McConathy, Jonathan

Abstract Purpose: Fibroblast activation protein (FAP) is an attractive target for radiopharmaceutical therapy. Phase I of the LuMIERE study (ClinicalTrials.gov, NCT04939610) investigated the safety of [177Lu]Lu-FAP-2286 (177Lu-FAP-2286) in heavily pretreated patients with advanced solid tumors and identified the recommended phase II dosage (RP2D). Patients and Methods: LuMIERE is a prospective, open-label, nonrandomized, phase I/II, multicenter study. Phase I followed a Bayesian optimal interval design evaluating four escalating activity levels of 177Lu-FAP-2286 (3.70, 5.55, 7.40, and 9.25 GBq). Patients were selected by positive [68Ga]Ga-FAP-2286 (68Ga-FAP-2286, also known as [68Ga]Ga-HKG301) PET/CT imaging on all target lesions [maximum standardized uptake value (SUVmax) ≥1.5× SUVmean of mediastinal blood pool]. 177Lu-FAP-2286 was administered intravenously every 6 weeks for ≤6 cycles. The primary endpoint was dosage-limiting toxicities (DLT) and treatment-emergent adverse events (TEAE). Results: Of 35 patients imaged with 68Ga-FAP-2286, 27 received 177Lu-FAP-2286 (3.70 GBq, n = 3; 5.55 GBq, n = 6; 7.40 GBq, n = 7; 9.25 GBq, n = 11). Two DLTs were observed: one patient who received 5.55 GBq of 177Lu-FAP-2286 experienced grade 4 lymphopenia, and one patient who received 9.25 GBq experienced grade 3 hemoptysis; these were the only treatment-related grade ≥3 TEAEs. All-cause grade ≥3 TEAEs were reported for 11 patients (40.7%). The RP2D for 177Lu-FAP-2286 monotherapy was determined to be 9.25 GBq. Preliminary Response Evaluation Criteria in Solid Tumors efficacy findings demonstrated a partial response in 1 patient and stable disease in 10 patients (maintained for at least two assessments in 6 patients). Conclusions: 177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.

TPS611 Background: GPC3 is an oncofetal protein expressed in up to 75% of hepatocellular carcinomas (HCCs) and associated with poor prognosis. Its selective expression in tumor and not in normal tissue makes it a promising target for radiopharmaceutical imaging and therapy (theranostics). The GPC3-selective diagnostic RYZ811 ([ 68 Ga]Ga-RAYZ-8009) and therapeutic α particle-emitting RYZ801 ([ 225 Ac]Ac-RAYZ-8009) are a theranostic pair. Previous studies show high uptake of RYZ811 in intrahepatic and extrahepatic HCCs, with low normal liver background uptake. In GPC3+ HCC mouse models, single administrations of RYZ801 significantly inhibited tumor growth. Methods: RYZ801-101 is a single-arm, open-label, phase 1/1b study of RYZ811 and RYZ801 in previously treated patients with GPC3+ unresectable HCC. The study has two parts: dose escalation (part 1) and dose expansion (part 2). Each part consists of two stages: RYZ811 imaging and RYZ801 treatment. The aim of imaging is to determine if RYZ811 safely and adequately identifies patients with GPC3+ tumors. The aim of treatment is to determine the safety, pharmacokinetics (PK), recommended phase 2 dose (RP2D; part 1), and preliminary antitumor activity (part 2) of RYZ801. Key eligibility criteria are: confirmed HCC; Barcelona Clinic Liver Cancer stage B or C; Child-Pugh A; ≥1 RECIST v1.1-measurable lesion (treatment stage); and disease progression after ≥1 systemic therapy in part 1 and 1 prior line in part 2. In part 1, approximately 60 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 30 of these will receive escalating doses of RYZ801 (2.6–5.5 MBq × 4 doses) in the treatment stage. In part 2, approximately 80 patients will receive RYZ811 (185 MBq) in the imaging stage; up to 40 of these will receive RYZ801 at the RP2D in the treatment stage. Primary RYZ811 objectives are to assess the safety/tolerability and biodistribution of RYZ811. Secondary objectives are to determine absorbed doses (ADs) to organs and tissues and any association between RYZ811 uptake and RYZ801 efficacy. Primary RYZ801 objectives are to identify the RP2D and safety/tolerability of RYZ801. Secondary objectives are to assess PK, ADs to critical organs and tumors, and preliminary antitumor activity. Enrollment for Part 1 is ongoing in the USA. Clinical trial information: NCT06726161 .

