Breast Cancer
Conditions
Brief summary
This is an open-label, multi-center, non-randomized study of the safety and tolerability of the combination of T-DM1 plus docetaxel for the treatment of participants with metastatic breast cancer (MBC) and of T-DM1 plus docetaxel with or without pertuzumab, for the treatment of participants with locally advanced breast cancer (LABC). The study comprises an initial dose finding (feasibility) part to determine the maximum tolerated dose (MTD) of T-DM1 and docetaxel, followed by an extension part aiming to consolidate the safety and efficacy of the recommended docetaxel/T-DM1 combination regimen.
Interventions
DRUGDocetaxel
Docetaxel will be administered on Day 1 of each 3-week cycle at a dose specified in the respective arms (as per summary of product characteristics \[SmPC\]).
DRUGPertuzumab
Pertuzumab at a loading dose of 840 mg IV infusion on Day 1 of Cycle 1 followed by maintenance dose of 420 mg IV infusion on Day 1 of each 3-week cycle.
DRUGTrastuzumab emtansine
T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (ECOG performance status of 2 will be allowed if only due to debilitating bone disease) * HER2-positive metastatic or locally advanced breast cancer For MBC participants: * Documented metastatic or inoperable locally advanced (without meeting LABC criteria) disease, amenable for treatment with docetaxel * History of disease progression within 3 months prior to study entry For LABC participants: * Newly diagnosed locally advanced breast cancer, Stage IIA-IIIC (American Joint Committee on Cancer \[AJCC\] staging system)
Exclusion criteria
* Significant cardiac disease * Inadequate bone marrow, liver or renal function For MBC participants: * Participants must not have received radiotherapy for the treatment of metastatic or locally recurrent/advanced disease other than for the relief of pain in progressing metastatic bone lesions and/or brain metastases * Brain metastases that are untreated, symptomatic or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastasis within 2 months of the first study treatment. For LABC participants: * Clinically or radiologically detectable metastasis (M1 disease) * Participants for whom surgery as primary intent procedure is the best option to treat their disease * Participants must not have received any systemic or loco-regional anti-cancer therapy for the treatment of locally advanced disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | Cycle 1 (up to 21 days) | DLTs included (as per National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] grading): Grade 4 thrombocytopenia, thrombocytopenia of any grade with concurrent hemorrhage or requiring blood platelet transfusion, or thrombocytopenia not recovered by Day 21 to at least 100,000/microliter (mcL); Grade 4 neutropenia lasting for more than 7 days; Febrile neutropenia; Grade greater than or equal to (\>/=) 3 neurotoxicity in the form of peripheral neuropathy or peripheral neurotoxicity not improving to baseline or Grade less than or equal to (\</=) 1 by Day 21; Any non-hematological toxicity of Grade \>/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade \</=1 by Day 21, despite adequate toxicity management; Any subjective intolerable toxicity felt by the investigator to be related to either study treatment; Any other treatment-related toxicity prohibiting the start of the Cycle 2 on Day 22; Fulminant skin rash. |
| Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | Baseline up to 28 days after last dose for MBC participants and for LABC participants who could not undergo surgery, and up to 6 weeks post-surgery for LABC participants who underwent surgery (maximum up to approximately 3 years) | An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population | Baseline until disease progression or recurrence (up to approximately 3 years) | BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% confidence interval (Cl) was determined using the Pearson-Clopper method. |
| Percentage of Participants With Treatment Failure - MBC Population | Baseline until end of treatment (up to 39.8 months) | Treatment failure was defined as the discontinuation of treatment for any reason, including the following qualifying events: PD, death from any cause, withdrawal from study treatment, or initiation of nonprotocol anti-cancer therapy. Percentage of participants with treatment failure was calculated as the (number of participants with treatment failure) divided by (total number of participants), and then multiplied by 100. |
| Time to Treatment Failure (TTF) - MBC Population | Baseline until end of treatment (up to 39.8 months) | TTF was defined as the time interval between the date of start of treatment and the date of PD, death from any cause, withdrawal from study treatment, or initiation of non-protocol anti-cancer therapy, whichever occurred first. Participants without an event at the time of the analysis were censored at the date of the last follow-up assessment. Median TTF was estimated using the Kaplan-Meier method. |
| Percentage of Participants With CR or PR or Stable Disease (SD) for at Least 6 Months [Clinical Benefit Rate (CBR)] - MBC Population | Baseline until disease progression, recurrence or death (up to approximately 3 years) | CBR was defined as percentage of participants experiencing SD of at least 6 months from the start of treatment plus CR or PR according to the RECIST v1.0 criteria. For TLs: CR- disappearance of all TLs. PR- at least 30% decrease in the sum of LDs of the TLs, taking as a reference the BL sum of LDs. PD- at least 20% increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. SD- neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For NTLs: CR- disappearance of all NTLs and normalization of tumor marker levels. SD- persistence of one or more NTLs and/or maintenance of tumor marker level above the normal limits. Percentage of participants= number of participants with CR/PR/SD divided by total number of participants, and then multiplied by 100. 95% CI was determined using the Pearson-Clopper method. |
| Duration of Response - MBC Population | Baseline until disease progression, recurrence or death (up to approximately 3 years) | Duration of response was calculated for participants with CR or PR based on the RECIST v1.0 criteria. Duration of response was defined as the time interval between the date the CR or PR was first recorded and the date on which PD was first noted or date of death, whichever occurred first. Participants with no documented PD after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. Median duration of response was estimated using the Kaplan-Meier method. |
| Percentage of Participants With Pathological CR (pCR) - LABC Population | Within 6 weeks of post-surgery (up to approximately 3 years) | The pCR was defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants and lymph nodes after surgery following primary systemic therapy. |
| Percentage of Participants With a BOR of CR or PR - LABC Population | Baseline until disease progression, recurrence or death (up to approximately 3 years) | BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method. |
| Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population | Baseline (Day 1 of Cycle 1), Post baseline (at first follow-up visit [28 days after last dose of study drug][up to approximately 145 weeks]) | Number of participants with ATA response was reported. Data for this outcome measure was planned to be reported for overall MBC and LABC participants and not by individual treatment arms. |
| Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 1: pre-dose (Hour [Hr] 0), 0.25, 4 hrs post end of infusion (EOI) of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Percentage of Participants With Progression-Free Survival (PFS) Event - MBC Population | Baseline until disease progression or death (up to approximately 3 years) | PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of progressive disease (PD) or death from any cause, whichever occurred first. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 (v1.0). For target lesions (TLs), PD was at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For non-target lesions (NTLs), PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Data for participants without PD or death was censored at the time of the last response assessment. Percentage of participants with PFS event was calculated as the (number of participants with PFS event \[PD or death\]) divided by (total number of participants), and then multiplied by 100. |
| t1/2 of Total Serum Trastuzumab | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| AUCinf of Total Serum Trastuzumab | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| CL of Total Serum Trastuzumab | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Vss of Total Serum Trastuzumab | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | DM1 is the metabolite of trastuzumab emtansine. |
| t1/2 of Plasma DM1 | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| AUCinf of Plasma DM1 | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| Cmax of Plasma Docetaxel | Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days) | Docetaxel infusion duration = 1 hr (as per summary of product characteristics \[SmPC\]) |
| CL of Plasma Docetaxel | Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days) | Docetaxel infusion duration = 1 hr (as per SmPC) |
| t1/2 of Plasma Docetaxel | Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days) | Docetaxel infusion duration = 1 hr (as per SmPC) |
| AUCinf of Plasma Docetaxel | Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days) | Docetaxel infusion duration = 1 hr (as per SmPC) |
| Vss of Plasma Docetaxel | Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days) | Docetaxel infusion duration = 1 hr (as per SmPC) |
| Cmax of Total Serum Trastuzumab | Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs) | — |
| PFS - MBC Population | Baseline until disease progression or death (up to approximately 3 years) | PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of PD or death from any cause, whichever occurred first. Response was based on RECIST v1.0. For TLs, PD was at least a 20 % increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For NTLs, PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Median PFS time was calculated using Kaplan-Meier estimates. Data for participants without PD or death was censored at the time of the last response assessment. |
Countries
France, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Overall 152 participants were screened, of which 98 participants were enrolled (25 participants with metastatic breast cancer \[MBC\] and 73 participants with locally advanced breast cancer \[LABC\]) and included in the study.
