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)

1. Patients must have a history of histologically or cytologically confirmed AGC and must

have experienced documented objective radiographic or pathologic disease progression

during or after first-line therapy for their disease.

2. HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ alone

or IHC 2+ in combination with ISH+, prospectively confirmed by a Sponsor-designated

central laboratory prior to enrollment. ISH positivity is defined as a ratio of ≥2.0 for the

number of HER2 gene copies to the number of signals for CEP17.

a) Archival tumor samples obtained from primary or metastatic sites (original diagnostic

specimens) are preferred.

b) The block or slides should include a representative part of the tumor with an invasive

tumor area for central confirmation of HER2 status.

i. If formalin-fixed paraffin-embedded (FFPE) tissue blocks (or partial block)

are unavailable due to country or site regulations, a minimum of 8 freshly cut

unstained slides MUST be available for central review of HER2 status and up to

5 additional slides for mandatory biomarker research, if sufficient tissue is available.

3. Patients must have received at least one prior chemotherapy regimen for AGC; prior

therapy does not need to have included HER2-directed therapy.

4. Adjuvant or neoadjuvant chemotherapy or chemoradiation therapy for AGC is allowed.

Patients whose AGC progresses or recurs in less than 6 months after completion of their

adjuvant or neoadjuvant therapy are allowed to participate. In these cases, the adjuvant or

neoadjuvant therapy will count as one prior therapy.

General inclusion criteria

Age ≥ 18 years

7. ECOG performance status of 0 or 1.

8. Life expectancy of at least 12 weeks from the first dose of study treatment

9. Adequate organ function as determined by the following laboratory results, within 14 days

prior to randomization

a) Neutrophils ≥ 1500 cells/mm3

b) Platelets ≥ 100,000 cells/mm3

c) Hemoglobin ≥ 9.0 g/dL; patients may receive red blood cell transfusions to attain this

concentration

d) Serum creatinine ≤ 1.5 times the upper limit of normal (ULN)

e) INR < 1.5 and aPTT < 1.5 × ULN (unless on therapeutic anticoagulation medication)

f) Serum AST or ALT < 2.5 × ULN; if bone metastases are present and alkaline

phosphatase > 2.5 × ULN, AST and ALT must be < 1.5 × ULN

g) Serum alkaline phosphatase may be > 2.5 × ULN only if bone metastases are present

and both AST and ALT < 1.5 × ULN

h) Serum total bilirubin < 1.5 × ULN. Patients with increased total bilirubin > 1.5 × ULN

due to Gilbert’s syndrome are allowed if the direct (conjugated) bilirubin level is within

normal limits.

10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests,

and other study procedures, specifically including protocol specified pharmacokinetic

(PK) sampling.

Pregnancy test if the patient is of childbearing potential (including premenopausal women

who have had a tubal ligation)

a) A serum ß-human chorionic gonadotropin (ß-HCG) pregnancy test must be performed

at screening for women of childbearing potential, and for all women not meeting the

definition of postmenopausal (≥ 12 months of amenorrhea) and who have not

undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy.

Patients with a negative serum pregnancy test but a positive urine pregnancy test are

not eligible.

b) Subsequent tests will be urine pregnancy tests. Any positive urine pregnancy test

result must be confirmed by a serum ß-HCG test.

c) For all other women, documentation must be present in medical history confirming that

the patient is not of childbearing potential.

12. Women of childbearing potential and men with partners of childbearing potential must be

willing to use a highly effective, non-hormonal form of contraception or two effective forms

of contraception by the patient and/or partner and continue its use for the duration of study

treatment and for 6 months after the last dose of study treatment.