Primary Objective

The primary objective for this study is as follows:

• Phase II: To select a trastuzumab emtansine dose and schedule for Phase III assessment

of treatment for human epidermal growth factor receptor 2 (HER2)-positive advanced

gastric cancer (AGC), defined as locally advanced or unresectable or metastatic gastric

cancer, including adenocarcinoma of the gastroesophageal junction (GEJ) on the basis of

safety, pharmacokinetics, and efficacy

• Phase III: To compare the overall survival (OS) of patients treated with trastuzumab

emtansine at the dose and schedule selected in the Phase II portion of the study to that of

patients treated with physician’s choice of taxane (docetaxel or paclitaxel)

Secondary Objectives

The secondary objectives for this study are to compare trastuzumab emtansine with

physician’s choice of taxane with respect to the following parameters:

• Objective response rate (ORR) by investigator assessment among patients with

measurable disease at baseline

• Progression-free survival (PFS) by investigator assessment

• Duration of response (DOR) by investigator assessment

Response distribution of significant treatment-related symptoms, including diarrhea,

swallowing difficulty, sore mouth, hair loss, nausea, and vomiting, as measured with

European Organization for Research and Treatment of Cancer (EORTC) Quality of Life

Questionnaire Core Module 30 (QLQ-C30) and STO22 instruments

• Time to gastric cancer (GC) symptom progression (defined as the time from randomization

to the first documentation of an increase in EORTC QLQ-C30 and QLQ STO22)

for abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain,

change in bowel movement, and weight loss

• Global Health Status/Quality of Life as measured by EORTC QLQ C30• Characterization of clinical safety

Exploratory Objectives

The exploratory objectives for this study are as follows:

• To conduct biomarker analyses and assess for correlations between biomarker status and

efficacy and/or safety, including but not limited to the following:

• To explore whether the level of HER2 gene amplification assessed by in situ hybridization

(ISH) correlates with efficacy of study treatment

• To explore whether the level of HER2 protein expression assessed by

immunohistochemistry (IHC) correlates with efficacy of study treatment

• To evaluate whether low or high HER2/3 messenger RNA (mRNA) expression as

determined by a quantitative reverse transcription–polymerase chain reaction

(qRT PCR) analysis in archival tissue correlates with efficacy

• To explore whether levels of HER family members, other (related) receptor tyrosine

kinases, molecules that are involved directly or indirectly in downstream signaling of

HER2, or ligands of HER family proteins in archival tumor tissue correlate with

trastuzumab emtansine efficacy

• To investigate whether Fcγ receptor polymorphisms correlate with trastuzumab

emtansine efficacy and/or safety

• To conduct an exploratory exposure–effect analysis to investigate the relationship between

the pharmacokinetics of trastuzumab emtansine and clinical efficacy and safety

• To assess the immunogenicity rate/formation of antibodies to trastuzumab emtansine (ATA)

in GC patients

• To assess the effect of serum HER2 extracellular domain (ECD) concentration on

trastuzumab emtansine exposure in GC patients

• To explore differences in treatment-related toxicities using patient-reported outcome (PRO)

Common Terminology Criteria for Adverse Events (CTCAE)