Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors.

Background: Brontictuzumab is a monoclonal antibody that targets Notch1 and inhibits pathway activation. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, immunogenicity and preliminary efficacy of brontictuzumab in patients with solid tumors. Patients and methods: Subjects with selected refractory solid tumors were eligible. Brontictuzumab was administered intravenously at various dose levels and schedule during dose escalation, and at 1.5 mg/kg every 3 weeks (Q3W) during expansion. Evidence of Notch1 pathway activation as determined by an immunohistochemistry assay was required for entry in the expansion cohort. Adverse events were graded according to the NCI-CTCAE v 4.03. Efficacy was assessed by RECIST 1.1. Results: Forty-eight subjects enrolled (33 in dose escalation and 15 in the expansion phase). The MTD was 1.5 mg/kg Q3W. Dose-limiting toxicities were grade 3 diarrhea in two subjects and grade 3 fatigue in one subject. The most common drug-related adverse events of any grade were diarrhea (71%), fatigue (44%), nausea (40%), vomiting (21%), and AST increase (21%). Brontictuzumab exhibited nonlinear pharmacokinetics with dose-dependent terminal half-life ranging 1-4 days. Clinical benefit was seen in 6 of 36 (17%) assessable subjects: 2 had unconfirmed partial response (PR) and 4 subjects had prolonged (≥ 6 months) disease stabilization (SD). Both PRs and three prolonged SD occurred in adenoid cystic carcinoma (ACC) subjects with evidence of Notch1 pathway activation. Pharmacodynamic effects of brontictuzumab were seen in patients' blood and tumor. Conclusion: Brontictuzumab was well tolerated at the MTD. The main toxicity was diarrhea, an on-target effect of Notch1 inhibition. An efficacy signal was noted in subjects with ACC and Notch1 pathway activation. ClinicalTrials.gov identifier: NCT01778439.

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.

BACKGROUND: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). METHODS: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. RESULTS: 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed. CONCLUSIONS: ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors.

BACKGROUND: Fibroblast growth factors (FGFs) play important roles in multiple cancers by supporting tumor growth and angiogenesis. FP-1039 (GSK3052230) is a FGF ligand trap consisting of the extracellular domain of FGF receptor 1 (FGFR1) fused with the Fc region of IgG1. FP-1039 binds and neutralizes multiple FGFs that normally bind FGFR1. The primary objective of this phase I study was to evaluate the safety and tolerability of FP-1039. PATIENTS AND METHODS: Eligible patients with metastatic or locally advanced solid tumors for which standard treatments were ineffective were treated with weekly doses of FP-1039 for 4 weeks, followed by 2 weeks observation. RESULTS: Thirty-nine subjects received a mean of 6 infusions of FP-1039 at doses ranging from 0.5 to 16 mg/kg weekly, with no maximally tolerated dose identified. Grade 3 or greater treatment emergent adverse events were uncommon. Four dose-limiting toxicities were reported at doses of 0.75 mg/kg (urticaria), 1 mg/kg (intestinal perforation and neutropenia), and 16 mg/kg (muscular weakness). Drug exposure was dose proportional, and the terminal elimination half-life was 2.6-3.9 days following a single dose. Target engagement as measured by low free plasma FGF2 levels was achieved. FGF pathway dysregulation was uncommon. No objective responses were observed. CONCLUSION: In nonselected cancer patients with advanced disease, treatment with FP-1039 was well tolerated and toxicities associated with small molecule drugs that inhibit FGFR tyrosine kinases, including hyperphosphatemia, were not observed. Further studies of FP-1039 in patients selected for FGF pathway dysregulation, who are most likely to benefit, are now underway.

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.

BACKGROUND: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib. METHODS: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib. RESULTS: Forty-one patients enrolled at doses ⩽20 mg kg(-1). Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4-18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17-0.26 ml h(-1) kg(-1)), a half-life of 6.8-9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels. CONCLUSIONS: Recommended phase II dose is 20 mg kg(-1) q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.

Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective.

