A phase I pharmacokinetic study of copanlisib in Chinese patients with relapsed indolent non-Hodgkin lymphoma.

PURPOSE: Copanlisib, a pan-PI3K inhibitor, has previously shown clinical efficacy and a tolerable safety profile in patients with indolent non-Hodgkin lymphoma. However, the pharmacokinetics, safety, tolerability, and efficacy of copanlisib in Chinese patients have not been reported. METHODS: This was a single-arm, open-label, phase I study of copanlisib in Chinese patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Patients received a single intravenous 60 mg infusion of copanlisib over 1 h on days 1, 8, and 15 of a 28-day cycle, with 1 week of rest. Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis. Tumor response was determined by independent central radiologic review. RESULTS: Sixteen patients were enrolled and 13 were treated with 60 mg of copanlisib for a median of 15.0 weeks. With a Cmax of 566 µg/L and a AUC (0-24) of 1880 µg·h/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed. Treatment-emergent adverse events were reported for all 13 patients, the most common of which were hyperglycemia (100.0%), hypertension (76.9%), decreased neutrophil count (76.9%), and decreased white blood cell count (69.2%). Seven out of 12 evaluated patients achieved partial response, resulting in an overall response rate of 58.3% CONCLUSIONS: Copanlisib was well tolerated in Chinese patients with relapsed or refractory iNHL at the dose of 60 mg and demonstrated encouraging disease control, thus warranting further clinical investigation. CLINICAL TRIAL REGISTRATION NUMBER: NCT03498430 (April 13, 2018).

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment.

BACKGROUND: Darolutamide is a second-generation androgen receptor inhibitor approved for the treatment of nonmetastatic castration-resistant prostate cancer at a dosage of 600 mg orally twice daily. OBJECTIVE: We aimed to fully characterize the pharmacokinetic profile of darolutamide, its diastereomers, and its main active metabolite, keto-darolutamide. METHODS: Single-dose and multiple-dose pharmacokinetics of 14C-labeled and non-labeled darolutamide were evaluated in healthy subjects and patients with hepatic or renal impairment. RESULTS: Following darolutamide oral tablet administration, peak plasma concentrations were reached 4-6 h after dosing. Darolutamide elimination was characterized by a half-life of 13 h. Steady state was reached after approximately 2 days of twice-daily dosing. Pharmacokinetics of the diastereomers and keto-darolutamide followed similar trends to the parent compound. Darolutamide absorption from the tablet was lower than from the oral solution; tablet absolute bioavailability was ~30% in the fasted state but improved to 60-75% when given with food. The unbound fraction of darolutamide in plasma was 7.8%. The administered 1:1 ratio of the diastereomers (S,R)-darolutamide and (S,S)-darolutamide changed to ~1:6 in plasma following multiple dosing. Similar exposure and diastereomer ratios after single and multiple dosing indicate time-independent (no autoinduction) linear pharmacokinetics. Darolutamide exposure increased in patients with moderate hepatic or severe renal impairment vs healthy subjects; dose adaptation at treatment initiation should be considered in these patients. CONCLUSIONS: Darolutamide 600 mg twice daily demonstrates predictable linear pharmacokinetics and sustainably high plasma concentrations, suggesting the potential for constant inhibition of the androgen receptor signaling pathway. CLINICAL TRIALS REGISTRATION: NCT02418650, NCT02894385, NCT02671097.

227Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

Background: BAY 1862864 is an α-particle emitting 227Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). Materials and Methods: BAY 1862864 intravenous injections were administered at the starting 227Th radioactivity dose of 1.5 MBq (2 or 10 mg antibody), and the radioactivity dose escalated in ∼1.5 MBq increments (10 mg antibody) until the maximum tolerated dose (MTD) was reported. The primary objective was to determine the safety, tolerability, and MTD. Results: Twenty-one patients received BAY 1862864. Two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia) were reported in one patient in the 4.6 MBq (10 mg antibody) cohort. The MTD was not reached. Ten (48%) patients reported grade ≥3 treatment-emergent adverse events, with the most common being neutropenia, thrombocytopenia, and leukopenia, each occurring in 3 (14%) patients. Pharmacokinetics demonstrated the dose proportionality and stability of BAY 1862864 in the blood. The objective response rate (ORR) was 25% (5/21 patients) according to the LUGANO 2014 criteria, including 1 complete and 4 partial responses. The ORR was 11% (1/9) and 30% (3/10) in patients with relapsed high- and low-grade lymphomas, respectively. Conclusions: BAY 1862864 was safe and tolerated in patients with R/R-NHL. Clinical Trial Registration numbers: NCT02581878 and EudraCT 2014-004140-36.

