Clinical Trials /

Pembrolizumab and Magnetic Resonance Imaging With Ferumoxytol in Treating Patients With Non-small Cell Lung Cancer and Brain Metastases

NCT03325166

Description:

This pilot phase II trial study evaluates the usefulness of the ferumoxytol steady state magnetic resonance imaging (MRI) technique for response assessment after pembrolizumab and radiation therapy in non-small cell lung cancer that has spread to the brain (brain metastases). The interactions of monoclonal antibodies such as pembrolizumab, and the body's immune system may result in an anti-tumor effect. However, it may also increase inflammation around the tumor which cannot be differentiated from true tumor growth on standard MRI. This study evaluates ferumoxytol as an MRI contrast agent to differentiate this treatment related inflammation from true tumor growth.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Magnetic Resonance Imaging With Ferumoxytol in Treating Patients With Non-small Cell Lung Cancer and Brain Metastases
  • Official Title: The Use of Perfusion MRI Using Ferumoxytol and Small Molecular Weight Gadolinium (Gd) Agents to Assess Response to Pembrolizumab in Brain Metastases and Systemic Lesions in NSCLC: A Comparison of Imaging Modalities to Address Brain Metastases, Pseudoprogression, and Systemic Lesion Tumor Flare (Neuro-Check Pilot)

Clinical Trial IDs

  • ORG STUDY ID: STUDY00016709
  • SECONDARY ID: NCI-2017-01730
  • SECONDARY ID: STUDY00016709
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT03325166

Conditions

  • Lung Carcinoma Metastatic in the Brain
  • PD-L1 Positive
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
FerumoxytolFeraheme, Ferumoxytol Non-Stoichiometric MagnetiteTreatment (pembrolizumab, ferumoxytol MRI)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, ferumoxytol MRI)

Purpose

This pilot phase II trial study evaluates the usefulness of the ferumoxytol steady state magnetic resonance imaging (MRI) technique for response assessment after pembrolizumab and radiation therapy in non-small cell lung cancer that has spread to the brain (brain metastases). The interactions of monoclonal antibodies such as pembrolizumab, and the body's immune system may result in an anti-tumor effect. However, it may also increase inflammation around the tumor which cannot be differentiated from true tumor growth on standard MRI. This study evaluates ferumoxytol as an MRI contrast agent to differentiate this treatment related inflammation from true tumor growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV)
      measured by steady state magnetic resonance imaging (MRI) with ferumoxytol in predicting true
      vs pseudoprogression after stereotactic radiosurgery (SRS) and intravenous (IV) pembrolizumab
      in subjects with brain metastases from non-small cell lung cancer (NSCLC).

      SECONDARY OBJECTIVES:

      I. Evaluate the safety and tolerability of pembrolizumab when given with SRS in subjects with
      brain metastasis.

      II. Evaluate progression free survival, overall survival, best response in brain disease,
      best response in systemic disease, and duration of best responses of brain and systematic
      diseases.

      TERTIARY OBJECTIVES:

      I. Compare the immune response as determined by the volume, pattern and intensity of delayed
      (24 hour [hr]) ferumoxytol uptake between subjects who develop true vs pseudoprogression.

      II. Investigate the serum immunological parameters and correlate clinical as well as
      radiological response with systemic immune response to pembrolizumab as measured by
      immunological panel.

      III. Compare the changes percentage expression in PDL-1 in the biopsy tissue before and after
      therapy at the time of progression.

      IV. In subjects with measurable systemic lesions, investigate the feasibility of measuring
      vascular volume fraction (VVF), vessel size index (VSI) and vessel density index (VDI) as
      surrogate for response (true vs. pseudoprogression, as measured with Response Evaluation
      Criteria in Solid Tumors [RECIST] 1.1 criteria).

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat
      every 3 weeks for up to 2 years (or up to 32 courses) in the absence of disease progression
      or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI at baseline,
      12 weeks after radiation, at suspected radiographic progression, and 6 weeks after suspected
      radiographic progression.

      After completion of study treatment, patients are followed up at 30 days, every 12 weeks for
      up to 1 year, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, ferumoxytol MRI)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks for up to 2 years (or up to 32 courses) in the absence of disease progression or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI at baseline, 12 weeks after radiation, at suspected radiographic progression, and 6 weeks after suspected radiographic progression.
  • Ferumoxytol
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Have a histologically confirmed diagnosis of NSCLC

          -  Have up to five measurable (by Response Assessment in Neuro-Oncology Criteria [RANO])
             brain metastasis planned for stereotactic radiosurgery

          -  Subjects should have PD-L1 expression (tumor proportion score [TPS] >= 50%, determined
             by the Food and Drug Administration [FDA] approved Merck 22C3 antibody PD-L1 test) in
             the first-line setting and have a TPS > 1% by 22C3 or equivalent PD-L1 expression by
             an approved immunohistochemistry (IHC) test, in the second-line setting in order to be
             eligible for pembrolizumab treatment on the current protocol; patients with < 1% PD-L1
             expression are not eligible

          -  Subjects may already be receiving PD-(L)1 (including pembrolizumab or other PD-[L]1
             inhibitors such as nivolumab, atezolizumab, avelumab, durvalumab) for the treatment of
             systemic disease; systemic disease must be in complete remission or be stable by
             RECIST 1.1; a washout period of at least 3 weeks is required from the last dose of
             PD-(L)1 inhibitor

          -  Subjects with EGFR or ALK genomic tumor aberrations should have documented disease
             progression on FDA-approved therapy for these aberrations; subjects with EGFR or ALK
             genomic tumor aberrations who develop isolated brain metastases with good response
             outside the central nervous system (CNS) while on FDA-approved therapy for these
             aberrations may be included at the discretion of the treating oncologist

          -  Be willing to provide tissue from archival biopsy tissue or newly obtained excisional
             biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 6
             weeks (42 days) prior to initiation of treatment on day 1

          -  At least 30 days from any major surgeries including brain biopsy and have complete
             resolution of its effects

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment)

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
             levels > 1.5 X institutional ULN

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
             ULN OR =< 5 X ULN for subjects with liver metastases

          -  Albumin >= 2.5 mg/dL

          -  International normalized ratio (INR) or prothrombin rime (PT) =< 1.5 X ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication; if
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication; subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year; male subjects should agree to use an adequate
             method of contraception starting with the first dose of study therapy through 120 days
             after the last dose of study therapy

          -  Subject may also provide consent/assent for future correlative research; subjects may
             participate in the main trial without participating in future correlative research

        Exclusion Criteria:

          -  Has any evidence of progressive systemic disease (by RECIST 1.1); those with stable
             systemic lesion may be considered for enrollment

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment

          -  Has evidence of leptomeningeal disease on MRI or in cerebrospinal fluid (CSF)

          -  If tumor demonstrates EGFR or ALK genomic tumor aberrations, subject should have
             documented disease progression on FDA-approved therapy for these aberrations

          -  Has a diagnosis of immunodeficiency and is not on continuous daily immunosuppressive
             therapy within 7 days prior to the first dose of trial treatment; (subjects may
             receive steroids before or after SRS to prevent or manage cerebral edema; inhalational
             steroids are permitted)

          -  Has previously progressed on a PD-1 or PD-L1 checkpoint inhibitor for systemic disease

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has hypersensitivity to pembrolizumab, gadolinium, or ferumoxytol or any of their
             excipients

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier

               -  Note: The use of denosumab is an exception to this criterion

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
             baseline) from adverse events due to a previously administered agent

               -  Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  Note: Subjects with =< grade 2 hematologic toxicities are an exception to this
                  criterion and may qualify for the study

               -  Note: Subjects with =< grade 2 fatigue are an exception to this criterion and may
                  qualify for the study

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject?s
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed

          -  Subjects with clinically significant signs of uncal herniation, such as acute
             pupillary enlargement, rapidly developing motor changes (over hours), or rapidly
             decreasing level of consciousness, are not eligible

          -  Subjects with known allergic or hypersensitivity reactions to parenteral iron,
             parenteral dextran, parenteral iron-dextran, or parenteral iron-polysaccharide
             preparations; subjects with significant drug or other allergies or autoimmune diseases
             may be enrolled at the investigator?s discretion

          -  Subjects who have a contraindication for 3 tesla (3T) MRI: metal in their bodies (a
             cardiac pacemaker or other incompatible device), are severely agitated, or have an
             allergy to gadolinium containing contrast material

          -  Subjects with known iron overload (genetic hemochromatosis); in subjects with a family
             history of hemochromatosis, hemochromatosis must be ruled out prior to study entry
             with normal values of the following blood tests: transferrin saturation (TS) test and
             serum ferritin (SF) test; all associated costs will be paid by the study

          -  Subject who have received ferumoxytol within 3 weeks of study entry

          -  Subjects with three or more drug allergies from separate drug classes
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Sensitivity and specificity of relative cerebral blood volume
Time Frame:Up to 2 years
Safety Issue:
Description:Will be analyzed using proportions and exact 95% confidence intervals. Sensitivity analysis will be based on subjects (lesions) with surgical results, and specificity analysis will be based on lesions with pseudo-progression determined based on surgical results or follow-up scan.

Secondary Outcome Measures

Measure:Safety and tolerability of pembrolizumab when given with stereotactic radiosurgery (SRS) in subjects with brain metastasis
Time Frame:Up to 2 years
Safety Issue:
Description:Safety and tolerability will be determined using the Common Terminology Criteria for Adverse Events V4.0 (CTCAE) grades. They will be analyzed using percentages of patients who developed adverse events and exact 95% confidence intervals.
Measure:Progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Progression free survival will be measured in months from the date of diagnosis to the date of documented progression for each patient. Results will be analyzed using the Kaplan-Meier product limit estimates for all patients, taking censoring into account.
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Overall survival will be measured in months from date of diagnosis to date of death. Results will be analyzed using the Kaplan-Meier product limit estimates for all patients, taking censoring into account.
Measure:Best response in brain disease
Time Frame:Up to 2 years
Safety Issue:
Description:Best response in brain disease will be measured based on brain MRI scan showing the best response to treatment and analyzed using proportions of categories of best response (e.g., complete remission, partial remission, progression, stable disease etc.) and exact 95% confidence intervals.
Measure:Best response in systematic disease
Time Frame:Up to 2 years
Safety Issue:
Description:Best response in systematic disease will be measured based on body CT scan showing the best response to treatment and analyzed using proportions of categories of best response (e.g., complete remission, partial remission, progression, stable disease etc.) and exact 95% confidence intervals.
Measure:Duration of best response of brain and systemic disease
Time Frame:Up to 2 years
Safety Issue:
Description:The duration of best response in brain and the duration of best response in systemic disease will be measured in months from the date on which criteria are met for complete response, partial response or stable disease until the first date that recurrent or progressive disease is objectively documented. Durations of best response will be analyzed using the Kaplan-Meier product limit estimates, taking censoring into account.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated