Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma

Context: No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective: To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design: Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting: Three centers. Patients: Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention: Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures: Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results: The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received \u3e18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions: These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg

Diagnostic Performance of the Visual Reading of 123I-Ioflupane SPECT Images With or Without Quantification in Patients With Movement Disorders or Dementia

Visual interpretation of 123I-ioflupane SPECT images has high diagnostic accuracy for differentiating parkinsonian syndromes (PS), from essential tremor and probable dementia with Lewy bodies (DLB) from Alzheimer disease. In this study, we investigated the impact on accuracy and reader confidence offered by the addition of image quantification in comparison with visual interpretation alone. Methods: We collected 304 123I-ioflupane images from 3 trials that included subjects with a clinical diagnosis of PS, non-PS (mainly essential tremor), probable DLB, and non-DLB (mainly Alzheimer disease). Images were reconstructed with standardized parameters before striatal binding ratios were quantified against a normal database. Images were assessed by 5 nuclear medicine physicians who had limited prior experience with 123I-ioflupane interpretation. In 2 readings at least 1 mo apart, readers performed either a visual interpretation alone or a combined reading (i.e., visual plus quantitative data were available). Readers were asked to rate their confidence of image interpretation and judge scans as easy or difficult to read. Diagnostic accuracy was assessed by comparing image results with the standard of truth (i.e., diagnosis at follow-up) by measuring the positive percentage of agreement (equivalent to sensitivity) and the negative percentage of agreement (equivalent to specificity). The hypothesis that the results of the combined reading were not inferior to the results of the visual reading analysis was tested. Results: A comparison of the combined reading and the visual reading revealed a small, insignificant increase in the mean negative percentage of agreement (89.9% vs. 87.9%) and equivalent positive percentages of agreement (80.2% vs. 80.1%). Readers who initially performed a combined analysis had significantly greater accuracy (85.8% vs. 79.2%; P = 0.018), and their accuracy was close to that of the expert readers in the original studies (range, 83.3%-87.2%). Mean reader confidence in the interpretation of images showed a significant improvement when combined analysis was used (P < 0.0001). Conclusion: The addition of quantification allowed readers with limited experience in the interpretation of 123I-ioflupane SPECT scans to have diagnostic accuracy equivalent to that of the experienced readers in the initial studies. Also, the results of the combined reading were not inferior to the results of the visual reading analysis and offered an increase in reader confidenc

The role of resting myocardial blood flow and myocardial blood flow reserve as a predictor of major adverse cardiovascular outcomes.

Cardiac perfusion PET is increasingly used to assess ischemia and cardiovascular risk and can also provide quantitative myocardial blood flow (MBF) and flow reserve (MBFR) values. These have been shown to be prognostic biomarkers of adverse outcomes, yet MBF and MBFR quantification remains underutilized in clinical settings. We compare MBFR to traditional cardiovascular risk factors in a large and diverse clinical population (60% African-American, 35.3% Caucasian) to rank its relative contribution to cardiovascular outcomes. Major adverse cardiovascular events (MACE), including unstable angina, non-ST and ST-elevation myocardial infarction, stroke, and death, were assessed for consecutive patients who underwent rest-dipyridamole stress 82Rb PET cardiac imaging from 2012-2015 at the Hospital of the University of Pennsylvania (n = 1283, mean follow-up 2.3 years). Resting MBF (1.1 ± 0.4 ml/min/g) was associated with adverse cardiovascular outcomes. MBFR (2.1 ± 0.8) was independently and inversely associated with MACE. Furthermore, MBFR was more strongly associated with MACE than both traditional cardiovascular risk factors and the presence of perfusion defects in regression analysis. Decision tree analysis identified MBFR as superior to established cardiovascular risk factors in predicting outcomes. Incorporating resting MBF and MBFR in CAD assessment may improve clinical decision making

In vivo visualization of PARP inhibitor pharmacodynamics

BACKGROUND [18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODS Two single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTS Thirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION [18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATION ClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDING Metavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge