A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Potentially Pertuzumab, in Participants With Advanced Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label, Multi-Center Phase I/II Study of the Safety and Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) With Docetaxel, and Potentially Pertuzumab, for Treatment for Patients With Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Pertuzumab
* Drug: Trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days)<br>Participants with human epidermal growth factor receptor 2 (HER2)-positive MBC will receive docetaxel (Doc) 75 milligrams per square meter (mg/m^2) intravenous (IV) infusion on Day 1 and T-DM1 2.4 milligrams per kilogram (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 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | Drug: Docetaxel<br>* 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]).<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|
| Experimental: MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days)<br>Participants with HER2-positive MBC will receive 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 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | Drug: Docetaxel<br>* 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]).<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|
| Experimental: MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day)<br>Participants with HER2-positive MBC will receive 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 will be stopped and T-DM1 2.4 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | Drug: Docetaxel<br>* 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]).<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|
| Experimental: MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day)<br>Participants with HER2-positive MBC will receive 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 will be stopped and T-DM1 3.6 mg/kg will be continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. | Drug: Docetaxel<br>* 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]).<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|
| Experimental: LABC: T-DM1 + Doc (Doublet Regimen)<br>Participants with HER2-positive LABC will receive 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 will be administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. | Drug: Docetaxel<br>* 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]).<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|
| Experimental: LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)<br>Participants with HER2-positive LABC will receive 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 will be administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. | Drug: Docetaxel<br>* 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]).<br>Drug: Pertuzumab<br>* 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.<br>Drug: Trastuzumab emtansine<br>* T-DM1 will be administered on Day 1 or Day 2 of each 3-week cycle at a dose specified in the respective arms.<br>* Other names: T-DM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (up to 21 days) | 
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline until disease progression or death (up to approximately 3 years) | 
| 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. | Baseline until disease progression or death (up to approximately 3 years) | 
| 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. | Baseline until disease progression or recurrence (up to approximately 3 years) | 
| 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. | Baseline until end of treatment (up to 39.8 months) | 
| 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. | Baseline until end of treatment (up to 39.8 months) | 
| 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. | Baseline until disease progression, recurrence or death (up to approximately 3 years) | 
| 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. | Baseline until disease progression, recurrence or death (up to approximately 3 years) | 
| 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. | Within 6 weeks of post-surgery (up to approximately 3 years) | 
| 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. | Baseline until disease progression, recurrence or death (up to approximately 3 years) | 
| 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. | 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]) | 
| 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) | 
| 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) | 
| 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) | DM1 is the metabolite of 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) | 
| 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 | Docetaxel infusion duration = 1 hr (as per summary of product characteristics [SmPC]) | 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) | 
| t1/2 of Plasma Docetaxel | Docetaxel infusion duration = 1 hr (as per SmPC) | 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) | 
| AUCinf of Plasma Docetaxel | Docetaxel infusion duration = 1 hr (as per SmPC) | 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) | 
| CL of Plasma Docetaxel | Docetaxel infusion duration = 1 hr (as per SmPC) | 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) | 
| Vss of Plasma Docetaxel | Docetaxel infusion duration = 1 hr (as per SmPC) | 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) |