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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.
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ADP-Ribosil Ciclasa 1 , Neoplasias Óseas/diagnóstico por imagen , Modelos Animales de Enfermedad , Glicoproteínas de Membrana , Mieloma Múltiple/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Animales , Anticuerpos Monoclonales , Deferoxamina , Xenoinjertos , Humanos , Estudios Prospectivos , Sensibilidad y Especificidad , Carga Tumoral , CirconioRESUMEN
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.
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Tumores Neuroendocrinos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo , Humanos , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapia , Octreótido/uso terapéutico , Estudios Prospectivos , Receptores de PéptidosRESUMEN
PURPOSE: Somatostatin receptor antagonists have shown promise for imaging neuroendocrine tumors (NETs) in preclinical studies, but clinical data is still very limited. In this study, we assess the feasibility of using the novel somatostatin antagonist 68Ga-DOTA-JR11 for PET imaging of NETs. METHODS: Twenty patients with advanced NETs underwent whole-body PET/CT imaging 60 min after injection of 169 MBq (median) 68Ga-DOTA-JR11 as part of a prospective study. Volumes of interest were drawn around up to four 68Ga-DOTA-JR11-avid lesions per patient (with uptake greater than liver) and standardized uptake values were estimated. Additionally, target-to-normal tissue ratios were calculated. A subset of six patients had additional imaging (25-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney, and a whole-body PET/CT scan at 30 min post-injection) to determine the time course of tracer distribution and facilitate radiation dose estimates. Absorbed doses were calculated using OLINDA/EXM 1.0. RESULTS: In contrast to the known biodistribution of somatostatin receptor agonists, little or no uptake above background was seen in the pituitary gland, spleen, adrenals, and uninvolved liver; e.g., median spleen SUVmean 1.4 (range: 0.7-1.8), liver SUVmean 1.1 (0.7-1.9). A total of 42 tumor lesions were analyzed with median SUVmax 13.0 (range: 2.9-94), TNR blood 9.3 (1.8-87), TNR spleen 4.9 (1.9-48), TNR kidney 2.2 (0.52-28), and TNR liver 10.5 (2.3-107). Tumor uptake reached plateau levels by 20-30 min post-injection. The highest absorbed dose estimates (mGy/MBq) to normal tissues were: urinary bladder wall (0.30; SD 0.06) and kidneys (0.050; SD 0.013). The effective dose (ICRP 103) was 0.022 (SD 0.003) mSv/MBq. CONCLUSIONS: 68Ga-DOTA-JR11 demonstrated rapid tumor uptake, high tumor/background ratios, and rapid clearance from blood. The low liver background is advantageous and may facilitate detection of liver metastases. Dosimetric data compare favorably with published data for 68Ga-DOTATATE and 68Ga-DOTATOC.
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Radioisótopos de Galio/farmacocinética , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Dosis de Radiación , Adulto , Anciano , Estudios de Factibilidad , Femenino , Radioisótopos de Galio/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroendocrinos/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/efectos adversos , Radiometría , Seguridad , Distribución Tisular , Adulto JovenRESUMEN
A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of â¼185 MBq and 10 mg of [89Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T1/2 ß of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T1/2 for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Antígenos de Neoplasias/inmunología , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Oxidorreductasas/inmunología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Radioisótopos/farmacocinética , Radiofármacos/farmacocinética , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/secundario , Circonio/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Reacciones Cruzadas/inmunología , Humanos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/metabolismo , Inmunoglobulina G/uso terapéutico , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radioisótopos/administración & dosificación , Radiofármacos/administración & dosificación , Distribución Tisular , Circonio/administración & dosificaciónRESUMEN
BACKGROUND: The current study aims to assess the safety, pharmacokinetics, feasibility, and reproducibility of immunoPET imaging with copper-64 (64Cu) trastuzumab. METHODS: An IV injection of 296-370 MBq/5 mg 64Cu-trastuzumab was administered between 1 to 4 hours after routine trastuzumab treatment. Whole-body PET scans were performed immediately post-injection and at 24 hours post-injection. Serial pharmacokinetics were performed. Of 11 patients (median age of 52; range of 31-61), 8 underwent a repeat study with 64Cu-trastuzumab to assess image and pharmacokinetic reproducibility. Patients were monitored for toxicity. RESULTS: Patients experienced no allergic reactions or significant adverse effects from 64Cu-trastuzumab. Eight patients successfully completed a