Interleukin 13 PE for Adults With Advanced Cancers

Background:

- There are no effective systemic therapies for unresectable or recurrent adrenocortical
cancer (ACC).

- ACC is an aggressive malignancy, with high mortality and significant morbidity from
hypercortisolism.

- High levels of interleukin-13 receptor alpha 2 (IL13R alpha 2) are observed in ACC and
in malignant pheochromocytoma, pancreatic ductal adenocarcinoma and hepatocellular
carcinoma.

- IL13R alpha 2 regulates cellular proliferation and invasion of ACC cells.

- IL-13-PE is highly effective in causing cell death in IL13R alpha2 positive ACC cells,
and causes tumor regression and prolonged survival in an ACC xenograft nude mice model.

- We hypothesize that IL-13-PE will cause cancer regression in patients with metastatic
and locally advanced ACC and other malignancies with high IL13R alpha 2 expression
level.

Objectives:

- To determine the safety and maximal tolerated dose of IL-13-PE in patients with
metastatic and locally advanced ACC and other malignancies with high IL13R alpha 2
expression level.

- To determine response rate and progression free survival in patients with recurrent,
metastatic, or primary unresectable ACC treated with IL-13-PE.

- Evaluate response to IL-13-PE with functional imaging as compared to axial imaging.

- Determine if response to IL-13-PE treatment is associated with IL13R alpha 2 expression
level.

Eligibility:

- Age greater than or equal to 18

- Pathological confirmation of ACC or malignant pheochromocytoma, pancreatic ductal
adenocarcinoma and hepatocellular carcinoma for the Phase I portion of the study. Tumor
positive (greater than or equal 30%) for IL13R alpha 2 protein expression.

- Measurable disease at presentation

- Last dose of chemotherapy or last radiotherapy treatment more than 4 weeks prior to
starting treatment with this protocol

- Prior or concurrent mitotane therapy is allowed

Design:

- This will be an open label phase I/II study to determine the maximal tolerated dose of
IL- 13-PE and preliminary response to IL-13-PE focused on ACC for the phase II portion
of the study.

- IL-13-PE will be administered intravenously on week 1, days 1, 3, and 5 of a 4 week
cycle. One cycle (4 weeks) will equal one course. Patients may receive up to 4 courses
of treatment (16 weeks).

- Re-staging axial and functional imaging will be performed after the patient has
completed one course.

- INCLUSION CRITERIA:

- Age greater than or equal to 18

- Pathological confirmation of ACC or malignant pheochromoctyoma, pancreatic
adenocarcinoma and hepatocellular carcinoma. Tumor positive for IL13R alpha 2 by
immunohistochemistry (greater than or equal to 30% of the tumor). Confirmation
of tumor positivity will be done at the Laboratory of Pathology, NCI.

- Subjects with hepatocellular carcinoma must have a Child-Pugh classification of
A

- Measurable disease by RECIST criteria at presentation

- Patients must have failed standard treatment

- surgical resection if possible for ACC and malignant pheochromocytoma

- surgical resection if possible for pancreatic adenocarcinoma and hepatocellular
carcinoma

- Failed at least one FDA approved systemic chemotherapy regimen for pancreatic
adenocarcinoma (e.g. fluorouracil, erlotinib, gemcitabine and/or mitomycin) and
hepatocellular carcinoma (e.g. sorafenib)

- Last dose of chemotherapy or last radiotherapy treatment more than 4 weeks prior
to starting treatment with this protocol

- Prior or current mitotane therapy is allowed if patients are on the therapy to
control hypercortisolemia and have not had a response to the therapy and are
tolerating their dose.

- No concurrent other investigational therapy.

- No currently-active CNS metastasis, patients may have a history of treated brain
metastases

- Life expectancy more than 12 weeks

- Performance Status (ECOG) 0-2

- Good organ function, including:

- Hgb greater than or equal to 8.0 gm/dL; ANC greater than or equal to 1,000/mm3;
Plts greater than or equal to 75,000/mm3

- AST and ALT less than or equal to 3 x Upper Limit Normal

- Bilirubin less than or equal to Upper Limit Normal.

- Creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels
above institutional normal.

- No infection requiring parenteral antibiotics.

- Seronegative for HIV antibody

- Seronegative for Hepatitis B and Hepatitis C.

- Not pregnant or nursing. Sexually-active patients must agree to use an effective
method contraception prior to and for 4 months following treatment.

- Able to give informed consent.

EXCLUSION CRITERIA:

- Current coexisting malignancy other than basal cell carcinoma.

- Women of child-bearing potential who are pregnant or breastfeeding. Additionally,
patients who become pregnant while on study protocol will be discontinued
immediately.

- Active systemic infections, coagulation disorders or other major medical illnesses

- Proteinuria greater than or equal to 2 plus; urinary protein greater than or equal to
1.0 g/24 hours