BIBF 1120 for Recurrent High-Grade Gliomas

Study Description

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Brief Summary:

BIBF 1120 is a newly discovered compound that may stop cancer cells from growing abnormally. This drug is currently being used in treatment for other cancers in research studies and information from those other research studies suggests that this agent, BIBF 1120, may help to stop recurrent malignant glioma cells from multiplying and it may also prevent the growth of new blood vessels at the site of the tumor. In this research study, the investigators are looking to see how well BIBF 1120 works in patients with recurrent malignant gliomas.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma	Drug: BIBF 1120	Phase 2

Detailed Description:

This is a two arm, multicenter, open label phase II trial in adult patients with recurrent supratentorial high-grade glioma. One arm (the "bevacizumab naïve" arm) will enroll patients who have not received prior bevacizumab therapy, and the other arm (the "post-bevacizumab" arm) will enroll patients who have experienced progression on bevacizumab.

All subjects will receive BIBF 1120 at 200mg orally, twice daily in cycles of 28 days. Subjects will come to the clinic on Day 1 of each cycle (or within 2 days prior) for blood and urine tests and a physical and neurologic exam. Bloods will also be checked within 2 days before or after Day 15 of Cycles 1 and 2. An additional blood sample will be taken on Days 1 and 8 of Cycle 1, at the start of every even-numbered cycle, and at the end of active study treatment. Subjects will have gadolinium-enhanced brain MRI scans performed with tumor measurements at screening, at the start of even-numbered cycles, and at the end of active study treatment(unless already obtained within 4 weeks of completing study treatment). 40 study subjects will have diffusion- and perfusion-weighted MRI at baseline, after 1 week on therapy (± 2 days), within 2 days prior to the start of every even-numbered cycle, and at the end of treatment (unless already obtained within 4 weeks of completing study treatment).

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	37 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Trial of Triple Receptor Tyrosine Kinase Receptor Inhibitor BIBF 1120 in Recurrent High-Grade Gliomas
Study Start Date :	May 2012
Actual Primary Completion Date :	July 2013
Actual Study Completion Date :	July 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Bevacizumab Naive; Bevacizumab naive subjects	Drug: BIBF 1120; 200 mg BID oral for 28 day cycle
Experimental: Prior Bevacizumab; Patients previously treated with bevacizumab	Drug: BIBF 1120; 200 mg BID oral for 28 day cycle

Outcome Measures

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Primary Outcome Measures :

1. 6-Month Progression Free Survival [ Time Frame: Six months ]
   To determine the efficacy of BIBF 1120 in bevacizumab-naive participants with recurrent glioblastoma (GBM) as measured by 6-month progression-free survival (PFS6).
2. 3-Month Progression Free Survival [ Time Frame: 3 months ]
   To determine the efficacy of BIBF 1120 in bevacizumab-treated participants with recurrent GBM as measured by 3-month progression free survival (PFS3).

Secondary Outcome Measures :

1. Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response [ Time Frame: 2 years ]
   Best radiographic response in both populations. There were no participants with partial or complete responses, so the results are being reported in the proportion of participants who experienced stable disease (SD) as their best response (as opposed to progressive disease).
2. Overall Survival [ Time Frame: 2 years ]
   Overall survival in both populations
3. Time-to-tumor Progression [ Time Frame: 2 years ]
   Time-to-tumor progression in both populations.
4. Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) [ Time Frame: 2 years ]
   Safety profile in both populations - as adverse events are posted separately in detail, these results will demonstrate serious adverse events (defined as grades 3-5) that were judged at least possibly related to Nintedanib (BIBF 1120).

Other Outcome Measures:

1. Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG) [ Time Frame: Arm A - 6 months; Arm B - 3 months ]
   To explore the efficacy of BIBF 1120 in bevacizumab-naïve and bevacizumab-treated participants with recurrent anaplastic gliomas (AG) survival was assessed at 6 months for Arm A and 3 months for Arm B.
2. Exploratory Objective #2: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Tumor Genotype and/or Expression Profile [ Time Frame: 2 years ]
   To explore the extent to which the tumor's genotype and expression profile correlate with outcome.
3. Exploratory Objective #3: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Serum Angiogenic Peptides, Circulating Endothelial Cells, and/or Circulating Progenitor Cells [ Time Frame: 2 years ]
   To explore the correlation between serum angiogenic peptides, circulating endothelial cells, and circulating progenitor cells with response to therapy.
4. Exploratory Objective #4: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Perfusion MRI, Diffusion MRI [ Time Frame: 2 years ]
   To explore the correlation between perfusion MRI, diffusion MRI and response to therapy.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histopathologically-confirmed, supratentorial, recurrent glioblastoma; subjects with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is determined to be glioblastoma
• Demonstration of recurrent disease on MRI following prior therapy
• Development of progressive disease after having received prior RT, and must have an interval of at least 12 weeks from the completion of any radiation therapy to study entry (unless progressive tumor growth is outside the radiation field or there is histopathological confirmation of recurrent tumor).
• Bi-dimensionally measurable disease (minimum measurement of 1 cm in one dimension) on MRI performed within 14 days prior to first treatment. (If receiving corticosteroids, participants must be on a stable or decreasing dose of corticosteroids for at least 5 days prior to baseline MRI.)
• Life expectancy of at least 12 weeks
• KPS >/= 60
• Normal organ and marrow function as defined by protocol
• Recovered from toxic effects of prior therapy
• Sufficient tumor availability (at least 15-20 unstained paraffin slides from any prior surgery)

Exclusion Criteria:

• Receiving other investigational agent
• More than 2 prior relapses
• Prior therapy with inhibitor of VEGF, VEGFR, PDGFR, or FGFR (including bevacizumab)
• Pregnant or breast-feeding
• Unwilling to agree to adequate contraception, if subject is of child-bearing potential
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BIBF 1120
• Use of EIAEDs within 14 days of registration
• Evidence of recent hemorrhage on baseline MRI of the brain
• Uncontrolled intercurrent illness
• Uncontrolled hypertension
• History of hypertensive encephalopathy
• History of any of the following within 6 months prior to enrollment: myocardial infarction or unstable angina, stroke or transient ischemic attack, significant vascular disease or peripheral arterial thrombosis, abdominal fistula, gastrointestinal perforation, or intra-abdominal abcess, intracerebral abscess
• Evidence of bleeding diathesis or coagulopathy
• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to the first treatment day, or anticipation of need for major surgical procedure during the course of the study
• Minor surgical procedures, stereotactic biopsy, fine needle aspiration, or core biopsy within 7 days prior to the first treatment day
• Serious non-healing wound, ulcer, or bone fracture
• History of a different malignancy unless disease-free for at least 5 years (unless cervical cancer in situ, or basal cell or squamous cell carcinoma of the skin)
• HIV positive

Contacts and Locations

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Locations

United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908-4324

Sponsors and Collaborators

Patrick Y. Wen, MD

Boehringer Ingelheim

Wake Forest University Health Sciences

University of Virginia

Massachusetts General Hospital

The Cleveland Clinic

Investigators

Principal Investigator:	Patrick Y Wen, M.D.	Dana-Farber Cancer Institute

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Norden AD, Schiff D, Ahluwalia MS, Lesser GJ, Nayak L, Lee EQ, Rinne ML, Muzikansky A, Dietrich J, Purow B, Doherty LM, LaFrankie DC, Pulverenti JR, Rifenburg JA, Ruland SF, Smith KH, Gaffey SC, McCluskey C, Ligon KL, Reardon DA, Wen PY. Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas. J Neurooncol. 2015 Jan;121(2):297-302. doi: 10.1007/s11060-014-1631-y. Epub 2014 Oct 22.

Responsible Party:	Patrick Y. Wen, MD, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT01380782 History of Changes
Other Study ID Numbers:	11-055; BIBF 1199.94 ( Other Identifier: Boehringer-Ingleheim )
First Posted:	June 27, 2011
Results First Posted:	August 18, 2014
Last Update Posted:	August 18, 2014
Last Verified:	August 2014

Keywords provided by Patrick Y. Wen, MD, Dana-Farber Cancer Institute:

brain tumor; recurrent disease

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial	Neoplasms, Nerve Tissue; Bevacizumab; Nintedanib; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action