The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), "other" psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these (n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC.

3520 Background: Prior studies have confirmed the efficacy and safety of ceritinib in patients (pts) with advanced ALK+ non-small cell lung cancer (Soria, et al, Lancet 2017; Shaw et al, Lancet Oncol 2017; Cho et al, JTO 2019). Ceritinib also demonstrated antitumor activity in pediatric pts with ALK+ inflammatory myofibroblastic tumor (IMT) and ALCL (Georger et al, ASCO 2015 [abstract#10005]). Long-term clinical benefits of ceritinib treatment were shown in pts with anaplastic large cell lymphoma (ALCL) (Richly et al, Blood 2015). The aim of the current study was to examine ceritinib efficacy and safety in pts with advanced ALK+ non-lung solid tumors and hematological malignancies. Methods: In this open-label, multi-arm, phase 2 (NCT02465528) trial, adult pts with ALK gene abnormalities who had received ≥1 prior systemic therapy were administered oral ceritinib 750 mg/day, under fasted conditions. Primary endpoint: investigator assessed disease control rate (DCR); secondary endpoints: investigator assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety. Results: Overall, 22 pts (ALCL [n = 1], IMT [n = 4], glioblastoma multiforme [GBM, n = 12] and others [n = 5]) were enrolled; median (m) age: 52.5 years; male: 50%; Stage ≥IV: 95.4%. Key efficacy results are shown in the Table. mTTR in pts with confirmed complete response (CR) or partial response (PR) [n = 4] was 7.4 (range, 6–25) weeks. mDOR was not reached. mPFS (95% CI) was 2.6 (1.6, 3.7) weeks. Most common adverse events (AEs; ≥30%) were: diarrhea and nausea (59.1% each), vomiting (50.0%) and increased alanine aminotransferase (31.8%). Most common grade ≥3 AEs (≥10%): hyperglycemia (18.2%), increased gamma-glutamyl transferase, thrombocytopenia, and anemia (13.6% each). Clinical trial information: NCT02465528 . Conclusions: Ceritinib 750 mg/day under fasted conditions showed antitumor activity in pts with ALK+ ALCL and IMT; however, data interpretation is limited due to the small sample size. Safety findings were consistent with the known ceritinib safety profile. [Table: see text]

Immune checkpoint inhibitors (ICIs) are increasingly used in the initial treatment of mRCC. The aim of this study was to evaluate the safety and efficacy of the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) pazopanib (PAZ) in patients with advanced or mRCC following previous ICI treatment. This was an international, single arm, phase II trial (NCT03200717). Patients with histologically confirmed locally recurrent or metastatic clear cell RCC and prior ICI therapy received PAZ 800 mg once daily until progression, unacceptable toxicity, death, or study withdrawal. The primary endpoint was progression-free survival (PFS) based on local investigator assessment; secondary endpoints were overall response rates (ORR) based on local investigator assessment, overall survival (OS), and safety. This primary analysis was conducted when all patients had received ≥6 treatment cycles (median follow-up, 10.2 months). A total of 62 patients previously treated with ICI were enrolled and received PAZ as 2nd line (2L) (n=47; 25% had prior anti-VEGF therapy) or 3rd line (3L) (n=15, 100% had prior anti-VEGF therapy) treatment. IMDC prognosis at baseline was favorable, intermediate, or poor in 32.3%, 56.5%, and 11.3% of patients, respectively. In patients receiving 2L PAZ, median PFS was 7.4 months (95% CI: 3.7, 13.8) and survival probability at 12 months was 65.8% (95% CI: 48.5%, 78.4%). In the 3L setting, median PFS was 4.6 months (95% CI: 3.3, 9.2) and survival probability at 12 months was 75.8% (95% CI: 40.4%, 91.9%). ORR was 19% in the 2L and 0% in the 3L setting. The most common treatment-related adverse events (AEs) were diarrhea (40%), liver abnormalities (34%), fatigue (31%), decreased appetite (26%), and nausea (24%). Nineteen patients (31%) reported AEs leading to treatment withdrawal, of which 10 (16%) were due to liver abnormalities; 44 patients (71%) had AEs requiring dose adjustment or interruption. Grade 3/4 transaminase elevations per lab data occurred in 15/62 patients (24.2%), but no deaths were related to transaminitis. PAZ has activity after progression on ICIs in mRCC. AE profiles are in line with the expectations for this TKI.

