Molecular Imaging of the Underlying Mechanism of Cardiotoxicity in Patients With Light Chain Amyloidosis Using PET/CT

Molecular Imaging of the Underlying Mechanism of Cardiotoxicity in Patients With Cardiac Amyloidosis Using Positron Emission Tomography (PET/CT)

The research study is being conducted to test how two different types of Positron Emission Tomography (PET/CT) scans could be used to image a type of heart disorder called amyloidosis (AL). There will be two groups in the study. One group will have PET/CT scans using an imaging drug called 18F-NOS and the other group will have PET/CT scans using a drug called Florbetaben. subject will be assigned to one of the groups when she/he agrees to be in the study.

Study Overview

• Status: Recruiting
• Conditions: Cardiac Amyloidosis
• Intervention / Treatment: Drug: FNOS; Drug: Florbetaben

Detailed Description

Immunoglobulin light chain (LC) amyloidosis (AL) is an underdiagnosed monoclonal plasma cell proliferative disorder caused by extracellular deposition of AL fibrils in various tissues and organs, causing disease by progressively damaging the structure and function of the affected tissue/organ. The heart is the most commonly involved organ (~75%),9 and the extent and severity of cardiac involvement continue to be the main limitation for successful treatment. Although it remains high, the 6-month mortality rate has improved significantly over the last decade (24% vs. 37%; P<0.001) due to earlier diagnosis, better treatment options, and the advent of sensitive serologic biomarkers to assess for early treatment response,10 in particular serum free light chains (FLC), which permit the differentiation of patients who achieve complete response (CR) and very good partial response (VGPR) from those with partial or no response. N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) has also become a key biomarker for detection and risk-stratification of patients with cardiac AL amyloidosis, and is now routinely employed in clinical trials as a surrogate end point for survival. A large retrospective landmark analysis established that achievement of a CR or VGPR at 6 months post-initiation of therapy, or achievement of an NTproBNP response 6 months post-initiation of therapy, defined as a 30% reduction and absolute reduction ≥ 300 pg/mL from baseline for subjects with baseline levels ≥ 650 pg/mL, was strongly associated with improved overall survival (insert Palladini et al, JCO 2012).

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Erin Schubert; Phone Number: 215-573-6569; Email: erinshu@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Erin Schubert; Phone Number: 215-573-6569; Email: erinschu@pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants will be at least 18 years of age
2. Have an established diagnosis of AL amyloidosis based on standard criteria and planning to start systemic therapy.

3. Have cardiac involvement as defined by all of the following:

   • Past documented or presently noted clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
   • Either an endomyocardial biopsy demonstrating AL amyloidosis or an echocardiogram demonstrating a mean left ventricular wall thickness at diastole >12mm in the absence of other causes (e.g. severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening
   • NT-proBNP ≥ 650 pg/mL

4. Participants should fall into 1 of the following 2 categories:

   1. Treatment-naïve or have completed no more than 1 cycle of initial therapy, OR
   2. Relapsed after 1 or more prior therapies, and at least 6 months from last treatment
5. Have serum free light chain (FLC) differential (defined as amyloid-forming FLC minus non-amyloid-forming FLC) ≥ 50 mg/L.
6. Participants must be informed of the investigational nature of this study and be willing to provide written informed consent and participate in this study in accordance with institutional and federal guidelines prior to study-specific procedures.

Exclusion Criteria:

1. Females who are pregnant or breast feeding at the time of the PET/CT scan will not be eligible for this study; a urine pregnancy test will be performed in women of child-bearing potential before the injection of radiotracer.
2. Inability to tolerate imaging procedures in the opinion of an investigator or treating physician
3. Any current medical condition, illness, or disorder as assessed by medical record review and/or self-reported that is considered by a physician investigator to be a condition that could compromise participant safety or successful participation in the study
4. Less than 6 months life expectancy as deemed by a treating physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inflammation group; Patient diagnosed with Cardiac Amyloidosis	Drug: FNOS; The imaging drug used for this group is called 18F-NOS, it is an experimental imaging drug that has not yet been approved by the Food and Drug Administration (FDA) for use except in a research study. Subject will not receive the results or feedback from the study participation, the images may be reviewed with subject or her/his doctor upon request but will not be used to make decisions about subject medical care.; Other Names: [18F]-6-(2-fluoro-propyl)-4-methylpyridin-2-amine
Experimental: Amyloid group; Patient diagnosed with Cardiac Amyloidosis	Drug: Florbetaben; The imaging drug used for this group is called Florbetaben, it is an FDA approved radioactive PET tracer used to image amyloid plaques in the body. Although not yet FDA approved for this purpose, it has already been used clinically to image amyloid in other parts of the body. Subject will not receive the results or feedback from the study participation, the images may be reviewed with subject or her/his doctor upon request but will not be used to make decisions about subject medical care.; Other Names: Neuraceq

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure uptake of [18F]NOS and Florbetaben in patients with AL before and ~4 months (2 +/- weeks) after starting standard therapy using PET/CT	Measure uptake of [18F]NOS and Florbetaben in patients with AL before and ~4 months (2 +/- weeks) after starting standard therapy and describe the distributions of uptake values at each time point. Compute post-/pre-treatment fold change in [18F]NOS and Florbetaben uptake and describe its distribution.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Describe fold changes in [18F]NOS uptake in patients who have a complete response or very good partial response vs patients who have a partial or no response to therapy at ~4 months.	Describe fold changes in [18F]NOS uptake in patients who have a complete response or very good partial response vs patients who have a partial or no response to therapy at ~4 months.	4 months
Describe fold changes in [18F]NOS uptake in patients who have an NT-proBNP response at ~4 months vs patients who have no response or progression	Describe fold changes in [18F]NOS uptake in patients who have an NT-proBNP response at ~4 months vs patients who have no response or progression	4 months
Describe fold changes in Florbetaben uptake in patients who have an NT-proBNP response at ~4 months vs patients who have no response or progression	Describe fold changes in Florbetaben uptake in patients who have an NT-proBNP response at ~4 months vs patients who have no response or progression	4 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Paco Bravo, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: September 18, 2019
• First Submitted That Met QC Criteria: September 24, 2019
• First Posted (Actual): September 26, 2019

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Wounds and Injuries; Proteostasis Deficiencies; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Amyloidosis; Cardiotoxicity
• Other Study ID Numbers: 833485

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No