Laboratory-Treated Autologous Lymphocytes, Aldesleukin, and Sargramostim (GM-CSF) in Treating Advanced Solid Tumors

OBJECTIVES:

Primary

Determine the safety and maximum tolerated dose of EGFRBi-armed autologous activated T-cells
(ATC) when administered in combination with low-dose aldesleukin and sargramostim (GM-CSF)
in patients with recurrent, refractory, or extensive (metastatic) advanced solid tumors.

Secondary

Assess clinical outcome based on tumor responses, overall survival, and progression-free
survival.

Monitor changes in sera concentrations of the tumor-associated biomarkers respective of the
primary neoplasm (i.e. carcinoembryonic antigen(CEA); prostate specific antigen (PSA);
Her2/neu (HER2); etc.) in association with EGFRBi-armed ATC administration throughout the
study and at time points thereafter.

Monitor patient sera for human anti-mouse antibodies (HAMA).

Evaluate immune response, which may reflect immune augmentation in response to EGFRBi-armed
ATC infusions, in peripheral blood mononuclear cell (PBMC) samples as well as purified
immune cell populations.

Investigate proliferation in response to ex vivo stimulation with tumor-specific antigens,
sera cytokine profiles (Th1 vs Th2), cytotoxicity of patient PBMC, and interferon gamma
ELISPOTS as a surrogate marker for assessing generation of EGFR-specific cytotoxic
T-lymphocytes (CTL).

OUTLINE: Peripheral blood mononuclear cells (PBMCs) are collected by 1 or 2 leukaphereses
for the generation of activated T cells (ATCs). The PBMCs are activated with OKT3 (anti-CD3)
and expanded in aldesleukin for up to 14 days. The ATCs are then armed with EGFRBi.

Patients receive EGFRBi-armed autologous ATCs IV over 30-60 minutes twice weekly for 4 weeks
(a total of 8 infusions) in the absence of disease progression or unacceptable toxicity.
Patients also receive low-dose aldesleukin subcutaneously (SC) once daily and sargramostim
(GM-CSF) SC twice weekly beginning 3 days before the first ATC infusion and continuing for 1
week after the last ATC infusion.

After completion of study therapy, patients are followed periodically.

NOTE: For the purpose of determining safety and maximum tolerated dose of EGFRBi-armed ATC,
patients enrolled at each dose level from this study will be combined with patients enrolled
at each dose level in RWH 349-32 (NCT00569296): A phase I study of Anti-CD3 x
Cetuximab-Armed Activated T Cells, Low Dose IL-2, and GM-CSF for EGFR-Positive, Advanced
Non-Small Cell Lung Cancer (NSCLC) to count toward each dose level cohort. A total of three
patients enrolled form either of the two trials will be treated at each dose level, but at
least one NSCLC patient representative from protocol 349-32 will be enrolled and evaluated
at each dose level.

Inclusion Criteria

- Histologically or cytologically confirmed solid tumor type (ex. Head and Neck
Squamous Cell Carcinoma, Colorectal, Pancreatic, Gastric, Esophageal, Renal,
Prostate, Breast and Ovarian cancers, etc.); high risk, recurrent, refractory, or
metastatic disease after ≥ 1 prior first-line regimen (chemotherapy or radiotherapy)

- Documented EGFR-positive disease (any expression level) by immunohistochemistry (IHC)

- No clinical evidence of active brain metastases; patients with brain metastases are
eligible provided they have received definitive radiotherapy or chemotherapy and/or
have undergone surgical resection for brain metastases

- No prior hematological malignancy

- Karnofsky performance status (PS) 60-100% OR RCOG PS 0-2

- Life expectancy ≥ 3 months

- Not pregnant or nursing

- Fertile patients must use contraception

- Granulocytes ≥ 1,000/mm3

- Platelet count ≥ 50,000/mm3

- Hemoglobin ≥ 8g/dL

- BUN ≤ 2.0 times normal

- Serum creatinine ≤ 2.0mg/dL

- Bilirubin ≤ 1.5 times normal (with or without liver metastases)

- Hepatitis B surface antigen and HIV negative

- LVEF ≥ 45% at rest by MUGA

- No evidence of depressed left ventricular function

- No other malignancy, except for the following:

- History of curatively treated in situ squamous cell carcinoma or basal cell carinoma
of the skin

- History of other curatively treated malignancy (except those with a hematologic
origin) for with the patient has remained in complete remission > 5 years after
completing therapy (as documented by history, physical exams, tumor markers, and
radiology scanning)

Exclusion Criteria

- Serious medical or psychiatric illness that would preclude giving informed consent or
receiving intensive treatment

- Recent myocardial infarction (within the past year)

- Current angina/coronary symptoms requiring medications

- Clinical evidence of congestive heart failure requiring medical management
(irrespective of MUGA results)

- Systolic blood pressure (BP) ≥ 140 mm Hg or diastolic BP ≥ 90 m Hg; patients with
elevated BP must have it controlled by anti-hypertensive medications for at least 7
days prior to the infusion

- Clinical evidence of active brain metastases

Prior/Concurrent Therapy

- More than 4 weeks since prior chemotherapy or radiotherapy

- At least 4 weeks since prior cetuximab or small molecule EGFR-inhibitors including,
but not limited to, gefitinib or erlotinib hydrochloride

- No concurrent radiotherapy

- No concurrent steroids except for treatment or adrenal failure, septic shock, or
pulmonary toxicity or hormones for non-disease-related conditions(e.g., insulin for
diabetes)