First or Second Recurrence of Glioblastoma
Conditions
Keywords
glioblastoma, recurrence
Brief summary
In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Detailed description
Despite intensive treatment efforts combining surgery, radio- and chemotherapy, the prognosis of patients suffering from glioblastoma (GBM) remains poor. Virtually all GBMs progress despite therapy. Patients receiving the standard therapy at primary disease have a median overall survival of 12-15 months. There is currently no defined standard treatment regimen for recurrent GBM. Tyrosine kinase receptor-targeted therapy is widely used in preclinical and clinical experimental brain tumor research. Increased tyrosine kinase activity has been asssociated with GBM oncogenesis and several tyrosine kinase receptors, e.g. VEGFR, FGFR, PDGFR are upregulated in malignant glioma. In the past and in the present, targeting of VEGF- and PDGF-signaling (amongst others) has shown promising preclinical and clinical results in human glioblasto-ma. In that context our own in vitro studies lead to the assumption that application of a multi-targeted tyrosine kinase inhibitor could be a most effective treatment approach for GBM patients. We were able to demonstrate that GBM cells from different tumor regions express different set of tyrosine kinase receptors that all could be targeted by the multi-targeted tyrosine kinase inhibitor TKI258, including PDGFRß, CSF 1R, KIT, FLT3, VEGFR, TrkA, RET and FGFRs. In combination with its ability to cross the blood-brain-barrier (BBB), the exploration of TKI258 for patients with recurrent GBM appears very promising. Recently, safety and feasibility of TKI258 was demonstrated in adult patients with advanced solid malignan-cies. The maximum tolerated dose (MTD) was determined and a recommended dose for phase II trials was established. Meanwhile, TKI258 is in phase III development in renal cell carcinoma, and in phase II devel-opment in advanced breast cancer, relapsed multiple myeloma and urothelial cancer. Since the toxicity profile for compounds that could cross the BBB might be different in patients with CNS diseases/disorders (e.g. brain tumors) compared to patients with malignancies outside the CNS, we here propose a phase I trial exploring TKI258 in patients with recurrent glioblastoma. In this study with a modified 3+3 dose finding design, a safe and tolerable dose of TKI258 in patients with relapsed glioblastoma should be established.
Interventions
DRUGDovitinib
daily oral intake of capsule
Sponsors
PD Dr. Martin Glas
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Subjects, male or female, Age ≥ 18 years * First or second recurrence of histologically confirmed glioblastoma * A Performance Scale of Karnofsky \> 60%, ECOG ≤ 2 or WHO \< 2 * Patients must have been on no steroids or a stable dose of steroids for at least 5 days before the baseline MRI scan * Prior treatment with radiotherapy and temozolomide and a maximum of two prior chemotherapies is permitted * Chemotherapy must have been completed at least 4 weeks prior to study inclusion if prior temozolomide and 6 weeks if prior nitrosoureas or mitomycin c. * No radiotherapy within the 4 weeks prior to the diagnosis of progres-sion. * Treatment with investigational drugs must have been completed at least 30 days prior to study inclusion if prior small molecules and at least 30 days if prior antibodies (e.g. bevacizumab) * Patient may have been operated for recurrence. If operated residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence a post-surgery. MRI should be available within 48 hours following surgery * Surgery completed at least 2 weeks before study inclusion and pa-tients should have fully recovered * Craniotomy or intracranial biopsy site must be adequately healed free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of study inclusion. * Adequate organ function as described below: * Adequate bone marrow reserve: ANC ≥ 1.5 x 10\^9/L, Platelets ≥ 100 x 10\^9/L, Haemoglobin \> 9 g/dL * Adequate liver function: Total bilirubin ≤ 1.5 x ULN (excepted for patients with Gilbert's syndrome), ALT and AST ≤ 3.0 x ULN * Adequate renal function: Creatinine ≤ 1.5 x ULN * For non operated patients recurrent disease must be at least one bi-dimensionally measurable contrast-enhancing lesion with clearly de-fined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on MRI scan done within two weeks prior to study inclusion. * Patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be switched to non-EIAED and stable at least 2 weeks prior to study inclusion and be stable on a constant dose. * No non tumor related surgery or other invasive procedures (major sur-gical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to study inclusion, or anticipation of the need for major surgery during the course of the study treatment. * No core biopsy or other minor surgical procedure within 7 days prior to randomization. Placement of a central vascular access device (CVAD) if performed at least 5 days prior to study treatment administration is allowed. * Before patient study inclusion and study related procedures (that would not have been performed as part as standard care), written in-formed consent must be given according to ICH/GCP, and nation-al/local regulations. * Subjects with the ability to follow study instructions and likely to attend and complete all required visits
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| safety and tolerance | 2 cycles of Dovitinib application (2 months) | The primary endpoint is safety and tolerance and will be based on the frequency of DLTs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor response (CR, PR) | 14 months | Tumor response (CR, PR) according RANO criteria |
| Overall safety | 14 months | Overall safety |
| Disease Control Rate (CR + PR + SD) | 14 months | Disease Control Rate (CR + PR + SD) |
| Progression free survival rate | 14 months | Progression free survival rate at 6 months (PFS-6) and overall survival after initiation of therapy |
| Quality of life | 14 months | Quality of life (health questionnaires) |
Countries
Germany
Outcome results
None listed