Trial Information

Combined Phase I/II Study of Epirubicin (Pharmorubicin®), Carboplatin (Paraplatin®) and Capecitabine (Xeloda®) (ECC) in the Treatment of Unresectable Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Cancer With Pharmacogenetic Correlates

Background Information:

Capecitabine is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine which is
converted to 5-fluorouracil. Capecitabine is readily absorbed from the gastrointestinal
tract and then hydrolyzed in the liver. Capecitabine has been studied in the treatment of
gastric/gastroesophageal cancer in addition to a wide variety of other malignancies (e.g.
GI, breast).

Objectives

Phase I:

Primary Objective:

- To define the maximum tolerated dose (MTD) of capecitabine with combined fixed doses of
epirubicin and carboplatin in patients with advanced solid cancers. With the
identification of the MTD, determination of the recommended phase II dose will be made
and used to further evaluate the specific anti-tumor activity of ECC in unresectable
locally advanced and/or metastatic gastric/gastroesophageal cancer.

Secondary Objectives:

- To describe the safety, toxicity profile, principle and dose-limiting toxicities (DLT)
of ECC when given on this schedule; and

- To determine the pharmacokinetic behavior of capecitabine when given in combination
with epirubicin and carboplatin as part of the ECC regimen.

Phase II:

Primary Objective

- To determine the anti-tumor activity of ECC when given at the RPTD in patients who have
unresectable locally advanced and/or metastatic gastric/gastroesophageal cancer who
have not received prior palliative chemotherapy.

Secondary Objectives

- To further characterize the toxicity profile of the ECC regimen;

- To determine time to progression, duration of response, and overall survival of
patients on this study;

- To determine the effects of thymidylate synthase (TS) polymorphisms on both toxicities
and efficacy of ECC in prospectively genotyped patients;

- To prospectively evaluate other potential pharmacogenetic correlates which may also
play a role in augmenting toxicity, including MTHFR; and

- To assess effects of uridine glucuronosyltransferase 2B7 (UGT 2B7) polymorphisms on
epirubicin metabolism.

Study Design:

This is a Phase I/II trial that will study the safety as well as the efficacy of the ECC
combination chemotherapy regimen.

Epirubicin: will be administered as an IV push at a fixed dose of 50mg/m2 on day 1 -
repeated every 21 days

Carboplatin: will be administered IV, at a fixed dose with an AUC of 5 (over a 1-hour
infusion in 500ml of 5% dextrose) on day 1 - repeated every 21 days

Capecitabine: will be administered as a twice daily oral medication (variable dose for phase
I portion of the trial, but fixed dose for phase II portion of the trial) for 14 consecutive
days (days 1-14) - repeated every 21 days

For the phase I portion of the study cohorts of 3 patients will be treated at each of 3
pre-determined dose levels of capecitabine and monitored for toxicity:

- Dose level 1: 750 mg/m2 bid

- Dose level 2: 850 mg/m2 bid

- Dose level 3: 1000 mg/m2 bid

- Dose level 4+: 25% dose escalation (rounded to the nearest twice a day dosing).

Statistical Analysis

Phase I:

Summary statistics such as frequency and intensity of toxicity occurring at each dose level
will be provided. The percentage of patients developing DLT at each dose level will be
computed. The dose-toxicity curve can be estimated accordingly using either parametric or
non-parametric methods.

Phase II: A Simon's optimal two-stage phase II study will be conducted in patients with
unresectable locally advanced or metastatic gastric or gastro-esophageal cancer at the RPTD
of the ECC regimen. A total sample size of 43 patients will be required, 13 in the first
stage and 30 in the second stage, if criteria for second stage accrual are met. If <=3/13
patients respond, this is deemed to correspond with the initial rejection limit and no
further patients will be enrolled. If >=4/13 patients respond, an additional 30 patients
will be enrolled in the second stage (total sample size = 43). Further statistical details
are specifically outlined in Section 8 of the protocol. The response rate, standard error
and its 95% confidence intervals (CI) will be calculated under the binomial distribution
model. The efficacy of the regimen will then be evaluated by comparing the point estimates
and 95% CI with historical data. Potential covariates for response will also be identified
and evaluated via the logistic regression model. Kaplan-Meier estimates will be computed to
estimate the secondary endpoints such as time to progression and survival. Cox-regression
model can be applied incorporating covariates in the model. Fisher's exact test will be
applied to compare the response rates between the different genetic TS polymorphisms
groupings.

Stopping Rules:

Treatment will be discontinued and the patient will come off the trial therapy due to severe
intercurrent illness, disease progression, unacceptable toxicity, patient request to stop,
and/or if the physician deems it in the best interest of patient to discontinue.

Inclusion/Exclusion Criteria

Patient Population:

Phase I - Histologically or cytologically confirmed solid tumor refractory to conventional
cytotoxic anticancer therapy, or for which there are no standard therapies with a reasonable
therapeutic index.

Phase II - Inoperable/unresectable locally advanced and/or metastatic, histologically (or
cytologically) confirmed adenocarcinoma or undifferentiated carcinoma of the stomach or
gastro-esophageal junction presenting for first line palliative systemic treatment. Prior
adjuvant chemoradiotherapy for gastric or gastroesophageal junction adenocarcinoma is
allowed as long as the patient has completed adjuvant therapy >= 6 months prior to study
entry. Patients need to have at least one site of measurable disease as defined by RECIST
criteria.

Inclusion:

In general, to participate in the study, patients must be 18 years or older, have an
expected life expectancy of > 12 weeks, WHO performance status 0-2, LVEF by MUGA > 50%,
adequate organ function: hematological (ANC > 1.5X 10^9/L, platelets > 100 x 10^9/L,
hepatic (bilirubin < 1.5 x ULN, AST/ALT < 3 x ULN), renal (calculated creatinine clearance >
60 ml/min). Negative pregnancy test for females with child-bearing potential. Prior
radiotherapy allowed but must be delivered to < 25% of bone marrow, must be completed > 4
weeks before study entry and patients must have recovered from all side effects of the
radiotherapy. Radiation must not be delivered to the sole response indicator lesion, unless
there is documented evidence of disease progression in that site after completion of
radiation. Patients must be able to reliably tolerate and comply with oral/feeding tube
administered medications (patients are considered eligible if the investigator deems that
there is no malabsorption syndrome and no GI obstruction that would impair the delivery of
orally administered chemotherapy). If patient has had prior anthracycline, cumulative dose
must be < 300mg/m2 of doxorubicin or its equivalent.

Exclusion:

Patients currently enrolled in another clinical trial involving active cancer treatment.
Treatment with doxorubicin > 300mg/m2 or its equivalent. Serious medical conditions
including myocardial infarction within 6 months prior to entry, unstable angina, active
cardiomyopathy, unstable ventricular arrhythmia, congestive heart failure, uncontrolled
hypertension, uncontrolled psychotic disorders, serious active infections, uncontrolled
diabetes or any other medical condition that might be aggravated by study treatment.
Pre-existing neuropathy > grade 1, history of seizures or patients receiving anti-epileptic
prophylaxis, active and or progressive brain or leptomeningeal metastasis, pregnant or
lactating women, patients with evidence or recent history of drug or alcohol abuse, prior
treatment with capecitabine or infusional 5-FU, known hypersensitivity to carboplatin, 5-FU,
anthracyclines or known DPD deficiency. Patients that lack physical integrity of the GI
tract leading to intestinal obstruction. Patients taking warfarin, Coumadin or other
coumarin derivatives. Presence of any mentally incapacitating psychological condition.

Recruitment:

The expected total number of patients to be enrolled (phase I and II) is 65.