Imaging Perfusion Restrictions From Extracellular Solid Stress - An Open-label Losartan Study

NCT03951142 | Unknown Phase 2 DMC

• 2 other identifiers: ImPRESS2018-003229-27
• Study Type: interventional
• Target: 165
• Locations: 1 country
• Sites: 1

Brief Summary

An open-label, single institutional phase II trial of losartan in patients with primary and metastatic brain tumors with an individual stepped-wedge, randomized, assessor-blinded, dose-finding design on three indications.

Conditions

Glioblastoma; Brain Metastases

Keywords

Magnetic Resonance Imaging; Brain Cancer; Angiotensin II receptor blocker; Losartan; Perfusion; Solid stress

Outcome Measures

Primary Outcomes (2)

• Relative cerebral blood flow by MRI

  Change from baseline in the radiographic biomarker relative cerebral blood flow (rCBF)

  Study AR: Baseline, Day 14-16, Day 28-30, Day 42-44. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7

• Relative solid stress by MRI

  Change from baseline in the radiographic biomarker relative solid stress

  Study AR: Baseline, Day 14-16, Day 28-30, Day 42-44. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7

Secondary Outcomes (21)

• Relative cerebral blood volume by MRI

  Study arm AR: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study arm BM: Baseline, Day 90±14, Day 180±14, Day 270±14.

• Mean transit time by MRI

  Study arm AR: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study arm BM: Baseline, Day 90±14, Day 180±14, Day 270±14.

• Contrast agent extravasation by MRI

  Study arm AR: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study arm BM: Baseline, Day 90±14, Day 180±14, Day 270±14.

• Relative vessel size index by MRI

  Study arm AR: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study arm BM: Baseline, Day 90±14, Day 180±14, Day 270±14.

• Relative mean vessel density by MRI

  Study arm AR: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 78-8/+1, Day 162-8/+1. Study arm AN: Baseline, Day 14-16, Day 28-30, Day 42-44, Day 148-8/+1, Day 232-8/+1. Study arm BM: Baseline, Day 90±14, Day 180±14, Day 270±14.

Study Arms (3)

Study A: Recurrent glioblastoma (denoted 'AR')

EXPERIMENTAL

Patients with recurrent glioblastoma (N=54) with be randomized (ratio 1:1:1) to doses of 25mg, 50mg or 100mg daily of losartan while on treatment. Losartan (tablet) will be administered every day, with 2 weeks (14 consecutive days) defined as a treatment cycle. Based on randomization, a minimum of three cycles and a maximum of 12 cycles will be administered for a total of 6 weeks (42 days) to 24 weeks (168 days), respectively. Patients randomized to 100mg of losartan will all receive treatment for the maximum duration. A stepped-wedge randomized design (ratio 1:1:1 for all doses over the three first cycles) is proposed to compare participants on- and off- study IMP and assess any dose-response relationship losartan. This study arm will also investigate any additional long-term beneficial effects of losartan while receiving chemotherapy (temozolomide or lomustine tablets).

Drug: Losartan

Study A: Newly diagnosed glioblastoma (denoted 'AN')

EXPERIMENTAL

Patients with newly diagnosed glioblastoma (N=54) with be randomized (ratio 1:1:1) to doses of 25mg, 50mg or 100mg daily of losartan while on treatment. Losartan (tablet) will be administered every day, with 2 weeks (14 consecutive days) defined as a treatment cycle. Based on randomization, a minimum of three cycles and a maximum of 17 cycles will be administered for a total of 6 weeks (42 days) to 34 weeks (238 days), respectively. Patients randomized to 100mg of losartan will all receive treatment for the maximum duration. A stepped-wedge randomized design (ratio 1:1:1 for all doses over the three first cycles) is proposed to compare participants on- and off- study IMP and assess any dose-response relationship losartan. This study arm will also investigate any additional long-term beneficial effects of losartan while receiving adjuvant chemotherapy (Temozolomide tablets).

