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

Study Overview
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Brief Summary
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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
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PRIMARY OBJECTIVE: 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 versus (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. EXPLORATORY 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. Cycles repeat every 3 weeks for up to 2 years (or up to 32 cycles) 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.

Official Title
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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)

Conditions
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Lung Carcinoma Metastatic in the Brain, Stage IV Lung Non-Small Cell Cancer AJCC v7

Intervention / Treatment
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* Drug: Ferumoxytol
* Other: Laboratory Biomarker Analysis
* Procedure: Magnetic Resonance Imaging
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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 ten measurable (by Response Assessment in Neuro-Oncology Criteria [RANO]) brain metastasis planned for stereotactic radiosurgery Have PD-L1 expression of greater than 1% 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; 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 Food and Drug Administration (FDA)-approved therapy for these aberrations; subjects with EGFR or ALK genomic tumor aberrations who develop new brain metastases may be included at the discretion of the treating physician Have a performance status of 0-2 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) OR 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 Creatinine clearance should be calculated per institutional standard 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 Exclusion Criteria: 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 Subject 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab, ferumoxytol MRI)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (or up to 32 cycles) 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. | Drug: Ferumoxytol<br>* Given IV<br>* Other names: Ferumoxytol Non-Stoichiometric Magnetite;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and Specificity of Relative Cerebral Blood Volume | 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. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Pembrolizumab When Given With Stereotactic Radiosurgery (SRS) in Subjects With Brain Metastasis | 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. | Up to 2 years | 
| Duration of Best Response of Brain and Systematic Disease | 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. | Up to 2 years | 
| Best Response in Brain Disease | 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. | Up to 2 years | 
| Best Response in Systematic Disease | 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. | Up to 2 years | 
| Progression Free Survival | 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. | Up to 2 years | 
| Overall Survival | 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. | Up to 2 years |