[89Zr]ZrCl4 for direct radiolabeling of DOTA-based precursors.

INTRODUCTION: Zirconium-89 (89Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of 89Zr in the nuclear medicine community has been tepid. The driving factor for the absence of broader adaptation is mostly routed in its final formulation - [89Zr]zirconium oxalate. While serving as a suitable precursor solution for the gold standard chelator deferoxamine (DFO), [89Zr]Zr-oxalate is inaccessible for the most commonly used chelators, such as the macrocyclic DOTA, due to its pre-chelated state. Consequently, pioneering work has been conducted by multiple research groups to create oxalate-free forms of [89Zr]Zr4+, either via chemical conversion of oxalate into other counterion forms or via direct radiochemical isolation of [89Zr]ZrCl4, showing that [89Zr]Zr-DOTA complexes are possible and stable. However, this success was accompanied by challenges, including complex and labor-intensive radiochemical processing and radiolabeling procedures as well as the relatively minuscule conversion rates. Here, we report on the direct production of [89Zr]ZrCl4 avoiding oxalate and metal contaminants to enable efficient radiolabeling of DOTA constructs. METHODS: We based our direct production of [89Zr]ZrCl4 on previously reported methods and further optimized its quality by including an additional iron-removing step using the TK400 Resin. Here, we avoided using oxalic acid and effectively minimized the content of trace metal contaminants. Our two-step purification procedure was automated, and we confirmed excellent radionuclide purity, minimal trace metals content, great reactivity over time, and high specific molar activity. In addition, DOTA-based PSMA-617 and DOTAGA-based PSMA-I&T were radiolabeled to demonstrate the feasibility of direct radiolabeling and to estimate the maximum apparent specific activities. Lastly, the biodistribution of [89Zr]Zr-PSMA-617 was assessed in mice bearing PC3-PIP xenografts, and the results were compared to the previously published data. RESULTS: A total of 18 batches, ranging from 6.9 to 20 GBq (186 to 541 mCi), were produced. The specific molar activity for [89Zr]ZrCl4 exceeded 0.96 GBq (26 mCi) per nanomole of zirconium. The radionuclidic purity was >99 %, and the trace metals content was in the <1 ppm range. The [89Zr]ZrCl4 remained in its reactive chemical form for at least five days when stored in cyclic olefin polymer (COP) vials. Batches of 11.1 GBq (300 mCi) of [89Zr]Zr-PSMA-617 and 14.4 GBq (390 mCi) of [89Zr]Zr-PSMA-I&T, corresponding to specific activities of 11.1 MBq/µg (0.3 mCi/µg), and 14.4 MBq/µg (0.39 mCi/µg), respectively, were produced. [89Zr]Zr-PSMA-617 animal PET imaging results were in agreement with the previously published data. CONCLUSION: In this work, we report on a suitable application of TK400 Resin to remove iron during [89Zr]ZrCl4 radiochemical isolation. The breakthrough allows for direct radiolabeling of DOTA-based constructs with [89Zr]ZrCl4, leading to high apparent molar activities and excellent conversion rates.

Nuclear-Based Labeling of Cellular Immunotherapies: A Simple Protocol for Preclinical Use.

Labeling and tracking existing and emerging cell-based immunotherapies using nuclear imaging is widely used to guide the preclinical phases of development and testing of existing and new emerging off-the-shelf cell-based immunotherapies. In fact, advancing our knowledge about their mechanism of action and limitations could provide preclinical support and justification for moving towards clinical experimentation of newly generated products and expedite their approval by the Food and Drug Administration (FDA).Here we provide the reader with a ready to use protocol describing the labeling methodologies and practical procedures to render different candidate cell therapies in vivo traceable by nuclear-based imaging. The protocol includes sufficient practical details to aid researchers at all career stages and from different fields in familiarizing with the described concepts and incorporating them into their work.

Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

18F-BMS-986229 PET to Assess Programmed-Death Ligand 1 Status in Gastroesophageal Cancer.

Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18F-BMS-986229 accumulation on PET imaging also had lesions without 18F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression.

First-in-Human Evaluation of Site-Specifically Labeled 89Zr-Pertuzumab in Patients with HER2-Positive Breast Cancer.

