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Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

693 Background: Although modern cancer treatment has significantly prolonged patient’s life, it comes with a high financial cost. Based on an NIH report on Financial Burden of Cancer Care, treating PDAC costs $108K, $18K, and $125K for initial treatment, during follow up, and in last year of life, respectively. Of these, CA19-9 and CT studies are obtained concurrently to evaluate tumor burden whose cost can be reduced by decreasing imaging frequency when CA19-9 remains stable. As a pilot study, we evaluated whether changes in CA19-9, an inexpensive laboratory study commonly used for monitoring treatment response, correlates with tumor size change on imaging studies. A positive correlation may lead us to design future studies to evaluate whether stable CA19-9 can serve as an indicator for stable disease on CT scan such that imaging frequency (and cost) may be reduced. Methods: We retrospectively identified PDAC patients from our tumor registry from 2016 to 2019. Subjects were included if they met the following criteria: 1) diagnosed with PDAC 2) had at least 2+ CA19-9 and CT/MR follow up assessments with the laboratory and imaging studies within one month of each other, and 3) had measurable lesions as defined by RECIST 1.1 criteria. Due to limited resources, we limited the maximum number of lesions to 4 instead of the usual 5 for RECIST 1.1. Two-dimensional orthogonal tumor sizes were measured on axial images with the largest cross-section. Changes in the values were obtained serially (from the immediately prior study). Nonparametric correlations (Spearman’s rho) were used to evaluate monotonicity. The significance level was set at p < 0.05. Results: We screened 300 subjects from the tumor registry and identified 23 subjects suitable for our study. 13 subjects were female and 10 were male with ages ranging from 35 to 84. We identified 55 target lesions and 128 assessments (with both CA19-9 and imaging) from the 23 subjects. We analyzed the log absolute and log relative change in CA19-9 with change in tumor area. When absolute CA19-9 value, absolute change in CA19-9, and relative change in CA19-9 were tested against the absolute change in tumor size, the correlation was significant for the absolute value and absolute change of CA19-9 (p < 0.01), but not for relative change of CA19-9 (p < 0.11). When tested against relative change in tumor size, all three values were highly significant (p < 0.001). Conclusions: Our finding of direct correlations between changes of CA19-9 and relative change of tumor size on imaging suggests that CA19-9 can serve as a surrogate measure of relative change of tumor burden for patients undergoing treatment. This provides motivation for future studies evaluating the possibility that stable CA19-9 can represent stable tumor burden such that expensive imaging studies may be obtained at longer time intervals to reduce financial cost to patients.

142 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, and its outcome can be improved with better detection of incidental early CRC on routine CT of the abdomen and pelvis (CTAP). AI-second observer (AI) has the potential as shown in our companion abstract. The bottleneck in training AI is the time required for radiologists to segment the CRC. We compared two techniques for accelerating the segmentation process: 1) Sparse annotation (annotating some of the CT slice containing CRC instead of every slice); 2) Allowing AI to perform initial segmentation followed by human adjustment. Methods: 2D U-Net convolutional neural network (CNN) containing 31 million trainable parameters was trained with 58 CRC CT images from Banner MD Anderson (AZ) and MD Anderson Cancer Center (TX) (51 used for training and 7 for validation) and 59 normal CT scans from Banner MD Anderson Cancer Center. Twenty of the 25 CRC cases from public domain data (The Cancer Genome Atlas) were used to evaluate the performance of the models. The CRC was segmented using ITK-SNAP open-source software (v. 3.8). For the first objective, 3 separate models were trained (fully annotated CRC, every other slice, and every third slice). The AI-annotation on the TCGA dataset was analyzed by the percentage of correct detection of CRC, the number of false positives, and the Dice similarity coefficient (DSC). If parts of the CRC were flagged by AI, then it was considered correct. A detection was considered false positive if the marked lesion did not overlap with CRC; contiguous false positives across different slices of CT image were considered a single false positive. DSC measures the quality of the segmentation by measuring the overlap between the ground-truth and AI detected lesion. For the second objective, the time required to adjust the AI-produced annotation was compared to the time required for annotating the entire CRC without AI assistance. The AI-models were trained using ensemble learning (see our companion abstract for details of the techniques). Results: Our results showed that skipping slices of tumor in training did not alter the accuracy, false positives, or DSC classification of the model. When adjusting the AI-observer segmentation, there was a trend toward decreasing the time required to adjust the annotation compared to full manual segmentation, but the difference was not statistically significant (Table; p=0.121). Conclusions: Our results show that both skipping slices of tumor as well as starting with AI-produced annotation can potentially decrease the effort required to produce high-quality ground truth without compromising the performance of AI. These techniques can help improve the throughput to obtain a large volume of cases to train AI for detecting CRC.[Table: see text]

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid.

The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at −2, −1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3–7. The geometric mean ratio and 90 % confidence interval of Cmax and AUC of acetaminophen were within 80–125 % suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ∼1.25 h without affecting Cmax or AUC.

Background Aberrant CD40-CD154 pathway signaling has been linked to pathology in autoimmune disease. Blocking the CD40-CD154 pathway prevents T cell-dependent antibody responses, germinal center formation and prolongs renal allograft survival in non-human primates. CFZ533 is a novel, fully human, non-agonistic Fc-silent, anti-CD40 monoclonal antibody being developed for treatment of autoimmune diseases and prevention of rejection in solid-organ transplantation. Objectives To assess the safety, pharmacokinetics (PK) and pharmacodynamics activity (PD) of CFZ533 in humans. Methods A double-blind, placebo controlled, ascending, single-dose study was conducted in 48 healthy volunteers (HV) receiving 0.03, 0.1, 0.3, 1.0, 3.0 mg/kg i.v., 3.0 mg/kg s.c. CFZ533 or matching placebo (3:1) as well as in 12 rheumatoid arthritis (RA) patients receiving 10.0 mg/kg i.v. CFZ533 or placebo (1:1). HVs were immunized with a single intramuscular dose of a T-cell dependent neo-antigen, Keyhole Limpet Hemocyanin (KLH) with alum adjuvant on Day 3 and again between Day 29–85 depending on predicted loss of CD40 receptor occupancy (RO) as a function of CFZ533 dose. Blood samples for PK, CD40 RO and anti-KLH IgG and IgM profiling were collected at multiple time points during the study. Anti-KLH antibodies were assessed using a validated human ELISA system with an LOQ of 0.7 (IgG) and 2.1 (IgM) μg/mL. RA patients were evaluated for safety, PK and RO. Results All doses of CFZ533 and KLH were safe and well tolerated. CFZ533 PK concentrations were quantifiable at all dose levels tested. Complete (≥90%) peripheral CD40 RO by 3 mg/kg i.v. CFZ533 in HVs was maintained for 28 days. During this period of full RO, full suppression of the primary humoral response to KLH was evident in all treated subjects (KLH administered 2 days after CFZ533 dosing). After complete CFZ533 washout in 3 mg/kg cohort, all subjects mounted a robust anti-KLH response following a re-challenge on Day 85. Full RO in RA patients who received 10 mg/kg i.v. CFZ533 was maintained for at least 6 weeks and up to 10 weeks. Conclusions The favorable safety and tolerability profile of CFZ533 coupled with a predictable concentration-CD40 receptor occupancy relationship and suppression of a primary T cell-dependent antibody response supports future clinical trials of CFZ533 in select autoimmune diseases and transplantation. Disclosure of Interest A. Slade Employee of: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, P. Koo Employee of: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, Y. He Employee of: Novartis Pharmaceuticals Corporation, Cambridge, MA, USA, P. Espie Employee of: Novartis Pharmaceuticals Corporation, Basel, Switzerland, A. Auger-Sarrazin Employee of: Novartis Pharmaceuticals Corporation, Basel, Switzerland, J. Rush Employee of: Novartis Pharmaceuticals Corporation, Basel, Switzerland, P. Gergely Employee of: Novartis Pharmaceuticals Corporation, Basel, Switzerland