzumab: C1 (neoadjuvant) |
79.1
(25.7)
|
| Total Trastuzumab: C6 (neoadjuvant) |
79.1
(31.1)
|
| Trastuzumab emtansine: C1 (adjuvant) |
70.4
(22.7)
|
| Trastuzumab emtansine: C6 (adjuvant) |
73.1
(21.8)
|
| Total Trastuzumab: C1 (adjuvant) |
73.0
(23.2)
|
| Total Trastuzumab: C6 (adjuvant) |
82.6
(23.7)
|
| Title | Minimum Observed Serum Concentration (Cmin) of Trastuzumab |
|---|---|
| Description | Only participants who received trastuzumab were to be analyzed for this outcome. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | TCH + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). |
| Measure Participants | 214 |
| Trastuzumab (neoadjuvant period) |
45.8
(17.8)
|
| Trastuzumab (adjuvant period) |
21.8
(0.153)
|
| Title | Cmin of Trastuzumab Emtansine and Total Trastuzumab |
|---|---|
| Description | Only participants who received trastuzumab emtansine were to be analyzed for this outcome. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 222 |
| Trastuzumab emtansine (neoadjuvant) |
3.04
(7.43)
|
| Total Trastuzumab (neoadjuvant) |
12.3
(8.68)
|
| Trastuzumab emtansine (adjuvant) |
4.09
(11.7)
|
| Total Trastuzumab (adjuvant) |
8.70
(6.98)
|
| Title | Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations |
|---|---|
| Description | DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome. |
| Time Frame | 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 222 |
| C1: 15-30 min post-dose (neoadjuvant) |
4.64
(2.33)
|
| C6: 15-30 min post-dose (neoadjuvant) |
4.73
(2.61)
|
| C1: 15-30 min post-dose (adjuvant) |
4.49
(2.33)
|
| C6: 15-30 min post-dose (adjuvant) |
5.15
(8.28)
|
| Title | Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1) |
|---|---|
| Description | |
| Time Frame | 15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The pharmacokinetic population comprised all patients who received at least one treatment dose of trastuzumab emtansine (for patients in the T-DM1 + P arm) or trastuzumab (for patients in the TCH + P arm), and had at least one post-treatment serum or plasma sample. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 222 |
| C1: MCC-DM1 (Neoadjuvant Period) |
8.18
(7.23)
|
| C1: Lys-MCC-DM1 (Neoadjuvant period) |
NA
(NA)
|
| C6: MCC-DM1 (Neoadjuvant Period) |
8.22
(8.03)
|
| C6: Lys-MCC-DM1 (Neoadjuvant period) |
NA
(NA)
|
| C1: MCC-DM1 (Adjuvant Period) |
7.98
(6.46)
|
| C1: Lys-MCC-DM1 (Adjuvant period) |
NA
(NA)
|
| C6: MCC-DM1 (Adjuvant Period) |
7.90
(5.37)
|
| C6: Lys-MCC-DM1 (Adjuvant period) |
NA
(NA)
|
| Title | Percentage of Participants With ATA to Trastuzumab |
|---|---|
| Description | |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The participants included in this analysis were the participants who received at least one dose of trastuzumab and had at least one reported serum or plasma results. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 210 |
| Neoadjuvant Phase (baseline) |
11
5%
|
| Neoadjuvant Phase (post-baseline) |
2.6
1.2%
|
| Adjuvant Phase (baseline) |
5.4
2.4%
|
| Adjuvant Phase (post-baseline) |
5.0
2.3%
|
| Title | Percentage of Participants by Response for Hair Loss Single Item |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population of patients with both a baseline assessment and at least one post-treatment assessment in the respective single question are included in the analysis. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 221 | 223 |
| Not at all: Baseline |
81.4
36.8%
|
87.4
39.2%
|
| A little bit: Baseline |
7.7
3.5%
|
4.0
1.8%
|
| Somewhat: Baseline |
0
0%
|
0
0%
|
| Quite a bit: Baseline |
0.5
0.2%
|
0
0%
|
| Very much: Baseline |
0
0%
|
0
0%
|
| Not at all: Neoadjuvant Cycle 3 |
8.6
3.9%
|
65.0
29.1%
|
| A little bit: Neoadjuvant Cycle 3 |
11.3
5.1%
|
16.6
7.4%
|
| Somewhat: Neoadjuvant Cycle 3 |
0
0%
|
0
0%
|
| Quite a bit: Neoadjuvant Cycle 3 |
20.8
9.4%
|
0.4
0.2%
|
| Very much: Neoadjuvant Cycle 3 |
39.4
17.8%
|
0
0%
|
| Not at all: Neoadjuvant Cycle 5 |
20.4
9.2%
|
58.7
26.3%
|
| A little bit: Neoadjuvant Cycle 5 |
19.9
9%
|
19.3
8.7%
|
| Somewhat: Neoadjuvant Cycle 5 |
0
0%
|
0
0%
|
| Quite a bit: Neoadjuvant Cycle 5 |
15.8
7.1%
|
1.3
0.6%
|
| Very much: Neoadjuvant Cycle 5 |
26.2
11.9%
|
0.4
0.2%
|
| Not at all: Pre-Surgery |
30.8
13.9%
|
49.8
22.3%
|
| A little bit: Pre-Surgery |
13.6
6.2%
|
24.7
11.1%
|
| Somewhat: Pre-Surgery |
0
0%
|
0
0%
|
| Quite a bit: Pre-Surgery |
11.3
5.1%
|
2.2
1%
|
| Very much: Pre-Surgery |
21.3
9.6%
|
0
0%
|
| Not at all: Adjuvant Cycle 4 |
67.9
30.7%
|
50.2
22.5%
|
| A little bit: Adjuvant Cycle 4 |
5.0
2.3%
|
15.7
7%
|
| Somewhat: Adjuvant Cycle 4 |
0
0%
|
0
0%
|
| Quite a bit: Adjuvant Cycle 4 |
3.2
1.4%
|
2.2
1%
|
| Very much: Adjuvant Cycle 4 |
2.7
1.2%
|
1.3
0.6%
|
| Not at all: Adjuvant Cycle 8 |
70.1
31.7%
|
48.9
21.9%
|
| A little bit: Adjuvant Cycle 8 |
4.1
1.9%
|
14.3
6.4%
|
| Somewhat: Adjuvant Cycle 8 |
0
0%
|
0
0%
|
| Quite a bit: Adjuvant Cycle 8 |
0.9
0.4%
|
0.9
0.4%
|
| Very much: Adjuvant Cycle 8 |
0.9
0.4%
|
0
0%
|
| Not at all: End of Therapy |
69.7
31.5%
|
57.8
25.9%
|
| A little bit: End of Therapy |
5.4
2.4%
|
14.8
6.6%
|
| Somewhat: End of Therapy |
0
0%
|
0
0%
|
| Quite a bit: End of Therapy |
0.9
0.4%
|
0
0%
|
| Very much: End of Therapy |
1.8
0.8%
|
1.3
0.6%
|
| Not at all: Follow-up 2 |
55.7
25.2%
|
48.4
21.7%
|
| A little bit: Follow-up 2 |
9.0
4.1%
|
11.7
5.2%
|
| Somewhat: Follow-up 2 |
0
0%
|
0
0%
|
| Quite a bit: Follow-up 2 |
1.4
0.6%
|
0.4
0.2%
|
| Very much: Follow-up 2 |
1.8
0.8%
|
0.4
0.2%
|
| Not at all: Follow-up 4 |
52.9
23.9%
|
41.3
18.5%
|
| A little bit: Follow-up 4 |
7.2
3.3%
|
11.2
5%
|
| Somewhat: Follow-up 4 |
0
0%
|
0
0%
|
| Quite a bit: Follow-up 4 |
0
0%
|
2.7
1.2%
|
| Very much: Follow-up 4 |
1.4
0.6%
|
0.4
0.2%
|
| Title | Percentage of Participants With Selected Adverse Events (AEs) |
|---|---|
| Description | 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. |
| Time Frame | Baseline to end of study (approximately 47 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Population comprised all patients who received at least one full or partial dose of any study treatment. Patients were analyzed according to the treatment they actually received. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 219 | 223 |
| Hepatotoxicity |
14.2
6.4%
|
39.0
17.5%
|
| Pulmonary Toxicity |
0.9
0.4%
|
4.9
2.2%
|
| Cardiac Dysfunction |
4.6
2.1%
|
1.3
0.6%
|
| Neutropenia |
39.7
18%
|
8.1
3.6%
|
| Thrombocytopenia |
22.8
10.3%
|
17.9
8%
|
| Peripheral Neuropathy |
47.5
21.5%
|
28.7
12.9%
|
| Hemorrhage |
19.2
8.7%
|
33.2
14.9%
|
| IRR/Hypersensitivity |
13.7
6.2%
|
22.9
10.3%
|
| IRR/Hypersensitivity symptoms |
7.8
3.5%
|
19.3
8.7%
|
| Rash |
44.7
20.2%
|
36.8
16.5%
|
| Diarrhea |
76.7
34.7%
|
38.6
17.3%
|
| Mucositis |
43.8
19.8%
|
24.7
11.1%
|
| Title | Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales |
|---|---|
| Description | 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. |
| Time Frame | From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 193 | 205 |
| Cognitive Functioning |
59.1
26.7%
|
42.4
19%
|
| Physical Functioning |
72.5
32.8%
|
40.0
17.9%
|
| Role Functioning |
76.7
34.7%
|
47.8
21.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | This is the statistical analysis for cognitive functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Deterioration |
| Estimated Value | -16.63 | |
| Confidence Interval |
(2-Sided) 95% -26.32 to -6.94 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | This is the statistical analysis for physical functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Deterioration |
| Estimated Value | -32.54 | |
| Confidence Interval |
(2-Sided) 95% -41.74 to -23.34 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | TCH + P, T-DM1 + P |
|---|---|---|
| Comments | This is the statistical analysis for role functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Deterioration |
| Estimated Value | -28.88 | |
| Confidence Interval |
(2-Sided) 95% -37.95 to -19.80 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1 |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The participants included in this analysis were the participants who received at least one dose of trastuzumab emtansine and had at least one reported serum or plasma results. |
| Arm/Group Title | T-DM1 + P |
|---|---|
| Arm/Group Description | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 219 |
| Neoadjuvant Phase (Baseline) |
5.5
2.5%
|
| Neoadjuvant Phase (Post-Baseline) |
7.5
3.4%
|
| Adjuvant Phase (Baseline) |
11.7
5.3%
|
| Adjuvant Phase (Post-baseline) |
13.1
5.9%
|
| Title | Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales |
|---|---|
| Description | 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. |
| Time Frame | From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Intent-to-treat (ITT) Population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment. As per protocol, the analysis for this outcome measure was focused on the neoadjuvant period only. |
| Arm/Group Title | TCH + P | T-DM1 + P |
|---|---|---|
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). |
| Measure Participants | 194 | 205 |
| Appetite Loss |
61.1
27.6%
|
47.8
21.4%
|
| Any Hair Loss |
91.2
41.3%
|
40.5
18.2%
|
| Systemic Therapy Side-Effects |
89.7
40.6%
|
75.1
33.7%
|
| Constipation |
33.2
15%
|
32.7
14.7%
|
| Diarrhea |
79.3
35.9%
|
50.7
22.7%
|
| Dyspnea |
56.0
25.3%
|
31.2
14%
|
| Fatigue |
87.6
39.6%
|
68.8
30.9%
|
| Nausea/Vomiting |
66.3
30%
|
43.9
19.7%
|
| Pain |
56.0
25.3%
|
36.6
16.4%
|
| Insomnia |
42.5
19.2%
|
30.2
13.5%
|
Adverse Events
| Time Frame | From Baseline up to approximately 47 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Safety population was analyzed. | |||
| Arm/Group Title | TCH + P | T-DM1 + P | ||
| Arm/Group Description | Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles). | Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period). | ||
All Cause Mortality |
||||
| TCH + P | T-DM1 + P | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/219 (2.3%) | 6/223 (2.7%) | ||
Serious Adverse Events |
||||
| TCH + P | T-DM1 + P | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 70/219 (32%) | 30/223 (13.5%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 0/219 (0%) | 0 | 3/223 (1.3%) | 3 |
| Febrile neutropenia | 26/219 (11.9%) | 33 | 3/223 (1.3%) | 3 |
| Neutropenia | 7/219 (3.2%) | 7 | 0/223 (0%) | 0 |
| Thrombocytopenia | 1/219 (0.5%) | 1 | 1/223 (0.4%) | 1 |
| Cardiac disorders | ||||
| Cardiac failure | 2/219 (0.9%) | 2 | 1/223 (0.4%) | 1 |
| Sinus tachycardia | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Left ventricular dysfunction | 2/219 (0.9%) | 2 | 0/223 (0%) | 0 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Abdominal pain upper | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Colitis | 3/219 (1.4%) | 3 | 0/223 (0%) | 0 |
| Diarrhoea | 9/219 (4.1%) | 9 | 0/223 (0%) | 0 |
| Gastritis | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Gastrointestinal haemorrhage | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Haemorrhoids | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Ileus | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Nausea | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Small intestinal obstruction | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Stomatitis | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Vomiting | 4/219 (1.8%) | 4 | 1/223 (0.4%) | 1 |
| General disorders | ||||
| Asthenia | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Pyrexia | 2/219 (0.9%) | 2 | 0/223 (0%) | 0 |
| Non-cardiac chest pain | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Device related thrombosis | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Hepatobiliary disorders | ||||
| Nodular regenerative hyperplasia | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Immune system disorders | ||||
| Anaphylactic reaction | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Hypersensitivity | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Infections and infestations | ||||
| Bacteraemia | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Breast cellulitis | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Cellulitis | 2/219 (0.9%) | 2 | 0/223 (0%) | 0 |
| Clostridium difficile colitis | 1/219 (0.5%) | 2 | 0/223 (0%) | 0 |
| Clostridium difficile infection | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Device related infection | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Diarrhoea infectious | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Enterocolitis infectious | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Gastroenteritis | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Gastroenteritis norovirus | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Kidney infection | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Pneumonia | 2/219 (0.9%) | 2 | 2/223 (0.9%) | 2 |
| Postoperative wound infection | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Sepsis | 2/219 (0.9%) | 2 | 0/223 (0%) | 0 |
| Skin infection | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Subcutaneous abscess | 1/219 (0.5%) | 1 | 1/223 (0.4%) | 1 |
| Upper respiratory tract infection | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Wound infection | 0/219 (0%) | 0 | 3/223 (1.3%) | 3 |
| Breast abscess | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Subcutaneous haematoma | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Procedural intestinal perforation | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Seroma | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Investigations | ||||
| Lipase increased | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Neutrophil count decreased | 3/219 (1.4%) | 3 | 0/223 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Dehydration | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Hypermagnesaemia | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Hypomagnesaemia | 2/219 (0.9%) | 2 | 0/223 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Pain in extremity | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Intraductal proliferative breast lesion | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Cervix carinoma | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Neuroendocrine tumour | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Uterine leiomyoma | 1/219 (0.5%) | 1 | 0/0 (NaN) | 0 |
