| Eligibility |
Inclusion Criteria:
- Signed informed consent obtained prior to initiation of any study-specific procedures
and treatment as confirmation of the patient's awareness and willingness to comply
with the study requirements (inclusive of 2 biopsies, one at baseline and if they
qualify, one pre-randomization for part 2B)
- Women 18 years of age or older
- Histologically confirmed and documented disease to include: adenocarcinoma NOS (not
otherwise specified), clear cell adenocarcinoma, endometrioid adenocarcinoma,
malignant Brenner's tumor, mixed epithelial carcinoma, mucinous adenocarcinoma, serous
adenocarcinoma, transitional cell carcinoma, and undifferentiated carcinoma
- Patients must have platinum-resistant disease, (defined as progression within < 6
months from completion of a minimum of 4 platinum therapy cycles (+ 7 days); the date
should be calculated from the last administered dose of platinum therapy)
- Patients must have disease that is measurable according to RECIST 1.1 or assessable
according to the GCIG CA-125 criteria and require chemotherapy treatment; part 1:
patients must have one or more measurable target lesion; part 2: patients must have
two or more measurable target lesions; measurable disease is defined at least one
lesion that can be accurately measured in at least one dimension (longest dimension to
be recorded); each 'target' lesion must be >= 20 mm when measured by conventional
techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic
resonance imaging (MRI), or >= 10 mm when measured by spiral CT
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Newly obtained core or excisional biopsy of a tumor lesion for part 2A and if they
qualify, one pre-randomization biopsy for part 2B
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >=9 g/dL or >= 5.6 mmol/L
- Creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X
institutional upper limit of normal (ULN)
- Total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGOT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases
- International normalized ratio (INR)/prothrombin time (PT) =< 1.5 X ULN (unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time [PTT] is within therapeutic range of intended use of anticoagulants)
- PTT =< 1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or
PTT is within therapeutic range of intended use of anticoagulants)
- Life expectancy of >= 12 weeks
Exclusion Criteria:
- Patients who have disease progression prior to completion of intended frontline
therapy, including patients demonstrating disease progression after interval
cytoreduction
- Non-epithelial, including malignant mixed Mullerian tumors
- Ovarian tumors with low malignant potential (i.e. borderline tumors)
- For part 2 patients only: History of other clinically active malignancy within 5 years
of enrollment, except for tumors with a negligible risk for metastasis or death, such
as adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin
or carcinoma in situ of the cervix or breast, or early stage endometrial cancer (stage
IA/B, grade 1 or 2, endometrioid histology)
- Previous treatment with > 2 anticancer regimens for ovarian cancer
- Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3
weeks prior to initiation of study treatment, with the following exceptions:
hormone-replacement therapy or oral contraceptives; tyrosine kinase inhibitors (TKIs)
that have been discontinued > 7 days prior to cycle 1, day 1; screening scans must be
obtained after discontinuation of prior TKIs
- Any prior radiotherapy to the pelvis or abdomen
- Surgical procedure (including open biopsy, surgical resection, wound revision, or any
other major surgery involving entry into a body cavity) or significant traumatic
injury within 28 days prior to study enrollment, or anticipation of need for major
surgical procedure during the course of the study; minor surgical procedures including
placement of a vascular access device, within 2 days of the first study treatment
- Previous exposure to murine CA-125 antibody (only applicable to those patients with
non-measurable disease by RECIST)
- Current or recent (within 10 days prior to the first study drug dose) chronic daily
treatment with aspirin (> 325 mg/day)
- Current or recent treatment with another investigational drug within 30 days of first
study treatment dosing or earlier participation in this study
- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF
agents within 2 weeks prior to cycle 1, day 1; patients who have received acute and/or
lowrolment, or anticipation of need for major surgical, a one-time dose of
dexamethasone for nausea or chronic use of =< 10 mg/day of prednisone or
dose-equivalent corticosteroid) may be enrolled in the study after discussion with and
approval by the medical monitor; the use of inhaled corticosteroids and
mineralocorticoids (e.g., fludrocortisone) is allowed; prior corticosteroids as
anti-cancer therapy within a minimum of 14 days of first receipt of study drug
- Received therapeutic oral or IV antibiotics within 2 weeks prior to cycle 1, day 1;
patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible
- Patients with urine dipstick for proteinuria > 2+; patients with >= 2+ proteinuria on
baseline dipstick analysis should undergo a 24-hour urine collection and must