Participants by arm
| Arm | Count |
|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) Feasibility part: Participants with HER2-positive MBC received docetaxel 75 mg/m\^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m\^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m\^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | 6 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m\^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m\^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | 6 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m\^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | 3 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) Feasibility and extension part: Participants with HER2-positive MBC received docetaxel 60 mg/m\^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m\^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | 10 |
| LABC: T-DM1 + Doc (Doublet Regimen) Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m\^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. | 40 |
| LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m\^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. | 33 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension Part | Adverse Event | 0 | 0 | 0 | 1 | 4 | 4 |
| Extension Part | Non-compliance with drug | 0 | 0 | 0 | 0 | 0 | 1 |
| Extension Part | Progressive disease | 0 | 0 | 0 | 1 | 0 | 0 |
| Feasibility Part | Adverse Event | 1 | 1 | 0 | 1 | 0 | 2 |
| Feasibility Part | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Feasibility Part | Progressive disease | 4 | 4 | 2 | 3 | 0 | 0 |
| Feasibility Part | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | LABC: T-DM1 + Doc (Doublet Regimen) | LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 7.16 | 50.7 years STANDARD_DEVIATION 4.84 | 57 years STANDARD_DEVIATION 12.12 | 48 years STANDARD_DEVIATION 9.39 | 48.6 years STANDARD_DEVIATION 9.73 | 54.2 years STANDARD_DEVIATION 11.43 | 50.4 years STANDARD_DEVIATION 10.39 |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 3 Participants | 10 Participants | 40 Participants | 33 Participants | 98 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 3 / 3 | 10 / 10 | 40 / 40 | 33 / 33 |
| serious Total, serious adverse events | 2 / 6 | 2 / 6 | 2 / 3 | 4 / 10 | 9 / 40 | 9 / 33 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population
DLTs included (as per National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] grading): Grade 4 thrombocytopenia, thrombocytopenia of any grade with concurrent hemorrhage or requiring blood platelet transfusion, or thrombocytopenia not recovered by Day 21 to at least 100,000/microliter (mcL); Grade 4 neutropenia lasting for more than 7 days; Febrile neutropenia; Grade greater than or equal to (\>/=) 3 neurotoxicity in the form of peripheral neuropathy or peripheral neurotoxicity not improving to baseline or Grade less than or equal to (\</=) 1 by Day 21; Any non-hematological toxicity of Grade \>/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade \</=1 by Day 21, despite adequate toxicity management; Any subjective intolerable toxicity felt by the investigator to be related to either study treatment; Any other treatment-related toxicity prohibiting the start of the Cycle 2 on Day 22; Fulminant skin rash.
Time frame: Cycle 1 (up to 21 days)
Population: MBC and LABC feasibility population: All participants who received at least one dose of study medication and included in the feasibility part of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 2 participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 1 participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 0 participants |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 1 participants |
| LABC: T-DM1 + Doc (Doublet Regimen) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 2 participants |
| LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) | Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population | 2 participants |
Primary
Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population
An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.
