Intraperitoneal tgDCC-E1 and Intravenous Paclitaxel in Women With Platinum-Resistant Ovarian Cancer

Primary Objective

- To evaluate toxicity and establish the maximum tolerated dose (MTD) of intraperitoneal
tgDCC-E1A in combination with intravenous paclitaxel.

- To measure tumor response of intraperitoneal tgDCC-E1A in combination with intravenous
paclitaxel and compare to intravenous paclitaxel

Secondary Objective

- To measure time to progression and overall survival.

- To examine the biological effects of combined tgDCC- E1A and paclitaxel in ovarian
cancer cells as measured by laboratory testing.

Epithelial ovarian cancer is a significant public health problem. It is the sixth most common
cancer in women worldwide. Globally, it is estimated that 162,000 new cases are diagnosed per
year, and that 106,000 women die from the disease per year.

Signs and symptoms of ovarian cancer are often subtle. Seventy-five percent of subjects will
present with advanced stage III and IV disease. Standard treatment for stage III/IV subjects
consists of surgical debulking to the maximal extent possible and chemotherapy with
paclitaxel plus a platinum compound (cisplatin or carboplatin). Despite high initial response
rates, the overall survival for this group is poor, with only 20% of stage III and less than
5% of stage IV subjects surviving five years.

Treatment of recurrent ovarian cancer varies depending upon the interval between prior
treatment and recurrence. Twenty percent of subjects are classified as "platinum-refractory",
in that they fail to have even a partial response to a platinum-containing regimen. Subjects
with recurrent or progressive disease less than six months after initial therapy have a poor
response rate to repeat treatment with a platinum-containing regimen, and are generally
considered to have "platinum-resistant" disease. In contrast, subjects with recurrent disease
greater than six months after initial therapy have better response rates to repeat treatment
with platinum-containing regimens, and are generally considered to have "platinum-sensitive"
disease.

There is no consensus for the treatment of "platinum-refractory" or "platinum-resistant"
ovarian cancer, a class of individuals who are particularly challenging to treat. Prognosis
is poor, and treatment is primarily palliative in nature. Responses to a variety of single
chemotherapeutic agents, as well as to a combination of agents in largely phase II trials
have been similar, ranging from 10-35%. Intravenous (IV) paclitaxel, given alone or in
combination with other agents is a standard treatment for subjects who have relapsed. In an
attempt to increase the dose intensity of paclitaxel therapy, weekly IV paclitaxel has been
recommended. This treatment schedule is well tolerated, but the response rate in heavily
pretreated subjects is still only 28.9%.

Given that this group of subjects is poorly responsive to conventional chemotherapy, and
consequently has limited options, an alternative approach to treatment is warranted. The use
of a gene therapy agent with anti-tumor effects and the ability to sensitize cancer cells to
traditional chemotherapy is appealing.

- Overview of the Effect of E1A Gene Transfer on Cancer Cells:

E1A, a gene derived from Adenovirus type 5, has been shown to have potent anti-neoplastic
activity through a variety of mechanisms, including down-regulation of HER-2/neu
overexpression, induction of apoptosis, inhibition of metastasis, and reversion of tumor
cells toward a differentiated epithelial phenotype. The E1A gene has also been shown to have
an additive effect in vitro and in vivo on the apoptosis induced by chemotherapy and
radiotherapy. The E1A gene has been successfully transfected into human cells both in vitro
and in vivo using tgDCC-E1A (E1A-Lipid Complex), which consists of the E1A plasmid (pE1A-K2)
complexed to the cationic lipid gene delivery system comprised of DC-Cholesterol
3b[N-(N'N'-dimethylaminoethane)-carbamoyl] cholesterol hydrochloride and DOPE
(1,2-dioleoyl-sn-glycero-3-phosphoethanolamine).

- Rationale for Use of Cationic Lipids to Deliver DNA:

Cationic lipids can form complexes with negatively charged DNA plasmids and facilitate the
transfer of genes to target cells. They are useful agents for delivery of gene therapy
because they are synthesized chemically, are simple to manufacture, and pose no infectious
risk. The cationic derivative of cholesterol, 3b[N-(N'N'-dimethylaminoethane)-carbamoyl]
cholesterol hydrochloride (DC-Chol) is an ideal cationic lipid for therapeutic use, as the
cationic charge is provided by a non-toxic tertiary amine with a biodegradable carbamoyl
bond. DC-Chol can be used to prepare liposomes in combination with the neutral
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) with a DC-Chol to DOPE ratio of 6:4.
This liposome combination can be mixed with a plasmid encoding E1A to form tgDCC-E1A.

The final preparation of tgDCC-E1A can be made within a range of lipid:DNA ratios, all of
which have been shown in cell culture and in animal models to result in expression of E1A.
Clinical trials of tgDCC-E1A for injection into solid tumors have used a final preparation
with a lipid:DNA ratio of 1 nmol lipid to 1 microgram DNA [tgDCC-E1A (1:1)]. Early clinical
trials evaluating intracavitary administration (e.g. intraperitoneal infusion for ovarian
cancer) used a preparation with a lipid:DNA ratio of 10 nmol lipid to 1 microgram DNA
[tgDCC-E1A (10:1)]. More recent protocols of intraperitoneal delivery for ovarian cancer have
used a preparation with a lipid:DNA ratio of 3 nmol lipid to 1 microgram DNA [tgDCC-E1A
(3:1)], as will this protocol.

- Rationale for Intraperitoneal Delivery of tgDCC-E1A:

The peritoneal cavity is a common site of tumor recurrence after initial "radical" surgical
treatment of ovarian malignancies. Dissemination in this cavity is often widespread. Because
of the unusual natural course of ovarian cancer (characterized by its tendency to be confined
to the peritoneal cavity), control of metastatic disease in the peritoneal cavity is an
important and challenging problem, which can be improved by direct delivery of drug into the
peritoneal cavity.

Inclusion Criteria:

- Age greater than or equal to 18 years

- Recurrent epithelial ovarian cancer or primary peritoneal cancer with histologic
confirmation of the original tumor. Recurrent disease may be manifested as an elevated
cancer antigen (CA)-125 using the following criteria: (a) increase in CA-125 to at
least 2 times the upper limit of normal (assayed on 2 occasions at least 7 days apart)
for subjects with a history of normal pre-treatment values or values that normalized
with the most recent treatment - OR - (b) increase in CA-125 to 2 times the lowest
observed value on the most recent treatment (assayed on two occasions at least 7 days
apart) for subjects whose CA-125 did not normalize with the most recent treatment.

- Platinum-resistant disease, defined as recurrence less than six months after
discontinuation of treatment with platinum therapy or platinum-refractory disease
defined as progression on a platinum-containing regimen.

- A treatment-free interval of at least three weeks for cytotoxic therapies, radiation
therapy, or other experimental drugs prior to first treatment on this protocol.

- A Zubrod performance status of two or less.

Exclusion Criteria:

- Previous administration of tgDCC-E1A.

- Progression on any taxane-containing regimen, or recurrent within 6 months of
receiving a weekly taxane-containing regimen.

Previous radiation to more than 25% of marrow-bearing areas.

- Any of the following laboratory values: Hemoglobin <9.0 gm/dl, absolute neutrophil
count (ANC) <1.5 K/ml, platelet <100 K/ml, creatinine >2 mg/dl, bilirubin >2 mg/dl,
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)>2 times the upper
limit of normal, or abnormal coagulation profiles (>2 seconds beyond upper range of
normal Prothrombin Time (PT) or Partial thromboplastin time (PTT)).

- Known human immunodeficiency virus (HIV)-positive status or active systemic infection.

- History of other invasive malignancies, except for non-melanoma skin cancer, unless
there is no evidence of other cancer within the past 5 years.

- Patients with grade 2 or greater neurotoxicity.

- Patients with unstable angina or those who have had a myocardial infarction within the
past six months. Patients with evidence of abnormal cardiac conduction are eligible if
their disease has been stable for the past six months. Patients with an ejection
fraction under 40%.