Chemotherapy for Patients With Gastroesophageal Cancers Who Have Progressed After One Prior Chemo Regimen

Gastric cancer is the second most frequent cancer-related cause of death after lung cancer
worldwide with approximately 900,000 cases per year. The incidence of gastric cancer is
highest in East Asia, China and Japan. In the last two decades there has been a dramatic
increase in North America and Europe of adenocarcinoma of the distal esophagus and GE
junction which are indistinguishable from proximal gastric cancer.

Cabazitaxel (XRP6258) is a semi-synthetic novel taxoid. Like traditional taxane drugs, it
binds to and stabilizes tubilin structures resulting in inhibition of cold-induced
microtubule depolymerization and cell division with subsequent inhibition of tumor cell
proliferation. This novel agent, however, has poor affinity for P-glycoprotein--the protein
product of multidrug resistance gene ABCB1. P-glycoprotein is a membrane-associated drug
efflux pump and is thought to be a potential cause of taxane resistance in tumors. Also
unlike traditional taxanes, Cabazitaxel has exhibited penetration through the blood-brain
barrier (BBB.) Preclinical studies have demonstrated that Cabazitaxel was cytotoxic for cell
lines with acquired resistance to doxorubicin, vincristine, vinblastine, paclitaxel or
docetaxel.

Taxanes have demonstrated statistically significant antitumor activity as both monotherapy
and as part of combination triplet regimens in gastroesophageal carcinoma.Cabazitaxel has
emerged as a novel investigational semi-synthetic taxoid that has established activity in
cell lines refractory to traditional taxanes in preclinical studies and now in a phase III
study in patients with metastatic prostate cancer. Cabazitaxel, with its low affinity for the
P-glycoprotein drug efflux pump, may demonstrate superior response rates to docetaxel.
Furthermore, as demonstrated in prostate cancer, cabazitaxel appears to have substantial
activity in patients who have previously been treated with docetaxel.

Phase I and II trials have been conducted demonstrating safety and efficacy of Cabazitaxel
(XRP6258) in metastatic breast and prostate cancer. Neutropenia was the primary dose-limiting
toxicity with the recommended dose established at 20 and 25mg/m2. The latter dose was used in
the TROPIC trial, the pivotal phase III trial demonstrating improved overall survival and
median progression free survival in patients with hormone resistant prostate cancer
refractory to docetaxel who had received Cabazitaxel plus prednisone versus those who
received mitaxantrone plus prednisone. Cabazitaxel given at IV doses of 25mg/m2 has
demonstrated both safety and anti-tumor efficacy in phase I, II and now phase III trials

The primary goal is to evaluate the activity of Cabazitaxel for the treatment of advanced
gastroesophageal cancer that has progressed after at least one line of treatment for
metastatic disease. Activity will be defined as a complete or partial response. The
investigators will differentiate between a 10% level of activity and a 30% level of activity.

Inclusion Criteria:

- Patients are required to have histologically or pathologically confirmed metastatic
gastric or esophageal adenocarcinoma.

- Patients must demonstrate relapse or progression after at least one prior line of
chemotherapy for metastatic disease.

- Patients must have measurable disease by CT scan or MRI

- Absolute neutrophil count ≥ 1,500/uL, platelet ≥ 100,000/uL and Hgb > 8.0 g/dl.

- Total bilirubin ≤ upper institutional limit of normal (ULN), and AST or ALT ≤ 3x ULN;
if liver metastases then AST or ALT < 5x ULN

- Peripheral neuropathy must be ≤ Grade 1

- Creatinine < 2 x ULN

- ECOG performance status 0 to 2

- Minimum life expectancy of 12 weeks.

- Age older than 18 years.

- Voluntary, signed written informed consent.

- Women of childbearing potential must have a negative pregnancy test Men and women of
childbearing potential must be willing to consent to using effective contraception
while on treatment and for at least 3 months thereafter.

Exclusion Criteria:

- History of severe hypersensitivity reaction to Cabazitaxel or other drugs formulated
with polysorbate 80.

- Patients with known, untreated brain metastasis

- Any uncontrolled severe, intercurrent illness.

- Women who are breast-feeding.

- Patients who have undergone major surgery, chemotherapy, or radiotherapy within the
last 3 weeks.

- Patients on concurrent anticancer therapy