Abstract Background PET visual reads for multi‐center studies are conducted centrally by one or a few experts. In CLARiTI, a broader network of raters will perform the reads, necessitating methods to ensure their accuracy and reliability. Method All ADRC sites ( N = 37) will prospectively acquire amyloid PET scans for 800 cognitively unimpaired and 1200 cognitively impaired participants. Each site can use one of four amyloid PET tracers ([ 18 F]florbetaben, [ 18 F]florbetapir, [ 11 C]PIB, [ 18 F]NAV4694). PET scans will be visually interpreted by ten PET neuroimaging experts located across eight ADRCs, using their preferred hardware, software, and file format (DICOM, NIFTI). Calibration requires readers to perform blinded, independent visual interpretation of 180 amyloid PET scans (30 unique and 15 duplicate scans per tracer), previously read and selected by an expert (Table 1). An even mix of visually non‐elevated and elevated scans were selected, with quantitation spanning ‐26‐123 Centiloids (Figure 1), and 15% were visually borderline (similar proportion to ADNI4), with quantitation spanning 4‐48 Centiloids (mean 21). Kruskal‐Wallis H test showed no significant difference in the distribution of Centiloid values for scans in each tracer group, Χ 2 (3)=2.133, p = 0.545. Result Calibration scans were read by a second expert not serving in CLARiTI. There was 97% concordance and almost perfect agreement between readers (κ=0.932, p <0.001; Figure 2). Discordantly read scans were visually borderline elevated ( N = 2), borderline non‐elevated ( N = 1), and negative ( N = 1), with quantitation of 8‐21 Centiloids (mean 14). Intra‐rater reads were 98% concordant and had almost perfect agreement (κ=0.966, p <0.001). These findings hold promise for scaling‐up visual reads in CLARiTI, and we expect ≥80% concordance and substantial to almost perfect agreement (κ≥0.7) for inter/intra‐rater reliability. Conclusion Calibration is essential for accurate/reliable amyloid PET visual reads in large multi‐center studies with multiple raters. Through the calibration process, we will develop methods to improve the adjudication of borderline/challenging scans and formalize methods for visual reads of amyloid PET tracers that are investigational (i.e., [ 11 C]PIB, [ 18 F]NAV4694). Involving multiple raters across different sites, who use diverse hardware/software/file format combinations, will mirror the natural heterogeneity present in real‐world clinical practice. This calibration set can also serve as a standardized training tool for other studies incorporating amyloid PET visual reads.

Abstract Background PET visual reads for multi‐center studies are conducted centrally by one or a few experts. In CLARiTI, a broader network of raters will perform the reads, necessitating methods to ensure their accuracy and reliability. Method All ADRC sites ( N = 37) will prospectively acquire amyloid PET scans for 800 cognitively unimpaired and 1200 cognitively impaired participants. Each site can use one of four amyloid PET tracers ([ 18 F]florbetaben, [ 18 F]florbetapir, [ 11 C]PIB, [ 18 F]NAV4694). PET scans will be visually interpreted by ten PET neuroimaging experts located across eight ADRCs, using their preferred hardware, software, and file format (DICOM, NIFTI). Calibration requires readers to perform blinded, independent visual interpretation of 180 amyloid PET scans (30 unique and 15 duplicate scans per tracer), previously read and selected by an expert (Table 1). An even mix of visually non‐elevated and elevated scans were selected, with quantitation spanning ‐26‐123 Centiloids (Figure 1), and 15% were visually borderline (similar proportion to ADNI4), with quantitation spanning 4‐48 Centiloids (mean 21). Kruskal‐Wallis H test showed no significant difference in the distribution of Centiloid values for scans in each tracer group, Χ 2 (3)=2.133, p = 0.545. Result Calibration scans were read by a second expert not serving in CLARiTI. There was 97% concordance and almost perfect agreement between readers (κ=0.932, p <0.001; Figure 2). Discordantly read scans were visually borderline elevated ( N = 2), borderline non‐elevated ( N = 1), and negative ( N = 1), with quantitation of 8‐21 Centiloids (mean 14). Intra‐rater reads were 98% concordant and had almost perfect agreement (κ=0.966, p <0.001). These findings hold promise for scaling‐up visual reads in CLARiTI, and we expect ≥80% concordance and substantial to almost perfect agreement (κ≥0.7) for inter/intra‐rater reliability. Conclusion Calibration is essential for accurate/reliable amyloid PET visual reads in large multi‐center studies with multiple raters. Through the calibration process, we will develop methods to improve the adjudication of borderline/challenging scans and formalize methods for visual reads of amyloid PET tracers that are investigational (i.e., [ 11 C]PIB, [ 18 F]NAV4694). Involving multiple raters across different sites, who use diverse hardware/software/file format combinations, will mirror the natural heterogeneity present in real‐world clinical practice. This calibration set can also serve as a standardized training tool for other studies incorporating amyloid PET visual reads.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Abstract INTRODUCTION In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability. METHODS Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non‐elevated per tracer‐specific criteria. Inter‐ and intra‐rater agreement was assessed. RESULTS Inter‐rater agreement was substantial (Fleiss’ κ = 0.78), with full consensus on 69% of scans. Inter‐rater reliability was substantial to perfect across tracers (Fleiss’ κ = 0.70–0.87). Intra‐rater agreement was substantial to perfect (Cohen's κ = 0.79‐1). Scans with intermediate (10–40 Centiloid) quantitation had lower reader agreement. DISCUSSION A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies. Highlights Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10–40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

