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In contrast to mismatch repair deficient (dMMR) colorectal cancer (CRC), mismatch repair proficient (pMMR) CRC is usually unresponsive to anti-PD-1 immunotherapy. Recent preclinical data suggest that regorafenib may enhance the antitumor activity of anti-PD-1 immunotherapy. However, the safety and efficacy of regorafenib plus nivolumab have not been established in patients with refractory metastatic pMMR CRC. This study aimed to evaluate the safety and efficacy of regorafenib plus nivolumab in metastatic pMMR metastatic CRC. This was a phase I/Ib study with standard 3 + 3 design plus dose expansion of the maximum tolerated dose (MTD) in patients with refractory metastatic pMMR CRC. Patients were treated with regorafenib combined with nivolumab. The primary end-points were dose-limiting toxicity (DLT) and MTD. The secondary end-points were objective response rate, safety and overall survival (OS). A total of 52 patients were enrolled, and 51 patients received at least one dose of treatment. Three patients experienced DLT (all grade 3 rash). MTD was regorafenib 80 mg and nivolumab 240 mg every 2 weeks. Most common grade 3/4 treatment-related adverse events were hypertension (16%), rash (10%) and anaemia (6%). Among 40 evaluable patients, four (10%) achieved partial response, including one unconfirmed response, 21 (53%) achieved stable disease, and disease control rate was 63%. The median progression-free survival and OS were 4.3 and 11.1 months, respectively. Regorafenib plus nivolumab appears to be well tolerated with limited anticancer activity in metastatic pMMR CRC. ClinicalTrials.gov identifier: NCT03712943. • Mismatch repair proficient (pMMR) colon cancer (CRC) is unresponsive to immunotherapy. • Regorafenib (REGO) may enhance the antitumor activity of nivolumab (NIVO). • The dose-limiting toxicity of REGO/NIVO was rash. • REGO/NIVO showed limited anticancer activity in pMMR CRC. • REGO/NIVO showed anticancer activity in non-liver or lung metastatic pMMR CRC. [ABSTRACT FROM AUTHOR]

Autotaxin (ATX) and lysophosphatidic acid (LPA) play an important role in pathogenesis of idiopathic pulmonary fibrosis (IPF). FTP-198 is an oral, novel and selective ATX inhibitor indicated for treating IPF. The study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 in healthy subjects. A single-center, randomized, double-blind, placebo-controlled, single ascending-dose Phase I study was performed. Pharmacokinetics, pharmacodynamics, food effect on pharmacokinetics, elimination, safety and tolerability of FTP-198 were evaluated. A total of 30 subjects were enrolled and completed the study. After oral administration of single ascending-dose of 100 mg, 300 mg and 400 mg FTP-198 under fasted condition, FTP-198 was absorbed with median time to reach peak concentration (T max) of 1.75, 2.75 and 3.5 h, respectively and eliminated with mean elimination half-life (t 1/2) of 8.77, 10.58 and 10.57 h, respectively. Peak concentration (C max), plasma area under concentration–time curve from time 0 to the last measurable concentration (AUC 0-t) and to infinity (AUC 0-∞) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the C max , AUC 0-t and AUC 0-∞ and prolonged T max , but not affecting t 1/2 of FTP-198 compared with fasted state. The pharmacodynamic biomarker plasma lysophosphatidic acid (LPA) 18:2 decreased significantly for 100 mg to 400 mg FTP-198, with inhibition rate from baseline reaching approximately 80% at 24 h post dosing, and higher dose of FTP-198 increased the time to maintain inhibitory plateau. FTP-198 was eliminated from the body almost with no unchanged drug excreted in urine and a small amount of unchanged drug detected in feces of human. Moreover, FTP-198 exhibited favorable safety and tolerability in healthy subjects. Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 support further subsequent clinical development of FTP -198 in IPF patients. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights • BV was associated with a 47% partial response rate in patients with steroid-refractory cGVHD. • BV therapy was limited by treatment-emergent toxicities, including peripheral neuropathy. • Soluble CD30 level at enrollment was not associated with cGVHD severity or clinical response. Abstract We conducted a phase I study of brentuximab vedotin (BV), an antibody–drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft-versus-host disease (cGVHD). A modified 3 + 3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with.6 mg/kg every 3 weeks (dose level 0) and increasing by.3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n = 9), patient decision (n = 3), lack of response (n = 2), and death (n = 1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by ≥50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5 ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed. [ABSTRACT FROM AUTHOR]

Effective vaccines are needed to combat diarrheal diseases due to Shigella . Two live oral S. sonnei vaccine candidates, WRSs2 and WRSs3, attenuated principally by the lack of spreading ability, as well as the loss of enterotoxin and acyl transferase genes, were tested for safety and immunogenicity. Healthy adults 18–45 years of age, assigned to 5 cohorts of 18 subjects each (WRSs2 (n = 8), WRSs3 (n = 8) or placebo (n = 2)) were housed in an inpatient facility and administered a single oral dose of study agent 5 min after ingestion of oral bicarbonate. Ascending dosages of vaccine (from 10 3 CFU to 10 7 CFU) were evaluated. On day 8, treatment with ciprofloxacin (500 mg BID for 3 days) was initiated and subjects were discharged home 2 days after completing antibiotics. Subjects returned for outpatient visits on day 14, 28 and 56 post-vaccination for monitoring and collection of stool and blood samples. Both WRSs2 and WRSs3 were generally well tolerated and safe over the entire dose range. Among the 80 vaccinees, 11 subjects developed diarrhea, 8 of which were mild and did not affect daily activities. At the 10 7 CFU dose, moderate diarrhea occurred in one WRSs2 subject while at the same dose of WRSs3, 2 subjects had moderate or severe diarrhea. Vaccinees mounted dose-dependent mucosal and systemic immune responses that appeared to correlate with fecal shedding. S. sonnei vaccine candidates WRSs2 and WRSs3 are safe and immunogenic over a wide dose range. Future steps will be to select the most promising candidate and move to human challenge models for efficacy of the vaccine. [ABSTRACT FROM AUTHOR]

Background: Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk) and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC). Patients and methods: Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval-90 days) and 15 with resistant disease (platinum-free interval<90 days). Results: Doxorubicin 50 mg/m2 and PM01183 4.0mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n=2, 8%) and partial response (n=13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS=3.5 months). At third line, response rate was 20.0% (median PFS=1.2 months), all in resistant disease. Conclusion: Doxorubicin 50 mg/m2 and PM01183 4.0mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial. [ABSTRACT FROM AUTHOR]

Purpose To estimate the maximum tolerated dose (MTD) and to determine the recommended dose (RD) of stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinoma (NSCLC) with target volume (PTV) < 100 cc. Materials and methods The continual reassessment method (CRM) was used to determine the dose level that patients should be assigned to and to estimate the MTD. Dose limiting toxicity (DLT) was grade 3 radiation pneumonitis (RP) within 180 days after the start of SBRT, grade 2 RP was used as a surrogate DLT. The RD was equal to the MTD. The dose was prescribed at D 95 of the PTV. Results Fifteen patients were accrued. Only 1 experienced grade 2 RP at 60 Gy in 4 fractions. It was difficult to fulfill the dose constraints at 60 Gy in 4 fractions, and the maximum dose level assigned by CRM was changed to 55 Gy in 4 fractions. The lower limit of 95% of the credible interval exceeded the adjacent level, and the RD was determined as 55 Gy in 4 fractions. Conclusions The RD of SBRT for peripheral T2N0M0 NSCLC with PTV < 100 cc was determined to be 55 Gy in 4 fractions. [ABSTRACT FROM AUTHOR]

