Study of Ramucirumab in Ovarian Cancer

Current chemotherapies used to treat ovarian cancer participants include doxorubicin,
topotecan, and paclitaxel, to mention a few. Doxorubicin was studied in ovarian cancer
participants that were refractory to paclitaxel and platinum-based chemotherapy agents.
Inhibition of angiogenesis is considered a promising approach to the treatment of cancer.
Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and is
likely an important therapeutic target in persistent or recurrent epithelial ovarian,
fallopian tube, or primary peritoneal carcinoma. VEGF is overexpressed in ovarian tissue and
may be the most important single tumor angiogenic factor. Phase 1 studies currently nearing
completion with ramucirumab have demonstrated safety and tolerability at clinically relevant
doses, with preliminary evidence of clinical efficacy in ovarian cancer participants.
Therefore, ImClone Systems plans to conduct a Phase 2 trial to assess the safety and
efficacy of ramucirumab in participants with platinum-refractory persistent or recurrent
epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

Inclusion Criteria:

Each participant must meet the following criteria to be enrolled in this study:

1. The participant has recurrent or persistent epithelial ovarian, fallopian tube, or
primary peritoneal carcinoma. Histologic documentation of the original primary tumor
is required via a pathology report

2. The participant has at least one unidimensional-measurable target lesion [≥ 2
centimeter (cm) with conventional techniques, or ≥ 1 cm by spiral computed tomography
(CT) or magnetic resonance imaging (MRI)], as defined by Response Evaluation Criteria
in Solid Tumors (RECIST). Tumors within a previously irradiated field will be
designated as "nontarget" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of radiation
therapy

3. The participant has recovered to Grade ≤ 1 by the National Cancer Institute Common
Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0) from the
effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other
targeted therapies for ovarian cancer, with the exception of alopecia or peripheral
neuropathy (which must have resolved to Grade ≤ 2). Any other prior therapy directed
at the malignant tumor must be discontinued at least three weeks prior to the first
dose of study medication, or hormonal therapy discontinued at least one week prior to
the first dose of study medication. Continuation of hormone replacement therapy is
permitted

4. The participant has completed at least one platinum-based chemotherapeutic regimen
for management of primary disease, and must have at least one of the following: a
platinum-free interval of < 12 months after the final dose of primary platinum-based
therapy, progression during platinum-based therapy, or persistent disease after
platinum-based therapy

5. The participant has an Eastern Cooperative Oncology Group Performance Status (ECOG
PS) of 0-1 at study entry

6. The participant has adequate hematological functions [absolute neutrophil count (ANC)
≥ 1200 cells/microliter (uL), hemoglobin ≥ 9 grams/deciliter (g/dL), and platelets ≥
100,000 cells/uL]

7. The participant has adequate hepatic function [bilirubin ≤ 1.5 times the upper limit
of normal (ULN); aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 3.0
times ULN, or ≤ 5.0 times ULN if the transaminase elevation is due to liver
metastases]

8. The participant has adequate renal function [serum creatinine ≤ 1.5 x ULN or
creatinine clearance (measured or calculated) ≥ 60 milliliters/minute (mL/min)]

9. The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If
urine dipstick or routine analysis indicated ≥ 2+ proteinuria, then a 24-hour urine
must be collected and must demonstrate < 1000 milligrams (mg) of protein in 24 hours
to allow participation in the study

10. The participant has adequate coagulation function, as defined by international
normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN if
not receiving anticoagulation therapy. Participants on full-dose anticoagulation must
be on a stable dose of oral anticoagulant or low molecular weight heparin, and if on
warfarin must have therapeutic INR and have no active bleeding (defined as within 14
days of first dose of study medication) or pathological condition that carries a high
risk of bleeding (example, tumor involving major vessels or known varices)

11. For participants who have received anthracycline therapy, the left ventricular
ejection fraction (LVEF) must be within normal institutional range by a pretreatment
echocardiogram or multigated acquisition (MUGA) scan

12. If sexually active, the participant is post-menopausal, surgically sterile, or using
effective contraception in the opinion of the investigator

13. The participant is ≥ 18 years of age

14. The participant has a life expectancy of ≥ 3 months

15. The participant is able to provide informed written consent and is amenable to
compliance with protocol schedules and testing

Exclusion Criteria:

1. The participant has a concurrent active malignancy, other than adequately treated
nonmelanomatous skin cancer or other noninvasive carcinoma or in situ neoplasm. A
participant with previous history of malignancy is eligible provided that she has
been disease-free for > 3 years

2. The participant has received a noncytotoxic regimen (usually called targeted therapy
such as bevacizumab) for recurrent or persistent disease. (Participants may have
received a noncytotoxic regimen as primary treatment.)

3. The participant has received radiotherapy for the treatment of ovarian, fallopian
tube, or primary peritoneal cancer within 3 weeks (21 days) prior to the first dose
of study medication

4. The participant has received prior radiotherapy to any portion of the abdominal
cavity or pelvis other than for the treatment of ovarian, fallopian tube, or primary
peritoneal cancer within the last 3 years. [Prior radiation for localized cancer (for
example, of the breast, head and neck, or skin) is permitted, provided that it was
completed > 3 years prior to the first dose of study medication, and the participant
remains free of recurrent or metastatic disease.]

5. The participant has received prior chemotherapy for any abdominal or pelvic tumor,
other than for the treatment of ovarian, fallopian tube, or primary peritoneal cancer
< 3 years prior to the first dose of study medication. Prior adjuvant chemotherapy
for localized breast cancer is permitted, provided that it was completed >3 years
prior to the first dose of study medication, and that the participant remains free of
recurrent or metastatic disease

6. The participant has undergone major abdominal surgery within 4 weeks (28 days) prior
to first dose of study medication

7. The participant has a suspected impending bowel obstruction, based on clinical or
radiographic criteria

8. The participant has received any hormonal therapy directed at the malignant tumor
discontinued therapy within 1 week (7 days) prior to first dose of study medication

9. The participant has received any other prior therapy directed at the malignant tumor,
including immunologic agents, within 3 weeks (21 days) prior to first dose of study
medication

10. The participant has received previous treatment with ramucirumab

11. The participant has participated in clinical trials of experimental agents within 4
weeks (28 days) prior to first dose of study medication

12. The participant has a history of uncontrolled hereditary or acquired bleeding or
thrombotic disorders

13. The participant has an ongoing or active infection requiring systemic antibiotics,
symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly
controlled cardiac arrhythmia, myocardial infarction < 6 months, Grade ≥ 2 peripheral
vascular disease, poorly controlled hypertension despite standard medical management
poorly controlled thrombotic or hemorrhagic disorder, psychiatric illness or social
situations that would limit compliance with study requirements, or any other serious
uncontrolled medical disorders in the opinion of the investigator

14. The participant has any history of brain metastases or leptomeningeal disease.
Screening for central nervous system (CNS) involvement for testing asymptomatic
participants is not required

15. The participant has known human immunodeficiency virus infection or acquired
immunodeficiency syndrome-related illness

16. The participant is pregnant [confirmed by serum beta human chorionic gonadotropin
(β-HCG) test] or lactating