Individualized Drug Treatment for Treating Patients With Pancreatic Cancer

OBJECTIVES:

- Establish tumor xenografts from patients with resectable adenocarcinoma of the pancreas
who undergo surgical resection at Johns Hopkins Hospital.

- Determine the activity of a series of 10 anticancer drugs against these tumors in ex
vivo studies.

- Determine the response rate, time to treatment failure, and 6-month survival rate in
patients whose tumors were xenografted and treated in the mouse when treated with the
most active agent identified in that model.

- Define determinants of susceptibility and resistance to the drugs in xenografted tumors.

OUTLINE:

- Part I (surgical resection, tumor xenografts generation, and drug selection): Patients
undergo surgical resection. The resected tumor tissue is implanted in laboratory mice to
generate tumor xenografts. The mice are then treated with a series of 10 approved
anticancer drugs, whose anticancer activity are ranked from the most to the least
effective based on response of the tumor xenografts. The most effective drug is
identified for the individual patient. Patients for whom no drug is found to be
effective are removed from the study. Patients who develop progressive disease after
surgical resection and after mice data is available proceed to part II.

- Part II (individual patient treatment): Patients receive the most effective drug
identified in part I in the absence of disease progression or unacceptable toxicity. The
drugs may include bortezomib, capecitabine, cetuximab, docetaxel, erlotinib
hydrochloride, gemcitabine hydrochloride, irinotecan hydrochloride, mitomycin C,
sirolimus, or thalidomide.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Part A

Inclusion Criteria

1. Suspected adenocarcinoma of the pancreas with resectable disease schedule to have
surgical resection at the Johns Hopkins Hospital.

2. Age ≥ 18 years old.

3. Ability to understand and willingness to sign a written informed consent document.

Part B

Inclusion Criteria

1. Participation in Part A of the study with informative mouse xenograft data.

2. Histologically or cytologically confirmed diagnosis of invasive adenocarcinoma of the
pancreas and peripancreatic adenocarcinoma, including distal cholangiocarcinoma,
duodenal carcinoma, and ampullary pancreatic not amenable to curative treatment.

3. ECOG performance status 0 or 1

4. Age ≥ 18 years old.

5. Expected survival > 12 weeks.

6. No prior treatment for recurrent disease.

7. Willingness of male and female subjects, who are not surgically sterile or
postmenopausal, to use reliable methods of birth control (oral contraceptives,
intrauterine devices, or barrier methods used with a spermicide) for the duration of
the study and for 30 days after the last dose of test article.

8. Adequate liver, renal and bone marrow functions.

WBC > 3,500 cells/mm3 ANC > 1,500 cells/mm3 Platelets > 100,000 cells/mm3 Hemoglobin ≥ 9
g/dl Serum creatinine 2 mg/dl Bilirubin 2 mg/dL ALT, AST, and alkaline phosphatase 5 times
the upper limit of normal

Exclusion criteria

1. Patients in whom histologic or cytologic diagnosis is not consistent with
adenocarcinoma.

2. Patients in whom histologic or cytologic diagnosis is consistent with non epithelial
origin tumors, including adenosquamous, islet cell, cystadenoma or cystadenocarcinoma,
carcinoid, small or large cell carcinoma, sarcoma, lymphoma and melanoma

3. Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

4. Patients who have had any previous surgery, excluding minor procedures, dental work,
skin biopsy, etc. within 4 weeks of enrollment.

5. Uncontrolled medical conditions that could potentially increase the risk of toxicities
or complications when treated with chemotherapy. Gastrointestinal tract disease resulting
in an inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease.

6. Active infections.

7. History of another neoplasm except for non-metastatic, nonmelanoma skin cancers, < 5
years prior to enrollment.

8. Unable to provide informed consent.

9. Treatment with chemotherapy within 30 days of day 1 treatment.

10. Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer
therapy (except alopecia).

11. Pregnant women are excluded from this study because the effects of the chemotherapy
agents to be tested on the developing fetus are not known. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the mother
with MMC, breast feeding should be discontinued if the mother is treated with the drug.

12. Patients must not have documented history of clinically significant cardiovascular
disease including myocardial infarction (within 12 months prior to randomization), unstable
angina, grade II or greater peripheral vascular disease, uncontrolled congestive heart
failure or uncontrolled hypertension (SBP>170, DBP>95).

13. Patients with non informative xenograft data including patients whose tumors do not
take in the mice, who progress before mice data is available or whose tumors do not respond
to any of the selected agents.