| Nervous system disorders | ||||
| Headache | 1/219 (0.5%) | 1 | 1/223 (0.4%) | 1 |
| Neuropathy peripheral | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Seizure | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Transient ischaemic attack | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Psychiatric disorders | ||||
| Anxiety | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Renal failure | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Reproductive system and breast disorders | ||||
| Adenomyosis | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Breast haematoma | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Epistaxis | 0/219 (0%) | 0 | 1/223 (0.4%) | 3 |
| Pleural effusion | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Pneumonitis | 0/219 (0%) | 0 | 2/223 (0.9%) | 2 |
| Pulmonary embolism | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Respiratory failure | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Bronchiectasis | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Dyspnoea | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
| Vascular disorders | ||||
| Deep vein thrombosis | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Hypertensive crisis | 0/219 (0%) | 0 | 1/223 (0.4%) | 1 |
| Shock haemorrhagic | 1/219 (0.5%) | 1 | 0/223 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| TCH + P | T-DM1 + P | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 217/219 (99.1%) | 212/223 (95.1%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 81/219 (37%) | 103 | 43/223 (19.3%) | 47 |
| Neutropenia | 59/219 (26.9%) | 92 | 13/223 (5.8%) | 20 |
| Thrombocytopenia | 24/219 (11%) | 36 | 18/223 (8.1%) | 23 |
| Eye disorders | ||||
| Dry eye | 14/219 (6.4%) | 16 | 16/223 (7.2%) | 16 |
| Lacrimation increased | 18/219 (8.2%) | 21 | 6/223 (2.7%) | 9 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 30/219 (13.7%) | 45 | 21/223 (9.4%) | 29 |
| Abdominal pain upper | 22/219 (10%) | 29 | 7/223 (3.1%) | 8 |
| Constipation | 43/219 (19.6%) | 48 | 34/223 (15.2%) | 52 |
| Diarrhoea | 163/219 (74.4%) | 372 | 86/223 (38.6%) | 179 |
| Dry mouth | 4/219 (1.8%) | 4 | 27/223 (12.1%) | 33 |
| Dyspepsia | 15/219 (6.8%) | 18 | 25/223 (11.2%) | 30 |
| Gastrooesophageal reflux disease | 16/219 (7.3%) | 18 | 7/223 (3.1%) | 8 |
| Haemorrhoids | 14/219 (6.4%) | 19 | 5/223 (2.2%) | 5 |
| Nausea | 139/219 (63.5%) | 249 | 103/223 (46.2%) | 248 |
| Stomatitis | 49/219 (22.4%) | 70 | 23/223 (10.3%) | 30 |
| Vomiting | 68/219 (31.1%) | 83 | 35/223 (15.7%) | 47 |
| Gingival bleeding | 1/219 (0.5%) | 1 | 15/223 (6.7%) | 17 |
| General disorders | ||||
| Asthenia | 61/219 (27.9%) | 115 | 42/223 (18.8%) | 73 |
| Chills | 9/219 (4.1%) | 9 | 27/223 (12.1%) | 32 |
| Fatigue | 95/219 (43.4%) | 143 | 83/223 (37.2%) | 116 |
| Influenza like illness | 10/219 (4.6%) | 12 | 16/223 (7.2%) | 21 |
| Mucosal inflammation | 30/219 (13.7%) | 37 | 22/223 (9.9%) | 29 |
| Oedema peripheral | 31/219 (14.2%) | 38 | 10/223 (4.5%) | 11 |
| Pyrexia | 34/219 (15.5%) | 43 | 38/223 (17%) | 53 |
| Immune system disorders | ||||
| Hypersensitivity | 11/219 (5%) | 17 | 6/223 (2.7%) | 8 |
| Infections and infestations | ||||
| Nasopharyngitis | 23/219 (10.5%) | 29 | 29/223 (13%) | 34 |
| Upper respiratory tract infection | 15/219 (6.8%) | 18 | 21/223 (9.4%) | 24 |
| Urinary tract infection | 17/219 (7.8%) | 20 | 12/223 (5.4%) | 16 |
| Injury, poisoning and procedural complications | ||||
| Radiation skin injury | 46/219 (21%) | 48 | 21/223 (9.4%) | 22 |
| Investigations | ||||
| Alanine aminotransferase increased | 24/219 (11%) | 37 | 64/223 (28.7%) | 83 |
| Aspartate aminotransferase increased | 21/219 (9.6%) | 37 | 55/223 (24.7%) | 74 |
| Neutrophil count decreased | 22/219 (10%) | 44 | 5/223 (2.2%) | 6 |
| Platelet count decreased | 26/219 (11.9%) | 37 | 23/223 (10.3%) | 38 |
| Weight decreased | 24/219 (11%) | 24 | 18/223 (8.1%) | 19 |
| White blood cell count decreased | 17/219 (7.8%) | 22 | 8/223 (3.6%) | 11 |
| Blood bilirubin increased | 1/219 (0.5%) | 3 | 20/223 (9%) | 28 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 40/219 (18.3%) | 46 | 33/223 (14.8%) | 41 |
| Hypokalaemia | 20/219 (9.1%) | 23 | 13/223 (5.8%) | 17 |
| Hypomagnesaemia | 13/219 (5.9%) | 13 | 0/223 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 41/219 (18.7%) | 55 | 31/223 (13.9%) | 37 |
| Back pain | 20/219 (9.1%) | 22 | 14/223 (6.3%) | 20 |
| Bone pain | 17/219 (7.8%) | 25 | 8/223 (3.6%) | 8 |
| Muscle spasms | 14/219 (6.4%) | 16 | 20/223 (9%) | 21 |
| Musculoskeletal pain | 20/219 (9.1%) | 22 | 10/223 (4.5%) | 10 |
| Myalgia | 37/219 (16.9%) | 41 | 28/223 (12.6%) | 42 |
| Pain in extremity | 13/219 (5.9%) | 16 | 15/223 (6.7%) | 15 |
| Nervous system disorders | ||||
| Dizziness | 27/219 (12.3%) | 30 | 22/223 (9.9%) | 28 |
| Dysgeusia | 44/219 (20.1%) | 58 | 31/223 (13.9%) | 39 |
| Headache | 37/219 (16.9%) | 53 | 68/223 (30.5%) | 95 |
| Hypoaesthesia | 19/219 (8.7%) | 21 | 7/223 (3.1%) | 9 |
| Neuropathy peripheral | 29/219 (13.2%) | 36 | 21/223 (9.4%) | 37 |
| Paraesthesia | 23/219 (10.5%) | 28 | 11/223 (4.9%) | 14 |
| Peripheral sensory neuropathy | 26/219 (11.9%) | 26 | 26/223 (11.7%) | 27 |
| Psychiatric disorders | ||||
| Depression | 16/219 (7.3%) | 17 | 10/223 (4.5%) | 10 |
| Insomnia | 31/219 (14.2%) | 37 | 36/223 (16.1%) | 40 |
| Anxiety | 14/219 (6.4%) | 15 | 13/223 (5.8%) | 15 |
| Reproductive system and breast disorders | ||||
| Breast pain | 12/219 (5.5%) | 13 | 17/223 (7.6%) | 18 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 21/219 (9.6%) | 26 | 30/223 (13.5%) | 38 |
| Dyspnoea | 18/219 (8.2%) | 21 | 18/223 (8.1%) | 22 |
| Epistaxis | 24/219 (11%) | 31 | 49/223 (22%) | 82 |
| Oropharyngeal pain | 11/219 (5%) | 17 | 10/223 (4.5%) | 11 |
| Rhinorrhoea | 12/219 (5.5%) | 16 | 11/223 (4.9%) | 14 |
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 146/219 (66.7%) | 149 | 37/223 (16.6%) | 38 |
| Dermatitis acneiform | 16/219 (7.3%) | 16 | 12/223 (5.4%) | 14 |
| Dry skin | 27/219 (12.3%) | 32 | 30/223 (13.5%) | 32 |
| Nail discolouration | 20/219 (9.1%) | 21 | 0/223 (0%) | 0 |
| Nail disorder | 11/219 (5%) | 13 | 2/223 (0.9%) | 2 |
| Pruritus | 26/219 (11.9%) | 34 | 20/223 (9%) | 22 |
| Rash | 57/219 (26%) | 77 | 43/223 (19.3%) | 60 |
| Erythema | 8/219 (3.7%) | 10 | 16/223 (7.2%) | 18 |
| Vascular disorders | ||||
| Hot flush | 45/219 (20.5%) | 47 | 22/223 (9.9%) | 25 |
| Hypertension | 15/219 (6.8%) | 18 | 14/223 (6.3%) | 14 |
Limitations/Caveats
The reported results are interim only.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-La Roche |
| Phone | 800 821-8590 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT02131064
Other Study ID Numbers:
- BO28408
- TRIO021
- 2012-004879-38
First Posted:
May 6, 2014
Last Update Posted:
Jul 2, 2019
Last Verified:
Jun 1, 2019