Radioimmunoconjugates targeting human epidermal growth factor receptor 2 (HER2) have shown potential to noninvasively visualize HER2-positive tumors. However, the stochastic approach that has been traditionally used to radiolabel these antibodies yields poorly defined and heterogeneous products with suboptimal in vivo performance. Here, we describe a first-in-human PET study on patients with HER2-positive breast cancer evaluating the safety, biodistribution, and dosimetry of 89Zr-site-specific (ss)-pertuzumab PET, a site-specifically labeled radioimmunoconjugate designed to circumvent the limitations of random stochastic lysine labeling. Methods: Six patients with HER2-positive metastatic breast cancer were enrolled in a prospective clinical trial. Pertuzumab was site-specifically modified with desferrioxamine (DFO) via a novel chemoenzymatic strategy and subsequently labeled with 89Zr. Patients were administered 74 MBq of 89Zr-ss-pertuzumab in 20 mg of total antibody intravenously and underwent PET/CT at 1 d, 3-4 d, and 5-8 d after injection. PET imaging, whole-body probe counts, and blood draws were performed to assess the pharmacokinetics, biodistribution, and dosimetry. Results: 89Zr-ss-pertuzumab PET/CT was used to assess HER2 status and heterogeneity to guide biopsy and decide the next line of treatment at progression. The radioimmunoconjugate was able to detect known sites of malignancy, suggesting that these tumor lesions were HER2-positive. The optimal imaging time point was 5-8 d after administration, and no toxicities were observed. Dosimetry estimates from OLINDA showed that the organs receiving the highest doses (mean ± SD) were kidney (1.8 ± 0.5 mGy/MBq), liver (1.7 ± 0.3 mGy/MBq), and heart wall (1.2 ± 0.1 mGy/MBq). The average effective dose for 89Zr-ss-pertuzumab was 0.54 ± 0.03 mSv/MBq, which was comparable to both stochastically lysine-labeled 89Zr-DFO-pertuzumab and 89Zr-DFO-trastuzumab. One patient underwent PET/CT with both 89Zr-ss-pertuzumab and 89Zr-DFO-pertuzumab 1 mo apart, with 89Zr-ss-pertuzumab demonstrating improved lesion detection and higher tracer avidity. Conclusion: This study demonstrated the safety, dosimetry, and potential clinical applications of 89Zr-ss-pertuzumab PET/CT. 89Zr-ss-pertuzumab may detect more lesions than 89Zr-DFO-pertuzumab. Potential clinical applications include real-time evaluation of HER2 status to guide biopsy and assist in treatment decisions.

First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response. Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16). Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted. Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies. Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.

Methods for the Production of Radiolabeled Bioagents for ImmunoPET.

Immunoglobulin-based positron emission tomography (ImmunoPET) is making increasingly significant contributions to the nuclear imaging toolbox. The exquisite specificity of antibodies combined with the high-resolution imaging of PET enables clinicians and researchers to localize diseases, especially cancer, with a high degree of spatial certainty. This review focuses on the radiopharmaceutical preparation necessary to obtain those images-the work behind the scenes, which occurs even before the patient or animal is injected with the radioimmunoconjugate. The focus of this methods review will be the chelation of four radioisotopes to their most common and clinically relevant chelators.

Noninvasive Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) in Esophagogastric Cancer Using 89Zr-Trastuzumab PET: A Pilot Study.

Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). 89Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, 18F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with 18F-FDG PET. More lesions were identified on 18F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on 18F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on 18F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered (n = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo (n = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion (n = 6) (P = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies.

Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals.

BACKGROUND: The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products. MAIN BODY: To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as "non-clinical" or "preclinical" are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed. CONCLUSION: This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way.

B7H3-Directed Intraperitoneal Radioimmunotherapy With Radioiodinated Omburtamab for Desmoplastic Small Round Cell Tumor and Other Peritoneal Tumors: Results of a Phase I Study.

PURPOSE: Desmoplastic small round cell tumor (DSRCT), a rare sarcoma of adolescents/young adults primarily involving the peritoneum, has a long-term survival of < 20% despite aggressive multimodality treatment. B7H3 is expressed on DSRCT cell surface, providing a target for antibody-based immunotherapy. PATIENTS AND METHODS: In this phase I study, we evaluated the safety, pharmacokinetics, and biodistribution of intraperitoneal (IP) radioimmunotherapy (RIT) with the anti-B7H3 murine monoclonal antibody 131I-omburtamab in patients with DSRCT or other B7H3-expressing tumors involving the peritoneum. After thyroid blockade, patients received 131I-omburtamab as a single IP injection at escalated activities from 1.11 to 3.33/GBq/m2. A prior tracer dose of IP 74 MBq124I-omburtamab was used for radioimmuno-positron emission tomography imaging. Each injection was followed by IP saline infusion. RESULTS: Fifty-two patients (48, three, and one with DSRCT, peritoneal rhabdomyosarcoma, and Ewing sarcoma, respectively) received IP 131I-omburtamab administered on an outpatient basis. Maximum tolerated dose was not reached; there were no dose-limiting toxicities. Major related adverse events were transient: grade 4 neutropenia (n = 2 patients) and thrombocytopenia (n = 1), and grade 1 (10%) and grade 2 (52%) pain lasting < 2 hours related to saline infusion. Hypothyroidism was not observed, and antidrug antibody was elicited in 5%. Mean (± SD) projected peritoneal residence time was 22.4 ± 7.9 hours. Mean projected absorbed doses for 131I-omburtamab based on 124I-omburtamab dosimetry to normal organs were low and well within tolerable limits. More than 80% 131I remained protein bound in blood 66 hours after RIT. On the basis of peritoneal dose and feasibility for outpatient administration, the recommended phase II activity was established at 2.96 GBq/m2. Patients with DSRCT receiving standard whole-abdominal radiotherapy after RIT did not experience unexpected toxicity. CONCLUSION: IP RIT 131I-omburtamab was well tolerated with minimal toxicities. Radiation exposure to normal organs was low, making combination therapy with other anticancer therapies feasible.

Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CT.

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies are successful in patients with HER2-positive malignancies; however, spatial and temporal heterogeneity of HER2 expression may prevent identification of optimal patients for these therapies. Purpose To determine whether imaging with the HER2-targeted PET tracer zirconium 89 (89Zr)-pertuzumab can depict HER2-positive metastases in women with HER2-negative primary breast cancer. Materials and Methods From January to June 2019, women with biopsy-proven HER2-negative primary breast cancer and biopsy-proven metastatic disease were enrolled in a prospective clinical trial (ClinicalTrials.gov NCT02286843) and underwent 89Zr-pertuzumab PET/CT for noninvasive whole-biopsy evaluation of potential HER2-positive metastases. 89Zr-pertuzumab-avid foci that were suspicious for HER2-positive metastases were tissue sampled and examined by pathologic analysis to document HER2 status. Results Twenty-four women (mean age, 55 years ± 11 [standard deviation]) with HER2-negative primary breast cancer were enrolled. Six women demonstrated foci at 89Zr-pertuzumab PET/CT that were suspicious for HER2-positive disease. Of these six women, three had biopsy-proven HER2-positive metastases, two had pathologic findings that demonstrated HER2-negative disease, and one had a fine-needle aspirate with inconclusive results. Conclusion Human epidermal growth factor receptor 2 (HER2)-targeted imaging with zirconium 89-pertuzumab PET/CT was successful in detecting HER2-positive metastases in women with HER2-negative primary breast cancer. This demonstrates the ability of targeted imaging to identify patients for targeted therapies that might not otherwise be considered. © RSNA, 2020 Online supplemental material is available for this article. See the editorial by Mankoff and Pantel in this issue.

First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.

PURPOSE: 124I-PU-H71 is an investigational first-in-class radiologic agent specific for imaging tumor epichaperome formations. The intracellular epichaperome forms under cellular stress and is a clinically validated oncotherapeutic target. We conducted a first-in-human study of microdose 124I-PU-H71 for PET to study in vivo biodistribution, pharmacokinetics, metabolism, and safety; and the feasibility of epichaperome-targeted tumor imaging. EXPERIMENTAL DESIGN: Adult patients with cancer (n = 30) received 124I-PU-H71 tracer (201±12 MBq, <25 µg) intravenous bolus followed by PET/CT scans and blood radioassays. RESULTS: 124I-PU-H71 PET detected tumors of different cancer types (breast, lymphoma, neuroblastoma, genitourinary, gynecologic, sarcoma, and pancreas). 124I-PU-H71 was retained by tumors for several days while it cleared rapidly from bones, healthy soft tissues, and blood. Radiation dosimetry is favorable and patients suffered no adverse effects. CONCLUSIONS: Our first-in-human results demonstrate the safety and feasibility of noninvasive in vivo detection of tumor epichaperomes using 124I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.

Comparison of 68Ga-DOTA-JR11 PET/CT with dosimetric 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy.

PURPOSE: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) in patients with NETs. METHODS: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68Ga-DOTA-JR11 PET/CT and serial imaging with 177Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation. RESULTS: A total of 95 lesions were analyzed on 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177Lu-satoreotide tetraxetan vs. 68Ga-DOTA-JR11 was high; even in those with low uptake on 68Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of 68Ga-DOTA-JR11 with projected 177Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of 177Lu-satoreotide tetraxetan with projected 177Lu-satoreotide tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001). CONCLUSION: Our study shows that 68Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with 177Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging.