Abstract Background: Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs. Methods: CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309. Conclusion: The study is currently enrolling in the dose escalation part. Citation Format: Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.

Abstract Background: Fibroblast activation protein (FAP) is a membrane-bound protease that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers. With limited expression observed in normal tissues, FAP is a promising therapeutic and imaging target for delivery of radionuclides to cancer tissues. FAP-2286, a low-molecular-weight cyclic peptide that potently and selectively binds to FAP, is attached to a linker and tetraazacyclododecane tetraacetic acid (DOTA) cage that can be used to conjugate radionuclides such as lutetium-177 (177Lu) or gallium-68 (68Ga) for therapeutic or imaging applications, respectively. 177Lu-FAP-2286 has demonstrated antitumor activity in preclinical studies. The LuMIERE study (NCT04939610) is the first phase 1/2 clinical trial of an FAP-targeted radionuclide therapy evaluating 177Lu-FAP-2286 in patients with FAP-expressing solid tumors that are identified with the imaging agent 68Ga-FAP-2286. Methods: Eligible adult patients with advanced or metastatic solid tumors and measurable disease (per RECIST v1.1) will be selected for treatment with 177Lu-FAP-2286 on the basis of FAP expression using 68Ga-FAP-2286. In phase 1, tumors must be refractory to or have progressed following prior treatment, with no satisfactory alternative treatment options. Phase 1 includes dose escalation of 177Lu-FAP-2286, starting at 3.7 GBq to a maximum of 9.25 GBq. Patients may receive up to 6 cycles of 177Lu-FAP-2286 administered on day 1 of each 6-week cycle. Three to 12 patients will be treated at each dose level in the dose-escalation portion. Tolerability will be assessed across multiple doses for determination of a recommended phase 2 dose (RP2D), which may be further evaluated in a phase 1 dose-expansion portion. FDG-PET/CT scans will be collected prior to treatment, and patients will be imaged by planar and SPECT/CT scans at multiple time points to calculate organ and tumor dosimetry to determine absorbed radiation dose. Disease status will be assessed per RECIST v1.1 every 6 weeks. The primary objective of phase 1 is to evaluate the safety of 177Lu-FAP-2286 and determine the RP2D. Secondary objectives include the assessment of radiation dosimetry, pharmacokinetics, and preliminary efficacy of 177Lu-FAP-2286 and the evaluation of safety and tumor uptake of 68Ga-FAP-2286. Phase 2 will evaluate the efficacy, safety, and dosimetry of 177Lu-FAP-2286 in patients with select FAP-expressing solid tumors. Citation Format: Jonathan McConathy, Mallika Dhawan, Ajit H. Goenka, Emerson A. Lim, Yusuf Menda, Beth Chasen, Moh'd Khushman, Akiva Mintz, Yousef Zakharia, John J. Sunderland, Owen Bowles, Jim Xiao, Andrew D. Simmons, Kenton Wride, Aaron Enke, Thomas A. Hope. LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT251.