Prolonged Response to Regorafenib in a Patient with Iodine Refractory Thyroid Cancer.

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline.

A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors.

Regorafenib 160 mg orally once daily (QD) 3 weeks on/1 week off is approved in colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma. We established the safety and pharmacokinetics (PK) of regorafenib combined with cetuximab in advanced refractory solid tumors. This was a phase 1, open-label, dose-escalation study (NCT01973868) in patients with advanced/metastatic solid tumors who progressed after standard therapy. Regorafenib was administered at various dose levels QD continuously or intermittently (3 weeks on/1 week off) combined with intravenous cetuximab 250 mg/m2 weekly. The primary objectives were safety, PK and maximum tolerated dose (MTD). The secondary objective was tumor response. Dose-limiting toxicities (DLTs) were evaluated in Cycle 1. Of 42 treated patients, 31 received regorafenib intermittently (120 mg, n = 8; 160 mg, n = 23) and 11 continuously (60 mg, n = 5; 100 mg, n = 6) plus cetuximab. The continuous arm was terminated due to low tolerable dose. In the intermittent arm, one DLT (grade 3 hand-foot skin reaction) was observed at 120 mg but none at 160 mg, therefore 160 mg/day was declared as the MTD in combination with cetuximab. The most common all-grade treatment-emergent adverse events were fatigue (52%), hypophosphatemia (48%) and diarrhea (40%). One grade 3 cetuximab-related dermatitis acneiform was observed. No clinically relevant drug-drug interactions were observed. Five patients (21%) had a partial response. Regorafenib 160 mg QD (3 weeks on/1 week off) plus standard dose of cetuximab was well tolerated with no unexpected toxicities and promising signs of efficacy.

Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Time-to-event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose-reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand-foot skin reactions).

Phase 1, open-label, dose-escalation study of sorafenib in combination with eribulin in patients with advanced, metastatic, or refractory solid tumors.

Combining sorafenib and eribulin mesylate may provide synergistic antitumor activities with limited overlapping toxicities. This phase 1b, open-label, dose-escalation study evaluated safety, pharmacokinetics, maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), and preliminary efficacy of sorafenib plus standard-dose eribulin mesylate in patients with advanced, metastatic, or refractory tumors. Patients received sorafenib 200 mg twice daily (BID; n = 5), 600 mg/day (n = 8), and 400 mg BID (MTD; n = 27). Dose-limiting toxicities were increased alanine aminotransferase and acute coronary syndrome (both grade 3) in the 400-mg BID dose-escalation and expansion cohorts, respectively. No significant increase in mean QTcF duration was observed with eribulin plus sorafenib versus eribulin alone; there were no drug-drug interactions. Five patients achieved partial response; 16 achieved stable disease. The combination of sorafenib and eribulin mesylate presented no unexpected safety concerns and no significant impact on QT/QTc intervals or drug-drug interactions. Sorafenib 400 mg BID plus standard-dose eribulin is the RP2D.

No Effect of Levothyroxine and Levothyroxine-Induced Subclinical Thyrotoxicosis on the Pharmacokinetics of Sorafenib in Healthy Male Subjects.

