Ferumoxytol MRI in Assessing Response to Pembrolizumab in Patients With Glioblastoma

Study Overview
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Brief Summary
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This pilot phase II trial studies how well ferumoxytol magnetic resonance imaging (MRI) works in assessing response to pembrolizumab in patients with glioblastoma. Diagnostic procedures, such as ferumoxytol MRI, may help measure a patient's response to pembrolizumab treatment.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV) measured by steady state MRI with ferumoxytol in identifying true versus (vs) pseudoprogression in patients with newly diagnosed glioblastoma multiforme (GBM) receiving pembrolizumab with standard of care chemo-radiation. SECONDARY OBJECTIVES: I. Determine the safety and toxicity of pembrolizumab when used in combination with standard of care chemo radiation. II. Determine the progression free survival (PFS), overall survival (OS), clinical response and duration of best response. 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 (serum biomarker) and correlate clinical as well as radiological response with systemic immune response to pembrolizumab as measured by immunological panel. III. Compare the changes in PDL-1 expression in the biopsy tissue before and after therapy at the time of progression and correlate PD-L1 expression with response rates and survival. IV. 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 determined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and immune related response criteria [irRC]). OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 years or 35 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI scans at baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or chemoradiotherapy, every 9 weeks thereafter until suspected radiographic progression, and then within 4 weeks from 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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Response Assessment to Pembrolizumab With Standard of Care Therapy in Glioblastoma Using Ferumoxytol Steady State Imaging- A Pilot Study

Conditions
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Glioblastoma

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 life expectancy of at least 6 months Have a histologically confirmed diagnosis of: Newly diagnosed glioblastoma (World Health Organization [WHO] grade IV) Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 on stable or reducing dose of steroids for symptom management (not more than 8 mg of dexamethasone or equivalent per day) for 5 days prior to enrollment; change in glucocorticoid dose for any purpose other than to modulate symptoms from an adverse event; Note: The use of physiologic doses (e.g., prednisone 10 mg) of corticosteroids may be approved after consultation with Merck & Co; use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV contrast dye) is permitted At least 14 days from any major surgeries including brain biopsy before the start of study drug pembrolizumab 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 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 glutamic pyruvic 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 time (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, including but not limited to, abstinence from heterosexual activity starting with the first dose of study therapy through 120 days after the last dose of study therapy Subject is eligible for and agrees to receive standard of care radiation and temozolamide after biopsy or maximum safe surgical resection Exclusion Criteria: Has a diagnosis of immunodeficiency including human immunodeficiency virus (HIV) (HIV 1/2 antibodies) and is not on continuous daily immunosuppressive therapy within 7 days prior to the first dose of trial treatment; (an exception to this is the use of steroids for brain edema and resulting symptom); subjects may receive a stable or reducing dose of steroids (up to 8 mg dexamethasone or equivalent for at least 5 days prior to signing consent) to prevent or manage cerebral edema; subjects requiring over 8mg of dexamethasone per day on or five days prior to signing consent are excluded) Has a known history of active TB (Bacillus tuberculosis) Hypersensitivity to pembrolizumab 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 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 (e.g. 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 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 (Ferumoxytol Investigator's Drug Brochure, 2009); subjects with significant drug or other allergies or autoimmune diseases may be enrolled at the investigator's discretion Subjects who have a contraindication for 3T MRI: metal in their bodies (a cardiac pacemaker or other incompatible device), are severely agitated 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: Diagnostic (Ferumoxytol MRI, pembrolizumab)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 years or 35 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI scans at baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or chemoradiotherapy, every 9 weeks thereafter until suspected radiographic progression, and then within 4 weeks from 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 ferumoxytol 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 ferumoxytol steady state imaging | Will be analyzed using proportions and exact 95% confidence intervals. Analysis of sensitivity will be based on patients with surgical results, and specificity analysis will be based on patients with pseudoprogression determined based on surgical results or follow-up clinical scan, as detailed in the power and sample size calculation section. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Will be assessed using the Kaplan-Meier product limit estimates. | Up to 5 years | 
| Overall survival | Will be assessed using the Kaplan-Meier product limit estimates. | Up to 5 years | 
| Duration of best response | Will be analyzed using proportions and exact 95% confidence intervals. | Up to 5 years | 
| Rate of adverse events | Will be analyzed using proportions and exact 95% confidence intervals. | Up to 5 years |