Metastatic Breast Cancer
Conditions
Keywords
Trastuzumab DM1 (T-DM1), Trastuzumab emtansine, Armed Herceptin, HER2, HER2+, HER2 Positive Breast Cancer
Brief summary
This Phase Ib-IIa, multi-institutional, open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics and feasibility of trastuzumab emtansine (T-DM1) administered by intravenous (IV) infusion in combination with paclitaxel (and pertuzumab, if applicable) in patients with human epidermal growth factor receptor 2-positive (HER2-positive), locally advanced or metastatic breast cancer.
Interventions
DRUGpaclitaxel
Intravenous repeating dose
Intravenous repeating dose
Intravenous escalating dose
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically documented HER2-positive locally advanced or metastatic breast cancer * Tumor tissue blocks or 15-20 unstained tissue slides for confirmatory central laboratory HER2 status testing and other exploratory assessments * Prior trastuzumab in any line of therapy (Phase Ib patients only) * No prior T-DM1 or pertuzumab therapy * Measurable or evaluable disease * Cardiac ejection fraction \>=50% by either echocardiogram or multigated acquisition scan * Life expectancy \>= 90 days as assessed by the investigator
Exclusion criteria
* Fewer than 21 days since the last anti-tumor therapy, including chemotherapy, biologic, experimental, immune, hormonal or radiotherapy for the treatment of breast cancer, with the following exceptions: hormone-replacement therapy or oral contraceptives are allowed; palliative radiation therapy involving \<=25% of marrow-bearing bone is allowed if completed within \>= 14 days prior to first study treatment * History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab, murine proteins, or any of the excipients that resulted in trastuzumab being permanently discontinued * Peripheral neuropathy of Grade \>= 2 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase Ib patients) * Peripheral neuropathy of Grade \>/=1 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase IIa patients) * History of exposure to the following cumulative doses of anthracyclines: Doxorubicin \> 500 mg/m\^2; Liposomal doxorubicin \> 900 mg/m\^2; Epirubicin \> 720 mg/m\^2 * History of clinically significant cardiac dysfunction * Brain metastases that are untreated, or progressive, or have required any type of therapy (including radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment. * History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, basal cell carcinoma, or synchronous or subsequent HER2-positive breast cancer or other malignancy with a similar expected curative outcome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Change From Baseline in Cardiac Function | Baseline (30 days prior to study dose), end of Cycle 2, and then every three cycles in Phase Ib and every four cycles in Phase IIa throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first | Change in cardiac functions i.e., left ventricular ejection fraction (LVEF) and segmental wall abnormalities were assessed by echocardiogram or multigated acquisition scans. LVEF was assessed as change from baseline as 0 to \<15%, \>=15 to \<25%, \>=25%, and missing values. |
| Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | Plasma AUC0-inf of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1). |
| An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | Plasma t1/2 of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1). |
| Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | Plasma CL of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis for in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1). |
| An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-inf\]) X (AUMC\[0-inf\])/AUC\[0-inf\]) where D is the dose of study drug, AUMC(0-inf) is the area under the first moment curve extrapolated to infinity and AUC(0-inf) is the area under the plasma concentration-time curve from time zero to infinite time. The Vss of paclitaxel (65 mg/m2 and 80 mg/m2) is observed in Cycle 1 (in the absence of T-DM1) and Cycle 2 (in the presence of T-DM1). |
| Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. |
| Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment | Up to 23 days | DLT is defined as one of the following toxicities related to study drug during Cycle 1, according to the NCI CTCAE, Version 3: Grade 3 or higher non-hematologic AEs; Grade 3 or higher elevation of serum bilirubin, hepatic transaminases, or alkaline phosphatase; Grade 4 or higher thrombocytopenia; Grade 4 or higher neutropenia; any subjectively intolerable toxicity related to T-DM1, paclitaxel, or pertuzumab; any treatment-related toxicity prohibiting the start of the second cycle of treatment and/or prompting to a dose delay or modification during the DLT observation period, such as prompting a dose reduction at Cycle 2 Day1. |
| Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | Days 1 to 21 | The MTD was defined as the highest dose of T-DM1 and paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when T-DM1 (Q3W or QW) and paclitaxel (QW) was administered with and without pertuzumab treatment. |
| Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | Days 1 to 21 | The MTD was defined as the highest dose of paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when paclitaxel (QW) and T-DM1 (Q3W or QW) was administered with and without pertuzumab treatment. |
| Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab | From Day 1 to 15 weeks | Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B. |
| Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later | Participants were assessed for toxicity prior to each dose of T-DM1 and paclitaxel; dosing occurred only if the clinical assessment and laboratory test values were acceptable. Dose modifications included dose delayed or any dose reduction. Participants in whom significant toxicities had not recovered to the treatment range defined by the dose modification guidelines at the time of their next scheduled dose, had their dose of T-DM1 and/or paclitaxel delayed or reduced for up to 21 days. |
| Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | Cmax of serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W. |
| Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W. |
| Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Pre- and post-dose (0.25 and 4 hours and Day 8 [before paclitaxel infusion) for Cycle 1 and pre- and post-dose (0.25 and 4 hours) for Cycle 2 (each cycle of 21 days) | AUC0-21 for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W. |
| Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | Cmax for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis when T-DM1 was administered QW. |
| Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose) | Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW |
| Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose) | AUClast for serum T-DM1 and serum total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW |
| Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | Plasma Cmax of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) for Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1) was estimated by non-compartmental analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Objective Response | Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first | Duration of OR is only calculated for participants with OR and is defined as the time from the first tumor assessment that supports the participant's OR to disease progression or death. |
| Percentage of Participants With Clinical Benefit | Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first | Clinical benefit is defined as CR, PR, or stable disease (SD) of 6 months or more duration as assessed by the investigator. CR and PR are identified in previous outcome measure. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. PD is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. |
| Progression-free Survival (PFS) | Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first | PFS is defined as the time from the first day of study treatment to documented disease progression or death on study i.e., death due to any cause within 30-days of last dose of study treatment, whichever occurs first. |
| Percentage of Participants With Objective Response Rate (ORR) | Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first | Participants with measurable disease (at least one lesion 2 centimeters \[cm\] or more on computed tomography (CT) scan or 1 cm or more on spiral CT scan) were considered for OR. ORR is defined as the percentage of patients with a complete response (CR)/partial response (PR) determined on two consecutive tumor assessments at least 4 weeks apart based on modified Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). CR defined as disappearance of all target and non-target lesions and normalization of tumor marker level. PR defined as at least 30 percent decrease in sum of the longest diameters of the target lesions taking as reference the baseline sum longest diameters. |
Countries
United States
Participant flow
Recruitment details
This study was conducted from 21 Jul 2009 to 04 Jun 2013 at 5 centers (4 centers for Phase Ib and 5 centers for Phase IIa) in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib Regimen 1 Participants received T-DM1 Q3W + paclitaxel QW intravenously. | 26 |
| Phase Ib Regimen 2 Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. | 10 |
| Phase Ib Regimen 3 Participants received T-DM1 QW + paclitaxel QW intravenously. | 21 |
| Phase Ib Regimen 4 Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. | 3 |
| Phase IIa Group A Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW intravenously. | 22 |
| Phase IIa Group B Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW + pertuzumab Q3W intravenously. | 22 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1b | Adverse Event | 2 | 1 | 0 | 1 | 0 | 0 |
| Phase 1b | Death | 1 | 0 | 2 | 0 | 0 | 0 |
| Phase 1b | Disease Progression | 13 | 2 | 14 | 0 | 0 | 0 |
| Phase 1b | Physician Decision | 4 | 0 | 1 | 0 | 0 | 0 |
| Phase 1b | Protocol Violation | 2 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 2a | Adverse Event | 0 | 0 | 0 | 0 | 2 | 0 |
| Phase 2a | Death | 0 | 0 | 0 | 0 | 1 | 1 |
| Phase 2a | Disease Progression | 0 | 0 | 0 | 0 | 6 | 5 |
| Phase 2a | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 |
| Phase 2a | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2a | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Phase Ib Regimen 1 | Phase Ib Regimen 2 | Phase Ib Regimen 3 | Phase Ib Regimen 4 | Phase IIa Group A | Phase IIa Group B | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 12.3 | 51.3 years STANDARD_DEVIATION 11.9 | 54.1 years STANDARD_DEVIATION 8.5 | 49.3 years STANDARD_DEVIATION 4 | 51.7 years STANDARD_DEVIATION 11.8 | 55.1 years STANDARD_DEVIATION 7.7 | 53.2 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 26 Participants | 10 Participants | 19 Participants | 3 Participants | 21 Participants | 22 Participants | 101 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 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 | 26 / 60 | 10 / 10 | 21 / 21 | 3 / 3 | 22 / 22 | 22 / 22 |
| serious Total, serious adverse events | 7 / 26 | 5 / 10 | 7 / 21 | 2 / 3 | 6 / 22 | 6 / 22 |
Outcome results
Primary
An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-inf\]) X (AUMC\[0-inf\])/AUC\[0-inf\]) where D is the dose of study drug, AUMC(0-inf) is the area under the first moment curve extrapolated to infinity and AUC(0-inf) is the area under the plasma concentration-time curve from time zero to infinite time. The Vss of paclitaxel (65 mg/m2 and 80 mg/m2) is observed in Cycle 1 (in the absence of T-DM1) and Cycle 2 (in the presence of T-DM1).
