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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03951142
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : October 2, 2019
Sponsor:
Information provided by (Responsible Party):
Kyrre Eeg Emblem, Oslo University Hospital

Tracking Information
First Submitted Date  ICMJE May 10, 2019
First Posted Date  ICMJE May 15, 2019
Last Update Posted Date October 2, 2019
Actual Study Start Date  ICMJE October 1, 2019
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Relative cerebral blood flow by MRI [ Time Frame: Study AR: Baseline, Day 12-14, Day 26-28, Day 40-42. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7 ]
    Change from baseline in the radiographic biomarker relative cerebral blood flow (rCBF)
  • Relative solid stress by MRI [ Time Frame: Study AR: Baseline, Day 12-14, Day 26-28, Day 40-42. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7 ]
    Change from baseline in the radiographic biomarker relative solid stress
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03951142 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Relative cerebral blood volume by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative cerebral blood volume (rCBV)
  • Mean transit time by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative mean transit time (rMTT)
  • Contrast agent extravasation by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker contrast agent extravasation
  • Relative vessel size index by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative vessel size index
  • Relative mean vessel density by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative mean vessel density
  • Relative mean vessel caliber by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative mean vessel caliber
  • Apparent diffusion coefficient by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker apparent diffusion coefficient
  • Fractional anisotropy by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker fractional anisotropy
  • Relative shear modulus by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative shear modulus
  • Relative stiffness by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative stiffness
  • Relative viscosity by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative viscosity
  • Relative strain tensor by MRI [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7. ]
    Change from baseline in the radiographic biomarker relative strain tensor
  • Drug tolerance [ Time Frame: Study arm AR: 168 days + 14 days Study arm AN: 238 days + 14 days Study arm BM: 270 days + 14 days ]
    Drug tolerance of losartan according to NCI-CTCAE v4.0
  • Neurologic performance by KPS [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7. Study arm AN: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7, Day 239±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7, Day 360±7. ]
    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.
  • Neurologic performance by ECOG [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7. Study arm AN: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7, Day 239±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7, Day 360±7. ]
    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).
  • Neurologic performance by NANO [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7. Study arm AN: Baseline, Day 12-14, Day 43-45, Day 71±7, Day 180±7, Day 239±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7, Day 360±7. ]
    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.
  • RANO [ Time Frame: Study arm AR: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 78±7, Day 162±7, Day 360±7. Study arm AN: Baseline, Day 12-14, Day 26-28, Day 40-42, Day 148±7, Day 232±7, Day 360±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7, Day 360±7. ]
    Change from baseline in radiographic status on MRIs of intracranial disease corresponding to treatment response using the Response Assessment in Neuro-Oncology (RANO) criteria.
  • Steroid dosage [ Time Frame: 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. ]
    Total dose
  • Steroid dosage [ Time Frame: 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. ]
    Change in dosage during study treatment.
  • Quality of life (QoL) [ Time Frame: Study arm AR: Baseline, Day 43-45, 180±7. Study arm AN: Baseline, Day 43-45, Day 180±7, Day 239±7. Study arm BM: Baseline, Day 90±7, Day 180±7, Day 270±7, Day 360±7 ]
    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."
  • Progression free survival (PFS) [ Time Frame: All studies: Day +180, up to 24 months ]
    6-months progression free survival (6M-PFS) and within 2 years
  • Overall survival (OS) [ Time Frame: All studies: at 12 months, at 24 months, up to 24 months. ]
    12-months overall survival (12M-OS), 24-months overall survival (24M-OS) and within 2 years.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Imaging Perfusion Restrictions From Extracellular Solid Stress - An Open-label Losartan Study
Official Title  ICMJE Imaging Perfusion Restrictions From Extracellular Solid Stress - An Open-label Losartan Study
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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
An open-label, single institutional phase II trial with an individual stepped-wedge, randomized, assessor-blinded, dose-finding design on three indications
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Glioblastoma
  • Brain Metastases
Intervention  ICMJE 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.
Study Arms  ICMJE
  • Experimental: Study A: Recurrent glioblastoma (denoted 'AR')

    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).

    Intervention: Drug: Losartan
  • Experimental: Study A: Newly diagnosed glioblastoma (denoted 'AN')

    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).

    Intervention: Drug: Losartan
  • Experimental: Study B: Brain metastases (denoted 'BM')

    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).

    Intervention: Drug: Losartan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 13, 2019)
165
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≥5 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. Deemed eligible for neurosurgery (Study A - newly diagnosed glioblastoma) or stereotactic radiosurgery (Study B) by the treating physician
  9. Scheduled for chemotherapy (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 less than 3 months since last radiotherapy fraction (Study A - recurrent glioblastoma only)
  10. A diagnosis of immunodeficiency or hypersensitivity to the PD-1 inhibitors pembrolizumab, or analogs such as atezolizumab, or any of its excipients (Study B patients on immunotherapy only)
  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. 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Petter Brandal, MD, PhD +4722935843 pebra@ous-hf.no
Contact: Kyrre E Emblem, PhD +4722029492 kemblem@ous-hf.no
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03951142
Other Study ID Numbers  ICMJE ImPRESS
2018-003229-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Study protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF) will be made available at the time of research data publication
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (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
Responsible Party Kyrre Eeg Emblem, Oslo University Hospital
Study Sponsor  ICMJE Kyrre Eeg Emblem
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Petter Brandal, MD, PhD Oslo University Hospital, Oslo, Norway
PRS Account Oslo University Hospital
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP