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64Cu-LLP2A for Imaging Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03804424
Recruitment Status : Recruiting
First Posted : January 15, 2019
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
The investigators are performing a trial with goals to demonstrate the feasibility of imaging multiple myeloma (MM) patients with 64Cu-LLP2A-positron emission tomography (PET)/magnetic resonance (MR). The investigators suggest that 64Cu-LLP2A will allow for an accurate molecular imaging of MM lesions, which will have an important impact on early stage disease detection and in the long term on the initiation and choice of therapy in these patients.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: 64Cu-LLP2A Device: PET/MR Procedure: Blood samples for serum stability Procedure: Blood samples for metabolite analysis Procedure: Urine sample Procedure: Tumor biopsy Procedure: Electrocardiogram Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single (Investigator)
Masking Description: Images will be assessed by independent observers (nuclear medicine expert in evaluating PET images using novel radiotracers, and MR radiologist expert in evaluating MR images), who will initially be blinded to all clinical information available (such as tumor size and location), which will be followed by un-blinded combined reading of the PET and MR images
Primary Purpose: Diagnostic
Official Title: Early Phase I Evaluation of 64Cu-LLP2A for Imaging Multiple Myeloma
Actual Study Start Date : November 20, 2018
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : November 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1: Pilot 64Cu-LLP2A Imaging
  • 12 adult individuals (6 patients with known MM; 6 healthy volunteers)
  • All subjects who enter the study in Cohort 1 will be injected with 11 mCi (RANGE 8.8-13.2 mCi) of 64Cu-LLP2A and undergo body imaging twice within 0-30 hrs following administration of 64Cu-LLP2A to study tracer biodistribution and calculate human dosimetry Body imaging will be performed approximately at the following time points:

    • Immediately after 64Cu-LLP2A administration (2 subjects 1 healthy volunteer and 1 subject with MM)
    • 1 to 3 hours after 64Cu-LLP2A administration (4 subjects)
    • 3 to 8 hours after 64Cu-LLP2A administration (4 subjects)
    • 18 to 30 hours after 64Cu-LLP2A administration (2 subjects: 1 healthy volunteer and 1 subject with MM)
  • 10 of the subjects will also undergo dynamic study for 60 mins immediately after administration of 64Cu-LLP2A.
Drug: 64Cu-LLP2A
-64Cu-LLP2A, will be manufactured following batch production record at the cyclotron GMP facility (Washington University School of Medicine GMP radiochemistry/cyclotron facility)

Device: PET/MR
-All PET imaging will be performed with a Siemens mMR PET/MR scanner

Procedure: Blood samples for serum stability
-3 venous samples obtained from an IV site separate from the site of 64Cu-LLP2A injection (2 mL each) will be obtained at the following time points: Cohort 1: prior to injection, at completion of dynamic scanning in those who undergo dynamic imaging and at completion of one of the body imaging time points. In those who do not undergo dynamic imaging, prior to injection, and after completing body imaging at 2 of the 3 time points. Cohort 2: subjects will have samples drawn prior to injection, at completion of dynamic scanning, and at completion of body imaging.

Procedure: Blood samples for metabolite analysis
-Typically, 2 blood samples obtained from an IV site separate from the site of 64Cu-LLP2A injection (preferably 1 within the first 5 min and 1 at the completion of the first hour of imaging) will be obtained.

Procedure: Urine sample
-Cohort 1 only

Procedure: Electrocardiogram
-A standard 12-lead ECG will be obtained on all subjects at baseline (within 30 mins prior to injection of 64Cu-LLP2A), and at least 60 minutes post injection or prior to study discharge
Other Name: ECG

Experimental: Cohort 2: Quantitative 64Cu-LLP2A Imaging
  • 20 patients with MM will be recruited
  • Subjects who enter on study in Cohort 2 will undergo a 60-min dynamic image over the known site of disease (OR pelvis and lower lumbar spine, if no site of disease is known). Following a simple DIXON MRI scan for attenuation correction, subjects will be injected with a dose of 11 mCi of 64Cu-LLP2A (RANGE 8.8 - 13.2 mCi) and a list mode dynamic imaging acquisition will begin for a total of 60 mins. Following the dynamic study, or at the optimal time point determined from cohort 1 imaging, after a simple DIXON scan for body (top of the head to below the knees) attenuation correction, emission scans (2-5 min per bed position) will be performed
Drug: 64Cu-LLP2A
-64Cu-LLP2A, will be manufactured following batch production record at the cyclotron GMP facility (Washington University School of Medicine GMP radiochemistry/cyclotron facility)

Device: PET/MR
-All PET imaging will be performed with a Siemens mMR PET/MR scanner

Procedure: Blood samples for serum stability
-3 venous samples obtained from an IV site separate from the site of 64Cu-LLP2A injection (2 mL each) will be obtained at the following time points: Cohort 1: prior to injection, at completion of dynamic scanning in those who undergo dynamic imaging and at completion of one of the body imaging time points. In those who do not undergo dynamic imaging, prior to injection, and after completing body imaging at 2 of the 3 time points. Cohort 2: subjects will have samples drawn prior to injection, at completion of dynamic scanning, and at completion of body imaging.

Procedure: Blood samples for metabolite analysis
-Typically, 2 blood samples obtained from an IV site separate from the site of 64Cu-LLP2A injection (preferably 1 within the first 5 min and 1 at the completion of the first hour of imaging) will be obtained.

Procedure: Tumor biopsy
-Cohort 2 only and only if there hasn't been a recent biopsy of disease

Procedure: Electrocardiogram
-A standard 12-lead ECG will be obtained on all subjects at baseline (within 30 mins prior to injection of 64Cu-LLP2A), and at least 60 minutes post injection or prior to study discharge
Other Name: ECG




Primary Outcome Measures :
  1. Feasibility of imaging MM patients with 64Cu-LLP2A-PET/MR as measured by average organ activity concentration of 64Cu-LLP2A [ Time Frame: Up to 30 hours after imaging ]
    -Average organ activity concentration will be measured and decay corrected by utilizing regions of interest (ROIs) drawn around all organs visible on 64Cu-LLP2A images. Activity organ residence times will be calculated by numerical or analytical integration of the time-activity curves. Uptake/clearance functional fits of mono or bi-exponential functions will be performed and analytical integration, accounted for physical delay, will be performed. The calculated residence times will be used with the program OLINDA/EXM for 64Cu and using the adult human (male/femal) model to calculate the individual organ radiation dose, the whole-body dose, and the effective dose

  2. Feasibility of imaging MM patients with 64Cu-LLP2A-PET/MR as measured by the number of participants who experience an adverse event related to 64Cu-LLP2A [ Time Frame: Through 48 hours after last administration of 64Cu-LLP2A (estimated to be at most 4 days) ]
    -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

  3. Feasibility of imaging MM patients with 64Cu-LLP2A-PET/MR as measured by the optimal image time after injection of 64Cu-LLP2A [ Time Frame: Up to 30 hours after imaging ]
    -The optimal imaging time after injection yields the best image quality and tumor-to-non-tumor ratio for visual and quantitative analysis of the lesions

  4. Feasibility of imaging MM patients with 64Cu-LLP2A-PET/MR as measured by image quality of 64Cu-LLP2A-PET/MR images [ Time Frame: Up to 30 hours after imaging ]
    • Overall PET image quality will be graded visually (using 4-point scale with 1 being the worst and poor quality, not acceptable for diagnostic interpretation and 4 being good image quality, similar to routine clinical studies).
    • The images will be assessed by independent observers (a nuclear medicine expert in evaluating PET images using novel radiotracers, and a MR radiologist expert in evaluating MR images
    • The images will then be correlated to MRI (and biopsy if available) to assess whether the lesions identified on 64Cu-LLP2A correspond to myeloma lesions

  5. Feasibility of imaging MM patients with 64Cu-LLP2A-PET/MR as measured by lesion detection of 64Cu-LLP2A-PET/MR images [ Time Frame: Up to 30 hours after imaging ]
    -Lesion detection is measured by lesion uptake in comparison with the surrounding tissue


Secondary Outcome Measures :
  1. Comparison of tumor burden (SUVmax) of 64Cu-LLP2A to clinical stage [ Time Frame: Up to 30 hours after imaging ]
    -SUVmax is a mathematical measurement of tumor burden seen on images and calculated by the following equation SUVmax= r / (a'/w) where r= radioactivity concentration in tumor (kBq/ml) as measured by the PET scanner within a defined region of interest, a'=the decay corrected amount of injected 64Cu-LLP2A and w= weight of the patient in grams When PET imaging shows uptake of 64Cyu-LLP2A in site(s) of known tumor the SUVmax will be compared to overall clinical stage as a way to compare accuracy of imaging to known clinical stage

  2. Comparison of tumor burden (SUVmax) of 64Cu-LLP2A to clinical tumor measurement of tumor burden as measured by M-protein of myeloma [ Time Frame: Up to 30 hours after imaging ]
    SUVmax is a mathematical measurement of tumor burden seen on images and calculated by the following equation SUVmax= r / (a'/w) where r= radioactivity concentration in tumor (kBq/ml) as measured by the PET scanner within a defined region of interest, a'=the decay corrected amount of injected 64Cu-LLP2A and w= weight of the patient in grams When PET imaging shows uptake of 64Cyu-LLP2A in site(s) of known tumor the SUVmax will be compared to clinical measurement of tumor burden as seen by the laboratory values for M-protein (lab measurement for myeloma gamma globulin which is increased in multiple myleom due to an abnormal monoclonal proliferation of plasma cells)

  3. Comparision of tumor burden (SUVmax) of 64Cu-LLP2A to clinical measurement of tumor burden as measured by the plasma cell fraction within the bone marrow [ Time Frame: Up to 30 hours after imaging ]
    • Hierarchical models will be used to estimate the correlation of SUVmax with M-protein expression
    • Variance components models will be fit to identify component (proportion) of total variance



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adult patients 18 years of age or older with MM, defined according to International Myeloma Working Group (IMWG) diagnostic criteria as the presence of ≥ 10% clonal bone marrow cells, organ damage (hypercalcemia, renal failure, anemia, or bone lesions [CRAB]) and presence of 60% bone marrow involvement, regardless of CRAB. Evidence of organ damage: Hypercalcemia [serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)]. Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177µmol/L (> 2 mg/dL). Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT or more than one focal lesion on MRI that is at least 5 mm or greater in size. Other biomarkers of malignancy: serum free light chain ratio > 100 (Cohort 1 MM group or cohort 2)
  • Healthy Volunteer Subjects: Adult 18 years of age or older with no known hematologic disorder such as anemia, leukemia, etc. who is considered healthy based on assessment by PI. (Cohort 1 only).
  • Able to give informed consent.
  • Does not have any exclusions related to PET/MR imaging: No implanted medical devices such as: pacemaker, defibrillator, neurostimulator, artificial heart valve, cerebral aneurysm clips, no accidental exposure to metal fragments.
  • If applicable for administration of contrast with MRI imaging subject must have a calculated GFR of at least 60 mg/mL/1.73 m^2.
  • Not currently pregnant or nursing: Subject must be surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post-menopausal (cessation of menses for more than 1 year), non-lactating, or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of 64Cu-LLP2A) is negative.

Exclusion Criteria:

  • Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of the other cancer present within the last 5 years.
  • Unable to tolerate up to 90 min of PET/MR imaging per imaging session.
  • Not claustrophobic.

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): NCT03804424


Contacts
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Contact: Farrokh Dehdashti, M.D. 314-362-1474 dehdashtif@wustl.edu
Contact: Jennifer Frye, CNMT, CCRC 314-747-1604 fryej@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Farrokh Dehdashti, M.D.    314-362-1474    dehdashtif@wustl.edu   
Contact: Jennifer Frye, CNMT, CCRC    314-747-1604    fryej@wustl.edu   
Principal Investigator: Farrokh Dehdashti, M.D.         
Sub-Investigator: Ravi Vij, M.D.         
Sub-Investigator: Korresh Shoghi, Ph.D.         
Sub-Investigator: Monica Shokeen, Ph.D.         
Sub-Investigator: Richard Laforest, Ph.D.         
Sub-Investigator: Kim Trinkaus, Ph.D.         
Sub-Investigator: Kathryn Fowler, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Farrokh Dehdashti, M.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03804424     History of Changes
Other Study ID Numbers: 201807197
First Posted: January 15, 2019    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:
  • A primary means of sharing data will be through publication in peer-reviewed journals. As required by the NIH Public Access Policy, the investigators will submit to the NIH National Library of Medicine's PubMed Central an electronic version of final manuscripts upon acceptance for publication, resulting from research supported by these funds, in whole or in part, with direct costs from NIH.
  • It is expected that approximately 1-2 presentations at national meetings
  • Early phase I evaluation of 64Cu-LLP2A for imaging multiple myeloma will generate imaging, safety and dosimetry data from PET/CT and MR studies of 64Cu-LLP2A. Serum markers such as M-protein, plasma cell density and immunohistochemistry will be correlated with imaging, in order to understand the interaction of 64Cu-LLP2A with VLA-4 in vivo. It is the explicit intention that these data will be placed in a readily accessible public database.
Supporting Materials: Study Protocol
Time Frame: All efforts will be made to rapidly release data through publications of the results as quickly as it is possible to analyze the experiments.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases