Search

Eric D Shah,1 Bruce H Chamberlain,2 Michelle Rhiner,3 Neil E Slatkin,4,5 Nancy Stambler,6 Robert J Israel7 1Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 2Genesis Healthcare, Davenport, IA, USA; 3Department of Family Medicine, Loma Linda University Health, Loma Linda, CA, USA; 4School of Medicine, University of California Riverside, Riverside, CA, USA; 5Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 6Clinical Research, Progenics Pharmaceuticals, Inc., A Subsidiary of Lantheus Holdings, Inc, New York, NY, USA; 7Clinical and Medical Affairs, Bausch Health US, LLC, Bridgewater, NJ, USACorrespondence: Eric D Shah, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03766, USA, Tel +1 603-650-5261, Email eric.d.shah@hitchcock.orgPurpose: To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.Patients and Methods: We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately.Results: The safety population (patients receiving ≥ 1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P< 0.0001; noncancer, 48.0% vs 10.0%; P< 0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P< 0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was < 1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in < 4 and < 7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts.Conclusion: SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist, cancer, chronic pain

Objective Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain. Methylnaltrexone, a selective, peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of opioid-induced constipation. This retrospective analysis of 12 randomized, double-blind, placebo-controlled studies of methylnaltrexone evaluated the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain. Methods The risk of all-cause mortality within 30 days after the last dose of study medication during the double-blind phase was compared between methylnaltrexone and placebo groups. The data were further stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnoses. Results Pooled data included 2,526 methylnaltrexone-treated patients of which 33 died, and 1,192 placebo-treated patients of which 35 died. The mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone compared with placebo (hazard ratio: 0.399, 95% confidence interval: 0.25, 0.64; P = .0002), corresponding to a 60% risk reduction. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer or chronic diagnoses. Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender. Conclusions Methylnaltrexone reduced all-cause mortality vs placebo treatment across multiple trials, suggesting methylnaltrexone may confer survival benefits in patients with opioid-induced bowel disorders taking opioids for cancer-related or chronic noncancer pain.

Participant Flow

CONDOR study group, Supplementary tables, Study Protocol, & Medical Management Questionnaires

Purpose:Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen–targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.Experimental Design:Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.Results:A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2–98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%–87.0% (lower bound of 95% CI: 77.8–80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers).Conclusions:Performance of 18F-DCFPyL-PET/CT achieved the study’s primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer.See related commentary by True and Chen, p. 3512

Bruce H Chamberlain,1 Michelle Rhiner,2 Neal E Slatkin,3,4 Nancy Stambler,5 Robert J Israel6 1Genesis Healthcare, Davenport, IA, USA; 2Loma Linda University Health, Department of Family Medicine, Loma Linda, CA, USA; 3University of California Riverside, School of Medicine, Riverside, CA, USA; 4Salix Pharmaceuticals, Medical Affairs, Bridgewater, NJ, USA; 5Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings Inc., Clinical Research, New York, NY, USA; 6Bausch Health US, LLC, Clinical and Medical Affairs, Bridgewater, NJ, USACorrespondence: Robert J IsraelBausch Health US, LLC, Clinical and Medical Affairs, 400 Somerset Corporate Boulevard, Room 6-1001, Bridgewater, NJ, 08807, USATel +1 908 541-2288Fax +1 585 338-0668Email Robert.Israel@bauschhealth.comPurpose: Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral μ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC.Patients and Methods: This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety.Results: After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥ 2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; P < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, P < 0.0001; noncancer: 1.25 vs > 24 hours, P = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, P < 0.0001; noncancer: 8.4 vs 5.0, P < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal.Conclusion: Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist, cancer, chronic pain