demonstrate =< 1 g of protein in the 24-hour urine; alternatively, proteinuria testing
can be performed according to local standards
- Patients with known auto-immune disease
- Patients with known history of human immunodeficiency virus (HIV), hepatitis B virus
(HBV) and hepatitis C virus (HCV) infection
- Patient has received an organ transplant
- Patient has a history of hematological malignancy within the last 5 years prior to
study entry; prior allogeneic bone marrow transplantation or prior solid organ
transplantation
- Patient has a history of hematological malignancy within the last 5 years prior to
study entry
- History of or active autoimmune disease including, but not limited to, systemic lupus
erythematous, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, and vasculitis or
glomerulonephritis; patients with autoimmune thyroid disease on a stable thyroid
replacement regimen; controlled vitiligo, eczema, psoriasis, or seborrheic dermatitis
with only dermatologic manifestations; or controlled type I diabetes on a stable
insulin regimen may be eligible for the study with approval by the medical monitor
- History or evidence upon physical/neurological examination of central nervous system
(CNS) disease unrelated to cancer, unless adequately treated with standard medical
therapy (e.g. uncontrolled seizures)
- Symptomatic CNS metastasis
- Pre-existing peripheral neuropathy >= Common Terminology Criteria (CTC) grade 2 for
those patients who received prior paclitaxel
- Spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for >= 2 weeks prior to screening
- Increased corrected QT (QTc) interval (QTc > 470 ms), patients with baseline resting
bradycardia < 45 beats per minute (bpm), or baseline resting tachycardia > 100 bpm
- Family history of long QT syndrome or other risk factors for torsades de pointes,
and/or the use of concomitant medications that prolong the QT/QTc interval
- Signs or symptoms of serious active infection requiring oral or i.v. antibiotics
within 2 weeks prior to cycle 1 day 1 and/or hospitalization at study entry including,
but not limited to, hospitalization for complications of infection, bacteremia, active
tuberculosis or severe pneumonia
- Pregnant or lactating females; serum pregnancy test to be assessed within 7 days prior
to study treatment start, or within 14 days (with a confirmatory urine pregnancy test
within 7 days prior to study treatment start)
- For women who are not postmenopausal (< 12 months of non therapy-induced amenorrhea,
with no identified cause other than menopause) and have not undergone surgical
sterilization (removal of ovaries and/or uterus): agreement to remain abstinent
(refrain from heterosexual intercourse) or use two adequate non hormonal methods of
contraception, including at least one method with a failure rate of < 1% per year,
during the treatment period and for at least 4 months after the last dose of study
drug
- Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, established, proper use of
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine
devices, and copper intrauterine devices; the reliability of sexual abstinence needs
to be evaluated in relation to the duration of the clinical trial and the preferred
and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation,
symptothermal, or postovulation methods) and withdrawal are not acceptable methods of
contraception
- History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular
accident (CVA)/stroke or transient ischemic attack (TIA) or sub-arachnoid hemorrhage
within =< 6 months prior to the first study treatment
- Uncontrolled hypertension (sustained systolic > 150 mmHg and/or diastolic > 100 mmHg
despite antihypertensive therapy) or clinically significant (i.e. active)
cardiovascular disease, including: myocardial infarction or unstable angina within =<
6 months prior to the first study treatment; New York Heart Association (NYHA) grade
II or greater congestive heart failure (CHF); serious cardiac arrhythmia requiring
medication (with the exception of atrial fibrillation or paroxysmal supraventricular
tachycardia); significant vascular disease (e.g., aortic aneurysm, requiring surgical
repair or recent peripheral arterial thrombosis) within 6 months prior of study
enrollment; prior history of hypertensive crisis or hypertensive encephalopathy
- History of bowel obstruction, including sub-occlusive disease, related to the
underlying disease and history of abdominal fistula, gastrointestinal perforation or
intra-abdominal abscess; evidence of recto-sigmoid involvement by pelvic examination
or bowel involvement on CT scan or clinical symptoms of bowel obstruction
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)
- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month
of study enrollment for any tumor type
- Non-healing wound, ulcer or bone fracture
- Known hypersensitivity to any of the study drugs or excipients
- Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer,
etc.), physical examination or laboratory findings that may interfere with the planned
treatment, affect patient compliance or place the patient at high risk from
treatment-related complications
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