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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).

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).

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).

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.

Petter Brandal, MD, PhD

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.

For this study losartan, an angiotensin-II inhibitor, is defined as the Investigational Medicinal Product (IMP). The focus of the study is to assess the dose-response relationship of losartan on imaging-based measures of tissue perfusion and mechanical forces in patients with brain tumors. We hypothesize that losartan improves the effect of traditional cancer treatment by alleviating mechanical forces (solid stress) of the tumor microenvironment to improve tissue perfusion, while administration of losartan alone has little effect on cancer patients.

This is an open-label study and no active comparator or placebo will be used. Study participants include adult patients with newly diagnosed- and recurrent glioblastoma, as well as adult patients with metastatic brain tumors from non-small cell lung cancer. The study will assess the safety of losartan treatment and its dose-response relationship on conventional and experimental radiographic characteristics when used alone or as an add-on to standard cancer treatment.

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

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

Study protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF) will be made available at the time of research data publication

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

Change from baseline in the radiographic biomarker relative solid stress

Change from baseline in the radiographic biomarker relative cerebral blood volume (rCBV)

Change from baseline in the radiographic biomarker relative mean transit time (rMTT)

Change from baseline in the radiographic biomarker contrast agent extravasation

Change from baseline in the radiographic biomarker relative vessel size index

Change from baseline in the radiographic biomarker relative mean vessel density

Change from baseline in the radiographic biomarker relative mean vessel caliber

Change from baseline in the radiographic biomarker apparent diffusion coefficient

Change from baseline in the radiographic biomarker fractional anisotropy

Change from baseline in the radiographic biomarker relative shear modulus

Change from baseline in the radiographic biomarker relative stiffness

Change from baseline in the radiographic biomarker relative viscosity

Change from baseline in the radiographic biomarker relative strain tensor

Drug tolerance of losartan according to NCI-CTCAE v4.0

Change from baseline in neurologic performance scores by Karnofsky Performance Score (KPS). Range from \[00-0\]. The lower the Karnofsky score, the worse the survival for most serious illnesses.

Change from baseline in neurologic performance scores by Eastern Cooperative Oncology Group (ECOG) scores. It describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability in a range from 0 (best) to 5 (dead).

Change from baseline in neurologic performance scores by Neurologic Assessment in Neuro-Oncology (NANO) scale as an objective and quantifiable metric of neurologic function evaluable during a routine office examination. The NANO Scale evaluates 9 major domains of neurologic function, with each domain being scored on a range from 0 to 2 or 3.

Change from baseline in radiographic status on MRIs of intracranial disease corresponding to treatment response using the Response Assessment in Neuro-Oncology (RANO) criteria.

Change from baseline in the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ BN20). It scores 20 items that assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. Items are presented as questions on a scale ranging from 1 = "not at all" to 4 = "very much."

6-months progression free survival (6M-PFS) and within 2 years

12-months overall survival (12M-OS), 24-months overall survival (24M-OS) and within 2 years.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Imaging Perfusion Restrictions From Extracellular Solid Stress - An Open-label Losartan Study	NCT03951142	Glioblastoma Brain Metastase...	Losartan	18 Years -	Oslo University Hospital
Imaging Perfusion Restrictions From Extracellular Solid Stress - An Open-label Losartan Study	NCT03951142	Glioblastoma Brain Metastase...	Losartan	18 Years -	Oslo University Hospital

Spots Global Cancer Trial Database for solid stress

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