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

• ClinicalTrials.gov Identifier: NCT01669798
• Recruitment Status: Completed
• First Posted: August 21, 2012
• Results First Posted: October 16, 2018
• Last Update Posted: October 16, 2018
• Sponsor: AA Secord
• Collaborator: Boehringer Ingelheim
• Information provided by (Responsible Party): AA Secord, Duke University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer	Drug: BIBF 1120	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: February 2013
• Actual Primary Completion Date: September 10, 2017
• Actual Study Completion Date: February 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: BIBF 1120; BIBF 1120 will be administered at a daily oral dose of 200 mg BID until disease progression or adverse effects prohibit further therapy.	Drug: BIBF 1120; PO 200mg BID; Other Names: Vargatef™; Nintedanib

Outcome Measures

Primary Outcome Measures :

1. Percentage of Patients Who Survive Progression-free [ Time Frame: 6 months ]
   Measure of Progression Free Survival (PFS) by the percentage of patients who survive progression-free for at least 6 months after initiating study therapy in patients with bevacizumab-resistant, persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

Secondary Outcome Measures :

1. Objective Tumor Response Via RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 [ Time Frame: 1 year ]
   Evaluating the percentage of patients who have objective tumor response (complete or partial) based on RECIST 1.1 criteria.
2. Duration of Progression-Free Survival [ Time Frame: Through study completion, on average 2 years ]
   The duration of progression-free survival and overall survival measured in months; Progression-Free Survival (PFS) is defined as the duration of time from study entry to time of progression or death, whichever occurs first.
3. Objective Tumor Response Based on GCIG CA-125 Criteria [ Time Frame: 1 year ]
   The proportion of patients who have objective tumor response (complete or partial) based on Gynaecologic Cancer InterGroup(GCIG) CA-125 criteria which is: "A response according to CA 125 has occurred if there is at least a 50% reduction in CA 125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days.".
4. Adverse Event Frequency and Severity [ Time Frame: 1 year ]
   To determine frequency and severity of adverse events as assessed using NCI Common Toxicity Criteria version 4.

Other Outcome Measures:

1. Concentration of Select Growth Factors Reported Measured in Picograms Per Milliliter as a Function of Treatment Response [ Time Frame: 1 year ]
   Correlating baseline and on treatment levels of additional growth factors measured in picograms per milliliter that may be co- or counter- regulated with VEGF with response to treatment
2. Coagulation and Endothelial Cell Activation Markers [ Time Frame: 1 year ]
   To measure baseline and on treatment levels of additional growth factors that may be co- or counter- regulated with VEGF and correlate with response to treatment.
3. VEGF Levels Correlated With Treatment Outcome [ Time Frame: 1 year ]
   Baseline levels of VEGF were correlated with treatment outcome. Results are stratified in groups: "Partial Response (PR) or Stable Disease (SD)" and "Progressive Disease (PD)"
4. Concentration of Select Growth Factors Measured in Nanograms Per Milliliter Reported as a Function of Treatment Response [ Time Frame: 1 year ]
   Correlating baseline and on treatment levels of additional growth factors measured in nanograms per milliliter that may be co- or counter- regulated with VEGF with response to treatment
5. Concentration of VCAM-1 Reported as a Function of Treatment Response [ Time Frame: 1 year ]
   Correlating baseline and on treatment levels of VCAM-1 measured in micrograms per milliliter that may be co- or counter- regulated with VEGF with response to treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, North Carolina

Duke Cancer Institute

Durham, North Carolina, United States, 27710

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

Virginia Oncology Associates

Norfolk, Virginia, United States, 23502

Sponsors and Collaborators

AA Secord

Boehringer Ingelheim

Investigators

• Principal Investigator: Angeles A Secord, MD; Duke University

  Study Documents (Full-Text)

Documents provided by AA Secord, Duke University:

Study Protocol and Statistical Analysis Plan  [PDF] August 16, 2018

More Information

• Responsible Party: AA Secord, Associate Professor, Duke University
• ClinicalTrials.gov Identifier: NCT01669798
• Other Study ID Numbers: Pro00033060
• First Posted: August 21, 2012
• Results First Posted: October 16, 2018
• Last Update Posted: October 16, 2018
• Last Verified: October 2018

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by AA Secord, Duke University:

Recurrent epithelial ovarian carcinoma; Persistent epithelial ovarian carcinoma; Bevacizumab resistant epithelial ovarian carcinoma

Additional relevant MeSH terms:

Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Fallopian Tube Diseases; Nintedanib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action