Imaging Perfusion Restrictions from Extracellular Solid Stress - An open-label losartan study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Sep 2019 → ongoing

Decision date (initial)

2024-09-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

The Norwegian Cancer Society · The Research Council of Norway · South-Eastern Norway Regional Health Authority · Oslo University Hospital · The European Research Council

External identifiers

EU CT number

2023-507575-22-00

EudraCT number

2018-003229-27

ClinicalTrials.gov

NCT20180032

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response

To assess the dose-response relationship of the angiotensin II receptor inhibitor losartan on perfusion and mechanical solid stress in brain tumors.

Secondary objectives 3

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

Conditions and MedDRA coding

Glioblastoma - newly diagnosed and recurrent tumors (Study A)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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 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

Exclusion criteria 18

1. Hypersensitivity to the active substance (losartan) or to any of the excipients
2. Patients on antihypertensive agents that cannot be substituted with losartan.
3. Patients on medication that may induce hypotension and/or increase potassium levels and/or cause metabolismrelated pharmacokinetic drug-drug interactions with losartan. If medication with such effects can safely be discontinued or replaced, the patient can be included in the study after a washout period before baseline.
4. Patients with hepatic or renal impairment of any reason
5. Patients with symptomatic hypotension of any reason
6. Patients with primary hyperaldosteronism
7. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine
8. Inadequate recovery from toxicity and/or complications of previous therapy as determined by the treating physician
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change from baseline in the radiographic biomarker relative cerebral blood flow (rCBF) in the primary tumor area, and normalized to reference tissue [Time Frame: 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.tudy B (lung patients with metastases to the brain) Baseline, Day 90-14, Day 180-14, Day 270-14]
2. Change from baseline in the radiographic biomarker tissue stiffness, as derived from the shear wave modulus G of the MR-elastography readout in the primary tumor area, and normalized to reference tissue [Time Frame: Study A (patients with recurrent and newly diagnosed glioblastoma) Baseline, Day 14-16, Day 28-30, Day 42-44.Study B (lung patients with metastases to the brain) Baseline, Day 90-14, Day 180-14, Day 270-14]

Secondary endpoints 11

1. Change from baseline in experimental radiographic biomarkers from MRI, including total volume of enhancing tumor, the total volume of tumor edema, perfusion MRI, diffusion MRI, or MR Elastography., and normalized to reference tissue.
2. 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.
3. Best overall response of radiographic status on MRIs of intracranial disease or corresponding treatment response by the Response Assessment in Neuro-Oncology (RANO) criteria. (occurrence of radionecrosis, pseudoprogression or tumor progression).
4. Total dose and change in steroids dosage during study treatment duration.
5. Change from baseline in the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ BN20) core 30 version 3.0.
6. Six-months progression free survival (6MPFS)
7. Progression free survival (PFS) [Time Frame: up to 24 months]
8. Overall survival (OS) at 12 and 24 months
9. Overall survival [Time Frame: up to 24 months]
10. Drug tolerance of IMP (NCI-CTCAE v4.0) according to study and follow-up period, including number and frequency of losartan treatment emerging adverse events (TEAE), vital signs (, blood pressure, pulse) and conventional laboratory blood parameters.
11. Change from baseline in experimental biomarkers from blood and serum, including vascular endothelial growth factors, angiopoietins, placental growth factors, epidermal growth factor receptors, hyaluronan levels, collagens levels, and inflammatory cytokines.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Petter Brandal

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Kyrre Eeg Emblem

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications