A multicenter, single arm study of trastuzumab emtansine (T-DM1) in HER2 positive locally advanced or metastatic breast cancer patients who have received prior anti-HER2 and chemotherapy-based treatment

Breast cancer (BC) is the most common cancer in women worldwide, both in the
developed and the developing world (WHO, World Health Statistics. 2011), with
approximately 1.38 million new cases diagnosed in 2008. It is also the leading
cause of cancer death in females, accounting for 458,400 deaths (14% of all
cancer deaths) in 2008 (Jemal et al. 2011). Almost 100,000 of these BC-related
deaths occurred in patients whose tumors overexpressed the human epidermal
growth factor receptor 2 (HER2). Metastatic breast cancer (mBC) is incurable,
with the primary goal of treatment to extend life and palliate symptoms while
preserving quality of life.
The HER tyrosine kinase receptor family is comprised of four receptors: HER1,
HER2, HER3, and HER4. These receptors are important mediators of cell growth,
survival, and differentiation (Sundaresan et al. 1999). Activation of HER
receptors leads to receptor dimerization and cell signaling through the
PI3-kinase/AKT pathway for promotion of tumor cell survival and through the
mitogen-activated protein kinase pathway for cellular proliferation.
Overexpression of HER2 is observed in approximately 15-20% of human BCs.
Several lines of scientific and clinical evidence support a direct role for
HER2 overexpression in the aggressive growth and poor clinical outcomes
associated with these tumors (Slamon et al. 1987). The development of
trastuzumab in the 1990s provided women with HER2-overexpressing tumors with a
markedly better outcome than was possible with chemotherapy alone. Increases in
response rate, response duration, and progression free survival (PFS) were
associated with a 5-month survival advantage when trastuzumab was given in the
first-line metastatic setting, as demonstrated in the initial Phase III trial
(Slamon et al. 2001).
For patients with HER2-positive mBC, the combination of trastuzumab and a
taxane is a globally accepted first-line treatment, based on the survival
advantage demonstrated in two large pivotal trials (Slamon et al. 2001; Marty
et al. 2005). However, virtually all patients with HER2-positive mBC develop
progressive disease (PD) and require additional therapies. Importantly, such
tumors continue to express high levels of HER2 (Spector et al. 2005), and
neither the process of internalization nor the level of surface expression is
altered when HER2 is bound by trastuzumab (Austin et al. 2004). HER2-directed
combination therapy beyond progression for HER2-positive mBC is an accepted
palliative treatment approach.

The primary objective of this study is to evaluate the safety and tolerability
of trastuzumab emtansine.

This study is a single-arm, international, multicenter Phase IIIb study to
evaluate the safety and tolerability of trastuzumab emtansine.
This study will enroll patients with HER2 positive, unresectable, locally
advanced or mBC who have previously received prior anti-HER2 and chemotherapy
treatment and have progressed either on metastatic treatment, or within 6
months of completing adjuvant therapy.
Approximately 1000 patients will be enrolled into the study.
The study is estimated to last 4 to 5 years. Enrollment is estimated to take 2
years. The follow-up period will last 2 years after the last patient first
visit. Patients will receive study medication until unacceptable toxicity,
withdrawal of consent, disease progression, death, or up to a maximum of 2
years after last patient first visit, whichever occurs first. Patients who have
not progressed at the end of the trial will be offered options to continue with
trastuzumab emtansine treatment, see Section 4.2.4
The study design is presented in Figure 2. The schedule of assessments is
provided in Appendix 1.
All patients will be followed-up until study closure for survival every 6
months until death, loss to follow-up or withdrawal of consent. Patients who
discontinue study treatment for reasons other than disease progression will
continue to undergo tumor assessments every 3-6 months until study closure.

Trastuzumab emtansine will be administered intravenously every 3 weeks at a
dose of 3.6 mg/kg.

The following assessments are done during the study: Screening/Baseline:
Informed Consent • Submission of tumor tissue to test for HER-2 positivity •
Submission of tumor tissue for research purposes (other than HER-2 positivity
testing) • Medical history (including demographics) • Physical exam including
height (screening only) and weight • Heart function tests (ECG, ECHO or MUGA)
at screening and if necessary according to judgement of physician • Scans (CT
or MRI) and X-ray (at screening) • Blood tests (Screening and each treatment
cycle) • Blood samples for research purposes (at screening) • Medical history •
Vital signs (blood pressure, pulse, temperature) during screening and each
visit •Pregnancy test during screening and once per 3 cycles • Performance
status (questionnaire about ability to carry on daily activities) during
screening and specific visits • General health status will be performed at any
side effects that a patient has experienced • AEs / SAEs • Concomitant therapy
during Study • A small amount of pain can be experienced with both the MUGA
heart scan and bone scans when the tracer (a radioactive chemical which emits a
type of radioactivity) is injected but otherwise the test is painless • There
is a slight
risk of developing an allergic reaction to the contrast material or the tracer.
The reaction can be mild (itching, rash) or severe (difficulty breathing or
sudden shock). Death resulting from an allergic reaction is rare. Most
reactions can be controlled using medication • The extra radiation involved in
the MUGA and bone scans is very small and comparable to receiving a standard
chest X-ray.

The following common side effects (>= 10% of Patients) were seen with
Trastuzumab Emtansine: Dyspnea difficulty breathing while resting, Fatigue,
Lack or loss of strength, Skin rash, Nose bleed, Fever, Chills, Cough,
Insomnia, Nausea, vomiting, constipation, diarrhea, abdominal pain, Dry mouth,
sores in mouth, Temporary abnormal liver function tests, Low numbers of
platelets, Low numbers of red blood cells and hemoglobin, Neuropathy in arms
and legs (tingling, pain, numbness, itching, pins and needles), Low potassium
in blood, Pain in joints and muscle, Headache. The following side effects (>=
1% to <10% of Patients) were seen with Trastuzumab Emtansine: Heart disorders:
ejection fraction decreased, High blood pressure, Dry eye, increased tears,
blurred vision, pinkeye, Edema (arms and legs), Itchy skin, Dizziness, Altered
taste sensation, Upset stomach or indigestion, Neutropenia, High levels
alkaline phosphatase in blood, Reaction to infusion and hypersensitivity
(allergic reaction). Rare but Serious (< 1% of Patients): Pneumonitis
(inflammation of the lung), Severe liver dysfunction including localized high
blood pressure in liver and development of benign nodules.
Rare cases of severe liver toxicity, including death resulting from
drug-induced liver injury and worsening of brain function because the liver is
no longer able to remove toxic substances, have been observed in patients
treated with trastuzumab emtansine. Rare instances of severe toxicity and
cardiac death and Rare cases of severe lung inflammation including fatal cases
have been observed with trastuzumab emtansine.