A Phase II Trial of AMG 386 (IND# ), a Selective Angiopoietin ½ Neutralizing Peptibody, in Patients With Persistent/Recurrent Carcinoma of the Endometrium

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed endometrial carcinoma

- Recurrent or persistent disease

- Histologic confirmation of the original primary tumor is required

- Histologic or cytologic confirmation of the recurrent/progressive disease
is desired but not required

- Disease refractory to curative therapy or established treatments

- The following epithelial cell types are eligible:

- Endometrioid adenocarcinoma

- Serous adenocarcinoma

- Undifferentiated carcinoma

- Clear cell adenocarcinoma

- Mixed epithelial carcinoma

- Adenocarcinoma not otherwise specified (N.O.S.)

- Mucinous adenocarcinoma

- Squamous cell carcinoma

- Transitional cell carcinoma

- Must have measurable disease, defined as ≥ 1 lesion that can be accurately measured
in ≥ 1 dimension (longest diameter to be recorded) as ≥ 10 mm by CT scan, MRI, or
caliper by clinical exam OR ≥ 20 mm by chest x-ray

- Lymph nodes must be ≥ 15 mm in short axis when measured by CT scan or MRI

- Must have ≥ 1 target lesion to assess response as defined by RECIST

- Tumors within a previously irradiated field will be designated as "non-target"
lesions unless progression is documented or a biopsy is obtained to confirm
persistence ≥ 90 days following completion of radiation therapy

- Patients must not be eligible for a higher priority GOG protocol, if one exists
(e.g., any active GOG Phase III or Rare Tumor protocol for the same patient
population)

- Must have had 1 prior chemotherapy regimen for management of endometrial carcinoma

- Chemotherapy administered in conjunction with primary radiation as a
radio-sensitizer is counted as a chemotherapy regimen

- No history or evidence of CNS disease, including brain tumor or brain metastases,
upon physical examination

PATIENT CHARACTERISTICS:

- GOG performance status (PS) 0-2 (for patients who received 1 prior chemotherapy
regimen) OR GOG PS 0-1 (for patients who received 2 prior chemotherapy regimens)

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9.0 g/dL

- Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 60
mL/min

- Bilirubin ≤ 1.5 times ULN

- AST and ALT ≤ 3.0 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- INR ≤ 1.5 times ULN (or an in-range INR between 2 and 3 for patient on a stable dose
of therapeutic warfarin)

- PTT ≤ 1.5 times ULN

- Albumin ≥ 2.8 mg/dL

- Urine protein: proteinuria ≤ 1 on dipstick OR < 1 g by 24-hour urine collection

- Free of active infection requiring antibiotics except for uncomplicated UTI

- Peripheral neuropathy (sensory or motor) ≤ grade 1

- Fertile patients must agree to use effective non-hormonal double-barrier
contraception methods (e.g., condom plus diaphragm) from the time of signing the
informed consent through 6 months after the last dose of study drug

- Not pregnant or nursing

- Negative pregnancy test

- More than 3 years since other invasive malignancies except non-melanoma skin cancer
and other specific malignancies (e.g., localized breast, head and neck , or skin
cancer for which the patient remains free of recurrence or metastatic disease)

- No symptoms of partial or complete bowel obstruction, including any of the following:

- Fistula within the past 6 months

- Intra-abdominal abscess or bowel perforation

- Patients requiring total parenteral nutrition or parenteral hydration

- No uncontrolled seizures with standard medical therapy

- No clinically significant cardiovascular disease including, but not limited to, any
of the following:

- Myocardial infarction or unstable angina within the past 12 months

- NYHA class II-IV congestive heart failure

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation), or cardiac arrhythmias requiring anti-arrhythmic
medications (except for atrial fibrillation that is well controlled with
anti-arrhythmic medication)

- Peripheral vascular disease ≥ grade 2

- Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or
subarachnoid hemorrhage within the past 6 months

- History of arterial ischemia or thrombus

- No uncontrolled hypertension (systolic blood pressure (BP) > 150 mm Hg or diastolic
BP > 90 mm Hg)

- Anti-hypertensive medications to control hypertension allowed

- No serious non-healing wound, ulcer (including gastrointestinal), or bone fracture

- No known HIV, hepatitis C, or chronic or active hepatitis B infection

- No patient with any condition that, in the investigator's opinion, makes the patient
unsuitable for study participation

- No known sensitivity to any of the products to be administered during study

- No history of allergic reactions to bacterially produced proteins

- No significant traumatic injury within the past 28 days

- No significant bleeding within 6 months of enrollment or pathologic conditions that
carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor
involving major vessels

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from recent surgery, radiotherapy, or chemotherapy

- At least 1 week since any prior hormonal therapy directed at the malignant tumor

- Any other prior therapy directed at the malignant tumor, including chemotherapy and
immunologic agents, must be discontinued at least 3 weeks prior to registration

- Any prior radiation therapy must be completed at least 4 weeks prior to registration

- One prior cytotoxic regimen for management of recurrent or persistent disease allowed

- More than 28 days since prior major surgical procedure or open biopsy

- No anticipation of major surgical procedure during course of the study

- More than 7 days since prior minor surgical procedures

- Paracentesis and thoracentesis allowed at the discretion of the investigator and
as clinically indicated

- More than 30 days since prior immune modulators (e.g., systemic cyclosporine or
tacrolimus)

- No prior radiotherapy to any portion of the abdominal cavity or pelvis within the
past 3 years except for treatment of endometrial cancer

- Prior radiotherapy for localized cancer of the breast, head and neck, or skin
allowed, provided it was completed > 3 years ago and patient remains free of
recurrence or metastatic disease

- No prior chemotherapy for any portion of the abdominal cavity or pelvis within the
past 3 years except for treatment of endometrial cancer

- Prior adjuvant chemotherapy for localized breast cancer allowed, provided it was
completed > 3 years ago and patient remains free of recurrence of metastatic
disease

- Patients must have NOT received any non-cytotoxic (biologic or targeted) agents as
part of their primary treatment or for management of recurrent or persistent disease

- Non-cytotoxic (biologic or targeted) agents include (but are not limited to)
monoclonal antibodies, cytokines, and small-molecule inhibitors of signal
transduction

- Prior hormonal therapy is allowed; there is no limit on the number of prior
hormonal therapies allowed

- No prior or other concurrent angiopoietin 1/2-neutralizing peptibody AMG 386, other
molecules that inhibit the angiopoietins, or Tie2 receptor

- No prior cancer treatment that contraindicates this protocol therapy