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.
Treatment can be stopped due to disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination.
Brief Title
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
Categories
Completion Date
Completion Date Type
Actual
Conditions
Breast Neoplasms
Eligibility Criteria
Inclusion Criteria:
* Histologically confirmed invasive breast cancer with a primary tumor size of greater than (\>) 2 cm
* HER2-positive breast cancer
* Participants with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as HER2 positive
* Stage at presentation: cT2-cT4, cN0-cN3, cM0, according to American Joint Committee on Cancer (AJCC) staging system
* Known hormone receptor status of the primary tumor
* Participant agreement to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Baseline Left Ventricular Ejection Fraction (LVEF) \>/= 55 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
* Effective contraception as defined by protocol
Exclusion Criteria:
* Stage IV (metastatic) breast cancer
* Participants who have received prior anti-cancer therapy for breast cancer except those participants with a history of breast lobular carcinoma in situ (LCIS) that was surgically managed or ductal carcinoma in situ (DCIS) treated exclusively with mastectomy. In case of prior history of LCIS/DCIS, \>5 years must have passed from surgery until diagnosis of current breast cancer
* Participants with multicentric (multiple tumors involving more than 1 quadrant) or bilateral breast cancer
* Participants who have undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
* Axillary lymph node dissection or positive sentinel lymph node prior to start of neoadjuvant therapy
* History of concurrent or previously non-breast malignancies except for appropriately treated (1) non-melanoma skin cancer and (2) in situ carcinomas, including cervix, colon, and skin. A participant with previous invasive non-breast cancer is eligible provided he/she has been disease-free \>/= 5 years
* Treatment with any investigational drug within 28 days prior to randomization
* Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0
* Any significant concurrent medical or surgical conditions or findings that would jeopardize the participant's safety or ability to complete the study
* Current pregnancy or breastfeeding
* 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
Inclusion Criteria
Inclusion Criteria:
* Histologically confirmed invasive breast cancer with a primary tumor size of greater than (\>) 2 cm
* HER2-positive breast cancer
* Participants with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as HER2 positive
* Stage at presentation: cT2-cT4, cN0-cN3, cM0, according to American Joint Committee on Cancer (AJCC) staging system
* Known hormone receptor status of the primary tumor
* Participant agreement to undergo mastectomy or breast-conserving surgery after neoadjuvant therapy
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Baseline Left Ventricular Ejection Fraction (LVEF) \>/= 55 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA)
* Effective contraception as defined by protocol
* 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02131064
Org Class
Industry
Org Full Name
Hoffmann-La Roche
Org Study Id
BO28408
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome 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.
Outcome Measure
Percentage of Participants With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples
Outcome Time Frame
Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
Secondary Ids
Secondary Id
TRIO021
Secondary Id
2012-004879-38
Secondary Outcomes
Outcome 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.
Outcome Time Frame
From randomization until death (up to approximately 47 months)
Outcome Measure
Overall Survival
Outcome Description
BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer.
Outcome Time Frame
Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)
Outcome Measure
Percentage of Participants Who Received Breast-Conserving Surgery (BCS)
Outcome 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.
Outcome Time Frame
From randomization up to disease progression or recurrence or death (up to approximately 47 months)
Outcome Measure
Event-Free Survival
Outcome 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.
Outcome Time Frame
From surgery to the first documented occurrence of IDFC event (up to approximately 47 months)
Outcome Measure
Invasive Disease-free Survival (IDFS)
Outcome 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.
Outcome 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
Percentage of Participants by Response for Neuropathy Single Item
Outcome 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.
Outcome 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
Percentage of Participants by Response for Skin Problem Single Items
Outcome 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.
Outcome Time Frame
From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Outcome Measure
Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score
Outcome 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.
Outcome Time Frame
From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Outcome Measure
Time to Clinically Meaningful Deterioration in GHS/QoL Score
Outcome 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.
Outcome Time Frame
From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Outcome Measure
Time to Clinically Meaningful Deterioration in Function Subscale
Outcome Description
Only participants who received trastuzumab were to be analyzed for this outcome.
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
Maximum Observed Serum Concentration (Cmax) of Trastuzumab
Outcome Description
Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
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
Cmax of Trastuzumab Emtansine and Total Trastuzumab
Outcome Description
Only participants who received trastuzumab were to be analyzed for this outcome.
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
Minimum Observed Serum Concentration (Cmin) of Trastuzumab
Outcome Description
Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
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
Cmin of Trastuzumab Emtansine and Total Trastuzumab
Outcome Description
DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
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
Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations
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
Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)
Outcome 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
Percentage of Participants With ATA to Trastuzumab
Outcome 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.
Outcome 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
Percentage of Participants by Response for Hair Loss Single Item
Outcome 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.
Outcome Time Frame
Baseline to end of study (approximately 47 months)
Outcome Measure
Percentage of Participants With Selected Adverse Events (AEs)
Outcome 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.
Outcome Time Frame
From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Outcome Measure
Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales
Outcome 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.
Outcome 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
Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1
Outcome 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.
Outcome Time Frame
From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
Outcome Measure
Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jesus Anampa Mesias
Investigator Email
janampa@montefiore.org
Investigator Phone
718-920-4826 / 718-405-8505