Time frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. n denotes number of participants who received the indicated study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 1 (n = 29) | 167 L/m^2 | Standard Deviation 56.3 |
| Phase Ib Regimen 1 | An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 2 (n = 24) | 220 L/m^2 | Standard Deviation 57.3 |
| Phase Ib Regimen 1 | An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 1 (n = 18) | 166 L/m^2 | Standard Deviation 78.9 |
| Phase Ib Regimen 1 | An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 2 (n = 17) | 196 L/m^2 | Standard Deviation 56.5 |
Primary
An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)
Plasma t1/2 of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Time frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. n denotes number of participants who received the indicated study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 2 (n = 17) | 10.8 hr | Standard Deviation 30.8 |
| Phase Ib Regimen 1 | An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 1 (n = 29) | 9.89 hr | Standard Deviation 17.1 |
| Phase Ib Regimen 1 | An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 2 (n = 24) | 11.7 hr | Standard Deviation 25.1 |
| Phase Ib Regimen 1 | An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 1 (n = 18) | 8.94 hr | Standard Deviation 20 |
Primary
Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)
Plasma AUC0-inf of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Time frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. n denotes number of participants who received the indicated study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 1 (n = 29) | 3440 hr*ng/mL | Standard Deviation 32.3 |
| Phase Ib Regimen 1 | Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 2 (n = 24) | 3520 hr*ng/mL | Standard Deviation 38 |
| Phase Ib Regimen 1 | Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 1 (n = 18) | 3890 hr*ng/mL | Standard Deviation 48 |
| Phase Ib Regimen 1 | Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 2 (n = 17) | 4220 hr*ng/mL | Standard Deviation 49.8 |
Primary
Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen
AUC0-21 for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Time frame: Pre- and post-dose (0.25 and 4 hours and Day 8 [before paclitaxel infusion) for Cycle 1 and pre- and post-dose (0.25 and 4 hours) for Cycle 2 (each cycle of 21 days)
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 241 day*mcg/mL | Standard Deviation 57.2 |
| Phase Ib Regimen 1 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 633 day*mcg/mL | Standard Deviation 496 |
| Phase Ib Regimen 2 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 216 day*mcg/mL | Standard Deviation 118 |
| Phase Ib Regimen 2 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 518 day*mcg/mL | Standard Deviation 359 |
| Phase Ib Regimen 3 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 264 day*mcg/mL | Standard Deviation 77.4 |
| Phase Ib Regimen 3 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 460 day*mcg/mL | Standard Deviation 308 |
| Phase Ib Regimen 4 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 401 day*mcg/mL | Standard Deviation 249 |
| Phase Ib Regimen 4 | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 271 day*mcg/mL | Standard Deviation 51.2 |
| Phase IIa Group A | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 382 day*mcg/mL | Standard Deviation 140 |
| Phase IIa Group A | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 959 day*mcg/mL | Standard Deviation 609 |
| Phase IIa Group B | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 523 day*mcg/mL | Standard Deviation 288 |
| Phase IIa Group B | Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 764 day*mcg/mL | Standard Deviation 372 |
Primary
Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
AUClast for serum T-DM1 and serum total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW
Time frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose)
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 275 day*µg/mL | Standard Deviation 170 |
| Phase Ib Regimen 1 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 84.6 day*µg/mL | Standard Deviation 15.2 |
| Phase Ib Regimen 2 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 91.9 day*µg/mL | Standard Deviation 41.8 |
| Phase Ib Regimen 2 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 149 day*µg/mL | Standard Deviation 94.1 |
| Phase Ib Regimen 3 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 295 day*µg/mL | Standard Deviation 121 |
| Phase Ib Regimen 3 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 150 day*µg/mL | Standard Deviation 28.3 |
| Phase Ib Regimen 4 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 242 day*µg/mL | Standard Deviation 18 |
| Phase Ib Regimen 4 | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 460 day*µg/mL | Standard Deviation 250 |
| Phase IIa Group A | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 270 day*µg/mL | Standard Deviation 62.2 |
| Phase IIa Group A | Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 165 day*µg/mL | Standard Deviation 42.4 |
Primary
Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen
Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Time frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase Ib Regimen 1 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | 2.4 nano gram per milliliter (ng/mL) |
| Phase Ib Regimen 2 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | 3.4 nano gram per milliliter (ng/mL) |
| Phase Ib Regimen 3 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | 2.7 nano gram per milliliter (ng/mL) |
| Phase Ib Regimen 4 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | 3.2 nano gram per milliliter (ng/mL) |
| Phase IIa Group A | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen | 5.1 nano gram per milliliter (ng/mL) |
Primary
Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen
Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW
Time frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose)
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase Ib Regimen 1 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | 1.0 ng/mL |
| Phase Ib Regimen 2 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | 1.8 ng/mL |
| Phase Ib Regimen 3 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | 3.0 ng/mL |
| Phase Ib Regimen 4 | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | 2.7 ng/mL |
| Phase IIa Group A | Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen | 4.0 ng/mL |
Primary
Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)
Plasma Cmax of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) for Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1) was estimated by non-compartmental analysis.
Time frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. n denotes number of participants who received the indicated study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) | 65 mg, Cycle 1 (n = 29) | 1430 ng/mL | Standard Deviation 53.5 |
| Phase Ib Regimen 1 | Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) | 65 mg, Cycle 2 (n = 24) | 1280 ng/mL | Standard Deviation 59.8 |
| Phase Ib Regimen 1 | Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) | 80 mg, Cycle 1 (n = 18) | 1540 ng/mL | Standard Deviation 64.4 |
| Phase Ib Regimen 1 | Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) | 80 mg, Cycle 2 (n = 17) | 1590 ng/mL | Standard Deviation 56.7 |
Primary
Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen
Cmax of serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Time frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Population: Pharmacokinetics (PK) population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 53.5 microgram per millilitre (Mcg /mL) | Standard Deviation 3.1 |
| Phase Ib Regimen 1 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 73.9 microgram per millilitre (Mcg /mL) | Standard Deviation 33.4 |
| Phase Ib Regimen 2 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 44.9 microgram per millilitre (Mcg /mL) | Standard Deviation 4.8 |
| Phase Ib Regimen 2 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 61 microgram per millilitre (Mcg /mL) | Standard Deviation 23.2 |
| Phase Ib Regimen 3 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 43.6 microgram per millilitre (Mcg /mL) | Standard Deviation 16.3 |
| Phase Ib Regimen 3 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 62 microgram per millilitre (Mcg /mL) | Standard Deviation 15.2 |
| Phase Ib Regimen 4 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 54.6 microgram per millilitre (Mcg /mL) | Standard Deviation 13.6 |
| Phase Ib Regimen 4 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 55.2 microgram per millilitre (Mcg /mL) | Standard Deviation 12.3 |
| Phase IIa Group A | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 62.2 microgram per millilitre (Mcg /mL) | Standard Deviation 18.9 |
| Phase IIa Group A | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 91 microgram per millilitre (Mcg /mL) | Standard Deviation 45.4 |
| Phase IIa Group B | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | T-DM1 | 76.1 microgram per millilitre (Mcg /mL) | Standard Deviation 31.5 |
| Phase IIa Group B | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen | Total trastuzumab | 87.4 microgram per millilitre (Mcg /mL) | Standard Deviation 39.5 |
Primary
Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
Cmax for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis when T-DM1 was administered QW.
Time frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 24.3 mcg/mL | Standard Deviation 2.61 |
| Phase Ib Regimen 1 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 57.8 mcg/mL | Standard Deviation 31.7 |
| Phase Ib Regimen 2 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 39.9 mcg/mL | Standard Deviation 24.1 |
| Phase Ib Regimen 2 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 26 mcg/mL | Standard Deviation 11.2 |
| Phase Ib Regimen 3 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 66.1 mcg/mL | Standard Deviation 25.2 |
| Phase Ib Regimen 3 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 39.4 mcg/mL | Standard Deviation 7.09 |
| Phase Ib Regimen 4 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 97.6 mcg/mL | Standard Deviation 45.7 |
| Phase Ib Regimen 4 | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 63.7 mcg/mL | Standard Deviation 8.72 |
| Phase IIa Group A | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | Total trastuzumab | 92.1 mcg/mL | Standard Deviation 69.4 |
| Phase IIa Group A | Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen | T-DM1 | 87.8 mcg/mL | Standard Deviation 75.3 |
Primary
Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
The MTD was defined as the highest dose of paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when paclitaxel (QW) and T-DM1 (Q3W or QW) was administered with and without pertuzumab treatment.
Time frame: Days 1 to 21
Population: Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 80 mg/m^2 |
| Phase Ib Regimen 2 | Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 80 mg/m^2 |
| Phase Ib Regimen 3 | Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 80 mg/m^2 |
| Phase Ib Regimen 4 | Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 80 mg/m^2 |
Primary
Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
The MTD was defined as the highest dose of T-DM1 and paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when T-DM1 (Q3W or QW) and paclitaxel (QW) was administered with and without pertuzumab treatment.
Time frame: Days 1 to 21
Population: Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 3.6 mg/kg |
| Phase Ib Regimen 2 | Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 3.6 mg/kg |
| Phase Ib Regimen 3 | Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 2.4 mg/kg |
| Phase Ib Regimen 4 | Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab | 2.4 mg/kg |
Primary
Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab
Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.
Time frame: From Day 1 to 15 weeks
Population: Safety Population: All participants of the phase IIa part of the study who received at least a single dose of study medication and did not have disease progression in the first 12 weeks of study treatment were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab | 11 participants |
| Phase Ib Regimen 2 | Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab | 11 participants |
Primary
Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel
Participants were assessed for toxicity prior to each dose of T-DM1 and paclitaxel; dosing occurred only if the clinical assessment and laboratory test values were acceptable. Dose modifications included dose delayed or any dose reduction. Participants in whom significant toxicities had not recovered to the treatment range defined by the dose modification guidelines at the time of their next scheduled dose, had their dose of T-DM1 and/or paclitaxel delayed or reduced for up to 21 days.
Time frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
Population: Safety Population: All participants who received at least a single dose of study medication were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib Regimen 1 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 20 participants |
| Phase Ib Regimen 1 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 13 participants |
| Phase Ib Regimen 2 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 5 participants |
| Phase Ib Regimen 2 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 7 participants |
| Phase Ib Regimen 3 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 19 participants |
| Phase Ib Regimen 3 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 14 participants |
| Phase Ib Regimen 4 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 3 participants |
| Phase Ib Regimen 4 | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 2 participants |
| Phase IIa Group A | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 18 participants |
| Phase IIa Group A | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 15 participants |
| Phase IIa Group B | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | Paclitaxel | 19 participants |
| Phase IIa Group B | Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel | T-DM1 | 12 participants |
Primary
Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.
Time frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
Population: Safety Population: All participants who received at least a single dose of study medication were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 7 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | NA participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 1 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 3 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 20 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 0 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 26 participants |
| Phase Ib Regimen 1 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 19 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 5 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 5 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 1 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 0 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 10 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 7 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | 1 participants |
| Phase Ib Regimen 2 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 2 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 21 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 14 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 2 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 7 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 15 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 1 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 1 participants |
| Phase Ib Regimen 3 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | NA participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 1 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 3 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 3 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 1 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 2 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 2 participants |
| Phase Ib Regimen 4 | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | 1 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 1 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 22 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 13 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 6 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | NA participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 2 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 13 participants |
| Phase IIa Group A | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 6 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to pertuzumab discontinuation | 0 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Death | 1 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 4 | 2 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs Grade 3 | 13 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any AEs | 22 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | Any SAEs | 6 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to T-DM1 discontinuation | 0 participants |
| Phase IIa Group B | Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death | AEs leading to paclitaxel discontinuation | 13 participants |
Primary
Number of Participants With Change From Baseline in Cardiac Function
Change in cardiac functions i.e., left ventricular ejection fraction (LVEF) and segmental wall abnormalities were assessed by echocardiogram or multigated acquisition scans. LVEF was assessed as change from baseline as 0 to \<15%, \>=15 to \<25%, \>=25%, and missing values.
Time frame: Baseline (30 days prior to study dose), end of Cycle 2, and then every three cycles in Phase Ib and every four cycles in Phase IIa throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first
Population: Safety Population: All participants who received at least a single dose of study medication were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib Regimen 1 | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 0 participants |
| Phase Ib Regimen 1 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 0 participants |
| Phase Ib Regimen 1 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 8 participants |
| Phase Ib Regimen 1 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 1 participants |
| Phase Ib Regimen 1 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 17 participants |
| Phase Ib Regimen 2 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 7 participants |
| Phase Ib Regimen 2 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 0 participants |
| Phase Ib Regimen 2 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 3 participants |
| Phase Ib Regimen 2 | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 1 participants |
| Phase Ib Regimen 2 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 0 participants |
| Phase Ib Regimen 3 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 5 participants |
| Phase Ib Regimen 3 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 0 participants |
| Phase Ib Regimen 3 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 14 participants |
| Phase Ib Regimen 3 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 2 participants |
| Phase Ib Regimen 3 | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 3 participants |
| Phase IIa Group A | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 15 participants |
| Phase IIa Group A | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 3 participants |
| Phase IIa Group A | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 0 participants |
| Phase IIa Group A | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 2 participants |
| Phase IIa Group A | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 5 participants |
| Phase IIa Group B | Number of Participants With Change From Baseline in Cardiac Function | LVEF, missing | 0 participants |
| Phase IIa Group B | Number of Participants With Change From Baseline in Cardiac Function | New segmental wall abnormality | 1 participants |
| Phase IIa Group B | Number of Participants With Change From Baseline in Cardiac Function | LVEF, increase | 4 participants |
| Phase IIa Group B | Number of Participants With Change From Baseline in Cardiac Function | LVEF, 0 to <15% | 18 participants |
| Phase IIa Group B | Number of Participants With Change From Baseline in Cardiac Function | LVEF, >=15 to <25% | 0 participants |
Primary
Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment
DLT is defined as one of the following toxicities related to study drug during Cycle 1, according to the NCI CTCAE, Version 3: Grade 3 or higher non-hematologic AEs; Grade 3 or higher elevation of serum bilirubin, hepatic transaminases, or alkaline phosphatase; Grade 4 or higher thrombocytopenia; Grade 4 or higher neutropenia; any subjectively intolerable toxicity related to T-DM1, paclitaxel, or pertuzumab; any treatment-related toxicity prohibiting the start of the second cycle of treatment and/or prompting to a dose delay or modification during the DLT observation period, such as prompting a dose reduction at Cycle 2 Day1.
Time frame: Up to 23 days
Population: Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included. Participants in Phase 1b (Regimen 1, Regimen 2, Regimen 3 and Regimen 4 \[60 participants\]) were considered for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment | 0 participants |
| Phase Ib Regimen 2 | Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment | 0 participants |
| Phase Ib Regimen 3 | Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment | 0 participants |
| Phase Ib Regimen 4 | Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment | 0 participants |
Primary
Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)
Plasma CL of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis for in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).
