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Abnormalities in the passage of urine can occur in adult horses because of disorders of the urinary tract itself or diseases in other body systems, including neurological, musculoskeletal and gastrointestinal. Stranguria, pollakiuria and polyuria can be difficult to differentiate from each other in the clinical setting; careful history taking and observation of the horse is essential. Stranguria is most commonly caused by cystoliths, and has a good prognosis with surgical removal. Bacterial cystitis is the main cause of pollakiuria; this is rarely a primary condition so predisposing causes should be investigated. Psychogenic polydipsia is the most common cause of polyuria in horses without pituitary pars intermedia dysfunction but should be differentiated from renal disease and diabetes insipidus. Urinary incontinence should prompt a full neurological examination and typically carries a poor prognosis.
12007 Background: CIT is a common consequence of antineoplastic regimens for gastrointestinal (GI) cancers, occurring in >60% of colorectal cancer patients receiving multiagent chemotherapy. CIT can lead to chemotherapy dose reduction, delay, omission, and discontinuation, potentially worsening outcomes. There are no widely available licensed therapies for this unmet need. Aim: To evaluate the safety and efficacy of the thrombopoietin receptor agonist romiplostim (ROMI) in patients with GI cancers to limit chemotherapy dose modifications from CIT. Methods: This was a phase 3, placebo (PBO)-controlled RCT of patients receiving oxaliplatin-based multiagent regimens for GI cancers with persistent CIT, ie platelets (Plt) ≤85×10 9 /L on day 1 of a scheduled chemotherapy cycle (NCT03362177). Patients from 55 sites in 14 countries were randomized 2:1 to ROMI or PBO for 3 chemotherapy cycles, stratified by baseline Plt (< or ≥50×10 9 /L) and cancer type. Study drug started at 2 μg/kg subcutaneous weekly, adjusted weekly by 1 μg/kg up to 10 μg/kg to target Plt ≥100×10 9 /L in 12 weeks (≤4 weeks at 10 μg/kg). Chemotherapy started when Plt ≥100×10 9 /L (Plt response) or after week 4 per investigator. The primary endpoint was no CIT-induced dose modification of any myelosuppressive agent in either the second or third chemotherapy cycle per independent adjudication committee. Results: Patients (N=165; 109 ROMI, 56 PBO) had colorectal (75%), gastroesophageal (13%), or pancreatic (12%) cancer; 60% were male, 90% White, 4% Black, and 24% Hispanic, with mean (SD) age of 61.4 (11.1) years. Baseline median (range) Plt was 69 (8–85)×10 9 /L; 11% had Plt <50×10 9 /L. Stage IV disease rates were ROMI 65%, PBO 55%. Most (75%) patients completed study drug; 3% discontinued due to adverse events (AEs). The primary endpoint was achieved in 92/109 (84%) patients receiving ROMI vs 20/56 (36%) receiving PBO (odds ratio 10.2; 95% CI 4.6-22.5; P<0.001). Median (range) Plt nadirs were ROMI 87 (14–167)×10 9 /L, PBO 58 (22–95)×10 9 /L; P=0.005. For those with Plt responses (ROMI 97%, PBO 77%), median (95% CI) time to first Plt response was ROMI 1.1 (not estimable) weeks, PBO 2.1 (1.1-3.0) weeks; P<0.001. Treatment-related (TR) AE rates were ROMI: 12%, PBO: 7%, most frequently nausea (2%, 2%) and headache (2%, 0%). TR serious AEs and TRAEs leading to death or discontinuation of study drug or chemotherapy were not observed in either arm. Conclusions: In this first global phase 3 RCT of ROMI vs PBO for CIT, ROMI was well tolerated and efficacious in the treatment and prevention of CIT in GI cancers. These results are potentially practice-changing for a common serious condition encountered routinely in clinical practice worldwide that prevents delivery of on-time, full-dose anticancer therapy. Final results from long-term follow-up will be presented. Clinical trial information: NCT03362177 .
Systemically delivered therapeutics have limited access to the brain due to the tightly regulated blood brain barrier. There is a fine balance between production (20 mL/h), volume (150 mL), and removal/turnover (every 5h) of cerebrospinal fluid (CSF). The high turnover of CSF and the active efflux makes CNS therapeutics particularly challenging. Direct delivery of therapeutics to the CSF intrathecally is increasingly utilized in clinical practice but penetration deep into the brain parenchyma is poor. This poses a significant challenge for the efficacy of intrathecally delivered small molecules, antibodies and gene therapies. Ideally, a CSF delivery system would have the capability to deliver therapeutics broadly within the CSF compartment, while simultaneously also improving parenchymal delivery. We show with our device how we can move dye between the two ventricles in a controlled fashion resulting in improved distribution of methotrexate. Sheep (n=8) were used as a model, which have a brain size and geometry closer to humans when compared to rodents. EnClear’s drug delivery system utilizes two CSF access points; Group 1 accessed the right and left lateral ventricle (V2V) and Group 2 accessed the right or left lateral ventricle and lumbar thecal sac (V2L). An extracorporeal pump was used to control the speed and direction of CSF flow at 50 μL/mL. Sensors continuously monitored pressure, respiration, and heart rate. Imaging studies with Omnipaque dye determined the best parameters for controlling CSF flow. Administration of methotrexate was followed by a protocol to move CSF between the two access points. Methotrexate levels were measured with LC/MS in CSF, blood, brain regions, spinal cord, kidney, and liver. Omnipaque dye in V2V demonstrated the dye was observed to move between the two ventricles, whereas, in V2L, the dye disappeared within minutes from the ventricles. In Group 1 (V2V), safe pressures (< 25 mmHg or 34 cm water) were sustained in all subjects. In both groups, effective levels of >1 ug/mL methotrexate were measured in all brain tissues, including deeper brain tissues. There was a three-fold higher level of methotrexate in striatum with the V2V compared to V2L subjects. Consistently, CSF levels were two-fold higher at 2h. Importantly, methotrexate levels were significantly lower in lumbar spinal cord, kidney, and liver-potential sources of toxicity. In this large animal study, EnClear’s system delivered high(er) levels of methotrexate in the parenchyma of deep brain structures than traditional IT injection. To the authors knowledge, this first intraCSF drug delivery device to show improved distribution throughout the CNS including deep brain structures, while keeping lumbar spinal cord, liver, and kidney levels very low. Clinical trials with the device are currently being planned. Priya Kumthekar, Marcie Glicksman, Margaret Schwartz, Seema Nagpal, Isabella Glitza, Peter Forsyth, Ernesto Ruiz, Adam Sonabend. Dynamic control of cerebrospinal fluid to achieve personalized drug delivery in the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1784.
3513 Background: Soto, a KRASG12C inhibitor, had a 9.7% objective response rate (ORR) as monotherapy for chemorefractory patients (pts) with KRAS G12C-mutated mCRC. When combined with Pmab, a monoclonal anti-EGFR antibody, ORR increased to 30%, supporting the model that the doublet mitigates Soto-related feedback reactivation of the RAS-MAPK pathway and accumulation of activated EGFR. We hypothesize that Soto plus Pmab and FOLFIRI will further enhance Soto efficacy while maintaining a manageable safety profile. We report the first results for a KRASG12C inhibitor combined with an EGFR inhibitor and chemotherapy in pts with prior mCRC treatment. Methods: Pts included dose exploration and expansion cohorts from CodeBreaK 101 subprotocol H (NCT04185883) who received Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and standard-dose FOLFIRI (IV Q2W). Key eligibility criteria were KRAS G12C-mutated mCRC and ≥1 prior treatment for metastatic disease. Pts in dose expansion were KRASG12C inhibitor-naïve. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). Results: As of November 30, 2022, 33 pts (median age: 53 years; 48% female) were treated (6 in dose exploration, 27 in dose expansion). Median prior lines of systemic therapy was 2 (range: 1-6), with 33% and 67% of pts receiving 1 or ≥ 2 prior lines, respectively; 97% had prior fluoropyrimidine and 73% had prior irinotecan. Two pts in dose exploration received prior Soto. None of the 6 pts in dose level 1 of dose exploration had dose limiting toxicities (DLTs) during DLT evaluation (first 28 days), and Soto (960 mg PO daily) plus Pmab (6 mg/kg IV Q2W) and FOLFIRI (IV Q2W) was the recommended phase 2 dose. Treatment-related adverse events (TRAEs) of any grade occurred in 32 (97.0%) pts; 1 pt discontinued the full regimen due to grade 3 ALT increase. Fifteen (45.5%) had grade ≥ 3 TRAEs (most commonly dermatologic; n = 5). There were no fatal TRAEs. Safety findings were consistent with known profiles of Soto, Pmab, and FOLFIRI. No clinically meaningful PK interaction was observed between Soto and irinotecan. Of 31 pts evaluable for response, confirmed ORR (all partial responses) was 58.1% (95% CI: 39.1, 75.5). The 2 pts with prior Soto achieved partial response (n = 1) and stable disease (n = 1). Disease control rate was 93.5% (95% CI: 78.6, 99.2). With median follow-up of 5.7 and 7.4 months, respectively, progression-free and overall survival data are not yet mature. Fully enrolled data will be presented. Conclusions: In the first ever data set for this novel combination, Soto plus Pmab and FOLFIRI showed promising safety and efficacy in pretreated KRAS G12C-mutated mCRC, with a confirmed ORR of 58.1%. Adverse events were manageable and consistent with the expected safety profile of the drugs used, and there was no clinically meaningful Soto and irinotecan PK interaction. Clinical trial information: NCT04185883 .
