Ensayos clínicos

Inclusion Criteria:

• Signed informed consent.
• Age ≥ 18 years with life expectancy > 12 weeks.
• Histologically proven, newly diagnosed supratentorial glioblastoma based on the World Health Organization (WHO) classification (2016); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiotherapy treatment-naïve.
• Randomization must occur within 5 weeks of resection (subjects undergoing biopsy only are excluded).
• Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment.
• Available and willing to submit sufficient and of adequate quality tumor tissue representative of glioblastoma to perform MGMT promoter methylation status testing.
• Karnofsky performance status (KPS) ≥ 60.
• Stable or decreasing corticosteroids within 5 days prior to study treatment start.
• Willing to forego the use of Tumor Treating Fields therapy (Optune®).
• Adequate organ function within 14 days prior to randomization:
• Bone marrow:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L;
  • Platelets count ≥ 100 x 10^9/L;
  • Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion).
• Renal:
  • Serum creatinine < 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution.
• Hepatic:
  • Total serum bilirubin ≤ 2 x ULN unless the patient has documented Gilbert syndrome;  
  • Aspartate and alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN; ≤ 5.0 x ULN if there is liver involvement secondary to tumor;
  • Alkaline phosphatase (ALP) ≤ 2.5 x ULN; ≤ 5 x ULN in case of bone metastasis.
• Negative serum pregnancy test (for females of childbearing potential) within 14 days prior to randomization.
• Male and female subjects of reproductive potential must agree to use an effective method of contraception (e.g., oral contraceptives, intrauterine device, barrier method) throughout the study and for at least 3 months after the last dose of study treatment.
• Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis .
• Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label), have medically confirmed ovarian failure, or achieved postmenopausal status (defined as cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
• Willing and able to comply with protocol.

Exclusion Criteria:

• Unable to swallow tablets or capsules.
• Pregnant or breastfeeding.
• Prior chemotherapy (including carmustine-containing wafers (Gliadel®), immunotherapy (including vaccine therapy)) or investigation agent for GBM or GS (previous 5-aminolevulinic acid [ALA]-mediated photodynamic therapy [PDT] administered prior to surgery to aid in optimal surgical resection is permitted).
• Prior radiotherapy to the brain.
• Unable to discontinue use of EIAEDs, if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization.
• Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to randomization or expected requirement for use on study therapy.
• Use of any medication that can prolong the QT/QTc interval within 7 days prior to randomization or expected requirement for use on study therapy.
• Active bacterial, fungal or viral infection requiring systemic treatment.
• Personal or immediate family history of long QT syndrome, QTc interval > 450 msec (males) or > 470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF), or a history of unexplained syncope.
• Any contraindication to temozolomide listed in the local product label.
• Another malignancy except adequately treated non-melanoma skin cancer; subjects who have had another malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible.
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization.
• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for participation in this study.