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1. Interim results from trial of SL-801, a novel XPO-1 inhibitor, in patients with advanced solid tumours

Author

Jing Wang, S. Shemesh, D. Qi, J. Bullington, Kevin D. Courtney, J. Chen, Todd M. Bauer, C. Brooks, E. Chiorean, M. Sardone, Patricia LoRusso, and Minal A. Barve

Subjects
medicine.medical_specialty, Poor prognosis, business.industry, Tumor shrinkage, Stock options, Hematology, Clinical trial, Oncology, Family medicine, Interim, Maximum tolerated dose, medicine, Data monitoring committee, In patient, business, health care economics and organizations
Abstract

Background SL-801 is a novel, oral, small molecule that reversibly inhibits Exportin-1 (XPO-1), a nuclear export protein, overexpressed in a variety of solid and hematologic malignancies. XPO-1 is a mediator of nuclear-cytoplasmic transport of over 200 nuclear proteins and has been associated with aggressive tumor behavior and poor prognosis. SL-801 has demonstrated potent in vitro and in vivo activity. Interim results from the dose-escalation stage are reported. Methods STML-801-0115 is a first-in-human, multicenter dose and schedule finding study in patients with localized unresectable, or metastatic solid tumors that are refractory to or are relapsed after treatment with standard therapy. Objectives are to identify the maximum tolerated dose or optimal dose/schedule, and assess pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. SL-801 was initially orally administered on days 1-4 and 8-11 of a 21-day cycle (Schedule A). The dosing schedule has been amended to potentially allow a longer recovery time between dosing periods while maintaining dose intensity. Patients are now receiving SL-801 once daily on days 1-2, 8-9, 15-16 and 22-23 of a 28-day cycle (Schedule B). The starting dose in the study was 5 mg/day in Schedule A; current study dose level is 70 mg/day in Schedule B. Results 45 patients received 5-65 mg/day of SL-801 in Schedule A (median age 63 YO [range: 39-83], 51% females, median number of prior systemic therapies, 4 [range: 2-10]; 57% received 3 or more. Common treatment-emergent adverse events (TEAEs) were nausea (62%), vomiting (64%), fatigue (44%), decreased appetite (33%), and diarrhea (29%). Grade 3 TEAEs included nausea (9%), anemia (7%), and fatigue, diarrhea, hyponatremia and hypophosphatasemia (each 4%). Most TEAEs were grade 1-2; no grade 4-5 toxicities reported. 12 patients (27%) had stable disease (SD) and remained on study for 2-11 months including 5 with SD for 4+ months. 1 patient with basal cell carcinoma had SD for 11 months. 3 patients had radiographic tumor shrinkage of 14-20% in target lesions. Conclusions SL-801 reversibly binds XPO1, a clinically validated target in oncology. To date 27% of heavily pre-treated patients have achieved SD as best response. Enrollment and dose escalation continue. Clinical trial identification NCT02667873. Legal entity responsible for the study Stemline Therapeutics. Funding Stemline Therapeutics. Disclosure J. Wang: Speaker Bureau / Expert testimony: AstraZeneca. E. Chiorean: Research grant / Funding (institution): Boehringer-Ingelheim, Merck, BMS, Lilly, Stemline, Ignyta/Roche, Incyte, Halozyme; Advisory / Consultancy: AstraZeneca, Array, Ipsen, Eisai, Halozyme, Seattle Genetics, Vicus, Five Prime. P. LoRusso: Advisory / Consultancy: abbvie; Advisory / Consultancy, data safety monitoring board: agios; Advisory / Consultancy: alexion; Advisory / Consultancy: ariad; Advisory / Consultancy, data safety monitoring committee: Five prime; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy, data safety monitoring: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy, data safety monitoring committee: Tyme. K. Courtney: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Aragon; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (institution): PSMA Development; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Peloton; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Proacta; Spouse / Financial dependant, Receives patent royalties: Athena Diagnostics, Inc. D. Qi: Advisory / Consultancy: stemline. J. Bullington: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. M. Sardone: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. C. Brooks: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. S. Shemesh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. T.M. Bauer: Full / Part-time employment: Tennessee Oncology; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Loxo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto, Inc; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.

Published
2019
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3. Phase I study of the effects of renal impairment on the pharmacokinetic (PK) and safety of satraplatin in patients (Pts) with refractory non-hematologic cancer