Drug: Losartan

Study B: Brain metastases (denoted 'BM')

EXPERIMENTAL

Patients with brain cancer from non-small cell lung cancer (N=45) with all receive a dose of 50mg daily of losartan while on treatment. Losartan (tablet) will be administered every day, with 3 months (90 consecutive days) defined as a treatment cycle. A minimum of one cycle and a maximum of three cycles will be administered for a total of 3 months (90 days) to 9 months (270 days), respectively. A stepped-wedge randomized design (ratio 1:1:1 over the three first cycles) is proposed to compare participants on- and off- study IMP and assess any dose-response relationship losartan. This study arm will also investigate any additional long-term beneficial effects of losartan while receiving chemotherapy alone (carboplatin in combination with vinorelbin or pemetrexed or equivalent analogs) or in combination with pembrolizumab (2mg/kg/3rd week).

Drug: Losartan

Interventions

Losartan DRUG

This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text. Storage, handling and preparation requirements will be handled in concordance with the Pharmacy Manual for losartan.

Study A: Newly diagnosed glioblastoma (denoted 'AN'); Study A: Recurrent glioblastoma (denoted 'AR'); Study B: Brain metastases (denoted 'BM')

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Ability to undergo an MRI exam, including administration of a standard clinical dose of an MRI-specific contrast agent of gadolinium or similar
• 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
• Age ≥18 years
• 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.
• An ECOG performance status of ≤2 or equivalent KPS of ≥60%
• Life expectancy from start of treatment of more than 3 months
• 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 (Study B)
• 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)
• Organ functions of sufficient quality and robustness to undergo study treatment as determined by the study principal investigator (PI) or designee
• 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.
• Ability to understand and the willingness to sign a written informed consent document

You may not qualify if:

• Hypersensitivity to the active substance (losartan) or to any of the excipients
• Patients on antihypertensive agents that cannot be substituted with losartan.
• Patients on medication that may induce hypotension and/or increase potassium levels and/or cause metabolism-related 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.
• Patients with hepatic or renal impairment of any reason
• Patients with symptomatic hypotension of any reason
• Patients with primary hyperaldosteronism
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine
• Inadequate recovery from toxicity and/or complications of previous therapy as determined by the treating physician
• Patients with evidence of recurrence inside the radiotherapy target volume less than 3 months since last radiotherapy fraction (Study A - recurrent glioblastoma only)
• For Study B subjects only. A diagnosis of immunodeficiency or hypersensitivity to the PD-1 inhibitors or any of its excipients
• 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 treating the physician
• Patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy
• Patient with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study as determined by the treating physician
• Pregnant or breastfeeding patient
• Known additional active non-study related malignancy

Sponsors & Collaborators

• Kyrre Eeg Emblem: lead

Study Sites (1)

Oslo University Hospital

Oslo, 0372, Norway

Location

Related Publications (1)

• Lysvik EK, Mikalsen LTG, Rootwelt-Revheim ME, Emblem KE, Hjornevik T. Optimization of Q.Clear reconstruction for dynamic 18F PET imaging. EJNMMI Phys. 2023 Oct 20;10(1):65. doi: 10.1186/s40658-023-00584-1.

  PMID: 37861929 DERIVED

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms

Interventions

Losartan

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Study Officials

• Petter Brandal, MD, PhD

  Oslo University Hospital, Oslo, Norway

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Coordinating investigator

Model Details: An open-label, single institutional phase II trial with an individual stepped-wedge, randomized, assessor-blinded, dose-finding design on three indications

Study Record Dates

• First Submitted: May 10, 2019
• First Posted: May 15, 2019
• Study Start: October 1, 2019
• Primary Completion: October 1, 2024
• Study Completion: December 31, 2024
• Last Updated: November 1, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Supporting information will be made available at the time of research data publication. No end date for sharing of supporting information.
• Access Criteria: Open upon request or by journal criteria

Locations

NO (1)