The primary objective of the study is to assess the anti-tumor activity for patients with GBM with a translocation or amplification in FGFR1,2,3 or 4 based on PFS.The secondary objectives of the study are to assess the anti-tumor activity for…
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Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint will be the progression-free survival rate at 6 month
(PFS6 rate) based on patients pooled from Group 1 and Group 2.
Secondary outcome
The secondary efficacy endpoints will be the ORR of patients from Group 1 and
Group 2 with radiologically assessable enhancing disease using RANO criteria
and OS.
The secondary safety endpoints will be: type, frequency, and severity of AEs
and SAEs
The secondary tolerability endpoints will be: dose interruptions, reductions
and dose intensity, and evaluations of laboratory values
Background summary
Glioblastoma (GBM) is a highly malignant brain tumor of astrocytic origin which
accounts for over 50% of all gliomas. GBM has an annual incidence rate of 3 to
4 cases per 100,000 people resulting in 240,000 newly diagnosed cases worldwide
each year.
The current standard treatment for GBM is surgical resection followed by
radiotherapy with concurrent and adjuvant temozolomide (TMZ). For newly
diagnosed GBM, the addition of TMZ to surgery and radiation therapy prolongs
median survival from 12.1 to 14.6 months and increases the five-year survival
rate, from 2% to 10%. However, at recurrence, no cytotoxic or targeted
therapeutic has improved the 6-month-PFS rate of 10-20%, a median overall
survival of 6-9 months, and an average 5 year overall survival of 3.3% with the
possible exception of bevacizumab.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor
(VEGF), was approved in the US for the treatment of recurrent GBM. The
6-month-PFS rate in the multiple studies ranged from approximately 29% to 50%.
Despite the improvement in response provided by bevacizumab, most patients with
GBM experience relapse within months and options for salvage remain extremely
limited.
Genetically, GBM is characterized by complex chromosomal abnormalities. Common
mutations found in GBM include: EGFR overexpression (70%); TP53, RB, INK4a,
PDGF-R, VEGF-R, CMet, and HGF and PTEN. Recently it was reported that a small
subset of GBMs (3.1%) harbors oncogenic chromosomal translocations that fuse
in-frame the tyrosine kinase coding domains of fibroblast growth factor
receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil
(TACC) coding domains of TACC1 or TACC3, respectively.
Lentivectors expressing FGFR-TACC fusions injected directly into short term
astrocytic cell cultures as well as the brain parenchyma of mice have been
shown to fully recapitulate GBM. Subsequently FGFR-TACC induced GBM (and
derived cell lines) were successfully treated with FGFR inhibitors such as
BGJ398, abolishing the malignant phenotype. Finally, in-depth genomic analyses
of GBM tumor samples showed that (specifically for GBM) FGFR amplification
correlates tightly with the presence of FGFR-TACC translocation, suggesting
that all GBM patients that harbor an FGFR amplification do so as a result of
FGFR-TACC fusion.
In conclusion, FGFR-TACC fusions could potentially identify a subset of GBM
patients who would benefit from targeted FGFR kinase inhibition.
Study objective
The primary objective of the study is to assess the anti-tumor activity for
patients with GBM with a translocation or amplification in FGFR1,2,3 or 4 based
on PFS.
The secondary objectives of the study are to assess the anti-tumor activity for
patients with recurrent GBM with a translocation or amplification in FGFR1,2,3
or 4 based on ORR and OS and to characterize the safety and tolerability of
BGJ398.
Study design
This is an open-label non-randomized, multicenter, phase II study of BGJ398
administered to patients with recurrent GBM, whose tumors
demonstrate FGFR amplification or translocation. Patients will be enrolled in
two groups, group 1 will enroll patients who are not candidates for surgery and
group 2 will enroll patients who are surgical candidates.
Intervention
Group 1 will enroll patients who are not candidates for surgery. Patients in
group 1 will receive 125 mg BGJ398 on a three week on, one week off schedule.
Group 2 will enroll patients who are surgical candidates. Patients in group 2
will receive 125 mg BGJ398 for 5-10 days prior to surgery and will continue to
receive 125 mg BGJ398 on a three week on, one week off schedule following
surgery. The tumor will be evaluated for markers of FGFR pathway activation.
Study burden and risks
-Possible toxicity derived from the study treatment. The known adverse events
are documented in the informed consent form (ICF).
-The study assessments are used in routine practice: venepuncture, MRI (or CT)
scan, ECG. A flowchart with all assessments can be found in the ICF.
-Adequate contraception
-Frequent study visits
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1)Patients with histologically confirmed GBM and/or glioma subtypes at the time of diagnosis or prior relapse.
2) Documentation of FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, FGFR2, or FGFR3.
3) RANO defined tumor progression by MRI in comparison to a prior scan
4) Patients must have received prior external beam radiotherapy and temozolomide.;Other protocol defined criteria may apply.
Exclusion criteria
1) History of another primary malignancy
2) Prior or current treatment with a FGFR inhibitor
3) Neurological symptoms related to underlying disease requiring increasing doses of corticosteroids
4) Patients must not be taking Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an EIAED, the patient must be off of it for at least two weeks prior to study treatment.
Other protocol defined criteria may apply.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002200-13-NL |
| ClinicalTrials.gov | NCT01975701 |
| CCMO | NL47351.041.13 |