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

Glioblastoma Clinical Trial

— ImPRESS  

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT03951142
• Other study ID #: ImPRESS
• Secondary ID: 2018-003229-27
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: October 1, 2019
• Est. completion date: December 31, 2024

Study information

• Verified date: October 2023
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 165
• Est. completion date: December 31, 2024
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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 neurosurgical procedure (Study A - only) or stereotactic radiosurgery and immunotherapy (Study B) at time of study inclusion

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 (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

Exclusion Criteria:

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 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.

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 the PD-1 inhibitors or any of its 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 treating the physician

12. Patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy

13. 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

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. For Study B subjects only: No previous history of immunotherapy at time of study inclusion.

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Glioblastoma

Intervention

Drug:
• Losartan
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.

Locations

Country	Name	City	State
Norway	Oslo University Hospital	Oslo

Sponsors (1)

Lead Sponsor	Collaborator
Kyrre Eeg Emblem

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Relative cerebral blood volume by MRI	Change from baseline in the radiographic biomarker relative cerebral blood volume (rCBV)	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.
Secondary	Mean transit time by MRI	Change from baseline in the radiographic biomarker relative mean transit time (rMTT)	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.
Secondary	Contrast agent extravasation by MRI	Change from baseline in the radiographic biomarker contrast agent extravasation	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.
Secondary	Relative vessel size index by MRI	Change from baseline in the radiographic biomarker relative vessel size index	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.
Secondary	Relative mean vessel density by MRI	Change from baseline in the radiographic biomarker relative mean vessel density	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.
Secondary	Relative mean vessel caliber by MRI	Change from baseline in the radiographic biomarker relative mean vessel caliber	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.
Secondary	Apparent diffusion coefficient by MRI	Change from baseline in the radiographic biomarker apparent diffusion coefficient	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.
Secondary	Fractional anisotropy by MRI	Change from baseline in the radiographic biomarker fractional anisotropy	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.
Secondary	Relative shear modulus by MRI	Change from baseline in the radiographic biomarker relative shear modulus	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.
Secondary	Relative stiffness by MRI	Change from baseline in the radiographic biomarker relative stiffness	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.
Secondary	Relative viscosity by MRI	Change from baseline in the radiographic biomarker relative viscosity	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.
Secondary	Relative strain tensor by MRI	Change from baseline in the radiographic biomarker relative strain tensor	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.
Secondary	Drug tolerance	Drug tolerance of losartan according to NCI-CTCAE v4.0	Study arm AR: Day 168+14. Study arm AN: Day 238+14. Study arm BM: Day 270+14.
Secondary	Neurologic performance by KPS	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.	Study arm AR: Baseline, Day 14-16, Day 42-44, Day 85±4, Day 169±4. Study arm AN: Baseline, Day 14-16, Day 42-44, DAy 71±4, Day 155±4, Day 239±. Study arm BM: Baseline, Day 90-7, Day 180-1, Day 270-1, Day 360±7
Secondary	Neurologic performance by ECOG	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).	Study arm AR: Baseline, Day 14-16, Day 42-44, Day 85±4, Day 169±4. Study arm AN: Baseline, Day 14-16, Day 42-44, DAy 71±4, Day 155±4, Day 239±. Study arm BM: Baseline, Day 90-7, Day 180-1, Day 270-1, Day 360±7
Secondary	Neurologic performance by NANO	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.	Study arm AR: Baseline, Day 14-16, Day 42-44, Day 85±4, Day 169±4. Study arm AN: Baseline, Day 14-16, Day 42-44, DAy 71±4, Day 155±4, Day 239±. Study arm BM: Baseline, Day 90-7, Day 180-1, Day 270-1, Day 360±7
Secondary	RANO	Change from baseline in radiographic status on MRIs of intracranial disease corresponding to treatment response using the Response Assessment in Neuro-Oncology (RANO) criteria.	Study arm AR: Day 78-8/+1, Day 162-8/+1. Study arm AN: Day 148-8/+1, Day 232-8/+1. Study arm BM: Day 90±14, Day 180±14, Day 270±14.
Secondary	Steroid dosage	Change in dosage during study treatment.	Study arm AR: Baseline, Days 1-3, 29-31, 57±7, 85±7, 113±7, 141±7, 169±7. Study arm AN: Baseline, Days 29-31, 43-45, 71±7, 99±7, 127±7, 155±7, 183±7, 211±7, 239±7. Study arm BM: Baseline, Days 90±7, 180±7, 270±7, 360±7.
Secondary	Quality of life (QoL)	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."	Study arm AR: Baseline, Day 42-44, 169±4. Study arm AN: Baseline, Day 42-44, Day 155±4, Day 239±4. Study arm BM: Baseline, Day 90-7, Day 180-7, Day 270-7, Day 360±7
Secondary	Progression free survival (PFS)	6-months progression free survival (6M-PFS) and within 2 years	All studies: Day +180, up to 24 months
Secondary	Overall survival (OS)	12-months overall survival (12M-OS), 24-months overall survival (24M-OS) and within 2 years.	All studies: at 12 months, at 24 months, up to 24 months.