A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers.

LESSONS LEARNED: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma. BACKGROUND: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. METHODS: Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit. RESULTS: Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days). CONCLUSION: OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.

Safety and efficacy of targeted-dose busulfan and bortezomib as a conditioning regimen for patients with relapsed multiple myeloma undergoing a second autologous blood progenitor cell transplantation.

Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 µM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.

Examination of the Vitreolenticular Interface in Relation to Uneventful Phacoemulsification over One-Year Postoperative Period.

Background: Swept-source anterior segment optical coherence tomography (SS-AS-OCT) is a suitable examination for the vitreolenticular interface. Methods: In a prospective study using Anterion (Heidelberg Engineering, Heidelberg, Germany), 102 eyes of 102 patients were examined in pupil dilation, preoperatively and 6 times over 1-year follow-up. Preoperatively anterior hyaloid membrane (AHM) visibility was determined with Imaging App with high reliability. Postoperatively capsular bag-AHM distance was measured on six points by using Metrics App. Results: The AHM was visible in 18.6% preoperatively and postoperatively as well (Group 1), 49% of the preoperatively adherent AHMs became visible (Group 2A), 32.4% remained attached (Group 2B). Group 1: the average deepest point on the first day was 782.5 ± 324.1 microns, and it significantly differed from the later follow-up values. Group 2A: the average deepest value was 184.1 ± 220.1 microns, and there was no statistically significant difference between the postoperative visit values. The difference between the groups was statistically significant at every location and at each time point. Conclusions: AS-SS-OCT can be used to check BS both preoperatively (with limitations) and postoperatively.

[Superior vena cava syndrome associated with bilateral angle closure glaucoma]. / A vena cava superior szindrómához társuló kétoldali zárt zugú glaucoma.

Superior vena cava syndrome is a set of symptoms resulting from partial or complete blockage of the superior vena cava. In the majority of cases, it develops secondary to lung tumors and lymphoma. It is characterized by edema of the head, neck, and upper limbs, large veins, and dyspnoea. Ophthalmological changes related to the syndrome rarely occur: eyelid swelling, conjunctival chemosis and suffusion have been described previously, and in one case, elevated episcleral pressure was also reported. Our 57-year-old female patient's superior vena cava syndrome was resolved with stent placement, and her small cell lung tumor was treated with chemotherapy. As part of the syndrome, he complained of bilateral blurred vision with a history of 4 months. During his examination, we found a bilateral closed angle, an intraocular pressure of 60 mmHg on both sides, and severe visual impairment. We performed a lens exchange combined with better semolysis, which achieved a significant reduction in intraocular pressure and managed to preserve the remaining visual acuity. After Nd:YAG laser iridotomy on the left eye, we started antiglaucoma drop treatment to reduce pain. After phacoemulsification, the morphology of the anterior chamber in the right eye improved significantly, which could be quantified by anterior segment optical coherence tomography. The ophthalmic parameters remained stable during the treatment of the underlying disease. The purpose of this publication is to draw attention to the ophthalmic symptoms of vena cava syndrome as well as to present the ophthalmic condition that sometimes accompanies the syndrome causing rapid, severe visual impairment, which, to our knowledge, has not been described before. Orv Hetil. 2022; 163(49): 1967-1971.

Clinical experience with an anti-dysphotopic intraocular lens.

PURPOSE: Report experience regarding an anterior capsulotomy fixated intraocular lens (IOL) designed to prevent negative dysphotopsia (ND). METHODS: A prospective, nonrandomized clinical study was done at Péterfy Sándor Street Hospital-Clinic, and Jeno Manninger National Trauma Institute, Budapest, Hungary. The Morcher (Masket) 90S IOL has a circumferential groove on the optic that captures the anterior capsulotomy. Thus, part of the optic projects over and anterior to the capsule edge, while the bulk of the IOL is fixated within the capsular bag. We implanted the first version of the 90S IOL into the 40 eyes of 38 patients. These 40 eyes made up the primary investigational cohort. An additional 22 eyes received a modified version of the 90S IOL. The main outcome measure was the presence of ND. There was also a control group of 40 patients who received a single-piece monofocal aspheric hydrophobic acrylic IOL (877 FAB, Medicontur, Budapest, Hungary). RESULTS: None of our 66 test patients experienced ND during the follow-up period. After specific questioning, six patients reported nondebilitating PD that improved or disappeared completely in 5 cases. For the 40 eyes of the control group, there were 10 cases of ND on the first postoperative day and in 2 cases ND persisted for more than 1 year postoperatively. CONCLUSION: The 90S IOL can be used successfully to prevent ND. Since it is fixated by the anterior capsulotomy, additional advantages such as prevention of anterior capsule contraction, limited tilt, stable toric axis, perfect centration on the visual axis, and a more predictable lens position, among others, may be expected, and are under investigation.

Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) and biologic activity of OPB-31121, an oral inhibitor of STAT3, administered twice daily (BID) to subjects with advanced solid tumors. METHODS: Subjects received escalating doses of OPB-31121 BID for the first 21 days of each 28-day cycle in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), safety, pharmacokinetics, and antitumor activity were assessed. RESULTS: Thirty subjects were treated twice daily with OPB-31121 at 6 dose levels: 50 mg (n = 4); 70 mg (n = 3); 140 mg (n = 3); 200 mg (n = 4); 300 mg (n = 9); 350 mg (n = 7). There were no DLTs observed until 300 mg BID (Grade 3 lactic acidosis). At the next dose level (350 mg BID), two subjects had DLTs (Grade 3 vomiting and Grade 3 diarrhea). Thus, 300 mg BID was declared the MTD. OPB-31121-related adverse events included nausea (80 %), vomiting (73 %), diarrhea (63 %), and fatigue (33 %), all of which were primarily grade 1/2. Pharmacokinetics demonstrated high inter-subject variability with exposures 146- to 4,788-fold lower than target concentrations from tumor-bearing mouse models. No objective responses were observed, and all subjects who completed two cycles of treatment had disease progression at their first assessment. CONCLUSIONS: Twice-daily administration of OPB-31121 was feasible up to doses of 300 mg. The pharmacokinetic profile was unfavorable, and no objective responses were observed.