repeat 64Cu-trastuzumab study, with acceptable reproducibility of both the biodistribution and pharmacokinetic clearance. Study 1 versus study 2 showed similar serum concentration post-injection (mean 42.4±7.8 %ID/L vs. 44.7±12.6 %ID/L) and similar T1/2 (single exponential 46.1 vs. 44.2 hours), P>0.5. The volume of distribution (median 2.50 L) was in the range reported for trastuzumab and close to the estimated plasma volume of 2.60 L. Of 11 patients, two had 64Cu-trastuzumab localization corresponding to known tumor sites - one in liver and one in breast. CONCLUSIONS: Preliminary results suggest that scanning with 64Cu-trastuzumab is feasible, safe, and reproducible. Tumor uptake of 64Cu-trastuzumab was observed, but tumor detection exhibited low sensitivity in this study in which imaging was performed in the presence of trastuzumab therapy.
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Neoplasias de la Mama/diagnóstico por imagen , Radioisótopos de Cobre , Tomografía de Emisión de Positrones/métodos , Trastuzumab , Adulto , Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Reproducibilidad de los Resultados , Distribución Tisular , Trastuzumab/farmacocinéticaRESUMEN
PURPOSE: There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of 18F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC. EXPERIMENTAL DESIGN: Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0-30 min dynamic acquisition, followed by 10 min static acquisitions starting at â¼95 min and â¼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k 3 and Tumor-to-Blood Ratio (TBR)), perfusion (K 1 ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia. RESULTS: One hundred and thirty-five lesions in total were analyzed. TBR, k 3 and DV decreased on early response scans, while no significant change was observed for K 1 . The k 3 -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k 3 and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k 3 indicated the presence of hypoxia. CONCLUSION: Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.
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Quimioradioterapia , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/terapia , Misonidazol/análogos & derivados , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Misonidazol/farmacocinética , Factores de Tiempo , Distribución Tisular , Resultado del TratamientoRESUMEN
PURPOSE: The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the "best-fit" parameters and model-derived quantities for optimizing biodistribution of intravenously injected (124)I-labeled antitumor antibodies. METHODS: As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as "A33") were performed in 11 colorectal cancer patients. Serial whole-body PET scans of (124)I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code. RESULTS: Excellent agreement was observed between fitted and measured parameters of tumor uptake, "off-target" uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy. CONCLUSION: This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting "best-fit" nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Biológicos , Terapia Molecular Dirigida , Tomografía de Emisión de Positrones , Medicina de Precisión , Animales , Anticuerpos Monoclonales/metabolismo , Neoplasias Colorrectales/patología , Humanos , Radioisótopos de Yodo , Cinética , RatonesRESUMEN
PURPOSE: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. METHODS: Ten patients with metastatic prostate cancer received 5 mCi of (89)Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by (89)Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of (89)Zr-huJ591 was done. Optimal time for imaging post-injection was determined. RESULTS: The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of (89)Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5 h (range 1.1-14 h) and 62 ± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5 cGy/mCi, renal cortex 3.5 ± 0.4 cGy/mCi, and bone marrow 1.2 ± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on (89)Zr-huJ591, while the remaining 11 lesions were (89)Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on (89)Zr-huJ591 study, while the conventional imaging modality was negative. CONCLUSION: (89)Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 ± 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer.
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Anticuerpos Monoclonales , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Radioisótopos , Circonio , Anciano , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Dosis de RadiaciónRESUMEN
Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an 111In-radiolabeled anti-hK2 monoclonal antibody, [111In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [111In]-DOTA-h11B6 (185 MBq of 111In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [111In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [111In]-DOTA-h11B6 administration. Results: Twenty-two participants received [111In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [111In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.
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Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Distribución Tisular , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Calicreínas de Tejido/antagonistas & inhibidores , Radioisótopos de Indio , Marcaje Isotópico , Compuestos Heterocíclicos con 1 Anillo/química , Radiofármacos/farmacocinética , Radiofármacos/uso terapéuticoRESUMEN
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.
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Neoplasias de la Mama , Inmunoconjugados , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Lisina , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Distribución Tisular , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoconjugados/uso terapéuticoRESUMEN
PURPOSE: ²²³Ra-Dichloride (²²³Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. METHODS: Ten patients received either 50, 100, or 200 kBq of ²²³Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed. RESULTS: Pharmacokinetic studies showed rapid clearance of ²²³Ra from the vasculature, with a median of 14% (range 9-34%), 2% (range 1.6-3.9%), and 0.5% (range 0.4-1.0%) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52% of administered ²²³Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4% of administered ²²³Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. CONCLUSION: ²²³Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.
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Antineoplásicos/farmacocinética , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Relación Dosis-Respuesta en la Radiación , Determinación de Punto Final , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos/efectos adversos , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radiofármacos/efectos adversos , Radiofármacos/uso terapéutico , Radio (Elemento)/efectos adversos , Radio (Elemento)/uso terapéutico , Distribución TisularRESUMEN
PURPOSE: 131I-MIP-1095 is a targeted radiotherapeutic that contains 131I, a ß-particle emitter, and MIP-1095, a urea-based ligand for prostate-specific membrane antigen. We report the first phase 1, dose-escalation study of 131I-MIP-1095 in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study enrolled men with mCRPC refractory to second-generation antiandrogen(s) and taxane chemotherapy. Dosimetry/biodistribution assessments were performed. Safety and tolerability were determined in subjects who qualified for therapeutic administration of 131I-MIP-1095 with maximum tolerated activity examined in a dose-ascending manner (3 + 3 design methodology). Disease outcomes including prostate-specific antigen (PSA) change, tumor response, survival, and circulating tumor cell concentration were assessed. RESULTS: A total of 9 subjects with mCRPC were included in this study. On the basis of dosimetry results, 5 of 9 patients were treated: 3 in cohort 1 (50 mCi) and 2 in cohort 2 (75 mCi). Accrual stopped at the cohort 2 activity level in response to the US Food and Drug Administration mandate for 131I-MIP-1095 manufacturing concerns. Parotid/salivary glands (3.5 Gy/Bq), liver (2.2 Gy/Bq), kidneys (1.3 Gy/Bq), and spleen (0.7 Gy/Bq) demonstrated the greatest extent of 131I-MIP-1095 exposure. There were no deaths, serious adverse events, or drug discontinuations due to treatment-emergent adverse events. Grade 1-2 thrombocytopenia, anemia, leukopenia, and dry mouth most commonly occurred. One subject (33.3%) exhibited maximum decline for the PSA response of 50% or greater. CONCLUSION: 131I-MIP-1095 demonstrated favorable dosimetry, biodistribution, and safety, as well as a modest PSA response supporting further investigation for treatment of men with mCRPC.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03030885, Registered January 25, 2017 (https://clinicaltrials.gov/ct2/show/NCT03030885).
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Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Antineoplásicos/efectos adversos , Radioisótopos de Yodo/efectos adversos , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radiofármacos/efectos adversos , Distribución Tisular , Resultado del TratamientoRESUMEN
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.
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Neoplasias de la Mama , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Femenino , Trastuzumab , Proyectos Piloto , Fluorodesoxiglucosa F18 , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Gástricas/metabolismo , Receptor ErbB-2/metabolismoRESUMEN
A single-institution prospective pilot clinical trial was performed to demonstrate the feasibility of combining [177Lu]Lu-PSMA-617 radiopharmaceutical therapy (RPT) with stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic castration-sensitive prostate cancer. Methods: Six patients with 9 prostate-specific membrane antigen (PSMA)-positive oligometastases received 2 cycles of [177Lu]Lu-PSMA-617 RPT followed by SBRT. After the first intravenous infusion of [177Lu]Lu-PSMA-617 (7.46 ± 0.15 GBq), patients underwent SPECT/CT at 3.2 ± 0.5, 23.9 ± 0.4, and 87.4 ± 12.0 h. Voxel-based dosimetry was performed with calibration factors (11.7 counts per second/MBq) and recovery coefficients derived from in-house phantom experiments. Lesions were segmented on baseline PSMA PET/CT (50% SUVmax). After a second cycle of [177Lu]Lu-PSMA-617 (44 ± 3 d; 7.50 ± 0.10 GBq) and an interim PSMA PET/CT scan, SBRT (27 Gy in 3 fractions) was delivered to all PSMA-avid oligometastatic sites, followed by post-PSMA PET/CT. RPT and SBRT voxelwise dose maps were scaled (α/ß = 3 Gy; repair half-time, 1.5 h) to calculate the biologically effective dose (BED). Results: All patients completed the combination therapy without complications. No grade 3+ toxicities were noted. The median of the lesion SUVmax as measured on PSMA PET was 16.8 (interquartile range [IQR], 11.6) (baseline), 6.2 (IQR, 2.7) (interim), and 2.9 (IQR, 1.4) (post). PET-derived lesion volumes were 0.4-1.7 cm3 The median lesion-absorbed dose (AD) from the first cycle of [177Lu]Lu-PSMA-617 RPT (ADRPT) was 27.7 Gy (range, 8.3-58.2 Gy; corresponding to 3.7 Gy/GBq, range, 1.1-7.7 Gy/GBq), whereas the median lesion AD from SBRT was 28.1 Gy (range, 26.7-28.8 Gy). Spearman rank correlation, ρ, was 0.90 between the baseline lesion PET SUVmax and SPECT SUVmax (P = 0.005), 0.74 (P = 0.046) between the baseline PET SUVmax and the lesion ADRPT, and -0.81 (P = 0.022) between the lesion ADRPT and the percent change in PET SUVmax (baseline to interim). The median for the lesion BED from RPT and SBRT was 159 Gy (range, 124-219 Gy). ρ between the BED from RPT and SBRT and the percent change in PET SUVmax (baseline to post) was -0.88 (P = 0.007). Two cycles of [177Lu]Lu-PSMA-617 RPT contributed approximately 40% to the maximum BED from RPT and SBRT. Conclusion: Lesional dosimetry in patients with oligometastatic castration-sensitive prostate cancer undergoing [177Lu]Lu-PSMA-617 RPT followed by SBRT is feasible. Combined RPT and SBRT may provide an efficient method to maximize the delivery of meaningful doses to oligometastatic disease while addressing potential microscopic disease reservoirs and limiting the dose exposure to normal tissues.
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Neoplasias de la Próstata Resistentes a la Castración , Radiocirugia , Masculino , Humanos , Radiofármacos/efectos adversos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/patología , Dipéptidos/uso terapéutico , Antígeno Prostático Específico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Castración , Lutecio/uso terapéuticoRESUMEN
PURPOSE: The aim of this study was to evaluate the use of a Bayesian penalized likelihood reconstruction algorithm (Q.Clear) for 89Zr-immunoPET image reconstruction and its potential to improve image quality and reduce the administered activity of 89Zr-immunoPET tracers. METHODS: Eight 89Zr-immunoPET whole-body PET/CT scans from three 89Zr-immunoPET clinical trials were selected for analysis. On average, patients were imaged 6.3 days (range 5.0-8.0 days) after administration of 69 MBq (range 65-76 MBq) of [89Zr]Zr-DFO-daratumumab, [89Zr]Zr-DFO-pertuzumab, or [89Zr]Zr-DFO-trastuzumab. List-mode PET data was retrospectively reconstructed using Q.Clear with incremental ß-values from 150 to 7200, as well as standard ordered-subset expectation maximization (OSEM) reconstruction (2-iterations, 16-subsets, a 6.4-mm Gaussian transaxial filter, "heavy" z-axis filtering and all manufacturers' corrections active). Reduced activities were simulated by discarding 50% and 75% of original counts in each list mode stream. All reconstructed PET images were scored for image quality and lesion detectability using a 5-point scale. SUVmax for normal liver and sites of disease and liver signal-to-noise ratio were measured. RESULTS: Q.Clear reconstructions with ß = 3600 provided the highest scores for image quality. Images reconstructed with ß-values of 3600 or 5200 using only 50% or 25% of the original counts provided comparable or better image quality scores than standard OSEM reconstruction images using 100% of counts. CONCLUSION: The Bayesian penalized likelihood reconstruction algorithm Q.Clear improved the quality of 89Zr-immunoPET images. This could be used in future studies to improve image quality and/or decrease the administered activity of 89Zr-immunoPET tracers.
RESUMEN
Theranostics is a precision medicine discipline that integrates diagnostic nuclear medicine imaging with radionuclide therapy in a manner that provides both a tumor phenotype and personalized therapy to patients with cancer using radiopharmaceuticals aimed at the same target-specific biological pathway or receptor. The aim of quantitative nuclear medicine imaging is to plan the alpha or beta-emitting therapy based on an accurate 3-dimensional representation of the in-vivo distribution of radioactivity concentration within the tumor and normal organs/tissues in a noninvasive manner. In general, imaging may be either based on positron emission tomography (PET) or single photon emission computed tomography (SPECT) invariably in combination with X-ray CT (PET/CT; SPECT/CT) or, to a much lesser extent, MRI. PET and SPECT differ in terms of the radionuclides and physical processes that give rise to the emission of high energy photons, as well as the sets of technologies involved in their detection. Using a variety of standardized quantitative parameters, system calibration, patient preparation, imaging acquisition and reconstruction protocols, and image analysis protocols, an accurate quantification of the tracer distribution can be obtained, which helps prescribe the therapeutic dose for each patient.
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Medicina Nuclear , Medicina de Precisión , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Radiofármacos/uso terapéutico , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
PURPOSE: Previous studies have shown that tumors less than 1 mm diameter derived from HT29 colorectal cancer cells are extremely hypoxic when grown intraperitoneally or intradermally in nude mice, whereas those of greater size (approximately 1-4 mm diameter) are not significantly hypoxic. The object of this study was to determine if digital autoradiography using the radiolabeled hypoxia imaging tracer iodo-azomycin galactopyranoside ((131)I-IAZGP) could detect hypoxia in this model. METHODS: Microscopic HT29 tumors were grown as disseminated peritoneal disease and intradermally in nude mice. Tumors ranged in size from a few hundred microns to several millimeters in diameter. Animals were intravenously administered (131)I-IAZGP and pimonidazole 2 h before sacrifice. Following sacrifice, the intratumoral distribution of (131)I-IAZGP was assessed by digital autoradiography and compared with immunofluorescence microscopic images of pimonidazole binding and carbonic anhydrase IX (CAIX) expression. RESULTS: The distributions of (131)I-IAZGP, pimonidazole, and CAIX expression were similar. Tumors less than 1 mm diameter displayed high (131)I-IAZGP uptake; these tumors also stained strongly for pimonidazole and CAIX. Larger tumors (approximately 1-4 mm diameter) were not significantly hypoxic and had low (131)I-IAZGP accumulation. CONCLUSION: (131)I-IAZGP can detect hypoxia in microscopic tumors. Microscopic tumors are useful models for the validation of hypoxia radiotracers, and digital autoradiography is an appropriate technique for studying the distribution of hypoxia radiotracers in microscopic tumors.
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Galactósidos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Nitroimidazoles , Intensificación de Imagen Radiográfica , Animales , Antígenos de Neoplasias/metabolismo , Autorradiografía , Transporte Biológico , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/metabolismo , Hipoxia de la Célula , Línea Celular Tumoral , Femenino , Galactósidos/metabolismo , Humanos , Inmunohistoquímica , Ratones , Neoplasias/metabolismo , Nitroimidazoles/metabolismo , Trazadores RadiactivosRESUMEN
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.