Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Glioblastoma, Gliosarcoma
Conditions
Keywords
brain tumor, recurrent disease
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.
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).
Interventions
DRUGBIBF 1120
200 mg BID oral for 28 day cycle
Sponsors
Boehringer Ingelheim
Wake Forest University Health Sciences
University of Virginia
Massachusetts General Hospital
The Cleveland Clinic
Patrick Y. Wen, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-Month Progression Free Survival | 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). |
| 3-Month Progression Free Survival | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years | Overall survival in both populations |
| Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response | 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). |
| Time-to-tumor Progression | 2 years | Time-to-tumor progression in both populations. |
| Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 2 years | To explore the correlation between serum angiogenic peptides, circulating endothelial cells, and circulating progenitor cells with response to therapy. |
| Exploratory Objective #4: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Perfusion MRI, Diffusion MRI | 2 years | To explore the correlation between perfusion MRI, diffusion MRI and response to therapy. |
| Exploratory Objective #2: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Tumor Genotype and/or Expression Profile | 2 years | To explore the extent to which the tumor's genotype and expression profile correlate with outcome. |
| Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG) | 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. |
Countries
United States
Participant flow
Recruitment details
Study activated at Dana-Farber Cancer Institute in May 2012 and was eventually activated at Massachusetts General Hospital, Cleveland Clinic, and University of Virginia. The bevacizumab-treated arm closed to accrual in December 2012 and the bevacizumab-naive arm closed in March 2013, both due to futility.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Bevacizumab-naive Bevacizumab-naive participants | 22 |
| Arm B Bevacizumab-treated Bevacizumab-treated participants | 14 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 10 | 9 | 10 | 3 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm B Bevacizumab-treated | Total | Arm A Bevacizumab-naive |
|---|---|---|---|
| Age, Continuous | 52 years | 52 years | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 33 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Karnofsky Performance Status | 90 Units on a scale | 90 Units on a scale | 90 Units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 30 Participants | 19 Participants |
| Sex: Female, Male Female | 3 Participants | 18 Participants | 15 Participants |
| Sex: Female, Male Male | 11 Participants | 18 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 14 / 14 |
| serious Total, serious adverse events | 8 / 22 | 5 / 14 |
Outcome results
Primary
3-Month Progression Free Survival
To determine the efficacy of BIBF 1120 in bevacizumab-treated participants with recurrent GBM as measured by 3-month progression free survival (PFS3).
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | 3-Month Progression Free Survival | 0 percentage of participants |
Primary
6-Month Progression Free Survival
To determine the efficacy of BIBF 1120 in bevacizumab-naive participants with recurrent glioblastoma (GBM) as measured by 6-month progression-free survival (PFS6).
Time frame: Six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | 6-Month Progression Free Survival | 0 percentage of participants |
Secondary
Overall Survival
Overall survival in both populations
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | Overall Survival | 6.9 months |
| Arm A (Bevacizumab-naive) - AG | Overall Survival | 11.3 months |
| Arm B (Bevacizumab Treated) - GBM | Overall Survival | 2.6 months |
| Arm B (Bevacizumab Treated) - AG | Overall Survival | 7.3 months |
Secondary
Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response
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).
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response | 33 % of patients with best response SD |
| Arm A (Bevacizumab-naive) - AG | Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response | 40 % of patients with best response SD |
| Arm B (Bevacizumab Treated) - GBM | Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response | 10 % of patients with best response SD |
| Arm B (Bevacizumab Treated) - AG | Proportion of Participants Experiencing Stable Disease (SD) as Their Best Radiographic Response | 25 % of patients with best response SD |
Secondary
Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial)
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).
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Abdominal pain | 1 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Reversible transaminase elevation | 8 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Hypertension | 1 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Hypophosphatemia | 3 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Intracranial hemorrhage | 1 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Colonic perforation | 2 number of incidents |
| Arm A (Bevacizumab-naive) - GBM | Safety Profile as Summarized With Descriptive Statistics (Using Toxicity Data Gathered on Trial) | Pulmonary embolism | 1 number of incidents |
Secondary
Time-to-tumor Progression
Time-to-tumor progression in both populations.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | Time-to-tumor Progression | 28 days |
| Arm A (Bevacizumab-naive) - AG | Time-to-tumor Progression | 28 days |
| Arm B (Bevacizumab Treated) - GBM | Time-to-tumor Progression | 28 days |
| Arm B (Bevacizumab Treated) - AG | Time-to-tumor Progression | 36 days |
Other Pre-specified
Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG)
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.
Time frame: Arm A - 6 months; Arm B - 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Bevacizumab-naive) - GBM | Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG) | 0 percentage of participants |
| Arm A (Bevacizumab-naive) - AG | Exploratory Objective #1: Progression-free Survival at 3- and 6-months for Participants With Recurrent Anaplastic Gliomas (AG) | 0 percentage of participants |
Other Pre-specified
Exploratory Objective #2: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Tumor Genotype and/or Expression Profile
To explore the extent to which the tumor's genotype and expression profile correlate with outcome.
Time frame: 2 years
Other Pre-specified
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
To explore the correlation between serum angiogenic peptides, circulating endothelial cells, and circulating progenitor cells with response to therapy.
Time frame: 2 years
Other Pre-specified
Exploratory Objective #4: Determination if Any Correlation Exists Between Patient Outcomes (Survival, PFS3, PFS6) and Perfusion MRI, Diffusion MRI
To explore the correlation between perfusion MRI, diffusion MRI and response to therapy.
Time frame: 2 years