ECI301 and Radiation for Advanced or Metastatic Cancer

Background:

- Patients with metastatic or locally advanced cancer frequently require palliative
radiotherapy to relieve symptoms; however, progression of disease is frequent in
patients with extended survival

- Radiation results in tumor cell death which can result in increased dendritic cell
activation and trafficking

- ECI301 is a derivative of Macrophage Inflammatory Protein-1?, a 70 amino acid chemokine
that is a ligand for CCR1 and CCR5, the chemokine receptors of immature dendritic cells.

- ECI301 has been shown to enhance the effect of radiotherapy in animal models.

Objectives:

- The primary objective is to determine the maximum tolerated dose (MTD) of ECI301
delivered in combination with 30 Gy of external beam radiation to patients with
metastatic or locally advanced cancer.

- The secondary objectives are:

- To describe the safety and tolerability of ECI301 delivered in combination with 30
Gy of external beam radiation to patients with metastatic or locally advanced
cancer

- To evaluate the humoral and cellular immune responses by:

- Measurement of circulating precursor dendritic cells before and after the
completion of ECI301

- Measurement of circulating MIP-? before and after the completion of ECI301

- Assessment of T-lymphocyte quantitative and qualitative changes by flow
cytometry and assays for IFN? production

- To define pharmacologic parameters following the intravenous dose of ECI301

- To determine if neutralizing anti-EC301 antibodies occur after treatment

- To describe the response at the radiated site and distant sites after radiation in
combination with ECI301

Eligibility:

- Age >18 years.

- ECOG performance status <2.

- Life expectancy of greater than 3 months

- Histologically confirmed metastatic or locally advanced cancer for which
radiotherapeutic management would be appropriate

- No recent history of myocardial infarction or unstable angina

Design:

- This is a Phase I trial to determine the maximum tolerated dose of ECI301 in combination
with external beam radiation therapy in patients with locally advanced or metastatic
solid tumors.

- Patients will be treated with radiation therapy in a standard manner with ECI301 given
daily during radiation. The dose of ECI301 will be escalated over the course of the
trial to determine the MTD of daily ECI301 in combination with radiotherapy.

- We anticipate that accrual to this trial of 30 patients will take approximately 2 years.

- INCLUSION CRITERIA:

2.1.1.1 Age greater than or equal to18 years.

2.1.1.2 ECOG performance status less than or equal to 2.

2.1.1.3 Life expectancy of greater than 3 months

2.1.1.4 Histologically confirmed cancer

2.1.1.5 Extracranial metastatic cancer or locally advanced cancer for which palliative
radiotherapeutic management would be appropriate (no more than two sites will be treated on
this trial)

2.1.1.6 Patients must have measurable or evaluable disease at the site(s) requiring
radiation

2.1.1.7 Adequate marrow and organ function defined as

- absolute neutrophil count (ANC) > 1.5 times 10(9)/L,

- platelet count > 100 times 10(9),

- hemoglobin >9 g/L.

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal

- serum bilirubin <1.5 times upper limit reference range (ULRR),

- alanine aminotransferase (ALT), aspartate aminotransferase (AST), or

alkaline phosphatase (ALP) <2.5 times the ULRR (<5 times the ULRR in the presence

of liver metastases)

2.1.1.8 Female patients of child bearing potential must either be surgically sterile to
prevent pregnancy, be at least 1-year post-menopausal, or have had no menses for 12 months,
or agree to use reliable methods of contraception (oral contraceptives, barrier methods,
approved contraceptive implant, long-term injectable contraception, copper banded
intrauterine device, tubal ligation or abstinence) from time of screening until 4 weeks
after discontinuing study treatment. It is not known whether ECI301 has the capacity to
induce hepatic enzymes so hormonal contraceptives should be combined with a barrier method
of contraception.

2.1.1.9 Male patients must agree to use barrier contraception (i.e. condoms) and refrain
from donating sperm from the start of dosing until 16 weeks after discontinuing study
treatment. If male patients wish to father children they should be advised to arrange for
freezing of sperm prior to the start of study treatment.

EXCLUSION CRITERIA:

2.1.2.1 Pregnant or lactating females

2.1.2.2 Contraindications to radiotherapy (i.e. prior radiotherapy to the intended
treatment site)

2.1.2.3 Untreated or previously treated but progressive intracranial metastases (Patients
with previously treated intracranial metastases should have no clinical evidence of
progression and be at least 4 weeks from therapy for intracranial metastases)

2.1.2.4 Need for emergent radiotherapy (defined as need for radiotherapy within 24 hours of
consultation at the judgment of the treating radiation oncologist)

2.1.2.5 Active treatment with immunosuppressive therapy and subjects taking systemic
corticosteroid therapy for any reason including replacement therapy for hypoadrenalism

2.1.2.6 Chemotherapy, radiation therapy, Tamoxifen or investigational therapy during the 4
weeks prior to initiation of protocol therapy

2.1.2.7 History of rheumatoid arthritis, systemic lupus erythematosus,
Sj(SqrRoot)(Delta)grens disease, sarcoidosis, vasculitis, polymyositis, temporal arteritis
or any other autoimmune disease

2.1.2.8 History of organ transplant

2.1.2.9 HIV, Hepatitis B, or Hepatitis C positivity

2.1.2.10 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

2.1.2.11 Use of excluded immune modulating medications within 4 weeks prior to protocol
therapy, or requirement for concurrent use.