BACKGROUND:Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).SUBJECTS, MATERIALS, AND METHODS:Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.RESULTS:Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups.CONCLUSION:PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting.IMPLICATIONS FOR PRACTICE:PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors' knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.

Patients with intermediate-risk advanced renal cell carcinoma are a heterogeneous population, having either 1 or 2 risk factors. It is unclear whether all patients in this risk category should be treated similarly. A secondary analysis of the PRINCIPAL study of pazopanib found that patients can be stratified by number of risk factors and Eastern Cooperative Oncology Group performance status to more accurately predict outcomes. Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients and Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. Results: Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS >= 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar. Conclusions: Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. >= 2) to more accurately predict outcomes. (C) 2019 Published by Elsevier Inc.

4561 Background: Although pazopanib (PAZ) has been evaluated in clinical trials of patients (pts) with renal cell carcinoma (RCC), limited real-world data on the effectiveness and safety of PAZ exist. The PRINCIPAL study (NCT01649778) assessed the effectiveness and safety of first-line PAZ in a real-world setting. Methods: In this nonrandomized, prospective study, pts with advanced and/or metastatic clear cell RCC were enrolled in PRINCIPAL within 30 days of initiating first-line PAZ. Data on progression, survival, and safety were collected approximately every 3 months (mos) until death, consent withdrawal, or loss to follow-up, for up to 30 mos. Pts in PRINCIPAL were separated into two groups based on key eligibility criteria from the Phase III COMPARZ trial (Motzer et al. NEJM. 2013;369:722). Key clinical trial eligible (CTE) criteria included no prior systemic therapy, presence of measurable disease per RECIST 1.1, Karnofsky performance status ≥70, adequate organ system function, no history or clinical evidence of central nervous system metastases, and no coronary or cerebral artery disease at baseline. CTE pts were compared to non-CTE (NCTE) pts. Clinical effectiveness (ie, median overall survival [mOS], median progression-free survival [mPFS], and overall response rate [ORR]), adverse event (AE) measures, and relative dose intensity (RDI) were assessed in both pt populations. Results: Of the 657 enrolled pts who received ≥1 dose of PAZ, 97 (14.8%) were CTE and 560 (85.2%) were NCTE. RDI ≥85% was achieved in 70.1% and 56.6% in the CTE and NCTE populations, respectively. Effectiveness was similar in the CTE and the NCTE populations (mPFS, 9.6 vs 10.7 mos; ORR, 33.0% vs 29.8%; mOS, 26.3 vs 32.9 mos). Serious AEs were reported by 23.7% of CTE and 28.2% of NCTE pts. AEs led to dose adjustment/interruption in 83.5% and 95.2%, respectively, and AEs led to treatment discontinuation in 8.2% of the CTE and 15.5% NCTE pts. Conclusions: The results of the PRINCIPAL study suggest that first-line PAZ for pts with advanced or metastatic RCC remains effective and safe in a real-world setting, showing similar outcomes to those reported in large randomized clinical trials. Clinical trial information: NCT01649778.

4574 Background: PRINCIPAL (NCT01649778) was the largest prospective real-world effectiveness and safety study of pazopanib (PAZ) in patients (pts) with renal cell carcinoma (RCC). Methods: Pts with advanced and/or metastatic clear cell RCC were enrolled within 30 days of initiating first-line PAZ. Follow-up data on progression, survival, and safety was collected approximately every 3 months until death, consent withdrawal, or loss to follow-up, for up to 30 months. Primary efficacy end points were median overall survival (mOS), median progression-free survival (mPFS), and overall response rate (ORR). Safety measures included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Results: Among 657 pts who received ≥1 dose of PAZ, 76.3% completed the study (33.0% completed 30 months of follow-up and 43.2% died). Median enrollment age was 66 years, with 57.2% aged ≥65 years. 4.1%, 62.6%, and 33.3% of pts were grouped as favorable, intermediate, or poor risk by Heng criteria, respectively. Most pts (84%) initiated treatment at 800 mg, and the median treatment time with or without dose interruption was 6.9 and 7.6 months, respectively. mPFS and mOS are shown in the Table. Among the measurable disease population (n = 168), ORR was 30.3%, median duration of response was 11.0 months (95% confidence interval [CI] 8.6-14.6), and time to response, evaluated every 3 months, was 3.0 months (95% CI 2.9-3.1). Most pts had an AE (74.0%) that led to dose adjustment/interruption in 49.3% and treatment discontinuation in 14.6%. The most frequent ( > 10%) drug-related AEs were hypertension (20.9%), diarrhea (11.3%), and increased alanine aminotransferase (11.0%). Conclusions: Real-world effectiveness and safety outcomes in the PRINCIPAL study were consistent with clinical trials and support the first-line use of PAZ across all risk groups of pts with advanced or metastatic RCC. Clinical trial information: NCT01649778. mPFS, months (95% CI) mOS, months (95% CI) All pts 10.4 (9.3-12.0) 29.9 (24.7-NR) Heng risk group · Favorable 16.1 (11.6-26.0) NR (28.6-NR) · Intermediate 12.5 (10.3-15.4) 32.9 (32.9-NR) · Poor 6.7 (5.8-9.1) 14.8 (12.2-19.5) NR, not reached.

Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution. CGS-20625 powder (20 mg) given orally exhibited slow, delayed absorption in both dog and man, with aCmax of 0.26±0.07 μg/ml atTmax of 3 hr in dog, and 0.01±0.004 μg/ml at 2 hr in man. Administration of CGS-20625 in PEG 400 solution improved absorption in dog and man, with aCmax of 1.2±0.10 μg/ml atTmax of 0.25 hr in dog, and aCmax of 0.10±0.04 μg/ml at 0.5 hr in man.Tmax after administration of the hard gelatin capsule formulation was 0.9 and 1.0 hr in dog and man, withCmax of 0.89±0.16 and 0.052±0.014 μg/ml, respectively. Absolute bioavailability of CGS-20625 powder in the dog was 0.67±0.21, whereas the bioavailabilities of the powder and the capsule relative to the PEG 400 solution were 0.84 and 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plasma levels were approximately 10-fold greater and oral clearance was approximately 5-fold less in the dog than in man. Furthermore, pharmacokinetic data were less variable and relative bioavailability was greater in dogs than in humans. Physiological factors in the gastrointestinal tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorption were similar between dog and man, in the order of powder <capsule<PEG 400 solution. In addition,in vivo absorption rates in both species reflectin vitro dissolution differences between the powder and the capsule. These data strongly support the use of the dog as a model for developing improved formulations of CGS-20625. Further investigation of the dog as a model to evaluate insoluble drug absorption is warranted.

The influence of dietary lipid manipulation with menhaden or safflower oil on changes in protein metabolism in rats receiving recombinant interleukin-1 β (IL-1β), tumor necrosis factor alpha/cachectin (TNF), or both combined (COINF) was examined. Whole-body protein kinetics, energy expenditure, nitrogen excretion, and liver and muscle protein synthesis were studied using tracer quantities of l-[1-14C]-leucine. Rats fed menhaden oil, high in ω-3 fatty acids, had significantly lower rates of leucine oxidation compared to safflower-fed rats after monokine infusion (P < .05). However, muscle protein synthetic rates and the specific activity of free leucine in plasma and muscle indicated greater net muscle-protein breakdown in animals fed fish oil or receiving monokines. Rats fed ω-3 fatty acids had significantly larger livers as percent of body weight and more total liver protein than safflower oil controls (P < .0001). Liver weight was further increased by monokines, particularly TNF and COINF (P < .001) in both diet groups, suggesting that net hepatic anabolism occurred at the expense of net skeletal protein catabolism. Monokines as a group and COINF significantly decreased whole-body leucine flux and incorporation into protein; no effect of menhaden oil was noted. In addition, monokines increased nitrogen excretion during the 24-hour experimental period (P < .05), and total energy expenditure rose significantly in all groups receiving IL-1β and COINF. The recombinant monokines IL-1β and TNF, particularly when coinfused, are able to reproduce many of the protein anabolic and catabolic consequences seen following infection and injury. A diet high in ω-3 fatty acids appears to beneficially modulate some of these changes by increasing net anabolism in the liver and reducing overall leucine oxidation.

