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)
Overview
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- OHSU Knight Cancer Institute
- Enrollment
- 2
- Locations
- 1
- Primary Endpoint
- Sensitivity and Specificity of Relative Cerebral Blood Volume
Overview
Brief Summary
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 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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)
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
Arms & Interventions
Treatment (pembrolizumab, ferumoxytol MRI)
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.
Intervention: Ferumoxytol (Drug)
Treatment (pembrolizumab, ferumoxytol MRI)
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.
Intervention: Laboratory Biomarker Analysis (Other)
Treatment (pembrolizumab, ferumoxytol MRI)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (pembrolizumab, ferumoxytol MRI)
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.
Intervention: Pembrolizumab (Biological)
Outcomes
Primary Outcomes
Sensitivity and Specificity of Relative Cerebral Blood Volume
Time Frame: Up to 2 years
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 Outcomes
- Duration of Best Response of Brain and Systematic Disease(Up to 2 years)
- Safety and Tolerability of Pembrolizumab When Given With Stereotactic Radiosurgery (SRS) in Subjects With Brain Metastasis(Up to 2 years)
- Progression Free Survival(Up to 2 years)
- Best Response in Brain Disease(Up to 2 years)
- Best Response in Systematic Disease(Up to 2 years)
- Overall Survival(Up to 2 years)
Investigators
Edward Neuwelt
Principal Investigator
OHSU Knight Cancer Institute