Time frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Population: PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. n denotes number of participants who received the indicated study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib Regimen 1 | Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 1 (n = 29) | 20.7 L/hr/m^2 | Standard Deviation 31.1 |
| Phase Ib Regimen 1 | Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 65 mg, Cycle 2 (n = 24) | 21 L/hr/m^2 | Standard Deviation 36.4 |
| Phase Ib Regimen 1 | Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 1 (n = 18) | 22.8 L/hr/m^2 | Standard Deviation 51.1 |
| Phase Ib Regimen 1 | Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) | 80 mg, Cycle 2 (n = 17) | 23 L/hr/m^2 | Standard Deviation 44.1 |
Secondary
Duration of Objective Response
Duration of OR is only calculated for participants with OR and is defined as the time from the first tumor assessment that supports the participant's OR to disease progression or death.
Time frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first
Population: An efficacy population: All participants who received at least a single dose of study medication were included. Participants with OR were considered for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib Regimen 1 | Duration of Objective Response | 7.1 months |
| Phase Ib Regimen 2 | Duration of Objective Response | NA months |
| Phase Ib Regimen 3 | Duration of Objective Response | 7.0 months |
| Phase Ib Regimen 4 | Duration of Objective Response | NA months |
| Phase IIa Group A | Duration of Objective Response | NA months |
| Phase IIa Group B | Duration of Objective Response | NA months |
Secondary
Percentage of Participants With Clinical Benefit
Clinical benefit is defined as CR, PR, or stable disease (SD) of 6 months or more duration as assessed by the investigator. CR and PR are identified in previous outcome measure. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. PD is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first
Population: An efficacy population: All participants who received at least a single dose of study medication were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Percentage of Participants With Clinical Benefit | 65.4 percentage of participants |
| Phase Ib Regimen 2 | Percentage of Participants With Clinical Benefit | 80.0 percentage of participants |
| Phase Ib Regimen 3 | Percentage of Participants With Clinical Benefit | 61.9 percentage of participants |
| Phase Ib Regimen 4 | Percentage of Participants With Clinical Benefit | 66.7 percentage of participants |
| Phase IIa Group A | Percentage of Participants With Clinical Benefit | 54.5 percentage of participants |
| Phase IIa Group B | Percentage of Participants With Clinical Benefit | 59.1 percentage of participants |
Secondary
Percentage of Participants With Objective Response Rate (ORR)
Participants with measurable disease (at least one lesion 2 centimeters \[cm\] or more on computed tomography (CT) scan or 1 cm or more on spiral CT scan) were considered for OR. ORR is defined as the percentage of patients with a complete response (CR)/partial response (PR) determined on two consecutive tumor assessments at least 4 weeks apart based on modified Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). CR defined as disappearance of all target and non-target lesions and normalization of tumor marker level. PR defined as at least 30 percent decrease in sum of the longest diameters of the target lesions taking as reference the baseline sum longest diameters.
Time frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first
Population: An efficacy population: All participants who received at least a single dose of study medication were included. Participants with measurable disease were considered for OR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib Regimen 1 | Percentage of Participants With Objective Response Rate (ORR) | 50.0 percentage of participants |
| Phase Ib Regimen 2 | Percentage of Participants With Objective Response Rate (ORR) | 70.0 percentage of participants |
| Phase Ib Regimen 3 | Percentage of Participants With Objective Response Rate (ORR) | 50.0 percentage of participants |
| Phase Ib Regimen 4 | Percentage of Participants With Objective Response Rate (ORR) | 66.7 percentage of participants |
| Phase IIa Group A | Percentage of Participants With Objective Response Rate (ORR) | 47.6 percentage of participants |
| Phase IIa Group B | Percentage of Participants With Objective Response Rate (ORR) | 52.4 percentage of participants |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from the first day of study treatment to documented disease progression or death on study i.e., death due to any cause within 30-days of last dose of study treatment, whichever occurs first.
Time frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first
Population: An efficacy population: All participants who received at least a single dose of study medication were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib Regimen 1 | Progression-free Survival (PFS) | 11.7 months |
| Phase Ib Regimen 2 | Progression-free Survival (PFS) | 11.9 months |
| Phase Ib Regimen 3 | Progression-free Survival (PFS) | 11.3 months |
| Phase Ib Regimen 4 | Progression-free Survival (PFS) | 11.0 months |
| Phase IIa Group A | Progression-free Survival (PFS) | 6.0 months |
| Phase IIa Group B | Progression-free Survival (PFS) | 6.6 months |