Time frame: Baseline up to 28 days after last dose for MBC participants and for LABC participants who could not undergo surgery, and up to 6 weeks post-surgery for LABC participants who underwent surgery (maximum up to approximately 3 years)
Population: All participants who received at least one dose of study medication were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 33.3 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 33.3 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 66.7 percentage of participants |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 40.0 percentage of participants |
| LABC: T-DM1 + Doc (Doublet Regimen) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| LABC: T-DM1 + Doc (Doublet Regimen) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 22.5 percentage of participants |
| LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | AEs | 100 percentage of participants |
| LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) | Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population | SAEs | 27.3 percentage of participants |
Secondary
Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 1 | 2.79 days | Standard Deviation 0.637 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 2 | 3.14 days | Standard Deviation 0.574 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 1 | 3.45 days | Standard Deviation 0.779 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 2 | 3.85 days | Standard Deviation 0.568 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 1 | 3.46 days | Standard Deviation 0.558 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine | Cycle 2 | 3.62 days | Standard Deviation 0.516 |
Secondary
Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 1 | 396 day*mcg/mL | Standard Deviation 124 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 2 | 471 day*mcg/mL | Standard Deviation 94.5 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 1 | 447 day*mcg/mL | Standard Deviation 144 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 2 | 556 day*mcg/mL | Standard Deviation 223 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 1 | 442 day*mcg/mL | Standard Deviation 90.7 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine | Cycle 2 | 488 day*mcg/mL | Standard Deviation 123 |
Secondary
AUCinf of Plasma DM1
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Plasma DM1 | Cycle 1 | 5.72 day*ng/mL | Standard Deviation 5.16 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Plasma DM1 | Cycle 2 | 17.8 day*ng/mL | Standard Deviation 4.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Plasma DM1 | Cycle 1 | 5.01 day*ng/mL | Standard Deviation 2.54 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Plasma DM1 | Cycle 2 | 20 day*ng/mL | — |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma DM1 | Cycle 1 | 9.38 day*ng/mL | Standard Deviation 9.33 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma DM1 | Cycle 2 | 18.5 day*ng/mL | Standard Deviation 4.28 |
Secondary
AUCinf of Plasma Docetaxel
Docetaxel infusion duration = 1 hr (as per SmPC)
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Plasma Docetaxel | Cycle 1 | 1050 hr*ng/mL | Standard Deviation 475 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Plasma Docetaxel | Cycle 2 | 1700 hr*ng/mL | Standard Deviation 1190 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Plasma Docetaxel | Cycle 2 | 1710 hr*ng/mL | Standard Deviation 875 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Plasma Docetaxel | Cycle 1 | 1560 hr*ng/mL | Standard Deviation 874 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma Docetaxel | Cycle 2 | 3260 hr*ng/mL | Standard Deviation 5100 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma Docetaxel | Cycle 1 | 1540 hr*ng/mL | Standard Deviation 421 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma Docetaxel | Cycle 1 | 2140 hr*ng/mL | Standard Deviation 669 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Plasma Docetaxel | Cycle 2 | 2420 hr*ng/mL | Standard Deviation 887 |
| LABC: T-DM1 + Doc (Doublet Regimen) | AUCinf of Plasma Docetaxel | Cycle 2 | 3840 hr*ng/mL | Standard Deviation 1930 |
| LABC: T-DM1 + Doc (Doublet Regimen) | AUCinf of Plasma Docetaxel | Cycle 1 | 4020 hr*ng/mL | Standard Deviation 2120 |
Secondary
AUCinf of Total Serum Trastuzumab
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Total Serum Trastuzumab | Cycle 1 | 785 day*mcg/mL | Standard Deviation 429 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | AUCinf of Total Serum Trastuzumab | Cycle 2 | 809 day*mcg/mL | Standard Deviation 308 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Total Serum Trastuzumab | Cycle 1 | 707 day*mcg/mL | Standard Deviation 201 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | AUCinf of Total Serum Trastuzumab | Cycle 2 | 1040 day*mcg/mL | Standard Deviation 359 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Total Serum Trastuzumab | Cycle 1 | 1210 day*mcg/mL | Standard Deviation 856 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | AUCinf of Total Serum Trastuzumab | Cycle 2 | 1570 day*mcg/mL | Standard Deviation 1180 |
