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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.
Full 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.
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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:
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 Exclusion Criteria:
Indication specific exclusion criteria:
Evidence of current/active intratumor hemorrhage by MRI
More than two relapses
Elongation of corrected QT-time (QTc) > 450 ms (male patients) and ≥ 460 ms (female patients), respectively
Patients with any clinically significant medical or surgical condition which, according to investigators´ discretion, should preclude participation - i.e. severe renal disease, severe pancreatic disease, active or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease (cirrhosis, chronic active hepatitis or chronic persistent hepatitis) - hepatitis B or C virus carriers with normal liver function tests, can be included.
Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:
Any of the following within 6 months prior to starting TKI258:
Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to starting Dovitinib (TKI258)
Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 (e.g. severe ulcer-ative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive (>1m) small bowel resection, inability to swal-low oral medications). Prior partial gastrectomy is not an exclusion cri-terion.
Patients with prior complete gastrectomy
Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count ≤1.5 x 109 /L or platelet count ≤ 100 x 109 /L or re-quiring regular blood transfusions to maintain haemoglobin > 9g/dL
Serum bilirubin ≥ 1.5 x ULRR (except for patients with known docu-mented cases of Gilbert's Syndrome)
ALT or AST ≥ 2.5 x ULRR.
Serum creatinine > 1.5 x ULRR or a creatinine clearance of ≤ 50 mL/min calculated by Cockcroft-Gault
Unresolved toxicity > CTCAE grade 1 from previous anti-cancer thera-py (including radiotherapy) except alopecia (if applicable)
Patients with another primary malignancy within 3 years prior to start-ing the study drug, with the exception of adequately treated in-situ car-cinoma of the uterine cervix, or completely excised (R0 resection) ba-sal or squamous cell carcinoma of the skin
Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
Other concomitant anti-cancer therapy except steroids
Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin or equivalent anticoagulants (e.g., coumadin, rivaroxaban, apixaban, dabigatran) or receive antiplatelet agents (e.g., high dose aspirin or clopidogrel or other) or have an INR >1.5. Treatment with acetylsalicyclic acid 100 mg daily or prophylactic use of low molecular weight heparin (LMWH) is allowed.
Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intrapelvic) ≤ 4 weeks prior to starting TKI258 or who have not recovered from the adverse effects of such therapy
Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months
Inability to undergo MRI
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up scheduled visits (at the discretion of the investigator)
Exclusion criteria regarding special restrictions for females:
Primary purpose
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12 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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