Author

D. S. Hong, M. Galsky, E. Chiorean, D. Mulkerian, D. Greene, F. E. Nathan, M. Petrone, and L. H. Camacho

Subjects
Cancer Research, Oncology
Abstract

2044 Background: Satraplatin (S) is a novel oral platinum analog with demonstrated activity in the treatment of pts with platinum-sensitive malignancies. A worldwide, double-blind, placebo-controlled randomized trial evaluating S as 2nd line therapy for hormone refractory prostate cancer (HRPC) has recently completed enrollment. The current study wasis designed to understand the effect of varying degrees of renal impairiment on the safety and PK of satraplatin. Methods: The study includes 4 levels of renal dysfunction, and 8 pts/cohort: Group 1 (G1) = Normal Renal Controls; G2 = Mild renal impairment (CrCl 50–80 mL/min); G3 = Mod. impairment (CrCl 30-2/d on d1–5 every 35 days. Results: 21 pts (of a planned total of 32) have been enrolled (13M/8F), median age 63 (range 45–72). Tumor types: Bladder (6), Renal (3), Breast (2), Prostate (2), Colon (2), Other (6). Among 15 evaluable pts, the cohort distribution is G1: 6 pts, G2: 4, G3: 4, and G4: 1. Twenty-six cycles of S have been delivered, and 11 pts have completed at least 2 cycles of therapy. Hematologic toxicities during the first 2 cycles include grade (G) 3/4 neutropenia (0 pts), G 3/4 thrombocytopenia (1), and G 3/4 anemia (1). No significant cardiac, renal, hepatic, or neurologic toxicity has been observed. Nausea, vomiting, and diarrhea were mild to moderate, and controlled with oral therapy. Of 4 pts with evaluable disease, 1 has stable disease, and 3 have progressed. Conclusions: S is well tolerated in pts with varying degrees of renal dysfunction. Updated safety and PK data will be presented at the meeting. [Table: see text]

Published
2006
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4. Common variants of ABCB4 and ABCB11 and plasma lipid levels: a study in sib pairs with gallstones, and controls.

Author

Acalovschi M, Tirziu S, Chiorean E, Krawczyk M, Grünhage F, and Lammert F

Subjects
ATP Binding Cassette Transporter, Subfamily B, Member 11, Alleles, Female, Genotype, Humans, Male, Middle Aged, Polymerase Chain Reaction, Siblings, ATP Binding Cassette Transporter, Subfamily B genetics, ATP-Binding Cassette Transporters genetics, Gallstones blood, Gallstones genetics, Genetic Variation, Lipids blood, Polymorphism, Genetic
Abstract

Most epidemiological surveys have confirmed the association of low HDL-cholesterol and high triglyceride levels with cholesterol gallstones. Our objective was to analyze the relationship between plasma lipid levels and common polymorphisms of ABCB11 (encoding the bile salt export pump, BSEP) and ABCB4 (encoding the phospholipid transporter into bile, MDR3) genes. Plasma lipids were measured in 108 index patients of sib pairs with gallstones and in 260 controls. Using PCR-based assays with 5'-nuclease and fluorescence detection (TaqMan), the ABCB11 coding SNP p.A444V and four haplotype-tagging SNPs covering the ABCB4 gene (c.504C > T, c.711T > A, p.R652G, rs31653 in intron 26) were genotyped. Plasma lipids were compared in carriers of the common versus rare allele of these polymorphisms using Student's t test and Pearson's correlation. BMI and triglyceride levels were higher and HDL-cholesterol levels were lower in affected siblings than in controls. Among cases, triglyceride and cholesterol levels were higher in carriers of the common versus rare (hetero/homozygous carriers) allele of the SNPs p.A444V of ABCB11 and C.504C > T of ABCB4. HDL-cholesterol was lower in carriers of the common allele of rs31653. In controls, significant differences of cholesterol and HDL-cholesterol levels were found in carriers of ABCB4 polymorphisms. Our results do not support the hypothesis of a link between ABCB4 and ABCB11 polymorphisms, lithogenic dyslipidemia, and gallstone risk.

Published
2009
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5. Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms? A preliminary study in siblings with gallstones.

Author

Acalovschi M, Ciocan A, Mostean O, Tirziu S, Chiorean E, Keppeler H, Schirin-Sokhan R, and Lammert F

Abstract

Background: The role of ABCG5 and ABCG8 genes in the determination of plasma lipid levels is currently under intensive investigation. The aim of this study was to evaluate plasma lipid levels in sibling pairs with gallstones and to assess their correlation with common gene polymorphisms in the ABCG5/ABCG8 genes., Methods: Plasma levels of cholesterol, HDL-cholesterol, and triglycerides were measured in 68 patients belonging to 34 sibling pairs with gallstones (affected sibling pairs, mean age 56.3 years) and in 68 gallstone carriers with stone-free siblings (age/gender-matched controls in a ratio of 2:1 with the index patients of the study group). Four and one non-synonymous sequence variants in ABCG8 and ABCG5 genes, respectively, were determined in the affected sibling pairs, employing allelic discrimination with 5' nuclease assays., Results: Plasma triglyceride levels were higher and HDL-cholesterol levels lower in the index patients than in controls. Plasma lipid levels were correlated in the members of the affected sibling pairs. Triglyceride levels were higher in carriers of the common alleles for ABCG5 Q604E and ABCG8 D19H sequence variants, and HDL-cholesterol was lower in carriers of the common alleles for ABCG5 Q604E than in carriers of the rare alleles., Conclusions: The significantly different plasma lipid levels in siblings with gallstones versus controls, as well as the correlation of plasma lipids in affected sibling pairs, confirm the genetic influence in gallstone disease. Polymorphisms in ABCG5/ABCG8 genes might contribute to the genetic variation in plasma lipid levels and in cholesterol saturation of the bile.

