Jonathan McConathy

Purpose: Cell tracking with zirconium-89 PET has the potential for widespread clinical and research applications, including imaging infection and inflammation and tracking cell-based therapies. This prospective first-in-human clinical trial assessed the dosimetry and safety profile of [ ⁸⁹ Zr]Zr-oxine-labeled autologous leukocytes in healthy female participants. Methods: Four healthy adult female participants (ages 37–53) received 10.9 ± 2.9 MBq of [ ⁸⁹ Zr]Zr-oxine-labeled autologous leukocytes and underwent whole-body PET/CT imaging at five time points (0, 4, 24, 48, and 72 h). Regions of interest were automatically segmented on CT using a machine learning-based approach and manually refined. Time-integrated activity coefficients were calculated using Simpson’s rule, with physical decay assumed beyond the final time point. Mean absorbed-dose and effective-dose coefficients were estimated using OLINDA 2.1. Results: Administration was well-tolerated among all participants. The highest mean absorbed-dose coefficients (mGy/MBq) with standard deviation were observed in the spleen (3.52 ± 1.38), liver (2.1 ± 0.45), adrenals (1.62 ± 0.24), uterus (1.48 ± 0.98), and kidneys (1.36 ± 0.12). The mean effective-dose coefficient was 0.92 ± 0.06 mSv/MBq, numerically lower than the predicted value of 1.14 mSv/MBq based on the distribution of [ ¹¹¹ In]In-oxine-labeled leukocytes in adult females ( P = 0.006, one-sample t-test). The use of [ ⁸⁹ Zr]Zr-oxine-labeled leukocytes enabled the visualization of leukocyte distribution and temporal dynamics. Conclusion: This study demonstrates the safety and favorable dosimetry of [ ⁸⁹ Zr]Zr-oxine-labeled leukocytes in healthy humans. These results support the further use of this approach for imaging autologous leukocytes using PET in a range of clinical and research settings. Trial registration: ClinicalTrials.gov NCT03807973. Registered January 16, 2019.

Table 2 from Targeting Fibroblast Activation Protein with [177Lu]Lu-FAP-2286 in Patients with Advanced Solid Tumors in the Phase I LuMIERE Trial

TEAEs occurring in ≥3 patients (all grades) or ≥1 patient (grade ≥3; 177Lu-FAP-2286 safety set, N = 27).

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.

Figure 2 from Targeting Fibroblast Activation Protein with [177Lu]Lu-FAP-2286 in Patients with Advanced Solid Tumors in the Phase I LuMIERE Trial

Theranostic workflow. *, FDG-PET/CT imaging was only performed for participants enrolled in phase I and could have been performed at any time during screening prior to cycle 1 day 1. This scan did not need to be repeated if the images were available from an FDG-PET/CT scan used for baseline disease assessments required for screening; †, participants who did not have FAP-positive tumors and/or did not meet entry criteria for adequate organ function discontinued the study and did not proceed to the treatment phase of long-term follow-up but had safety assessments performed at the end-of-treatment visit; ‡, positive uptake was defined as all target lesions having ≥1.5× higher SUVmax compared with the SUVmean of the mediastinal blood pool that was not attributable to other etiologies of tracer distribution; §, the end-of-treatment visit occurred 6 to 8 weeks after the last dose of 177Lu-FAP-2286 or within 1 week after the decision to discontinue treatment for any reason other than participant withdrawal of consent from the study or death, including withdrawal of consent for treatment, withholding the last dose of 177Lu-FAP-2286, or not being eligible for continuation to 177Lu-FAP-2286 therapy following administration of 68Ga-FAP-2286; ¶, Safety assessments were performed until death or loss to follow-up. Disease assessments were performed until radiographic disease progression as assessed by the investigator, death, loss to follow-up, withdrawal from the study, study closure, or initiation of subsequent anticancer treatments. ECOG, Eastern Cooperative Oncology Group.

Figure S1. Clinical laboratory measurements over time by activity level.

Figure S2. RECIST assessments over time (change from baseline in target lesions sum of diameters) by activity level and cancer type.