Clinical trial NCT01669798: BIBF 1120 in Bevacizumab Resistant, Persistent, or Recurrent Epithelial Ovarian Cancer
Official title: Phase II Evaluation of BIBF 1120 in the Treatment of Bevacizumab-Resistant, Persistent, or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ovarian Cancer
Fallopian Tube Cancer
Peritoneal Cancer
Keywords: Recurrent epithelial ovarian carcinoma
Persistent epithelial ovarian carcinoma
Bevacizumab resistant epithelial ovarian carcinoma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2012-08-21
Enrollment: 32
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The main purpose of this study is to see if BIBF 1120 can increase the number of women with bevacizumab resistant, persistent, or recurrent epithelial ovarian cancer who do not progress for at least six months.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Patients Who Survive Progression-free
timeFrame: 6 months
Secondary outcomes:
measure: Objective Tumor Response Via RECIST (Response Evaluation Criteria in Solid Tumors) 1.1
timeFrame: 1 year
measure: Duration of Progression-Free Survival
timeFrame: Through study completion, on average 2 years
measure: Objective Tumor Response Based on GCIG CA-125 Criteria
timeFrame: 1 year
measure: Adverse Event Frequency and Severity
timeFrame: 1 year
Other outcomes:
measure: Concentration of Select Growth Factors Reported Measured in Picograms Per Milliliter as a Function of Treatment Response
timeFrame: 1 year
measure: Coagulation and Endothelial Cell Activation Markers
timeFrame: 1 year
measure: VEGF Levels Correlated With Treatment Outcome
timeFrame: 1 year
measure: Concentration of Select Growth Factors Measured in Nanograms Per Milliliter Reported as a Function of Treatment Response
timeFrame: 1 year
measure: Concentration of VCAM-1 Reported as a Function of Treatment Response
timeFrame: 1 year
Locations:
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Duke University
name: Angeles A Secord, MD
role: PRINCIPAL_INVESTIGATOR
References: