Phase II Study of Irinotecan and Panitumumab

Esophageal cancer is a highly lethal malignancy that is increasing in incidence, especially
the histologic subtype of adenocarcinoma. Fully 50% of patients present with advanced,
incurable disease. Of the remainder who are diagnosed at curable stages, at most 30% are
long-term survivors. Advances in therapy for both local and advanced disease have been
stagnant in the past few decades. As such, there is an urgent need for advances in therapy.
The development of modern cytotoxic chemotherapy and in particular, biologically targeted
agents, provides hope for improving the outcome in these patients.

The semi-synthetic derivative of camptothecin, irinotecan, is active in esophageal
adenocarcinoma, both alone and in combination with cisplatin. Use as front-line therapy in
both multi-modality regimens and combination chemotherapy is common. More recently, the
elucidation of the role of the epidermal growth factor receptor (EGFR) pathway in esophageal
cancer has resulted in the pre-clinical and clinical study of the activity of EGFR directed
agents for treatment of esophageal cancer.

The anti-EGFR antibodies, panitumumab and cetuximab, are active as both single agents and in
combination with cytotoxic chemotherapy in patients with colorectal adenocarcinoma. In
particular, the combination of irinotecan and cetuximab is active for irinotecan refractory
colorectal cancer, while panitumumab is active compared with best supportive care. In our
clinic, we have empiric evidence for the unexpectedly significant activity of the
combination of cetuximab and irinotecan as third-line treatment for advanced esophageal
adenocarcinoma. Panitumumab has the clinical advantages, compared with cetuximab, of being
fully human,, thus resulting in a lower frequency of infusion reactions.

This recent experience with these targeted agents in solid tumors, while still promising,
has yielded relatively modest results.7-11 Notably, however, retrospective analyses of
clinical trials are consistently revealing that differences in treatment effect between
subgroups of patients can be associated with specific molecular profiles.12-18 These
findings suggest the potential for a more rational approach to trial design that would use
patient and tumor characteristics to select patients for therapy, thus enriching the
population of responders.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed diagnosis of locally
recurrent or metastatic adenocarcinoma of the esophagus which is incurable with
standard therapy.

- Patients must have measurable disease outside a previous radiation port, or which has
developed in the port since the conclusion of radiation and is biopsy-proven to be
recurrent cancer.

- One prior chemotherapy regimen for metastatic disease, with the exception of prior
irinotecan or panitumumab.

- Prior radiation therapy to no more than 20% of the bone marrow is allowed. No
treatment with wide field radiation within 4 weeks of entry onto this study.

- Full recovery from the effects of any prior surgery.

- Man or woman >18 years of age.

- ECOG performance status <2 (Karnofsky >60%)

- Life expectancy of >3 months

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L

- Hemoglobin ≥ 9.0 g/dL

- Creatinine < or = to 1.5 mg/dL

- Creatinine clearance > or = to 50 mL/min calculated by the Cockcroft-Gault method as
follows:

- Male creatinine clearance = (140 - age) x (weight in Kg) / (serum Cr x 72)

- Female creatinine clearance = (140 - age) x (weight in Kg) x 0.85 / (serum Cr x 72)

- Aspartate aminotransferase (AST) < or = to 3 x ULN (if liver metastases less than or
equal to 5 x ULN)

- Alanine aminotransferase (ALT) < or = to 3 x ULN (if liver metastases less than or
equal to 5 x ULN)

- Total bilirubin < or = to 1.5 x ULN

- Magnesium ≥ lower limit of normal

- Potassium > or = to lower limit of normal

- Because the effects of irinotecan and panitumumab on the developing human fetus are
unknown, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation.

Exclusion Criteria:

- History or known presence of central nervous system (CNS) metastases unless CNS
metastases have been irradiated and are stable.

- History of another primary cancer, except:

- Curatively treated in situ cervical cancer

- Curatively resected non-melanoma skin cancer

- Other primary solid tumor curatively treated with no known active disease present and
no treatment administered for greater than or equal to 5 years prior to enrollment

- Pre-existing peripheral neuropathy > grade 1.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to panitumumab or irinotecan.

- Patients receiving any medications or substances that are established or probable
inhibitors or inducers of P450 3A4 are ineligible.

- Prior anti-EGFr antibody therapy (eg, cetuximab) or treatment with small molecule
EGFr inhibitors (eg, gefitinib, erlotinib, lapatinib)

- Radiotherapy < or = to 14 days prior to enrollment.

- Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved
proteins/antibodies (or small molecules for Phase I studies) (eg, bevacizumab)< or =
to 30 days before enrollment

- Subjects requiring chronic use of immunosuppressive agents (eg, methotrexate,
cyclosporine)

- Any investigational agent or therapy < or = to 30 days before enrollment

- Prior therapy with Irinotecan or panitumumab.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or any
evidence of interstitial lung disease on baseline chest CT scan

- History of any medical or psychiatric condition or laboratory abnormality that in the
opinion of the investigator may increase the risks associated with the study
participation or investigational product(s) administration or may interfere with the
interpretation of the results.

- Women who test positive for serum or urine pregnancy test < 72 hours before
randomization or is breast feeding

- Known positive test(s) for acute or chronic active hepatitis B infection

- Major surgery within 28 days or minor surgery within 14 days of study enrollment

- Men or women of child-bearing potential (women who are post-menopausal < 52 weeks,
not surgically sterilized, or not abstinent) not consenting to use adequate
contraception (per institutional standard of care) during treatment and for six
months after the last investigational product(s) administration

- Any underlying condition which in the opinion of the principal investigator will
interfere with safety or with compliance with the study.