Dovitinib (TKI258) in the Treatment of Patients With Relapsed Glioblastoma

Exclusion Criteria

• •Subjects not able to give consent
• •Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial
• •Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
• •Simultaneously participation in another clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
• •Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
• •Known or persistent abuse of medication, drugs or alcohol
• •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:
• •* History or presence of serious uncontrolled ventricular arrhythmi-as
• •* Bradycardia (\<60/min): i) Clinically significant resting bradycardia (=\> 40/min) with syncopes or chronotropic incompetence or ii) asymptomatic bradycardia with a heart rate \< 40/min and/or paus-es in ventricular rate \> 3 s
• •* LVEF assessed by 2-D echocardiogram (ECHO) \< 50% or lower limit of normal (which ever is higher)
• •Any of the following within 6 months prior to starting TKI258:
• •* Myocardial infarction (MI),
• •* severe/unstable angina,
• •* Coronary Artery Bypass Graft (CABG),
• •* Congestive Heart Failure (CHF),
• •* Cerebrovascular Accident (CVA),
• •* Transient Ischemic Attack (TIA)
• •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)
• •Current or planned pregnancy or nursing women
• •Positive pregnancy test (blood-test) prior to receiving IMP
• •Females of childbearing potential, who are not using and not willing to use medically highly reliable methods of contraception for the entire study duration (such as injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases
• •Males, who are not using and/or not willing to use an effective form of barrier conception for the entire study duration (such as male con-doms) unless they are surgically vasectomised or there are any other criteria considered sufficiently reliable by the investigator in individual cases.