AZD2171 in Treating Patients With Recurrent Ovarian, Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To determine the efficacy of AZD2171 in platinum sensitive and platinum insensitive
disease, based on either RECIST criteria (for patients with measurable cancer
radiographically) or clinical response benefit (modified Gynecologic Cancer Intergroup
[GCIG] CA-125 response or stable disease for at least 16 weeks).

SECONDARY OBJECTIVES:

I. To assess progression-free survival. II. To assess modified GCIG CA-125 response rate.
III. To assess duration of modified GCIG CA-125 response. IV. To assess the safety of the
recommended phase 2 dose of AZD2171 in this asymptomatic patient population.

V. To explore the pharmacodynamic effects of AZD2171 by correlating clinical outcomes with
an angiogenic profile derived from serial assessments of soluble VEGFR2, circulating
endothelial cell levels, and VEGFR phosphorylation in circulating endothelial cells.

VI. To explore pharmacogenetic differences in kdr/flk-1, HIF1alpha, p53, and endothelial
nitric oxide synthase (eNOS) in PBMCs from subjects who consent separately for
pharmacogenetic studies.

VII. To determine whether oncogenic mutations predict response to AZD2171.

OUTLINE: This is a multicenter study. Patients are stratified according to disease
sensitivity (platinum-sensitive disease vs platinum-insensitive disease).

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 2 years.

PROJECTED ACCRUAL: A total of 71 patients will be accrued for this study.

Inclusion Criteria:

- must have histologically or cytologically confirmed epithelial ovarian cancer,
primary peritoneal serous cancer, or fallopian tube cancer

- must have either measurable cancer by RECIST criteria or an elevated CA125

- Subjects must be asymptomatic or minimally symptomatic

- Prior therapy:

- Prior chemotherapy must have included a first-line platinum-based regimen only

- Prior hormonal-based therapy for ovarian, primary peritoneal serous or fallopian
tube cancer is acceptable

- Up to two prior lines of chemotherapy in the recurrent setting are allowed

- Toxic side effects related to prior chemotherapy or hormonal therapy must have
resolved to less than or equal to grade 1 or to baseline (excluding alopecia),
or for peripheral neuropathy to less than or equal to grade 2

- Subjects may begin AZD2171 at least 3 weeks after their last dose of
chemotherapy or hormonal therapy

- Life expectancy of greater than 6 months

- ECOG performance status 0-1 (Karnofsky >= 70%)

- must have lab values within normal institutional limits

- eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or PK of AZD2171 will be determined
following review of their case by the Principal Investigator

- Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin
or carcinoma in situ of the breast or cervix are eligible; subjects with stage I or
II cancer treated with a curative intent are also eligible with no evidence of
recurrent disease

- No evidence of preexisting uncontrolled hypertension; if patient has hypertension, it
must be medically controlled

- AZD2171 has been shown to terminate fetal development in the rat, as expected for a
process dependent on VEGF signaling; for this reason, women of child-bearing
potential must have a negative pregnancy test prior to study entry; must agree to use
adequate contraception; should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately

- Ability to understand and the willingness to sign a written informed consent
document- No therapeutic anticoagulation; the use of low dose warfarin (1 mg/day),
intermittent doses of tPA (2 mg x 1), or heparin flushes to prophylax against central
venous catheter-associated clots is permitted

- Measurable or non-measurable disease on CT scan or MRI

- Consider patients who have the following risk factors to be at increased risk; these
patients should have increased monitoring:

- Prior treatment with anthracyclines

- Prior treatment with trastuzumab

- A New York Heart Association classification of II controlled with treatment

- Prior central thoracic radiation therapy (RT), including RT to the heart

- History of myocardial infarction within 12 months

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy, or major surgery within 3 weeks (6
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have
not recovered from adverse events due to agents administered more than 3 weeks
earlier

- Patients may not be receiving any other investigational agents nor have participated
in an investigational trial within the past 3 weeks; subjects may not have received
prior treatment affecting the VEGF pathway; subjects may not have received prior
treatment with antibodies that may interfere with CA-125 measurements; subjects may
not have received intraperitoneal therapy within the 4 weeks prior to starting
AZD2171 and/or the treating physician must confirm the patient has recurrent disease

- Patients may not be receiving any medication that may markedly affect renal function

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD2171

- Mean QTc > 500 msec (with Bazett's correction) in screening electrocardiogram or
history of familial long QT syndrome

- Uncontrolled intercurrent illness

- Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with
known abortifacient effects; breastfeeding should be discontinued if the mother is
treated with AZD2171

- Major surgical procedure or medical interference with the peritoneum or pleura within
4 weeks of baseline CA-125 assessments

- Subjects with a history of an active malignancy during the last 3 years except
non-melanomatous skin cancer , in situ breast or cervical cancer or stage I or II
cancer treated with a curative intent and no active cancer recurrence

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with AZD2171

- No therapeutic anti-coagulation; prophylaxis against central venous
catheter-associated clots is permitted

- A New York Heart Association classification of III or IV

- Conditions requiring concurrent use of drugs or biologics with proarrhythmic
potentiate