Secondary
Clearance (CL) of Serum Trastuzumab Emtansine
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 1 | 8.94 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 12 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 2 | 5.21 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 1.27 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 1 | 8.87 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 2.96 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 2 | 7.16 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 2.95 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 1 | 8.48 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 1.86 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Clearance (CL) of Serum Trastuzumab Emtansine | Cycle 2 | 7.68 milliliters/day/kilogram (mL/day/kg) | Standard Deviation 2.73 |
Secondary
CL of Plasma Docetaxel
Docetaxel infusion duration = 1 hr (as per SmPC)
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | CL of Plasma Docetaxel | Cycle 1 | 82.2 liters/hour/square meter (L/hr/m^2) | Standard Deviation 32.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | CL of Plasma Docetaxel | Cycle 2 | 59 liters/hour/square meter (L/hr/m^2) | Standard Deviation 29.9 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | CL of Plasma Docetaxel | Cycle 1 | 58.3 liters/hour/square meter (L/hr/m^2) | Standard Deviation 40.9 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | CL of Plasma Docetaxel | Cycle 2 | 51.2 liters/hour/square meter (L/hr/m^2) | Standard Deviation 38.5 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Plasma Docetaxel | Cycle 1 | 42.8 liters/hour/square meter (L/hr/m^2) | Standard Deviation 16.4 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Plasma Docetaxel | Cycle 2 | 32.6 liters/hour/square meter (L/hr/m^2) | Standard Deviation 13.1 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Plasma Docetaxel | Cycle 2 | 33.6 liters/hour/square meter (L/hr/m^2) | Standard Deviation 11.9 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Plasma Docetaxel | Cycle 1 | 39.5 liters/hour/square meter (L/hr/m^2) | Standard Deviation 16.8 |
| LABC: T-DM1 + Doc (Doublet Regimen) | CL of Plasma Docetaxel | Cycle 1 | 30.5 liters/hour/square meter (L/hr/m^2) | Standard Deviation 14.5 |
| LABC: T-DM1 + Doc (Doublet Regimen) | CL of Plasma Docetaxel | Cycle 2 | 27.9 liters/hour/square meter (L/hr/m^2) | Standard Deviation 9.13 |
Secondary
CL of Total Serum Trastuzumab
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | CL of Total Serum Trastuzumab | Cycle 1 | 6.78 mL/day/kg | Standard Deviation 13.3 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | CL of Total Serum Trastuzumab | Cycle 2 | 3.32 mL/day/kg | Standard Deviation 1.53 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | CL of Total Serum Trastuzumab | Cycle 1 | 5.45 mL/day/kg | Standard Deviation 1.46 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | CL of Total Serum Trastuzumab | Cycle 2 | 3.71 mL/day/kg | Standard Deviation 1.23 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Total Serum Trastuzumab | Cycle 1 | 4.22 mL/day/kg | Standard Deviation 2.13 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | CL of Total Serum Trastuzumab | Cycle 2 | 3.38 mL/day/kg | Standard Deviation 2.11 |
Secondary
Cmax of Plasma Docetaxel
Docetaxel infusion duration = 1 hr (as per summary of product characteristics \[SmPC\])
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Plasma Docetaxel | Cycle 1 | 500 ng/mL | Standard Deviation 216 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Plasma Docetaxel | Cycle 2 | 791 ng/mL | Standard Deviation 637 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Plasma Docetaxel | Cycle 1 | 1300 ng/mL | Standard Deviation 829 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Plasma Docetaxel | Cycle 2 | 1320 ng/mL | Standard Deviation 826 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma Docetaxel | Cycle 1 | 1470 ng/mL | Standard Deviation 551 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma Docetaxel | Cycle 2 | 1590 ng/mL | Standard Deviation 441 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma Docetaxel | Cycle 2 | 1960 ng/mL | Standard Deviation 552 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma Docetaxel | Cycle 1 | 1710 ng/mL | Standard Deviation 426 |
| LABC: T-DM1 + Doc (Doublet Regimen) | Cmax of Plasma Docetaxel | Cycle 1 | 2950 ng/mL | Standard Deviation 1540 |
| LABC: T-DM1 + Doc (Doublet Regimen) | Cmax of Plasma Docetaxel | Cycle 2 | 2790 ng/mL | Standard Deviation 979 |
Secondary
Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1)
DM1 is the metabolite of trastuzumab emtansine.