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Previous work in mouse models shows that urinary TNF-α levels become elevated when dietary salt (NaCl) intake increases. To examine if this relationship exists in humans, we conducted a secondary analysis of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial to determine levels of urinary TNF-α in 367 subjects categorized by race, sex, and blood pressure. The DASH-Sodium trial is a multicenter feeding trial in which subjects were randomly assigned to either the DASH or control diet, and high, medium, and low sodium in random order. Multivariable linear regression was used to model baseline TNF-α and a mixed model was used to model TNF-α as a function of dietary intervention. At baseline, with all subjects on a "typical American diet", urinary TNF-α levels were lowest in Black, p = 0.002 and male subjects, p 0.001. After randomization to either the DASH or control diet, with increasing levels of sodium, urinary TNF-α levels increased only in subjects on the control diet, p 0.05. As in the baseline analysis, TNF-α levels were highest in White females, then White males, Black females and lowest in Black males. The results indicate that urinary TNF-α levels in DASH-Sodium subjects are regulated by NaCl intake, modulated by the DASH diet, and influenced by both race and sex. The inherent differences between subgroups support studies in mice showing that increases in renal TNF-α minimize the extent salt-dependent activation of NKCC2.

BackgroundMethylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.ObjectiveThis analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.MethodsThe analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age (

Purpose Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor®) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC. Methods This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms. Results Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal. Conclusion Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.

Purpose: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen–targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging. Experimental Design: Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety. Results: A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2–98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%–87.0% (lower bound of 95% CI: 77.8–80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers). Conclusions: Performance of 18F-DCFPyL-PET/CT achieved the study’s primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer. See related commentary by True and Chen, p. 3512

61 Background: Piflufolastat F 18 is a PSMA-targeted radiopharmaceutical approved in the US for imaging prostate cancer (PCa) patients both at the time of initial staging and at disease recurrence. In a phase 3 study of patients with biochemically recurrent (BCR) PCa, we reported that nearly two-thirds (63.9%; 131/205) of participants had a change in their intended disease management plan based on pre- and post-piflulfolastat F 18 PET/CT management questionnaires (MMQs) completed by the treating physicians. The clinical utility of piflufolastat F 18 scanning in men with very low/low PSA levels (

INTRODUCTION AND OBJECTIVE:Several PSMA-targeted imaging agents are currently in development for initial staging of men at risk of harboring metastatic prostate cancer (PCa) not detected by convent...

5024 Background: The OSPREY clinical trial was a phase 2/3 prospective study of prostate specific membrane antigen (PSMA) PET/CT using piflufolastat F 18. Piflufolastat F 18 (aka 18F-DCFPyL or PyL) is a novel PSMA-targeting radiopharmaceutical approved for imaging of PCa pts both at initial staging and for disease recurrence. Here we describe SUV results by biopsy status, baseline PSA levels, and Gleason score (GS). Methods: Piflufolastat F 18-PET/CT was evaluated in men with NCCN high-risk PCa scheduled to undergo radical prostatectomy with pelvic lymphadenectomy (RP-PLND) (Cohort A) and men with radiologically suspected recurrent/metastatic PCa (Cohort B). A single IV dose of 9 mCi (333 MBq) of piflufolastat F 18 was administered followed by PET/CT acquisition 1-2 hours later. Piflufolastat F 18 uptake in various lesion locations as defined by maximum and peak SUV (SUVmax, SUVpeak) were determined by three blinded, independent central readers for each tissue (e.g., bone, lymph nodes (LN), soft tissue). To measure SUVs, the reader placed a volume of interest (VOI) on each identified lesion. SUVmax was defined as the maximum single-voxel SUV within the VOI. SUVpeak within the VOI was defined as the average SUV within a fixed-sized VOI (1 cm diameter sphere), representing the cluster with the highest average SUV. Results: 345 men underwent piflufolastat F 18-PET/CT. Cohort B (n = 93evaluable) SUVmax and SUVpeak were significantly higher for biopsy positive (+)(one biopsy lesion/pt) when compared to biopsy negative (-) lesions from bone and LN. SUVpeak for biopsied bone and LN (Cohort B) appeared to increase with rising baseline PSA. In high-risk PCa pts, SUVpeak for prostate (Cohort A; n = 252 evaluable) increased with baseline PSA and were highest for GS 9-10 (Table). Conclusions: Piflufolastat F 18-PET/CT uptake was significantly higher in biopsy + lesions and increased with baseline PSA. Prostate SUVpeak was highest for GS 9-10. Clinical trial information: NCT02981368. [Table: see text]

Richard L Rauck,1 Neal E Slatkin,2,3 Nancy Stambler,4 Robert J Israel3 1Carolinas Pain Institute, Winston-Salem, NC, USA; 2School of Medicine, University of California Riverside, Riverside, CA, USA; 3Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 4Clinical Research, Progenics Pharmaceuticals, New York, NY, USA Purpose: Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. Methods: Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. Results: TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. Conclusion: Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal. Keywords: analgesia, µ-opioid-receptor antagonist, nonmalignant, safety

Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC.To assess the safety and efficacy of a single methylnaltrexone dose.Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo.The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose.Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.

Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR).Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization betweenA total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2-98.4 ng/mL) underwentPerformance of

Introduction:Improved diagnostics are needed to better inform the treatment of men with biochemically recurrent (BCR) prostate cancer (PCa). 18F-DCFPyL is a novel PET agent that selectively binds w...

Background: Metaiodobenzylguanidine (MIBG; iobenguane), a guanethidine derivative, is a substrate for norepinephrine reuptake transporter which is highly expressed on the surface of neuroblastoma cells. AZEDRA® (HSA I-131 MIBG) has been approved by the FDA for the treatment of pheochromocytoma and paraganglioma, in pts 12 years and older with MIBG avid, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. The aim of this study was to establish the maximum tolerated dose in children with neuroblastoma, with secondary aims of assessing overall response and tumor and organ dosimetry. Here we report current long-term survival and toxicity data. Methods: Eligible pts were 1-30 years old with resistant neuroblastoma. A diagnostic dose of HSA I-131 MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. To prevent prolonged myelosuppression, autologous hematopoietic stem cells were infused 14 days after therapy. Response and toxicity were evaluated on day 60. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/µL within 28 days, or platelets to greater than 20,000/µL within 56 days, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: First pt was enrolled in June 2008. 15 pts total were evaluable at 12 (n=5), 15 (n=3), and 18 (n=7) mCi/kg. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight pts had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. MYC-N amplification was present in two of 11 pts with available results. Of the 15 treated pts, 1 had a complete response, 3 had a partial response, 1 had a mixed response and 6 had stable disease. The remaining 4 had progressive disease. Twelve of the 15 evaluable pts received non-protocol therapy after HSA I-131 MIBG, the remaining 3 died due to tumor without further therapy. At 3.6 years of follow-up the overall survival was 26.7% (95% CI, 8.3%-49.6%). As of March 2018, one remaining pt is in long term follow up with an overall survival of 8.4 years. This pt was previously reported to have a secondary malignancy of myelodysplastic syndrome which has been in remission since receiving an allogenic bone marrow transplant in March 2014. Conclusions: HSA I-131 MIBG contributed to long term median survival of two years and was well tolerated. Treatment showed promising activity in the absence of significant nonhematologic toxicity.

Background: Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors with a 5-yr survival rate as low as 12%. There is a high unmet medical need for effective treatment options for patients with advanced disease. AZEDRA®, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA-approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric patients with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Patients with advanced PPGL who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of patients with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 patients. Of those, 68 patients received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of patients receiving one and two therapeutic doses, respectively. As of October 10, 2019, median survival time for all patients was 43.2 months (95% CI 31.4, >60). Median survival time was 19.3 months (95% CI 4.5, 32.4) and 49.1 months (95% CI 36.9, >60) in patients receiving one and two doses, respectively. The overall survival was 73.8% at 2 yrs, 47.5% at 4 yrs and 41.5% at 5 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 7 patients with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL.

Aim: To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.

35 Background: The OSPREY clinical trial was a phase 2/3 prospective study of prostate specific membrane antigen (PSMA) PET/CT using piflufolastat F 18. Piflufolastat F 18 (aka 18F-DCFPyL or PyL) is a novel PSMA-targeting radiopharmaceutical approved for imaging of PCa pts both at initial staging and for disease recurrence. Here we describe SUV results by biopsy status, baseline PSA levels, and Gleason score (GS). Methods: Piflufolastat F 18 -PET/CT was evaluated in men with NCCN high-risk PCa scheduled to undergo radical prostatectomy with pelvic lymphadenectomy (RP-PLND) (Cohort A) and men with radiologically suspected recurrent/metastatic PCa (Cohort B). A single IV dose of 9 mCi (333 MBq) of piflufolastat F 18 was administered followed by PET/CT acquisition 1-2 hours later. Piflufolastat F 18 uptake in various lesion locations as defined by maximum and peak SUV (SUVmax, SUVpeak) were determined by three blinded, independent central readers for each tissue (e.g., bone, lymph nodes (LN), soft tissue). To measure SUVs, the reader placed a volume of interest (VOI) on each identified lesion. SUVmax was defined as the maximum single-voxel SUV within the VOI. SUVpeak within the VOI was defined as the average SUV within a fixed-sized VOI (1 cm diameter sphere), representing the cluster with the highest average SUV. Results: 345 men underwent piflufolastat F 18-PET/CT. Cohort B (n = 93 evaluable) SUVmax and SUVpeak were significantly higher for biopsy positive (+) (one biopsy lesion/pt) when compared to biopsy negative (-) lesions from bone and LN. SUVpeak for biopsied bone and LN (Cohort B) appeared to increase with rising baseline PSA. In high-risk PCa pts, SUVpeak for prostate (Cohort A; n = 252 evaluable) increased with baseline PSA and were highest for GS 9-10 (Table). Conclusions: Piflufolastat F 18-PET/CT uptake was significantly higher in biopsy + lesions and increased with baseline PSA. Prostate SUVpeak was highest for GS 9-10. Clinical trial information: NCT02981368. [Table: see text]

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% confidence interval, 16%–37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9–49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG. Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.

Context No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting Three centers. Patients Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

99mTc-trofolastat (99mTc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen, shows high potential to detect prostate cancer (PCa) noninvasively using SPECT. We therefore wanted to assess the performance of 99mTc-trofolastat SPECT/CT in a phase 2 multicenter, multireader prospective study in patients with intermediate- and high-grade PCa, before radical prostatectomy and extended pelvic lymph node (LN) dissection, with histopathology as the gold standard. Methods: PCa patients (n = 105) with an increased risk of LN involvement (LNI) underwent pelvic 99mTc-trofolastat SPECT/CT before radical prostatectomy with extended pelvic LN dissection. The sensitivity of 99mTc-trofolastat for detection of PCa on a patient and lobe basis, using visual and semiquantitative (tumor-to-background ratio [TBR]) scores, and of LNI was evaluated as well as the correlation of uptake within the gland to Gleason scores (GS) and assessment of the predictive potential of 99mTc-trofolastat uptake for LNI. Results: PCa was detected in 98 patients (94%) with acceptable variability between readers. There was a significantly higher visual score and TBR in positive lobes compared with tumor-negative lobes. Receiver-operating characteristic analysis showed that visual scores more accurately discriminated lobes with GS ≤ 3 + 3 from ≥ 3 + 4, whereas TBRs discriminated high-grade disease from normal lobes better. Visual scores and TBRs correlated significantly with GS. 99mTc-trofolastat SPECT/CT detected LNI with a sensitivity of 50% and specificity of 87%, and TBR values significantly predicted LNI with a sensitivity of 90%. Conclusion:99mTc-trofolastat SPECT/CT detects PCa with high sensitivity in patients with intermediate- and high-risk PCa compared with histology. It has the potential to be used as a surrogate marker for GS and predict LNI.

Background Subcutaneous methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, improves opioid-induced constipation (OIC) in patients with chronic noncancer pain. An oral methylnaltrexone formulation has been developed. Methods In this phase 3, double-blind trial, adults with chronic noncancer pain receiving opioid doses of ≥ 50 mg/day oral morphine equivalents with OIC were randomly assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by as-needed dosing for 8 weeks. Patients who had ≥ 3 rescue-free bowel movements (RFBMs)/week, with an increase of ≥ 1 RFBM/week from baseline for ≥ 3 of 4 weeks during the QD period, were responders. Results Overall, 803 patients were included in the analyses. A significantly greater percentage of patients had an increase in mean percentage of dosing days resulting in an RFBM within 4 hours of dosing during weeks 1 through 4 (QD period; primary endpoint) with methylnaltrexone (300 mg/day [24.6%; P = 0.002] and 450 mg/day [27.4%; P < 0.0001]) vs. placebo (18.2%). The percentage of responders (49.3% for 300 mg [P = 0.03] and 51.5% for 450 mg [P = 0.005] vs. 38.3% with placebo) and change from baseline in mean number of weekly RFBMs (difference vs. placebo, 0.5 for 300 mg [P = 0.03] and 0.5 for 450 mg [P = 0.02]) was significantly greater with methylnaltrexone 300 and 450 mg/day vs. placebo during the QD period. All dosages of oral methylnaltrexone were well tolerated. Conclusions Oral methylnaltrexone was efficacious and well tolerated for OIC in patients with chronic noncancer pain, particularly the 450-mg dose.

INTRODUCTION AND OBJECTIVES:99mTc-MIP-1404 (1404) is a small molecule SPECT imaging agent that binds to prostate-specific membrane antigen (PSMA) allowing for the detection of prostate cancer (PCa)...

Introduction: Iobenguane scan positive cancers including pheochromocytoma/paraganglioma (PPGL), neuroblastoma, and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous tumors that arise from neuroendocrine cells. Recently, high-specific-activity I-131 meta-iodobenzylguanidine (HSA I-131 MIBG, AZEDRA®) was approved in the US for treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL. We present a pooled analysis of all available clinical trials to further assess the safety profile of HSA I-131 MIBG. Methods: 118 patients from four HSA I-131 MIBG clinical trials (NCT00339131; NCT00458952; NCT00874614; NCT00659984) were included in a pooled analysis for safety assessments. Adverse events (AEs), laboratory tests, number and quantity of HSA I-131 MIBG doses, hypertensive events, blood pressure (BP), heart rate, ECG, and AEs of special interest (AESI) were analyzed using descriptive statistics. Results: Gastrointestinal (GI) toxicities, especially nausea and vomiting, were the most common AEs associated with HSA I-131 MIBG. GI toxicities were not reported after dosimetry doses. GI, blood and lymphatic system, and vascular disorders were higher in PPGL than in neuroblastoma after therapeutic dose 1 when compared to therapeutic dose 2. The incidence of potentially clinically significant changes in BP was similar following dosimetric and therapeutic doses and are consistent with the underlying hypertension associated with PPGL. No spike in systolic and diastolic BP was observed within the first 4 hours of HSA I-131 MIBG administration, and there were no acute hypertensive crises following dosing. A possibly drug-related mild increase in BP within 48 hours of therapeutic dosing was observed in 1 subject with PPGL. Variations in heart rate (>20 beats/min) were higher after therapeutic dose 1 than after other doses. No clinically significant trends were seen in mean ECG results or mean changes from baseline. All patients received at least one concomitant medication. About 40% of patients received β-blockers, 39% α-blockers, and about 27% other peripheral vasodilators. 87.3% of patients reported an AESI, defined as AEs that are related to the acute and/or chronic effects of radiation toxicity seen any time post dosing. The most common AESIs were nausea (66.1%), thrombocytopenia (50.0%), fatigue (50.0%), neutropenia (42.4%), and diarrhea (22.9%). The incidence of most AESIs were similar after each therapeutic dose. Conclusions: HSA I-131 MIBG demonstrated a favorable safety profile in iobenguane scan positive cancers. AEs followed an expected pattern comparable to other radioactive therapeutic agents. Most cardiovascular events, including hypertensive events mostly commonly observed in PPGL, were not considered related to HSA I-131 MIBG.

5023 Background: PSMA-targeted PET/CT is superior to conventional imaging modalities to localize biochemically recurrent (BCR) PCa after local therapy, particularly in pts with low PSA ( < 2 ng/mL). However, few studies have reported PSMA-targeted PET/CT accuracy compared to a pre-specified rigorous standard of truth (SOT) including histopathology, correlative imaging or treatment response in this population. Here, we report the CLR and PPV of PSMA-targeted 18F-DCFPyLPET/ CT, for each of the pre-defined SOT criteria for the CONDOR prospective phase 3 study. Methods: The study enrolled men with rising PSA after definitive therapy and negative or equivocal standard of care imaging (e.g., CT/MRI, bone scintigraphy, F-18 fluciclovine). A single 9 mCi (333 MBq) ± 20% dose of 18F-DCFPyL was injected, followed by PET/CT 1-2 hours later. Pts with positive 18F-DCFPyL-PET/CT scans based on local interpretation were scheduled for follow up within 60 days to verify suspected lesion(s) using a composite SOT. The primary endpoint was CLR defined as PPV with the requirement of anatomic lesion co-localization between 18F-DCFPyL-PET/CT and the SOT. The SOT consisted of, in descending priority: 1) histopathology, 2) subsequent correlative imaging findings determined by twocentral readers, or 3) post-radiation PSA response. The trial was successful if the lower bound of the 95% confidence interval for CLR exceeded 20% for at least two of three independent, blinded central 18F-DCFPyL-PET/CT reviewers. Results: 208 men (median PSA 0.8 ng/mL) underwent 18F-DCFPyL-PET/CT and the study achieved its primary endpoint: CLR was between 84.8% to 87.0% (lower bound of 95% CI: 77.8%-80.4%) among the three 18F-DCFPyL-PET/CT readers, against the composite SOT. The performance of 18F-DCFPyL-PET/CT by CLR (≥1 lesion co-localized) and PPV (≥1 lesion confirmed) was maintained through all 3 SOT categories. Histopathology (N = 31): 78.6-82.8% and 92.9-93.3% for CLR and PPV, respectively; correlative imaging (N = 100): 86.1-88.6% and 87.0-89.5% for CLR and PPV, respectively; and PSA response (N = 1): 100% for both CLR and PPV. Further analyses of the correlative imaging results showed CLR remained high across the different modalities used a) 18F-fluciclovine-PET/CT (N = 71): (86.8-90.9%); b) MRI (N = 23): (80.0-86.7%); and c) CT (n = 6): (80.0-100%). Conclusions: PSMA-targeted 18F-DCFPyL-PET/CT detected and localized metastatic lesions with high CLR and PPV regardless of which criterion defined CLR that was used, in men with BCR who had negative or equivocal baseline imaging. Clinicaltrials.gov: NCT03739684 Clinical trial information: NCT03739684.

e24083 Background: Opioid-induced constipation (OIC) is a common side effect of opioid treatment for cancer-related pain. Methylnaltrexone (MNTX) is a peripherally active µ-opioid receptor antagonist indicated for OIC that does not affect opioid central analgesia. We assessed if baseline Eastern Cooperative Oncology Group (ECOG) status impacted the rescue-free laxation (RFL) responses among cancer patients with OIC treated with repeated doses of MNTX. Methods: This pooled post hoc analysis from 2 randomized, placebo-controlled, institutional review board–approved clinical studies included cancer patients with OIC (study 302, NCT00402038; study 4000, NCT00672477). Study 302 compared subcutaneous MNTX 0.15 mg/kg vs placebo and study 4000 compared body weight‒based subcutaneous MNTX 8 mg (38–< 62 kg) or 12 mg (³ 62 kg) vs placebo. The data were stratified by baseline ECOG status (< 2 vs ≥ 2). Endpoints included the number of patients with RFL responses within 4 hours after ≥ 2 of the first 4 doses and the number of patients with RFL response within 4 hours of treatment for patients who received all 7 doses. Results: The intent-to-treat analysis included 43 patients with an ECOG < 2 (placebo = 20; MNTX = 23) and 187 patients with an ECOG ≥ 2 (placebo = 94; MNTX = 93). Those with an ECOG < 2 were younger (mean age 58 vs 65 years), predominantly male (60.5% vs 51.3%), and used a higher daily dose of oral morphine equivalent (190.7 vs 180.0 mg/d) compared with those with an ECOG ≥ 2. Cancer patients with an ECOG < 2 treated with MNTX had a significantly greater RFL response within 4 hours after ≥ 2 of the first 4 doses compared with placebo (56.5% vs 5.0%, P = 0.0003). Similar results were reported for patients with an ECOG ≥ 2 (57.0% vs 5.3%, P < 0.0001). Compared with placebo, the MNTX group had a greater proportion of patients with an RFL response, whether they had at least 1 RFL response or up to 7 RFL responses out of 7 doses, with significant treatment differences with each additional RFL per 7 doses among cancer patients with an ECOG ≥ 2 (Table). Conclusions: RFL response rates in cancer patients were significantly greater in the MNTX group vs the placebo group regardless of baseline ECOG status; responses were similar between the 2 groups despite a higher daily dose of opioids in the group with an ECOG > 2. Clinical trial information: NCT00402038; NCT00672477. [Table: see text]

Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.This analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.The analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age ( 65 years and ≥ 65 years). Endpoints included pain intensity scores, symptoms of opioid withdrawal, treatment-related adverse events (TRAEs), and rescue-free laxation (RFL) within 4 h of treatment.Overall, 1323 patients were 65 years of age (n = 908, methylnaltrexone; n = 415, placebo) and 304 patients were ≥ 65 years of age (n = 171, methylnaltrexone; n = 133, placebo). Nonsignificant pain intensity score reductions were observed in all groups. In the older cohort, measures of opioid withdrawal did not show statistical differences from baseline in either the methylnaltrexone or placebo groups. The most frequently reported TRAEs were abdominal pain, flatulence, and nausea. Relative to the first dose, gastrointestinal TRAEs potentially related to opioid withdrawal declined with the second dose and were comparable with placebo, regardless of age. RFL response within 4 h of methylnaltrexone treatment increased significantly in both age cohorts relative to placebo.Methylnaltrexone use did not adversely affect pain control, opioid withdrawal effects, or AEs while providing effective RFL, regardless of age. These results suggest that age does not appear to influence the safety and efficacy of methylnaltrexone for OIC. Further research is needed to assess the impact of other factors that alter BBB permeability, such as dementia, stroke, or drug interactions, on the safety and efficacy of methylnaltrexone.Study 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.

TPS187 Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate 18F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.

32 Background: Conventional imaging and bone scintigraphy are suboptimal modalities for identifying PCa. PSMA-based imaging is highly promising for PCa detection. 18F-DCFPyL is a novel PSMA-targeted radiopharmaceutical for positron emission tomography (PET) that may be useful in staging of PCa. The diagnostic performance, detection rate, and potential impact of 18F-DCFPyL on staging of pts with high- risk PCa have been previously reported. Here we report on the impact of 18F-DCFPyL on staging of pts with PCa recurrence or metastases on conventional imaging. Methods: 18F-DCFPyL-PET/CT was evaluated in 117 men with radiologic evidence of local recurrence or metastatic disease on baseline anatomical imaging (CT, MRI) or whole-body bone scintigraphy and in whom at least one lesion was deemed amenable to biopsy. A single dose of 9 mCi (333 MBq) of 18F-DCFPyL was administered via intravenous injection, followed by PET/CT acquisition 1 to 2 hours thereafter. Based on TNM staging: prostatic (T), pelvic LN (N), extra-pelvic LN (M1a), bone (M1b) and other visceral organs/soft tissue (M1c), 18F-DCFPyL-PET/CT detection rates including lesion counts were systematically analyzed. Three central, blinded, and independent readers evaluated the 18F-DCFPyL scans. Results: In this study, 82 (70%) patients had baseline radiographic M1 stage disease (14 patients with M1a, 50 patients with M1b, 18 patients with M1c) and 33 (28%) patients were M0 stage at baseline by central conventional imaging review; two patients were unevaluable. 18F-DCFPyL-PET/CT up-staged 58% (19/33) of pts from M0 to M1, of whom 91% (10/11) who underwent an extra-pelvic biopsy were confirmed to have M1 disease by pathology, including 9 patients with M1b and 1 patient with M1a. Of the patients who were staged M1 at baseline, 18F-DCFPyL-PET/CT upstaged 16% (10/64; M1a to M1b or M1c: n = 4; M1b to M1c: n = 6) of pts to a higher M1 sub-stage and down-staged 22% (18/82) to M0. Conclusions: 18F-DCFPyL-PET/CT identified M1 disease in the majority of patients examined who otherwise had locoregional disease. These data suggest that 18F-DCFPyL-PET/CT may be a useful tool in properly staging men with both metastatic and nonmetastatic relapsed disease, which could lead to superior treatment paradigms than currently exist using conventional imaging. Clinical trial information: NCT02981368.

5501 Background: Current imaging modalities are inadequate for localizing and characterizing occult disease in men with BCR PCa, particularly in pts with low PSAs (18F-DCFPyL (PyL) is a novel PET imaging agent that binds selectively with high affinity to PSMA, which is overexpressed in PCa cells. Methods: Men ≥18 years- with rising PSA after definitive therapy and negative or equivocal standard of care imaging (e.g., CT/MRI, bone scintigraphy) were enrolled. A single 9 mCi (333 MBq) ± 20% dose of PyL was injected, followed by PET/CT 1-2 hours later. Primary endpoint was correct localization rate (CLR), defined as percentage of pts with a 1:1 correspondence between at least one lesion identified by PyL-PET/CT and the composite standard of truth: pathology, correlative imaging, or PSA response. The trial was successful if the lower bound of the 95% confidence interval (LLCI) for CLR exceeded 20% for two of three independent, blinded central PyL-PET/CT reviewers. The secondary endpoint, impact of PyL-PET/CT on clinical management of pts was based on the treating physician’s documented clinical plans before and after PyL-PET/CT. Results: 208 men (median PSA 0.8 [0.2 - 98.4] ng/mL) underwent PyL PET/CT. The study achieved its primary endpoint: CLR of 84.8% to 87.0% among the three PyL-PET/CT readers; the LLCI for CLR by all three reviewers was >77%. Here we report the clinical impact. Based on local radiology assessment, PSMA-avid lesion(s) were identified in 69.3% (142/208) of pts. 63.9% (131/205) had a change in intended management after PyL-PET/CT, of which 78.6% (103/131) were attributable to positive PyL finding(s) and 21.4% (28/131) to negative PyL scans. Changes included: salvage local therapy to systemic therapy (n=58); observation before initiating therapy (n=49); noncurative systemic therapy to salvage local therapy (n=43); and planned treatment to observation (n=9). PyL was well tolerated with one drug-related SAE (hypersensitivity) and the most common AE being headache (n=4; 1.9%). Conclusions: PSMA-targeted PyL-PET/CT detected and localized occult disease in most men with BCR presenting with negative or equivocal conventional imaging. PyL-PET/CT led to changed management plans in the majority of pts, thus providing evidence that clinicians find PSMA PET imaging useful in men with recurrent or suspected metastatic PCa. Clinical trial information: NCT03739684 .

INTRODUCTION AND OBJECTIVE:Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors with a 5-yr survival rate as low as 12%. Effective treatment options for patients with advanced disea...