BIBF 1120 in Bevacizumab Resistant, Persistent, or Recurrent Epithelial Ovarian Cancer

Ovarian cancer patients with platinum-resistant and refractory disease have the lowest response rates to relapse chemotherapy: various chemotherapeutic agents, such as paclitaxel, liposomal doxorubicin, topotecan, docetaxel, platinum, etoposide, ifosfamide, gemcitabine, and vinorelbine are available but result in response rates of 7-40%. Unfortunately, relapse therapy is not curative and treatment is only palliative. Recently two phase II trials demonstrated that anti-angiogenic therapy with bevacizumab alone or in combination with chemotherapy in women with recurrent disease had response rates ranging from 16-24% with an acceptable toxicity profile. However, resistance can develop to VEGF inhibition. Therefore other novel anti-angiogenic agents, such as BIBF 1120, should be evaluated in the treatment of ovarian cancer.

Inclusion criteria

• Recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma w/ histologic documentation of the original primary tumor via the pathology report:

• serious, endometrioid, mucinous, or clear cell adenocarcinoma
• undifferentiated, mixed epithelial or transitional cell carcinoma
• Brenner's Tumor
• adenocarcinoma NOS
• Had treatment-free interval following response to bevacizumab (CR, PR, or SD) of < 6 months, or have progressed during treatment w/ a bevacizumab-containing therapy
• Measurable or detectable disease. Measurable is defined by RECIST 1.1. Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI. Detectable defined as no measurable disease but either ascities/pleural effusion or solid/cystic abnormalities that don't meet RECIST 1.1 - both within the setting of CA125 >2xULN
• Those with measurable disease must have at least one "target lesion" to assess response as defined by RECIST 1.1. Tumors in a previously irradiated field will be designated as "non-target" lesions
• Must have a ECOG Performance Status of 0 or 1
• Free of active infection requiring antibiotics. Exception: uncomplicated UTI
• Recovery from effects of recent surgery, radiotherapy, or chemotherapy

• Hormonal therapy directed at the malignant tumor must be d/c at least a week prior to registration. Hormone replacement therapy is permitted
• Other prior therapy directed at malignant tumor, including immunologic agents, must be d/c at least 3 weeks prior to registration; 4 weeks if prior therapy was w/ bevacizumab
• Prior therapy

• must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, high-dose therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment.
• Allowed, to receive, but not required to receive, 2 additional cytotoxic regimens for management of recurrent or persistent disease according to the following:

• Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy.
• Patients must NOT have received any non-cytotoxic therapy for management of recurrent or persistent disease other than bevacizumab. Patients are allowed to receive, but are not required to receive, biologic (non-cytotoxic) therapy as part of their primary treatment regimen.
• Must have adequate:

• Bone marrow function: Absolute neutrophil count (ANC) ≥ 1,500/mcl, equivalent to (CTCAE v4.0) grade 1. Platelets ≥ 100,000/mcl. Hemoglobin (Hb) ≥ 9.0 g/dL
• Renal function: creatinine ≤ 1.5 x upper limit of normal (ULN)
• Hepatic function: Bilirubin should be w/in normal limits (CTCAE v4.0, grade 1). ALT/AST, should be ≤ 1.5 x ULN (CTCAE v4.0, grade 1). For patients w/ liver metastases, ALT/AST should be ≤ 2.5 x ULN; Alkaline phosphatase should be ≤ 2.5 x ULN (CTCAE v4.0, grade 1)
• Neurologic function: Neuropathy ≤ CTCAE v4.0, grade 1
• Blood coagulation parameters: PT w/ international normalized ratio (INR) < 1.5 x ULN & a PTT < 1.5 x ULN (or an in-range PTT if on a stable dose of therapeutic heparin). Low molecular weight heparin (enoxaparin or alternative anticoagulants (other than warfarin)) are acceptable.
• Signed informed consent & authorization permitting release of personal health information
• Negative serum pregnancy test if of childbearing potential prior to study entry & use of effective form of contraception until 3 months after receiving last drug treatment
• Patients may have undergone a major or minor surgical procedure as long as:

• > 28 days prior to the first date of study therapy
• Core biopsy or IV Port placement greater than 7 days prior to the first date of study therapy

Exclusion criteria

• Previous treatment w/ BIBF 1120.
• Pregnant or breastfeeding.
• Received radiation to more than 25% of marrow-bearing areas
• History of other invasive malignancies, w/ the exception of non-melanoma skin cancer, if there is any evidence of other malignancy being present w/in the last five years.
• Received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for treatment of ovarian, fallopian tube, or primary peritoneal cancer w/in the last 5 years.
• Prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer or localized breast cancer w/in the last 5 years.
• A history of abdominal or tracheal-esophageal fistula, or gastrointestinal perforation
• A history of intra-abdominal abcess w/in 6 months of enrollment
• Serious, uncontrolled, concomitant disorder(s) such as diabetes mellitus
• Patients w/ clinically significant cardiovascular disease including: uncontrolled hypertension: systolic > 150 mm Hg/diastolic > 90 mm Hg; unstable angina or who have had a myocardial infarction w/in the past six months prior to registration; congestive heart failure; cardiac arrhythmia requiring medication (doesn't include asymptomatic atrial fibrillation); grade 2 or greater peripheral vascular disease (at least brief (<24 hours) episodes of ischemia managed non-surgically & w/o permanent deficit.
• Serious non-healing wound, ulcer, or bone factor.

o Granulating incisions healing by secondary intention w/ no evidence of fascial dehiscence or infection ARE eligible but require weekly wound examinations.

• Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• History/evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled w/ standard medical therapy, any brain metastases, CVA, TIA, or subarachnoid hemorrhage w/in 6 months of the first date of treatment on this study.
• Central pulmonary metastases/recent hemoptysis (≥1/2 tsp of red blood) w/in 28 days of registration.

• Clinically significant proteinuria (i.e. >Grade 1) or UPC ratio above 1.0
• Suspicion of transmural tumor bowel involvement based on the investigator's discretion.
• Clinical symptoms/signs of gastrointestinal obstruction & require IV hydration &/or nutrition.
• Patients taking warfarin are not eligible