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 1 | 3.55 nanograms per milliliter (ng/mL) | Standard Deviation 1.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 2 | 3.34 nanograms per milliliter (ng/mL) | Standard Deviation 0.815 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 1 | 3.42 nanograms per milliliter (ng/mL) | Standard Deviation 0.944 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 2 | 3.9 nanograms per milliliter (ng/mL) | Standard Deviation 1.19 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 1 | 4.51 nanograms per milliliter (ng/mL) | Standard Deviation 1.38 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cycle 2 | 4.65 nanograms per milliliter (ng/mL) | Standard Deviation 1.57 |
Secondary
Cmax of Total Serum Trastuzumab
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Total Serum Trastuzumab | Cycle 1 | 88.7 mcg/mL | Standard Deviation 22.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Cmax of Total Serum Trastuzumab | Cycle 2 | 85.8 mcg/mL | Standard Deviation 17.5 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Total Serum Trastuzumab | Cycle 1 | 89.2 mcg/mL | Standard Deviation 47.4 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Cmax of Total Serum Trastuzumab | Cycle 2 | 97.7 mcg/mL | Standard Deviation 29.4 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Total Serum Trastuzumab | Cycle 1 | 120 mcg/mL | Standard Deviation 46.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Cmax of Total Serum Trastuzumab | Cycle 2 | 113 mcg/mL | Standard Deviation 43.8 |
Secondary
Duration of Response - MBC Population
Duration of response was calculated for participants with CR or PR based on the RECIST v1.0 criteria. Duration of response was defined as the time interval between the date the CR or PR was first recorded and the date on which PD was first noted or date of death, whichever occurred first. Participants with no documented PD after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. Median duration of response was estimated using the Kaplan-Meier method.
Time frame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
Population: MBC population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Duration of Response - MBC Population | 12.4 months |
Secondary
Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine
Time frame: Cycle 1: pre-dose (Hour [Hr] 0), 0.25, 4 hrs post end of infusion (EOI) of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: Pharmacokinetic (PK) analysis population: PK-evaluable participants were defined as participants who received at least one dose of T-DM1 or docetaxel with at least one post-dose concentration data point. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 1 | 78.6 micrograms per milliliter (mcg/mL) | Standard Deviation 16.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 2 | 78.7 micrograms per milliliter (mcg/mL) | Standard Deviation 16.7 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 1 | 76.2 micrograms per milliliter (mcg/mL) | Standard Deviation 36.4 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 2 | 93.7 micrograms per milliliter (mcg/mL) | Standard Deviation 27.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 1 | 85.7 micrograms per milliliter (mcg/mL) | Standard Deviation 15.3 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine | Cycle 2 | 80.2 micrograms per milliliter (mcg/mL) | Standard Deviation 18.4 |
Secondary
Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population
Number of participants with ATA response was reported. Data for this outcome measure was planned to be reported for overall MBC and LABC participants and not by individual treatment arms.
Time frame: Baseline (Day 1 of Cycle 1), Post baseline (at first follow-up visit [28 days after last dose of study drug][up to approximately 145 weeks])
Population: All participants who received at least one dose of study medication were included. Here, number analyzed=participants evaluable for ATA at specified time-point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population | Baseline | 3 participants |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population | Post-baseline | 3 participants |
Secondary
Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population
BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% confidence interval (Cl) was determined using the Pearson-Clopper method.
Time frame: Baseline until disease progression or recurrence (up to approximately 3 years)
Population: MBC population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population | 80.0 percentage of participants |
Secondary
Percentage of Participants With a BOR of CR or PR - LABC Population
BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time frame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
Population: LABC population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With a BOR of CR or PR - LABC Population | 70.0 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Percentage of Participants With a BOR of CR or PR - LABC Population | 51.5 percentage of participants |
Secondary
Percentage of Participants With CR or PR or Stable Disease (SD) for at Least 6 Months [Clinical Benefit Rate (CBR)] - MBC Population
CBR was defined as percentage of participants experiencing SD of at least 6 months from the start of treatment plus CR or PR according to the RECIST v1.0 criteria. For TLs: CR- disappearance of all TLs. PR- at least 30% decrease in the sum of LDs of the TLs, taking as a reference the BL sum of LDs. PD- at least 20% increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. SD- neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For NTLs: CR- disappearance of all NTLs and normalization of tumor marker levels. SD- persistence of one or more NTLs and/or maintenance of tumor marker level above the normal limits. Percentage of participants= number of participants with CR/PR/SD divided by total number of participants, and then multiplied by 100. 95% CI was determined using the Pearson-Clopper method.