BACKGROUND: Patients receiving the multikinase inhibitor sorafenib for locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine often receive concomitant levothyroxine for thyrotropin (TSH) suppression. In the Phase 3 DTC trial (DECISION), sorafenib exposure was approximately twofold higher than that observed in other cancers. This study assessed sorafenib pharmacokinetics without and with concomitant levothyroxine to examine whether a levothyroxine interaction or levothyroxine-induced subclinical thyrotoxicosis results in increased sorafenib exposure in patients with DTC. METHODS: This was an open-label, two-period sequential treatment study in healthy male subjects. In period 1, day 1, subjects received a single oral dose of sorafenib 400 mg, followed by a minimal 10-day washout. In period 2, day 1, levothyroxine 300 µg was administered orally once daily (q.d.) for 14 days. After 10 days, a single oral concomitant dose of sorafenib 400 mg was given. Blood samples for sorafenib pharmacokinetic analyses were obtained pre-dose and at time points up to 96 hours after sorafenib dosing. Samples for thyroid tests were collected before and after levothyroxine dosing. RESULTS: Twenty-five subjects completed the study and were evaluable for pharmacokinetic analysis. Levothyroxine 300 µg q.d. was well tolerated and induced subclinical thyrotoxicosis, producing full suppression of TSH (M ± SD = 0.032 ± 0.027 mIU/L) and increased free thyroxine (from 0.94 ± 0.09 to 1.77 ± 0.33 ng/dL) and free triiodothyronine (from 2.87 ± 0.28 to 4.24 ± 0.66 pg/mL) levels by day 11 of period 2. The geometric mean (%CV) sorafenib maximum concentration (Cmax) without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively, with a corresponding geometric mean area under the curve of 68.1 (68.2) and 64.3 (66.3) mg·h/L. Median (range) time to Cmax was 4.00 (2.98-16.0) and 4.02 (1.98-36.0) hours, respectively. Mean (%CV) half-life was 24.0 (25.3) and 25.7 (21.0) hours. All study drug-related adverse events were mild and included headache and fatigue for sorafenib, and headache, increased alanine aminotransferase and glutamate dehydrogenase, fatigue, and nervousness for levothyroxine. CONCLUSIONS: Levothyroxine 300 µg q.d. for 14 days was well tolerated, induced subclinical thyrotoxicosis, and did not affect sorafenib pharmacokinetics. The findings suggest that concomitant use of levothyroxine with sorafenib is not likely responsible for the previously reported increase in sorafenib exposure in patients with DTC. However, the possible effects of long-term levothyroxine dosing were not assessed.

Effects of lead exposure on proliferation and differentiation of neural stem cells derived from different regions of embryonic rat brain.

Lead is a potent neurotoxin, causing brain damage and cognitive deficits in children even at low exposure levels. Although lead neurotoxicity can occur after prenatal or postnatal exposure, little is known of the effects of lead on embryonic neural stem cells (NSCs) or the extent to which NSCs originating in different brain regions may be differentially sensitive to the effects of lead exposure. The present study examined the effects of lead on proliferation and differentiation of neural stem cells (NSCs) originating from E15 rat cortex (CX), striatum (ST) or ventral mesencephalon (VM). Free-floating neurospheres were grown under standard conditions or in lead (0.01-100 microM)-containing conditioned media for 5 days and proliferation assessed by 3H-thymidine uptake. In other studies, control and lead-exposed neurospheres were collected, dissociated and re-plated in control or lead-containing differentiation media for 7 days. Cells were immunostained for visualization of mature neural and glial markers and counted. Lead exposure (0.01-10 microM) had no effect on neurosphere viability but caused a significant dose-dependent inhibition of proliferation in VM and ST but not CX neurospheres. The number of MAP2 positive neurons differentiated from lead-exposed neurospheres of VM and ST origin (but not CX) was significantly decreased from control as were the number of oligodendrocytes obtained, regardless of their region of origin. In contrast, lead exposure significantly increased the number of astrocytes obtained regardless of site of origin. These data suggest that even low levels of lead can differentially affect proliferation and differentiation of embryonic NSCs originating from different brain regions and supports the need for prevention of prenatal lead exposure.

Modulation of ATP levels alters the mode of hydrogen peroxide-induced cell death in primary cortical cultures: effects of putative neuroprotective agents.

Oxidative injury is believed to be a major factor in the pathogenesis of a variety of neurodegenerative diseases. Additionally, the mode of cell death in oxidant-stressed cells can vary. The present study was conducted to evaluate the use of a primary neuronal cell-based bioassay in which different modes of oxidant-induced cell death could be studied and in which putative neuroprotective agents could be screened. Addition of 50 microM H(2)O(2) to primary cortical neuronal cultures for 1 h under normal ATP conditions resulted in approximately 40% cell death, almost exclusively of an apoptotic nature. In this condition, cell death was effectively blocked by GM1 ganglioside, the semi-synthetic ganglioside derivative LIGA20, the dopamine receptor agonist pramipexole (PPX) and the caspase inhibitor Z-VAD-FMK but not by the poly (ADP-ribose) polymerase (PARP) inhibitor 3-aminobenzamide (3-AB). Pretreatment of cells with 0.01 microM oligomycin for 45 min prior to addition of 50 microM H(2)O(2) caused significant ATP depletion and approximately the same amount of cell death as H(2)O(2) alone. However, under these conditions, cell death was primarily non-apoptotic in nature and GM1, LIGA20 and Z-VAD-FMK had no protective effects. In contrast, AB and PPX effectively blocked cell death. These results suggest that cellular ATP plays a critical role in determining the mode of cell death in primary neurons and that these types of in vitro models may provide a useful system for screening putative neuroprotective agents.