Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial.

BACKGROUND: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood-brain barrier penetration. OBJECTIVE: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). METHODS: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18-45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. RESULTS: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. CONCLUSIONS: Darolutamide did not significantly alter CBF, consistent with its low blood-brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. TRIAL REGISTRATION NUMBER: NCT03704519; date of registration: October 2018.

Androgens, or male sex hormones, bind to androgen receptors within prostate cells and can cause growth of prostate cancer. The treatment of prostate cancer often includes drugs that bind to androgen receptors, called androgen receptor inhibitors, keeping androgens from binding to the receptors and preventing prostate cancer growth. In clinical studies, these drugs may have adverse effects on the central nervous system, or brain, including dizziness, falls, and impaired thinking and problem solving. This study compared the effects of two androgen receptor inhibitors, darolutamide and enzalutamide, and placebo on blood flow in the brain. Blood flow was measured by a type of magnetic resonance imaging in healthy men after receiving a single dose of treatment. Blood flow in the brain was reduced by enzalutamide compared with both placebo and darolutamide. Darolutamide did not decrease brain blood flow. This lack of effect on brain blood flow is in line with preclinical studies that showed darolutamide's limited ability to cross the blood­brain barrier, which is the naturally occurring barrier that protects the brain from harmful substances. In clinical studies of patients with prostate cancer treated with darolutamide, adverse effects on the brain have occurred in similar proportions of patients receiving darolutamide and placebo. In contrast, enzalutamide treatment has an increased risk of adverse effects on the brain versus placebo. The results of this study provide information on the effects of these androgen receptor inhibitors on brain blood flow that may be related to their adverse effects on the brain and its functioning.

89Zr-3,2-HOPO-Mesothelin Antibody PET Imaging Reflects Tumor Uptake of Mesothelin-Targeted 227Th-Conjugate Therapy in Mice.

The mesothelin (MSLN)-targeted 227Th conjugate is a novel α-therapy developed to treat MSLN-overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with 89Zr to evaluate whether PET imaging with 89Zr-MSLN matches 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Methods: Serial PET imaging with protein doses of 4, 20, or 40 µg of 89Zr-MSLN and 89Zr-control was performed up to 168 h after tracer injection in human tumor-bearing nude mice with high (HT29-MSLN) and low (BxPc3) MSLN expression. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time points in HT29-MSLN and in medium-MSLN-expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice. Results: 89Zr-MSLN PET imaging showed an SUVmean of 2.2 ± 0.5 in HT29-MSLN tumors. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. Pretreatment SUVmean was 2.2 ± 0.2 in HT29-MSLN tumors, which decreased in volume on 227Th-MSLN treatment. BxPc3 tumors showed an SUVmean of 1.2 ± 0.3 and remained similar in size after 227Th-MSLN treatment. Conclusion: 89Zr-MSLN PET imaging reflected MSLN expression and matched 227Th-MSLN tumor uptake and biodistribution. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

In Vitro and In Vivo Comparison of 3,2-HOPO Versus Deferoxamine-Based Chelation of Zirconium-89 to the Antimesothelin Antibody Anetumab.

Introduction: [227Th]Th-3,2-HOPO-MSLN-mAb, a mesothelin (MSLN)-targeted thorium-227 therapeutic conjugate, is currently in phase I clinical trial; however, direct PET imaging using this conjugate is technically challenging. Thus, using the same MSLN antibody, we synthesized 3,2-HOPO and deferoxamine (DFO)-based zirconium-89 antibody conjugates, [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb, respectively, and compared them in vitro and in vivo. Methods: [89Zr]Zr-3,2-HOPO-MSLN-mAb and [89Zr]Zr-DFO-MSLN-mAb were evaluated in vitro to determine binding affinity and immunoreactivity in HT29-MSLN and PDX (NCI-Meso16, NCI-Meso21) cells. For both the zirconium-89 conjugates, in vivo studies (biodistribution/imaging) were performed at days 1, 3, and 6, from which tissue uptake was determined. Results: Both the conjugates demonstrated a low nanomolar binding affinity for MSLN and >95% immunoreactivity. In all the three tumor types, biodistribution of [89Zr]Zr-DFO-MSLN-mAb resulted in higher tumor uptake(15.88-28-33%ID/g) at all time points compared with [89Zr]Zr-3,2-HOPO-MSLN-mAb(7-13.07%ID/g). [89Zr]Zr-3,2-HOPO-MSLN-mAb femur uptake was always higher than [89Zr]Zr-DFO-MSLN-mAb, and imaging results concurred with the biodistribution studies. Conclusions: Even though the conjugates exhibited a high binding affinity for MSLN, [89Zr]Zr-DFO-MSLN-mAb showed a higher tumor and lower femur uptake than [89Zr]Zr-3,2-HOPO-MSLN-mAb. Nevertheless, [89Zr]Zr-3,2-HOPO-MSLN-mAb could be used to study organ distribution and lesion uptake with the caveat of detecting MSLN-positive bone lesions. Clinical trial (NCT03507452).

Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.

A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer.

INTRODUCTION: This open-label phase II study assessed the efficacy and tolerability of eribulin, a non-taxane microtubule dynamics inhibitor with novel mechanism of action, as monotherapy in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Enrolled patients had progressed during or after platinum-based doublet chemotherapy. Initially, two patient cohorts (taxane-pre-treated and taxane-naïve) received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. To assess tolerability of a second dosing schedule, a cohort of taxane-pre-treated patients received eribulin on days 1 and 8 of a 21-day cycle. The primary endpoint was objective response rate (ORR) evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by independent radiographic review. RESULTS: One hundred three patients received eribulin. The ORR was 9.7% (all partial responses [PR]). Overall disease control rate (PR + stable disease) was 55.3%. Median duration of response, progression-free survival, and overall survival were 5.8, 3.4, and 9.4 months, respectively. The most common drug-related adverse events were neutropenia (54%; 49% grade 3/4); fatigue (49%; 11% grade 3, no grade 4); nausea (38%; 1% grade 3, no grade 4); alopecia (32%); anemia (29%, 4% grade 3/4) and neuropathy (23%; 2% grade 3, no grade 4). The 28-day schedule was associated with many dose delays, interruptions, or omissions due to neutropenia (day 15). The 21-day cycle was well-tolerated. CONCLUSIONS: Eribulin monotherapy administered on days 1 and 8 of a 21-day cycle is active and tolerated as second- or later-line chemotherapy for NSCLC.

Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine.

PURPOSE: The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine. PATIENTS AND METHODS: Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review. RESULTS: Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses [PRs]), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4). CONCLUSION: Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.

Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC). METHODS: MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. RESULTS: Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%. CONCLUSION: Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

Radiation doses in interventional radiology procedures: the RAD-IR Study. Part III: Dosimetric performance of the interventional fluoroscopy units.

PURPOSE: To present the physics data supporting the validity of the clinical dose data from the RAD-IR study and to document the performance of dosimetry-components of these systems over time. MATERIALS AND METHODS: Sites at seven academic medical centers in the United States prospectively contributed data for each of 12 fluoroscopic units. All units were compatible with International Electrotechnical Commission (IEC) standard 60601-2-43. Comprehensive evaluations and periodic consistency checks were performed to verify the performance of each unit's dosimeter. Comprehensive evaluations compared system performance against calibrated ionization chambers under nine combinations of operating conditions. Consistency checks provided more frequent dosimetry data, with use of each unit's built-in dosimetry equipment and a standard water phantom. RESULTS: During the 3-year study, data were collected for 48 comprehensive evaluations and 581 consistency checks. For the comprehensive evaluations, the mean (95% confidence interval range) ratio of system to external measurements was 1.03 (1.00-1.05) for fluoroscopy and 0.93 (0.90-0.96) for acquisition. The expected ratio was 0.93 for both. For consistency checks, the values were 1.00 (0.98-1.02) for fluoroscopy and 1.00 (0.98-1.02) for acquisition. Each system was compared across time to its own mean value. Overall uncertainty was estimated by adding the standard deviations of the comprehensive and consistency measurements in quadrature. The authors estimate that the overall error in clinical cumulative dose measurements reported in RAD-IR is 24%. CONCLUSION: Dosimetric accuracy was well within the tolerances established by IEC standard 60601-2-43. The clinical dose data reported in the RAD-IR study are valid.

Radiation doses in interventional radiology procedures: the RAD-IR study: part II: skin dose.

PURPOSE: To determine peak skin dose (PSD), a measure of the likelihood of radiation-induced skin effects, for a variety of common interventional radiology and interventional neuroradiology procedures, and to identify procedures associated with a PSD greater than 2 Gy. MATERIALS AND METHODS: An observational study was conducted at seven academic medical centers in the United States. Sites prospectively contributed demographic and radiation dose data for subjects undergoing 21 specific procedures in a fluoroscopic suite equipped with built-in dosimetry capability. Comprehensive physics evaluations and periodic consistency checks were performed on each unit to verify the stability and consistency of the dosimeter. Seven of 12 fluoroscopic suites in the study were equipped with skin dose mapping software. RESULTS: Over a 3-year period, skin dose data were recorded for 800 instances of 21 interventional radiology procedures. Wide variation in PSD was observed for different instances of the same procedure. Some instances of each procedure we studied resulted in a PSD greater than 2 Gy, except for nephrostomy, pulmonary angiography, and inferior vena cava filter placement. Some instances of transjugular intrahepatic portosystemic shunt (TIPS) creation, renal/visceral angioplasty, and angiographic diagnosis and therapy of gastrointestinal hemorrhage produced PSDs greater than 3 Gy. Some instances of hepatic chemoembolization, other tumor embolization, and neuroembolization procedures in the head and spine produced PSDs greater than 5 Gy. In a subset of 709 instances of higher-dose procedures, there was good overall correlation between PSD and cumulative dose (r = 0.86; P <.000001) and between PSD and dose-area-product (r = 0.85, P <.000001), but there was wide variation in these relationships for individual instances. CONCLUSIONS: There are substantial variations in PSD among instances of the same procedure and among different procedure types. Most of the procedures observed may produce a PSD sufficient to cause deterministic effects in skin. It is suggested that dose data be recorded routinely for TIPS creation, angioplasty in the abdomen or pelvis, all embolization procedures, and especially for head and spine embolization procedures. Measurement or estimation of PSD is the best method for determining the likelihood of radiation-induced skin effects. Skin dose mapping is preferable to a single-point measurement of PSD.

Radiation doses in interventional radiology procedures: the RAD-IR study: part I: overall measures of dose.

PURPOSE: To determine patient radiation doses for interventional radiology and neuroradiology procedures, to identify procedures associated with higher radiation doses, and to determine the effects of various parameters on patient doses. MATERIALS AND METHODS: A prospective observational study was performed at seven academic medical centers. Each site contributed demographic and radiation dose data for subjects undergoing specific procedures in fluoroscopic suites equipped with built-in cumulative dose (CD) and dose-area-product (DAP) measurement capability compliant with International Electrotechnical Commission standard 60601-2-43. The accuracy of the dosimetry was confirmed by comprehensive measurements and by frequent consistency checks performed over the course of the study. RESULTS: Data were collected on 2,142 instances of interventional radiology procedures, 48 comprehensive physics evaluations, and 581 periodic consistency checks from the 12 fluoroscopic units in the study. There were wide variations in dose and statistically significant differences in fluoroscopy time, number of images, DAP, and CD for different instances of the same procedure, depending on the nature of the lesion, its anatomic location, and the complexity of the procedure. For the 2,142 instances, observed CD and DAP correlate well overall (r = 0.83, P <.000001), but correlation in individual instances is poor. The same is true for the correlation between fluoroscopy time and CD (r = 0.79, P <.000001). The correlation between fluoroscopy time and DAP (r = 0.60, P <.000001) is not as good. In 6% of instances (128 of 2,142), which were principally embolization procedures, transjugular intrahepatic portosystemic shunt (TIPS) procedures, and renal/visceral artery stent placements, CD was greater than 5 Gy. CONCLUSIONS: Most procedures studied can result in clinically significant radiation dose to the patient, even when performed by trained operators with use of dose-reducing technology and modern fluoroscopic equipment. Embolization procedures, TIPS creation, and renal/visceral artery stent placement are associated with a substantial likelihood of clinically significant patient dose. At minimum, patient dose data should be recorded in the medical record for these three types of procedures. These data should include indicators of the risk of deterministic effects as well as the risk of stochastic effects.

Midterm follow-up of penetrating ulcer and intramural hematoma of the aorta.

OBJECTIVE: Most studies on variant forms of aortic dissection--penetrating ulcer and intramural hematoma--have focused on the initial presenting episode, with scant follow-up. This investigation provides midterm follow-up of penetrating ulcer and intramural hematoma to determine whether the aorta shows healing according to radiography, goes on to dilate, or tends to rupture during later follow-up. METHODS: Forty-five patients with penetrating ulcers (n = 26) or intramural hematomas (n = 19) were treated at our institution. Ten patients with penetrating ulcers were male and 16 were female, and their ages ranged from 54 to 87 years (mean 72 years). Eight patients with intramural hematomas were male and 11 were female, and their ages ranged from 54 to 88 years (mean 74 years). These patients all had symptoms of aortic disease. Patients with incidental imaging findings were not considered. RESULTS: In the group with penetrating ulcers, rupture occurred during the initial admission in 10 (38%) cases, 17 patients (65%) underwent surgery, and 22 patients (85%) survived to hospital discharge. Among those with intramural hematomas, rupture occurred during the initial admission in 5 cases (26%), 7 patients (37%) underwent surgery, and 16 patients (84%) survived to hospital discharge. Follow-up ranged from 1 month to 12.5 years (mean 3.4 years). No ischemic vascular complications occurred. Imaging follow-up was available for 26 of the 45 patients. Of these, 19% of lesions showed resolution, 23% had worsened, 39% had progressed to typical dissection, and 19% were unchanged. Six late deaths were known to be caused by rupture. In the group with penetrating ulcers, aortic diameter increased from 4.8 to 5.1 cm during the course of 14 months. In the group with intramural hematomas, aortic diameter increased from 5.3 to 5.9 cm during the course of 21 months. Overall survivals were 80% at 1 year, 73% at 3 years, and 66% at 5 years. CONCLUSIONS: Intramural hematoma and penetrating ulcer are lesions associated with advanced age. Women predominate. Penetrating ulcer and intramural hematoma rupture both early and late. Radiographically documented worsening, improvement, or frank dissection may occur with time. Aortic growth does occur (0.2 cm per year for penetrating ulcer and 0.4 cm per year for intramural hematoma). Vascular ischemic complications do not occur. Because of the high early rupture rate, the frequency of radiographic worsening, and the documented occurrence of late rupture, we now recommend surgical replacement of the aorta for these virulent vascular lesions as long as the patient's comorbidities do not preclude surgical intervention.