Patients with newly diagnosed or recurrent glioblastomas Patients with brain metastases from non-small-cell lung cancer
Conditions
Interventions
Trade Name: Cozaar
Pharmaceutical Form: Tablet
Sponsors
Oslo University Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. A histologically confirmed intracranial glioblastoma, WHO grade 4 (Study A), or a minimum of one radiographically confirmed metastasis to the brain from a primary non-small-cell lung cancer (Study B) 2. Ability to undergo an MRI exam, including administration of a standard clinical dose of an MRI-specific contrast agent of gadolinium or similar 3. Measurable intracranial disease (Study A – recurrent glioblastoma, and Study B only), defined as at least one lesion that can be accurately measured in at least one dimension as =10 mm with MRI – or – compromise more than 30 image voxels on perfusion MRI to ensure adequate parametric statistical assessments. For a perfusion MRI resolution of 1.2x1.2x5mm, this equals a tumor volume of 0.2 cubic centimeters (cc). 4. Age =18 years 5. Eligible for administration of the active substance (losartan) in concordance with study protocol, the criteria of the product label (Cozaar) and deemed fit for trial by the treating physician. 6. An ECOG performance status of =2 or equivalent KPS of =60% 7. Life expectancy from start of treatment of more than 3 months 8. Previous history of a neurosurgical procedure at time of study inclusion (Study A only) 9. Scheduled for chemotherapy and/or radiotherapy and/or stereotactic radiosurgery (Study A – recurrent glioblastoma), neurosurgery, radiotherapy and chemotherapy (Study A – newly diagnosed glioblastoma), immunotherapy and/or chemotherapy and/or stereotactic radiosurgery (Study B) 10. Pre-study documentation on O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation status and on the isocitrate dehydrogenase (IDH) gene mutation status of their disease (study A only) 11. Organ functions of sufficient quality and robustness to undergo study treatment as determined by the study principal investigator (PI) or designee 12. Female patients of childbearing potential (postmenarcheal, not postmenopausal (>12 continuous months of amenorrhea with no identified cause other than menopause), and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing IMP treatment and for at least 14 days after the last dose. Birth control methods considered to be highly effective include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence when it is the preferred and usual lifestyle of the subject. 13. Ability to understand and the willingness to sign a written informed consent document Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 84 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 69
Exclusion criteria
Exclusion criteria: 1. Hypersensitivity to the active substance (losartan) or to any of the excipients 2. Patients on other antihypertensive agents of any type. This includes substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine. Moreover, lithium, NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), fluconazole (inhibitor of CYP2C9), rifampicine (inducer of matabolism enzymes) and drugs that retain potassium (e.g. potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium are all prohibited during the study 3. Patients with hepatic or renal impairment of any reason 4. Patients with symptomatic hypotension of any reason 5. Patients with primary hyperaldosteronism 6. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine 7. Inadequate recovery from toxicity and/or complications of previous therapy as determined by the treating physician 8. Patients with evidence of recurrence less than 3 months since last radiotherapy fraction (Study A – recurrent glioblastoma only) 9. Patients with evidence of recurrence inside the radiotherapy target volume less than 3 months since last radiotherapy fraction (Study A – recurrent glioblastoma only) 10. For Study B subjects only: A diagnosis of immunodeficiency or hypersensitivity to PD-1 inhibitors or any excipients. 11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, coronary heart disease and cerebrovascular disease, unstable angina pectoris, cardiac arrhythmia, angioedema, intravascular volume depletion, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the treating physician 12. Patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy 13. Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study as determined by the treating physician 14. Pregnant or breastfeeding patient 15. Known additional active non-study related malignancy 16.Applies to Study B patients qualifying for immunotherapy only: Active autoimmune disease that has required systemic treatment in the last 2 years (including use of non-study related disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed 17. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 18. Unable to undergo brain MRI according to study protocol 19. Removed in Protocol version 6
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the dose-response relationship of the angiotensin II receptor inhibitor losartan on perfusion and mechanical solid stress in brain tumors.;Secondary Objective: 1. To assess the dose-response relationship of losartan on conventional and experimental radiographic characteristics in patients with glioblastoma and metastases to the brain 2. To assess the dose-response relationship of losartan as add-on to standard treatment on clinical or patient reported endpoints in patients with glioblastoma and metastases to the brain 3. To assess the safety of losartan treatment in patients with glioblastoma and metastases to the brain ;Primary end point(s): 1. Change from baseline in the radiographic biomarker relative cerebral blood flow (rCBF) 2. Change from baseline in the radiographic biomarker relative solid stress ;Timepoint(s) of evaluation of this end point: For primary endpoint 1: Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44 Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44 Study B (lung patients with metastases to the brain) Baseline, Day 90-7d, Day 180-7d, Day 270-7d For primary endpoint 2: Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44 Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44 Study B (lung patients with metastases to the brain) Baseline, Day 90-14d, Day 180-14d, Day 270-14d | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Change from baseline in experimental radiographic biomarkers from MRI, including perfusion MRI, diffusion MRI, or MR Elastography. [Time Frame: Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-14d, Day 180-14d, Day 270-14d • Drug tolerance of IMP (NCI-CTCAE v4.0) according to follow-up period, including number and frequency of losartan treatment emerging adverse events (TEAE), vital signs (weight, blood pressure, pulse) and conventional laboratory blood parameters [Time Frame: Study A (patients with recurrent glioblastoma) 168 days + 14 days Study A (patients with newly diagnosed glioblastoma) 238 days + 14 days Study B (lung cancer patients with metastases to the brain) 270 days + 14 days] • Change from baseline in neurologic performance scores by Karnofsky Performance Score (KPS), Eastern Cooperative Oncology Group (ECOG) and/or Neurologic Assessment in Neuro-Oncology (NANO) scores. [Time Frame: Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 42-44, Day 85±4, Day 169±4. Study A (patients with newly diagnosed glioblastoma) Baseline, Day 14-16, Day 42-44, Day 71±4, Day 155±4, Day 239±4. Study B (lung cancer patients with metastases to the brain) Baseline, Day 90-7, Day 180-7, Day 270-7, Day 360±7 • Change from baseline in radiographic status on MRIs of intracranial disease or corresponding treatment response (size of edema, occurrence of radionecrosis, pseudoprogression or tumor progression) by the Response Assessment in Neuro-Oncology (RANO) criteria. [Time Frame: Study A (patients with recurrent glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78±4, Day 162±4, Day 360±7. Study A (patients with newly diagnosed glioblastoma) B | — |
Countries
Norway
Contacts
Public ContactPaulina B Due-Tønnessen
Oslo University Hospital
Outcome results
None listed