Time frame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
Population: MBC population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With CR or PR or Stable Disease (SD) for at Least 6 Months [Clinical Benefit Rate (CBR)] - MBC Population | 92.0 percentage of participants |
Secondary
Percentage of Participants With Pathological CR (pCR) - LABC Population
The pCR was defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants and lymph nodes after surgery following primary systemic therapy.
Time frame: Within 6 weeks of post-surgery (up to approximately 3 years)
Population: LABC population: All participants with LABC who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With Pathological CR (pCR) - LABC Population | 60.0 percentage of participants |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Percentage of Participants With Pathological CR (pCR) - LABC Population | 60.6 percentage of participants |
Secondary
Percentage of Participants With Progression-Free Survival (PFS) Event - MBC Population
PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of progressive disease (PD) or death from any cause, whichever occurred first. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 (v1.0). For target lesions (TLs), PD was at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For non-target lesions (NTLs), PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Data for participants without PD or death was censored at the time of the last response assessment. Percentage of participants with PFS event was calculated as the (number of participants with PFS event \[PD or death\]) divided by (total number of participants), and then multiplied by 100.
Time frame: Baseline until disease progression or death (up to approximately 3 years)
Population: MBC population: All participants with MBC who received at least one dose of study medication were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With Progression-Free Survival (PFS) Event - MBC Population | 60.0 percentage of participants |
Secondary
Percentage of Participants With Treatment Failure - MBC Population
Treatment failure was defined as the discontinuation of treatment for any reason, including the following qualifying events: PD, death from any cause, withdrawal from study treatment, or initiation of nonprotocol anti-cancer therapy. Percentage of participants with treatment failure was calculated as the (number of participants with treatment failure) divided by (total number of participants), and then multiplied by 100.
Time frame: Baseline until end of treatment (up to 39.8 months)
Population: MBC population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Percentage of Participants With Treatment Failure - MBC Population | 64.0 percentage of participants |
Secondary
PFS - MBC Population
PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of PD or death from any cause, whichever occurred first. Response was based on RECIST v1.0. For TLs, PD was at least a 20 % increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For NTLs, PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Median PFS time was calculated using Kaplan-Meier estimates. Data for participants without PD or death was censored at the time of the last response assessment.
Time frame: Baseline until disease progression or death (up to approximately 3 years)
Population: MBC population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | PFS - MBC Population | 13.8 months |
Secondary
t1/2 of Plasma DM1
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Plasma DM1 | Cycle 1 | 1.12 days | Standard Deviation 0.702 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Plasma DM1 | Cycle 2 | 3.75 days | Standard Deviation 0.912 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Plasma DM1 | Cycle 1 | 1.2 days | Standard Deviation 0.985 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Plasma DM1 | Cycle 2 | 2.91 days | — |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma DM1 | Cycle 1 | 1.87 days | Standard Deviation 1.63 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma DM1 | Cycle 2 | 3.32 days | Standard Deviation 0.7 |
Secondary
t1/2 of Plasma Docetaxel
Docetaxel infusion duration = 1 hr (as per SmPC)
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Plasma Docetaxel | Cycle 1 | 6.83 hours (hr) | Standard Deviation 4.22 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Plasma Docetaxel | Cycle 2 | 7.7 hours (hr) | Standard Deviation 4.15 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Plasma Docetaxel | Cycle 1 | 5.17 hours (hr) | Standard Deviation 4.02 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Plasma Docetaxel | Cycle 2 | 7.88 hours (hr) | Standard Deviation 6.18 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma Docetaxel | Cycle 1 | 4.25 hours (hr) | Standard Deviation 5.61 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma Docetaxel | Cycle 2 | 5.9 hours (hr) | Standard Deviation 3.83 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma Docetaxel | Cycle 2 | 6.69 hours (hr) | Standard Deviation 5.55 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Plasma Docetaxel | Cycle 1 | 8.29 hours (hr) | Standard Deviation 5.75 |
| LABC: T-DM1 + Doc (Doublet Regimen) | t1/2 of Plasma Docetaxel | Cycle 1 | 8.76 hours (hr) | Standard Deviation 3.82 |
| LABC: T-DM1 + Doc (Doublet Regimen) | t1/2 of Plasma Docetaxel | Cycle 2 | 7.24 hours (hr) | Standard Deviation 3.58 |
Secondary
t1/2 of Total Serum Trastuzumab
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Total Serum Trastuzumab | Cycle 1 | 6.44 days | Standard Deviation 2.6 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | t1/2 of Total Serum Trastuzumab | Cycle 2 | 6.67 days | Standard Deviation 1.92 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Total Serum Trastuzumab | Cycle 1 | 6.38 days | Standard Deviation 1.41 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | t1/2 of Total Serum Trastuzumab | Cycle 2 | 7.83 days | Standard Deviation 1.68 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Total Serum Trastuzumab | Cycle 1 | 8.12 days | Standard Deviation 4.2 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | t1/2 of Total Serum Trastuzumab | Cycle 2 | 9.91 days | Standard Deviation 5.01 |
Secondary
Time to Treatment Failure (TTF) - MBC Population
TTF was defined as the time interval between the date of start of treatment and the date of PD, death from any cause, withdrawal from study treatment, or initiation of non-protocol anti-cancer therapy, whichever occurred first. Participants without an event at the time of the analysis were censored at the date of the last follow-up assessment. Median TTF was estimated using the Kaplan-Meier method.
