ClinicalTrials.gov
ClinicalTrials.gov Menu

Ferumoxytol MRI in Assessing Response to Pembrolizumab in Patients With Brain Tumors From Melanoma and Glioblastoma

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: NCT03347617
Recruitment Status : Recruiting
First Posted : November 20, 2017
Last Update Posted : December 22, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Edward Neuwelt, OHSU Knight Cancer Institute

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

Condition or disease Intervention/treatment Phase
Glioblastoma Malignant Primary Brain Neoplasm Melanoma Metastatic Malignant Neoplasm in the Brain Drug: Ferumoxytol Other: Laboratory Biomarker Analysis Procedure: Magnetic Resonance Imaging Biological: Pembrolizumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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 melanoma patients with brain metastases that receive pembrolizumab with standard of care stereotactic radiosurgery. (Arm 1) II. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV) measured by steady state MRI with ferumoxytol in identifying true vs pseudoprogression in patients with newly diagnosed glioblastoma multiforme (GBM) receiving pembrolizumab with standard of care chemo-radiation. (Arm 2)

SECONDARY OBJECTIVES:

I. Determine the safety and toxicity of pembrolizumab when used in combination with standard of care stereotactic radiation (arm 1) and chemo radiation (arm 2).

II. Determine the progression free survival (PFS), overall survival (OS), clinical response and duration of best response for each arm.

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 (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 courses 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, at suspected radiographic progression, and 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Response Assessment to Pembrolizumab With Standard of Care Therapy in Oligometastatic Brain Tumors From Melanoma, and Glioblastoma Using Ferumoxytol Steady State Imaging? A Pilot Study
Actual Study Start Date : December 20, 2017
Estimated Primary Completion Date : November 1, 2019
Estimated Study Completion Date : November 1, 2022


Arm Intervention/treatment
Experimental: Diagnostic (Ferumoxytol MRI, pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 years or 35 courses 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, at suspected radiographic progression, and within 4 weeks from suspected radiographic progression.
Drug: Ferumoxytol
Given IV
Other Names:
  • Feraheme
  • Ferumoxytol Non-Stoichiometric Magnetite

Other: Laboratory Biomarker Analysis
Correlative studies

Procedure: Magnetic Resonance Imaging
Undergo ferumoxytol MRI
Other Names:
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MRI
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Sensitivity and specificity of rCBV measured by ferumoxytol steady state imaging [ Time Frame: Up to 5 years ]
    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 lesions with pseudoprogression determined based on surgical results or follow-up clinical scan, as detailed in the power and sample size calculation section. Arms 1 and 2 will be analyzed separately.


Secondary Outcome Measures :
  1. Determine the safety and toxicity of pembrolizumab when used in combination with standard of care stereotactic radiation (arm 1) and chemo radiation (arm 2). [ Time Frame: Up to 5 years ]
    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.

  2. Progression free survival [ Time Frame: Up to 5 years ]
    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.

  3. Overall survival [ Time Frame: Up to 5 years ]
    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.

  4. Duration of best response [ Time Frame: Up to 5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    • Arm 1: melanoma, with =< 5 measurable (as defined by Response Assessment in Neuro-Oncology-Bone Marrow [RANO-BM]) new brain metastases clinically eligible for stereotactic radiosurgery (SRS); tissue diagnosis of the brain metastasis is not required for enrollment if history and imaging is consistent with melanoma and a histopathology is available from the systemic disease; however, a biopsy or surgical excision of one or more of the brain lesions may be performed, if clinically indicated; patient must consent to providing 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
    • Arm 2: 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 30 days from any major surgeries including brain biopsy and have complete resolution of its effects
  • 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 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
  • 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
  • Subject may also provide consent/assent for future correlative research; subjects may participate in the main trial without participating in future correlative research
  • ARM I INCLUSION CRITERIA: Subject is eligible for and agrees to receive standard of care stereotactic radio surgery with or without prior neuro-surgical intervention
  • ARM I INCLUSION CRITERIA: There are no restrictions on the number of prior lines of treatment for systemic disease
  • ARM I INCLUSION CRITERIA: If subjects have known brain metastases (mets) that were treated previously with local therapies, surgery, and/or radiation, these lesions must be stable for at least 30 days prior to enrollment
  • ARM I INCLUSION CRITERIA: Subjects are currently on checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or antibodies to tumor necrosis factor family including OX40) or tumor vaccine for systemic disease who develop new brain metastases, must have documented stable systemic disease within 30 days of signing consent
  • ARM I INCLUSION CRITERIA: Subjects who have completed prior checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or antibodies to tumor necrosis factor family including OX40) or tumor vaccine for systemic disease but are now off therapy with documented stable systemic disease within 30 days of signing consent may be enrolled after discussion with the Merck & Co clinical team
  • ARM II INCLUSION CRITERIA: Subject is eligible for and agrees to receive standard of care radiation and temozolamide after biopsy or maximum safe surgical resection

Exclusion Criteria:

  • 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
  • Evidence of leptomeningeal disease on MRI or in cerebrospinal fluid (CSF) for arm 1; ocular or mucosal disease specifically for patients with melanoma in arm 1
  • 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, 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
  • 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: 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 (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, 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
  • ARM I EXCLUSION CRITERIA: Any evidence of progressive systemic disease (by RECIST 1.1); those with stable systemic lesion(s) may be considered for enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03347617


Locations
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Edward A. Neuwelt    503-494-5626    trials@ohsu.edu   
Principal Investigator: Edward A. Neuwelt         
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Edward Neuwelt OHSU Knight Cancer Institute

Responsible Party: Edward Neuwelt, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03347617     History of Changes
Other Study ID Numbers: STUDY00016046
NCI-2017-02008 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00016046 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: November 20, 2017    Key Record Dates
Last Update Posted: December 22, 2017
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Neoplasms
Melanoma
Glioblastoma
Brain Neoplasms
Neoplasms, Second Primary
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Pembrolizumab
Ferrosoferric Oxide
Antineoplastic Agents
Hematinics
Parenteral Nutrition Solutions
Pharmaceutical Solutions