Published
2006
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6. Eosinophilic ascites in a patient with toxocara canis infection. A case report.

Author

Chira O, Badea R, Dumitrascu D, Serban A, Branda H, al Hajjar N, Chiorean E, and Cruciat C

Subjects
Adolescent, Animals, Antibodies, Helminth immunology, Ascites diagnostic imaging, Ascites pathology, Biopsy, Diagnosis, Differential, Endoscopy, Gastrointestinal, Eosinophilia diagnostic imaging, Eosinophilia pathology, Female, Humans, Laparoscopy, Toxocara canis immunology, Toxocariasis parasitology, Toxocariasis pathology, Ultrasonography, Ascites etiology, Eosinophilia etiology, Toxocariasis complications
Abstract

We report the case of a young female patient, admitted for a recent ascites of unknown origin. The acute onset was with colicky abdominal pain and peritoneal effusion, which led to the suspicion of perforated ulcer. A diagnostic laparoscopy was performed which showed free peritoneal fluid and normal abdominal viscera. At upper gastro-intestinal endoscopy, performed a few days later, patchy erythema in the antral region and duodenal edema were revealed. Duodenal biopsies showed marked eosinophilic infiltration. The ascitic fluid was straw coloured, sterile with 90% eosinophils. Eosinophilic gastroenteritis was suspected, but differential diagnosis required the exclusion of migrant parasites. The stool exams were negative but serology for Toxocara antibodies was positive. The treatment with albendazole (Zentel 400 mg twice a day for 5 days) led to the disappearance of signs and symptoms. The eosinophilic infiltrate of the gut was absent in duodenal biopsies taken two months later.

Published
2005

7. The prevalence of anti-Helicobacter pylori antibodies in the patients with ischemic heart disease.

Author

Andreica V, Sandica-Andreica B, Draghici A, Chiorean E, Georoceanu A, and Rusu M

Subjects
Alcohol Drinking adverse effects, Anti-Inflammatory Agents administration & dosage, Chi-Square Distribution, Female, Helicobacter Infections blood, Humans, Male, Middle Aged, Prevalence, Risk Factors, Smoking adverse effects, Water Supply, Antibodies, Bacterial blood, Helicobacter Infections complications, Helicobacter pylori, Myocardial Ischemia microbiology
Abstract

The authors proposed to assess the prevalence of anti-Hp antibodies (IgG class) in patients with ischemic heart disease. The study included 93 patients distributed into two groups: a) group A--61 patients with ischemic heart disease; b) group B--32 controls. The Hp infection diagnosis was established by determination of the Hp antibodies in the peripheral blood. Hp infection was correlated with the following factors: (a) smoking, alcohol consumption, antiinflammatory drugs intake and water source; (b) biological parameters (fibrinogen, alpha1-globulins, cholesterol, triglycerides, thrombocyte count). In the patients with ischemic heart disease the prevalence of the Hp infection was 78.3%, and in controls 56.2% (p<0.05). The patients consuming alcohol and smoking had a significantly higher prevalence than controls. Antiinflammatory drugs and water source did not influence the prevalence of the Hp infection. Among the biological parameters, fibrinogen and alpha1 globulins were significantly increased in the Hp-positive patients with ischemic heart disease. In conclusion, the serum prevalence of anti-Hp antibodies was higher in the patients with ischemic heart disease, smokers and alcohol consumers than in health individuals.

Published
2004

8. Whipple's disease. Case report.

Author

Andreica V, Pascu O, Hagiu C, Paşca D, Dumitra D, Dumitraşcu DL, Chiorean E, and Georoceanu A

Subjects
Abdominal Pain etiology, Endoscopy, Gastrointestinal, Fatigue, Humans, Male, Middle Aged, Penicillins therapeutic use, Treatment Outcome, Weight Loss, Whipple Disease diagnosis, Diarrhea etiology, Whipple Disease drug therapy, Whipple Disease pathology
Abstract

The paper reports the clinical case of a 58 -year-old male patient admitted for diarrhea (6-7 stools/day, diffuse abdominal pain, borborygma, weight loss (20 kgs in two years), asthenia and fatigue. Physical examination evidenced a poor nutritional state (body mass index 19 kg/m2). The abdomen was slightly distended. Biological tests evidenced moderate/severe anemia, hypoproteinemia and hypoalbuminemia. Endoscopic examination evidenced oedematous duodenal mucosa with white-yellowish deposits. Histology (HE stain) revealed the presence of foamy cells and the PAS-staining of the duodenal mucosa evidenced PAS-positive macrophages and numerous intracellular bacilli. Penicillin therapy 2 x 1 million U/day for 14 days, followed by tetracycline 4 x 250 mg/day improved the clinical picture, the patient had only one stool per day and gained weight. After 7 months of treatment the general condition was good and the patient had gained 17 kgs, the duodenal mucosa was normal. HE staining did not evidence foamy cells and no PAS-positive macrophages could be found.

Published
2002

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