Time frame: Baseline until end of treatment (up to 39.8 months)
Population: MBC population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Time to Treatment Failure (TTF) - MBC Population | 13.8 months |
Secondary
Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 1 | 22.1 mL/kg | Standard Deviation 6.74 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 2 | 17.7 mL/kg | Standard Deviation 4.73 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 1 | 33.2 mL/kg | Standard Deviation 9.13 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 2 | 31.4 mL/kg | Standard Deviation 16.9 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 1 | 33.2 mL/kg | Standard Deviation 8.36 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine | Cycle 2 | 28.8 mL/kg | Standard Deviation 9.32 |
Secondary
Vss of Plasma Docetaxel
Docetaxel infusion duration = 1 hr (as per SmPC)
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Vss of Plasma Docetaxel | Cycle 1 | 530 liters per square meter (L/m^2) | Standard Deviation 398 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Vss of Plasma Docetaxel | Cycle 2 | 380 liters per square meter (L/m^2) | Standard Deviation 257 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Vss of Plasma Docetaxel | Cycle 1 | 203 liters per square meter (L/m^2) | Standard Deviation 275 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Vss of Plasma Docetaxel | Cycle 2 | 253 liters per square meter (L/m^2) | Standard Deviation 234 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Plasma Docetaxel | Cycle 1 | 75 liters per square meter (L/m^2) | Standard Deviation 113 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Plasma Docetaxel | Cycle 2 | 93.2 liters per square meter (L/m^2) | Standard Deviation 64.7 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Plasma Docetaxel | Cycle 2 | 79 liters per square meter (L/m^2) | Standard Deviation 53.6 |
| MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Plasma Docetaxel | Cycle 1 | 126 liters per square meter (L/m^2) | Standard Deviation 86.7 |
| LABC: T-DM1 + Doc (Doublet Regimen) | Vss of Plasma Docetaxel | Cycle 1 | 116 liters per square meter (L/m^2) | Standard Deviation 73.3 |
| LABC: T-DM1 + Doc (Doublet Regimen) | Vss of Plasma Docetaxel | Cycle 2 | 84.8 liters per square meter (L/m^2) | Standard Deviation 39.1 |
Secondary
Vss of Total Serum Trastuzumab
Time frame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Population: PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Vss of Total Serum Trastuzumab | Cycle 2 | 24.6 mL/kg | Standard Deviation 5.05 |
| MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) | Vss of Total Serum Trastuzumab | Cycle 1 | 27 mL/kg | Standard Deviation 7.16 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Vss of Total Serum Trastuzumab | Cycle 1 | 41.3 mL/kg | Standard Deviation 9.24 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) | Vss of Total Serum Trastuzumab | Cycle 2 | 36.4 mL/kg | Standard Deviation 11.3 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Total Serum Trastuzumab | Cycle 2 | 35.2 mL/kg | Standard Deviation 12 |
| MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) | Vss of Total Serum Trastuzumab | Cycle 1 | 36.5 mL/kg | Standard Deviation 12.7 |