Background Current measurements of multiple myeloma disease burden are suboptimal. Daratumumab is a monoclonal antibody that targets CD38, an antigen expressed on nearly all myeloma cells. Purpose To demonstrate preclinical and first-in-human application of an antibody composed of the native daratumumab labeled with the positron-emitting radionuclide zirconium 89 (89Zr) through the chelator deferoxamine (DFO), or 89Zr-DFO-daratumumab, for immunologic PET imaging of multiple myeloma. Materials and Methods 89Zr-DFO-daratumumab was synthesized by conjugating 89Zr to daratumumab with DFO. A murine xenograft model using CD38-positive OPM2 multiple myeloma cells was used to evaluate CD38-specificity of 89Zr-DFO-daratumumab. Following successful preclinical imaging, a prospective phase I study of 10 patients with multiple myeloma was performed. Study participants received 74 MBq (2 mCi) of intravenous 89Zr-DFO-daratumumab. Each participant underwent four PET/CT scans over the next 8 days, as well as blood chemistry and whole-body counts, to determine safety, tracer biodistribution, pharmacokinetics, and radiation dosimetry. Because 89Zr has a half-life of 78 hours, only a single administration of tracer was needed to obtain all four PET/CT scans. Results 89Zr-DFO-daratumumab was synthesized with radiochemical purity greater than 99%. In the murine model, substantial bone marrow uptake was seen in OPM2 mice but not in healthy mice, consistent with CD38-targeted imaging of OPM2 multiple myeloma cells. In humans, 89Zr-DFO-daratumumab was safe and demonstrated acceptable dosimetry. 89Zr-DFO-daratumumab uptake was visualized at PET in sites of osseous myeloma. Conclusion These data demonstrate successful CD38-targeted immunologic PET imaging of multiple myeloma in a murine model and in humans. © RSNA, 2020 Online supplemental material is available for this article.

Safety and Feasibility of PARP1/2 Imaging with 18F-PARPi in Patients with Head and Neck Cancer.

PURPOSE: We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. PATIENTS AND METHODS: Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq), and dynamic PET/CT imaging was performed between 0 and 25 minutes postinjection. Static PET/CT scans were obtained at 30, 60, and 120 minutes postinjection. Blood samples for tracer concentration and metabolite analysis were collected. Blood pressure, ECG, oxygen levels, clinical chemistry, and complete blood count were obtained before and after tracer administration. RESULTS: 18F-PARPi was well-tolerated by all patients without any safety concerns. Of the 11 patients included in the analysis, 18F-PARPi had focal uptake in all primary lesions (n = 10, SUVmax = 2.8 ± 1.2) and all 18F-FDG-positive lymph nodes (n = 34). 18F-PARPi uptake was seen in 18F-FDG-negative lymph nodes of 3 patients (n = 6). Focal uptake of tracer in primary and metastatic lesions was corroborated by CT alone or in combination with 18F-FDG. The overall effective dose with 18F-PARPi PET was 3.9 mSv - 5.2 mSv, contrast was high [SUVmax(lesion)/SUVmax(trapezius muscle) = 4.5] and less variable than 18F-FDG when compared with the genioglossus muscle (1.3 vs. 6.0, P = 0.001). CONCLUSIONS: Imaging of head and neck cancer with 18F-PARPi is feasible and safe. 18F-PARPi detects primary and metastatic lesions, and retention in tumors is longer than in healthy tissues.

First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.

We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

Preclinical and first-in-human-brain-cancer applications of [18F]poly (ADP-ribose) polymerase inhibitor PET/MR.

BACKGROUND: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [18F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes. METHODS: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [18F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [18F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry. RESULTS: In a preclinical mouse model, we illustrated that [18F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [18F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen. CONCLUSIONS: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [18F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

Hyperpolarized MRI of Human Prostate Cancer Reveals Increased Lactate with Tumor Grade Driven by Monocarboxylate Transporter 1.

Metabolic imaging using hyperpolarized magnetic resonance can increase the sensitivity of MRI, though its ability to inform on relevant changes to biochemistry in humans remains unclear. In this work, we image pyruvate metabolism in patients, assessing the reproducibility of delivery and conversion in the setting of primary prostate cancer. We show that the time to max of pyruvate does not vary significantly within patients undergoing two separate injections or across patients. Furthermore, we show that lactate increases with Gleason grade. RNA sequencing data demonstrate a significant increase in the predominant pyruvate uptake transporter, monocarboxylate transporter 1. Increased protein expression was also observed in regions of high lactate signal, implicating it as the driver of lactate signal in vivo. Targeted DNA sequencing for actionable mutations revealed the highest lactate occurred in patients with PTEN loss. This work identifies a potential link between actionable genomic alterations and metabolic information derived from hyperpolarized pyruvate MRI.