Lapatinib With Carboplatin and Paclitaxel in Esophagus and Gastroesophageal Junction (GEJ)

OBJECTIVES:

1. Phase I: To assess the toxicity and feasibility of the addition of lapatinib to
carboplatin and paclitaxel in patients with recurrent/metastatic adenocarcinoma of the
esophagus and gastroesophageal junction.

2. Phase II: To assess the response rate to this regimen.

OUTLINE:

1. There will be an initial phase I safety cohort studies requiring up to 12 patients,
followed by a phase II cohort using the lapatinib dose defined in phase I. Carboplatin
and paclitaxel doses will not be escalated.

The initial dose of lapatinib of 750 mg daily by mouth will be given to 6 patients.
There will be no dose escalation of the lapatinib above 1000 mg daily. The lapatinib
dose for the phase II cohort of this trial will be based only on toxicities experienced
during the first cycle (3 weeks) of treatment.

2. Phase II: Once the optimal lapatinib dose has been chosen, all remaining patients will
initiate treatment at this dose level. Patients with stable or responding disease after
6 cycles will continue treatment with lapatinib alone until progression of disease or
intolerable side effects. Feasibility, toxicity and response rate of this combination
will be assessed.

PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

Inclusion Criteria:

- Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, or
gastroesophageal junction based on biopsy material or adequate cytologic exam.

- Patients must have incurable metastatic or recurrent adenocarcinoma of esophagus or
gastroesophageal junction.

- Patients must have an ECOG performance status of 0-1.

- Patients must have adequate bone marrow function as evidence by: absolute neutrophil
count > 1500/uL, and platelet count > 100,000/uL

- Patients must have adequate renal function as evidenced by a Cockcroft-Gault
calculated creatinine clearance > 30 mL/min.

- Patient must have adequate hepatic function as evidenced by: serum total bilirubin <
2.0 mg/dl, and AST/ALT < 3 X the institutional upper limit of normal. Patients with an
elevated unconjugated bilirubin (Gilbert's syndrome) will be eligible if hepatic
enzymes and function are otherwise completely normal (AST/ALT/Alk Phos within normal
limits), and there is no evidence of hemolysis.

- Patients must have cardiac ejection fraction > 50% as measured by echocardiogram or
MUGA scan.

- Patient must agree to stop medications or substances known to affect, or with the
potential to affect the activity or pharmacokinetics of lapatinib. (See Appendix I).

- Patients must be able to adhere to the study visit schedule and other protocol
requirements.

- Patients must have measurable/evaluable disease as per RECIST 1.1 criteria.

- Tumor must be tested for HER2 and EGFR before patient registration.

- Patients of childbearing potential must agree to use an effective form of
contraception during the study and for 90 days following the last dose of study
medication (an effective form of contraception is an oral contraceptive or a double
barrier method).

- Patients must be >18 years old.

- Women of childbearing potential must have a negative pregnancy test prior to
enrollment.

- Patients must have a life expectancy >12 weeks.

- Patients must be able to tolerate oral (or feeding-tube administered) medications.

Exclusion Criteria:

- Patients with any other diagnosis except for adenocarcinoma (squamous cell carcinoma,
small cell carcinoma, lymphoma, etc) will be ineligible.

- Patients with another active malignancy within the last 5 years will not be eligible
except for curatively treated basal cell carcinoma of the skin, cervical
intra-epithelial neoplasia, or localized prostate cancer with PSA <1.0 mg/dL on 2
successive evaluations at least 3 months apart, with the most recent evaluation within
4 weeks of entry.

- Patients may not have had any previous chemotherapy for recurrent or metastatic
disease and no chemotherapy or radiation therapy within the past 4 weeks.

- Patients may not have received any previous treatment with carboplatin, paclitaxel, or
a HER2 or EGFR inhibitor prior to enrollment.

- Patients may not be receiving any other investigational agents or other concurrent
anticancer therapy.

- Patients with brain metastases are excluded.

- Patients with > grade 2 peripheral neuropathy per NCI's Common Toxicity Criteria
Version 4.0 will be ineligible.

- Males with QTc > 450 or females with QTc > 470msec will be ineligible.

- Patients with active cardiac disease are excluded including current uncontrolled or
symptomatic angina, history of clinically significant arrhythmias requiring
medications, (with the exception of asymptomatic atrial tachycardias requiring
anticoagulation and/or beta-blockade), myocardial infarction < 6 months from study
entry, uncontrolled or symptomatic congestive heart failure, or any other cardiac
condition, which in the opinion of the treating physician, would make this protocol
unreasonably hazardous for the patient

- Women who are currently pregnant or lactating will be ineligible.

- Any other uncontrolled inter-current medical or psychiatric illness.

- Known HIV-positive patients will be excluded.

- Patients with any gastrointestinal disease resulting in an inability to take oral )or
feeding-tube administered medication, malabsorption syndrome, a requirement for IV
alimentation, prior surgical procedures affecting absorption, or uncontrolled
inflammatory GI disease (e.g., Crohn's, ulcerative colitis).

- Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.