Since the addition of lipid to intravenous feeding formulas, animal and human studies have shown impairment of the reticuloendothelial system (RES) due to slow rates of clearance and gradual accumulation of long chain triglycerides (LCT) in the liver. Medium chain triglycerides (MCT) accumulate only minimally in the liver and do not impair the RES. However, results from animal studies using technetium sulfur colloid (TSC) to assess RES function have been inconclusive. The present study reevaluates RES function after lipid infusion in guinea pigs as measured by organ distribution of TSC. Guinea pigs were fed 300 kcal/kg/day of total parenteral nutrition (TPN) for 2.5 days, with 50% of nonprotein calories as fat in the form of LCT or MCT, then injected intravenously with 2.5 or 25 microCi of TSC, and uptake by liver, spleen, and lungs was determined. Liver, lungs, and spleen all increased in size after TPN with LCT or MCT. Liver TSC uptake was significantly affected by the dose of TSC (p less than 0.05), with the high dose probably inducing an increased capacity of the liver to clear TSC from the blood. Liver uptake was not influenced by diet, but feeding MCT did significantly stimulate lung uptake of TSC (p less than 0.0001). This suggests that the hepatic TSC uptake system is not saturable, and may not be an appropriate measure of Kupffer cell function since the colloid is not phagocytosed. However, TSC blood clearance remains an excellent prognostic indicator for bacteremia and mortality in humans, and is useful for measuring global RES function.

We evaluated the effect of total parenteral nutrition (TPN) enriched with n-3 fatty acids on the physiologic response to endotoxin in guinea pigs. Animals were randomly assigned to receive TPN differing only in lipid source for 3.5 d. Group 1 received soybean fat emulsion (Intralipid) whereas group 2 received fish (menhaden) oil. During the last 7 h of TPN, animals were further randomized to have either saline or E coli endotoxin added to the infusate. Acid-base status and serum lactate concentrations were determined. Animals infused with soybean fat emulsions and endotoxin developed a significant metabolic acidosis, lactic acidemia, and decrease in mixed venous O2 compared with controls and fish-oil-treated animals (p less than 0.05). The significantly reduced serum lactate and higher mixed venous O2 in fish-oil-infused animals suggests that the underlying mechanism involves improvement in endotoxin-induced tissue hypoperfusion, presumably through alterations in prostaglandin metabolism.

Correlation of hepatocellular adenine nucleotides in donor liver with clinical posttransplant outcome has recently been reported. Our earlier work with rats has shown that pretreatment of donors with glucose effectively retards hepatocellular ATP losses in livers preserved in Collins' II solution through potentiation of their glycolytic capacity. The primary substrate--i.e., endogenous or exogenous glucose--was not identified. The current study was undertaken to compare the relative efficacy of the University of Wisconsin (UW) solution, which is devoid of glucose, with Collins' II in the support of adenine nucleotides through anaerobic glycolysis in flush-preserved rat liver. Adult rats were either pretreated with 25% dextrose or fasted prior to liver harvesting and preservation in either UW or Collins' II. Adenine nucleotide degradation and lactate production during preservation were assessed. For a given dietary pretreatment, losses of ATP and adenylate energy charge and lactate production were similar for UW- and Collins' II-preserved livers. Donor pretreatment with dextrose resulted in significantly higher ex vivo liver ATP, energy charge, and lactate regardless of the preservation solution. Salvageable nucleotide degradates were increased significantly in UW livers, presumably through the effects of allopurinol. These results demonstrate that effective support of adenine nucleotides by glycolysis in flush-preserved liver is independent of the presence of exogenous glucose but dependent upon the nutritional status of the donor prior to liver procurement.

Recent studies of human donor livers indicate an association between ex vivo hepatocellular adenosine triphosphate and posttransplant graft function. To test the hypothesis that prior glucose loading of donor liver would optimize its adenosine triphosphate production and adenylate energy charge during ex vivo organ preservation, adult male rats were randomized to receive either intravenous dextrose or saline for 44 h. After this infusion, a liver lobe was exposed and freeze-clamped (time 0). The remaining liver was quickly flushed, excised, and stored in Collins' II solution at 2 degrees C for 8 h. Additional lobes were freeze-clamped at 1, 4, and 8 h. Liver adenosine triphosphate, total nucleoside triphosphates, and energy charge losses were significantly reduced in the dextrose-treated rats in comparison with saline-treated rats during the first 4 h of preservation. Although the livers from rats receiving intravenous dextrose were able to generate lactate, their glycogen stores were not utilized appreciably, suggesting that exogenous glucose served as a substrate for anaerobic glycolysis. Unesterified choline levels of the fasted rat livers were significantly higher than those from the rats receiving intravenous dextrose by the first hour, indicative of increased membrane breakdown. These results indicate that prior infusion of glucose enhances the capacity of the ex vivo liver, presumably through the induction and stabilization of key glycolytic enzymes, to anaerobically generate adenosine triphosphate. Administration of glucose to liver donors before organ procurement may improve post-transplant graft function by reducing the loss of hepatocellular energy, retarding membrane damage, and fostering glycogen storage for use in the early postoperative period.