Panitumumab and Gemcitabine in Relapsed Ovarian Cancer

Epithelial ovarian cancer (EOC) remains a leading cause of gynecologic cancer mortality in
women, with more than 22,000 deaths per year in the United States alone. Due to the lack of
effective screening strategies and subtle early symptoms, eighty percent of newly diagnosed
patients have disease that is advanced. Despite cytoreductive surgery and adjuvant
paclitaxel-based and platinum-based chemotherapy, 5-year survival rates continue to be less
than 40%. For patients who become resistant to the platinum compounds (defined as
progressive disease while on a platinum-based chemotherapy regimen (refractory) or within 6
months of completing a platinum-based chemotherapy regimen (resistant)),the outlook is
particularly poor, and often heralds multi-drug resistant disease.

At the present time, the management of ovarian cancer in the platinum refractory disease
state is limited to palliative intent. Patients with advanced, bulky tumors, poor
performance status and nutritional compromise are unlikely to respond to therapy and may be
best served by supportive care. The clinical management of refractory disease requires both
patience and persistence. A patient with platinum refractory disease is begun on one of the
agents with activity and an evaluation of response is made every 6-8 weeks of therapy. As
long as the patient shows no signs of disease progression, the therapy can be continued
unless there is unacceptable toxicity. When progressive disease is observed, another of the
list of available agents can be used. It is likely that patients will receive multiple
single agents during the chronic phase of their illness. Every effort should be made to
balance disease response with toxicity and quality of life.

Based on this rational, this trial will be conducted to evaluate the safety and efficacy of
panitumumab, a human antibody targeted to the EGF-R, and Gemcitabine, in treating women with
recurrent platinum-refractory/resistant EOC. Our aim is to determine the safety and
feasibility of gemcitabine and panitumumab therapy in this population and once completed, to
proceed with an efficacy study using an expanded cohort.

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of metastatic, advanced, or
recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube
cancer.

- Prior first line therapy with a platinum and taxane based combination as adjuvant
therapy

- Measurable disease defined by RECIST criteria

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

- age > 18

- Karnofsky performance status > 70

- Up to three prior lines of cytotoxic therapy in the setting of recurrent disease.

- Estimated life expectancy of at least 3 months

- Women of child-bearing potential must have a negative pregnancy test

- Adequate hematopoietic function defined as:

- ANC ≥ 1500/mm3

- Platelets ≥ 100,000/mm3

- Hemoglobin ≥ 9 g/dL

- Magnesium ≥ lower limit of normal

- Calcium ≥ lower limit of normal

- Adequate renal and hepatic function defined as:

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- SGOT ≤ 3 times ULN

- Alanine aminotransferase (ALT) ≤3xULN (if liver metastases ≤5xULN)

- Alkaline phosphatase ≤ 3 times ULN

- Creatinine ≤ 1.5 mg/dL times ULN

- Creatinine clearance ≤ 50 mL/min

Exclusion Criteria:

- Prior anti-EGFr antibody therapy (e.g., cetuximab) or treatment with small molecule
EGFr inhibitors (e.g., gefitinib, erlotinib, lapatinib)

- Prior treatment with gemcitabine

- Radiotherapy ≤ 14 days prior to enrollment.

- More than three lines of systemic chemotherapy for recurrent or advanced disease.
Prior hormonal therapy is allowed.

- Prior immunotherapy, or experimental or approved proteins/antibodies

- Female subject is pregnant or breast-feeding.

- Patient has received other investigational drugs within 28 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Prior treatment with panitumumab

- Concurrent uncontrolled illness

- Ongoing or active infection

- History or active secondary cancer within the last 5 years, except for superficial
basal cell skin cancers, curatively resected non-melanoma skin cancer

- Psychiatric illness or social situation that would preclude study compliance.

- History or known presence of central nervous system (CNS) metastasis

- Subjects requiring chronic use of immunosuppressive agents (e.g., methotrexate,
cyclosporine)

- Clinically significant cardiovascular disease (including myocardial infarction,
unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac
arrhythmia) < 1 year before randomization

- History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or any
evidence of interstitial lung disease on baseline chest CT scan

- Known positive test(s) for human immunodeficiency virus infection, hepatitis C virus,
acute or chronic active hepatitis B infection

- Major surgery within 28 days or minor surgery within 14 days of study enrollment