Atherosclerotic renal artery stenosis (ARAS) is frequently associated with concomitant coronary and peripheral arterial disease with a significant impact on cardiovascular morbidity and mortality. Renal angioplasty of ARAS is more challenging because of increased incidence of technical failures, complications, and restenosis; while there is barely perceptible control of hypertension and only marginal improvement in renal function. This is because most of the patient population in recent randomized trials had unmanifested or clinically silent renovascular disease. Manifestations of RAS should be looked for and incorporated in the management plan particularly before deciding for revascularization. In the absence of clinical manifestation like renovascular hypertension, ischemic nephropathy, left ventricular failure, or unstable coronary syndromes; mere presence of RAS is analogous to presence of concomitant peripheral arterial disease which increases risk of adverse coronary events. Dormant-RAS in the absence of any manifestations can be managed with masterly inactivity. Chronological sequence of events and clinical condition of the patient help in decision making by identifying progressive renovascular disease. Selecting patients for renal artery stenting who actually will benefit from revascularization shall also decrease the unnecessary complications inherent with any interventional procedure. The present review is an attempt to analyze the current view on the diagnostic and management issues more specifically about the need and rationale behind angioplasty.

Brucella endocarditis - a series of five case reports.

Endocarditis due to brucellosis is considered a rare occurrence involving native, congenital and prosthetic valves. The diagnosis needs high degree of suspicion in culture negative endocarditis especially in those with history of exposure to farm animals. A positive culture in a susceptible patient confirms the diagnosis with 91% sensitivity. An early diagnosis and prompt treatment with appropriate antibiotics can restore the valve structural integrity with minimal damage. Here we present a series of five cases of culture proven Brucella endocarditis (four native valves, one prosthetic valve) and this report discusses the diagnostic and management issues involved.

Magnetic hydrogel particles improve nanopore sequencing of SARS-CoV-2 and other respiratory viruses.

Presented here is a magnetic hydrogel particle enabled workflow for capturing and concentrating SARS-CoV-2 from diagnostic remnant swab samples that significantly improves sequencing results using the Oxford Nanopore Technologies MinION sequencing platform. Our approach utilizes a novel affinity-based magnetic hydrogel particle, circumventing low input sample volumes and allowing for both rapid manual and automated high throughput workflows that are compatible with Nanopore sequencing. This approach enhances standard RNA extraction protocols, providing up to 40 × improvements in viral mapped reads, and improves sequencing coverage by 20-80% from lower titer diagnostic remnant samples. Furthermore, we demonstrate that this approach works for contrived influenza virus and respiratory syncytial virus samples, suggesting that it can be used to identify and improve sequencing results of multiple viruses in VTM samples. These methods can be performed manually or on a KingFisher automation platform.

A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

Gadolinium-enhanced three-dimensional magnetic resonance angiographic assessment of the pulmonary artery anatomy in cyanotic congenital heart disease with pulmonary stenosis or atresia: comparison with cineangiography.

Pulmonary stenosis (PS) or pulmonary atresia (PA) is an important component of complex cyanotic congenital heart disease, especially in tetralogy of Fallot or lesions with ventricular septal defect (VSD)-PS physiology. Management strategy in these patients depends on accurate assessment of PAs and identification of all sources of pulmonary blood flow. X-ray cineangiography is the "gold standard" for this purpose, but it has the inherent risks of an invasive procedure. Gadolinium-enhanced three-dimensional magnetic resonance angiography (Gd-MRA) has been shown to noninvasively and accurately evaluate various lesions of the vascular system. This study was undertaken to evaluate the accuracy of Gd-MRA compared with cineangiography in the evaluation of pulmonary anatomy. Nineteen patients having complex cyanotic heart disease with PS or PA were included in the study. All patients underwent Gd-MRA and cineangiography. Catheterisation and MRA findings regarding the anatomic variable of interest were analysed for agreement by Bland-Altman analysis. There was total agreement between the two modalities in the delineation of confluent PAs. McGoon's ratio and the Nakata index, which are standard measures of the adequacy of PA size, also showed excellent agreement between the two modalities. MRA was able to delineate all aorto-pulmonary collaterals in the setting of PA. MRA can delineate all sources of pulmonary blood supply in cyanotic congenital heart disease with PS and/or PA as well as provide accurate assessment of PA size for planning corrective surgery.

Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors.

BACKGROUND: Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. MATERIALS AND METHODS: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors. RESULTS: Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected. CONCLUSIONS: Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.

Hydrogel particles improve detection of SARS-CoV-2 RNA from multiple sample types.

Here we present a rapid and versatile method for capturing and concentrating SARS-CoV-2 from contrived transport medium and saliva samples using affinity-capture magnetic hydrogel particles. We demonstrate that the method concentrates virus from 1 mL samples prior to RNA extraction, substantially improving detection of virus using real-time RT-PCR across a range of viral titers (100-1,000,000 viral copies/mL) and enabling detection of virus using the 2019 nCoV CDC EUA Kit down to 100 viral copies/mL. This method is compatible with commercially available nucleic acid extraction kits (i.e., from Qiagen) and a simple heat and detergent method that extracts viral RNA directly off the particle, allowing a sample processing time of 10 min. We furthermore tested our method in transport medium diagnostic remnant samples that previously had been tested for SARS-CoV-2, showing that our method not only correctly identified all positive samples but also substantially improved detection of the virus in low viral load samples. The average improvement in cycle threshold value across all viral titers tested was 3.1. Finally, we illustrate that our method could potentially be used to enable pooled testing, as we observed considerable improvement in the detection of SARS-CoV-2 RNA from sample volumes of up to 10 mL.

Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors.

OBJECTIVE: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. PATIENTS AND METHODS: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 x 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 x 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. RESULTS: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 - 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. CONCLUSION: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.

Nonhematopoietic neoplasms in cats.

In a study of 3,145 feline necropsies conducted for 11 years by the pathology department of The Animal Medical Center, 289 tumors of nonhematopoietic origin were found in 264 cats. Malignant and epithelial tumors were more common than benign or mesenchymal tumors in all ages and breeds, and in both sexes. They were also more common in female cats than in males, even after mammary neoplasms were excluded. Analysis of groups of tumors according to their tissue of origin indicated some sex and breed dispositions not observed before. Pulmonary carcinomas and osteosarcomas were more frequent in domestic short haired cats than in other breeds, whereas intestinal carcinomas occurred more often in Siamese cats. Female predominated in pulmonary carcinomas, hemangiosarcomas, osteosarcomas, and squamous cell carcinomas, but males outnumbered the females in intestinal carcinomas.

Estrogen receptors in canine mammary tumors.

The presence of estrogen receptor in 67 canine mammary lesions was correlated with pathological features of the disease. All tissue specimens were analyzed for estrogen receptor content by a sucrose gradient ultracentrifugation method previously used in analyzing human breast cancer cytosols. Pathological features of the tissues were assessed by a veterinary pathologist without knowledge of results of estrogen receptor analysis. Sixty-two (92.5%) of the tissue samples analyzed were classified as epithelial neoplastic lesions, and 38 of these (61.3%), including 24 adenocarcinomas, were estrogen receptor for positive (i.e., estrogen receptor concentration equal to or greater than 10 fmol/mg cytosol protein). All five of the nonepithelial neoplastic lesions were estrogen receptor negative. Canine and human breast cancers share common histological types and have similar biological behavior. If a significant percentage of canine mammary cancer is also estrogen dependent, the dog may be a useful model for hormonal studies and for the development of models of endocrine therapy for human breast cancer.

Phase I/II trial of cyclophosphamide, mitoxantrone, and escalated doses of carboplatin supported by peripheral-blood stem cells in women with metastatic breast cancer.

PURPOSE: To intensify a regimen of high-dose cyclophosphamide, mitoxantrone, and carboplatin that had previously produced high complete and overall response rates in metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 43 years (range, 25 to 57 years) and previously untreated MBC who were responding to anthracycline-based or single-agent taxane chemotherapy received cyclophosphamide 1.5 g/m(2)/d and mitoxantrone 16 mg/m(2)/d combined with escalating doses of carboplatin 200 to 500 mg/m(2)/d, each given daily from days -6 to -3. Hematopoiesis was supported by mobilized peripheral-blood stem cells infused on day 0 and by use of granulocyte-macrophage colony-stimulating factor 300 microg/d subcutaneously starting on day 1. RESULTS: A total of six dose levels of carboplatin were examined. Grades 3 and 4 toxicity occurred in 10 patients and one patient, respectively, with grade 3 toxicity occurring in only five of 31 patients treated with < or = 400 mg/m(2) of carboplatin. Major dose-limiting toxicities were cardiac, pulmonary, and renal. Four patients developed congestive heart failure: two had persistently low ejection fraction 11 and 36 months after peripheral-blood stem-cell transplantation (PBSCT), and two recovered. Hematologic recovery to an absolute neutrophil count of greater than 0.5 x 10(9)/L occurred at a median of 11 days (range, 8 to 25 days) and to a platelet count of greater than 20 x 10(9)/L at a median of 10.5 days (range, 6 to 60 days). There were two toxic deaths from sepsis: one on day 27 (level 5) and one from cardiac arrest on day 42 (level 6). CONCLUSION: The maximum-tolerated dose of carboplatin was 400 mg/m(2)/d in combination with mitoxantrone 16 mg/m(2)/d and cyclophosphamide 1,500 mg/m(2), all drugs given over 4 days. This regimen is being tested in a phase III trial of high-dose chemotherapy and PBSCT versus standard treatment.