A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer

Study Overview
=================
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.

Official Title
-----------------
A Phase Ib-IIa, Open-label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of Trastuzumab Emtansine, Paclitaxel and Pertuzumab Administered Intravenously to Patients With Her2-positive, Locally Advanced or Metastatic Breast Cancer

Conditions
-----------------
Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: paclitaxel
* Drug: pertuzumab [Perjeta]
* Drug: trastuzumab emtansine [Kadcyla]
* Drug: paclitaxel
* Drug: trastuzumab emtansine [Kadcyla]


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase lb Regimen 1<br>Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously. | Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous escalating dose<br>Drug: paclitaxel<br>* Intravenous escalating dose<br>|
| Experimental: Phase Ib Regimen 2<br>Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. | Drug: pertuzumab [Perjeta]<br>* Intravenous repeating dose<br>Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous escalating dose<br>Drug: paclitaxel<br>* Intravenous escalating dose<br>|
| Experimental: Phase Ib Regimen 3<br>Participants received T-DM1 QW + paclitaxel QW intravenously. | Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous escalating dose<br>Drug: paclitaxel<br>* Intravenous escalating dose<br>|
| Experimental: Phase Ib Regimen 4<br>Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. | Drug: pertuzumab [Perjeta]<br>* Intravenous repeating dose<br>Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous escalating dose<br>Drug: paclitaxel<br>* Intravenous escalating dose<br>|
| Experimental: Phase IIa Group A<br>Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously. | Drug: paclitaxel<br>* Intravenous repeating dose<br>Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous repeating dose<br>|
| Experimental: Phase IIa Group B<br>Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously. | Drug: paclitaxel<br>* Intravenous repeating dose<br>Drug: pertuzumab [Perjeta]<br>* Intravenous repeating dose<br>Drug: trastuzumab emtansine [Kadcyla]<br>* Intravenous repeating dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later | 
| 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. | Up to 23 days | 
| 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. | Days 1 to 21 | 
| 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. | Days 1 to 21 | 
| 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. | From Day 1 to 15 weeks | 
| 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. | Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later | 
| 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. | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | 
| 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. | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | 
| 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. | 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) | 
| 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. | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) | 
| 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 | Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose) | 
| 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 | Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose) | 
| 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. | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | 
| 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). | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | 
| 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). | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | 
| 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). | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | 
| 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). | Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 | 
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Trastuzumab DM1 (T-DM1), Trastuzumab emtansine, Armed Herceptin, HER2, HER2+, HER2 Positive Breast Cancer