Background: Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. Patients and methods: Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. Results: Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ~110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. Conclusion: Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Patients with unresectable stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy often develop esophagitis that may lead to unplanned treatment interruptions, which may severely reduce rates of locoregional tumor control and survival. No effectivetreatment that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of normal tissue protection using epigallocatechin-3-gallate (EGCG) has been reported, its actual clinical practicability remains obscure. Methods and materials: This is a phase I study of EGCG in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (cisplatin and etoposide) was given concurrently with radiation. EGCG solution was swallowed three times a day after the occurrence of grade 2 esophagitis at six concentration levels and dose escalation followed a standard phase I design. Esophageal toxicity and patient-reported pain was recorded weekly. Results: Twenty-four patients with AJCC stage IIIA (six) and IIIB (eighteen) completed the course of therapy. Twelve had squamous histology, ten adenocarcinoma, and two not specified. Patients were treated in six cohorts at six dose levels of EGCG. RT was not interrupted with a median dose of 64Gy. There were no dose-limiting toxicities reported in all EGCG dosing tiers. Dramatic regression of esophagitis to grade 0/1 was observed in 22 of 24 patients, whereas grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy. The pain score was also reduced from a mean of 4.58 (N =24), 1.29 (N =24), 1.42 (N =24), 0.96 (N =23) to 1.13 (N =16) every week in turn. Conclusion: We conclude that the oral administration of EGCG is feasible, safe and effective. The phase II recommended concentration is 440μmol/L. [Copyright &y& Elsevier]

Background Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ∼20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methods Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. Results Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0–12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. Conclusion Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined. [ABSTRACT FROM AUTHOR]

Abstract: Background: Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). Patients and methods: Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4mg/kg) on day 1 then irinotecan–LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan–LV5FU2 every 2weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4mg/kg upfront. The median number of aflibercept cycles was 16 (range 1–44), 12 patients received ⩾20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept. Conclusion: Aflibercept 4mg/kg plus irinotecan–LV5FU2 every 2weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity. [Copyright &y& Elsevier]

Abstract: Background: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). Patients and methods: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2weeks. Results: Two grade 3/4 aflibercept-associated DLTs occurred with 4mg/kg: proteinuria lasting >2weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4mg/kg. Twenty-two patients had stable disease (five with 4mg/kg), lasting >3months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4mg/kg. Conclusion: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2weeks. [Copyright &y& Elsevier]

Purpose: We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Patients and methods: Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days. Results: Forty-five patients received BMS-599626 (100–660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated Cmax and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated. Conclusion: BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT). Patients and methods: Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66Gy at 2Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40mg/m2 followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5mg/m2 per level. Results: Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40mg/m2 and 45mg/m2), carboplatin (AUC=2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40mg/m2 and carboplatin, AUC=2). At Level 2 (paclitaxel, 45mg/m2 and carboplatin, AUC=2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45mg/m2 and 40mg/m2, respectively. Conclusions: This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40mg/m2 at AUC=2, respectively. Further studies are warranted to evaluate the efficacy of this regimen. [Copyright &y& Elsevier]

Abstract: Background: TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. Objectives: The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. Methods: Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. Results: Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t½ (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/kg), and 8 to 13 (days), respectively. Conclusion: The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed. [Copyright &y& Elsevier]

Purpose: To establish the feasibility and tolerability of gefitinib (ZD1839, Iressa) with radiation (RT) or concurrent chemoradiation (CRT) with cisplatin (CDDP) in patients with advanced non–small cell lung cancer (NSCLC). Patients and Methods: In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before RT at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus CRT in the form of RT and weekly CDDP 35 mg/m2 (Step 2). Gefitinib was maintained for up to 2 years until disease progression or toxicity. Results: Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and RT), no lung toxicities were seen, and there was no dose-limiting toxicity (DLT). Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1–2. In Step 2, two of nine patients (22.2%) had DLT. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions. Conclusions: Gefitinib (250 mg daily) in combination with RT and CDDP in patients with Stage III NSCLC is feasible, but CDDP likely enhances toxicity. The impact of gefitinib on survival and disease control as a first-line treatment in combination with RT remains to be determined. [ABSTRACT FROM AUTHOR]

Purpose: To perform a Phase I study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients with locally advanced rectal cancer, to determine the maximum tolerated dose and the recommended dose. Methods and Materials: Radiotherapy was delivered to a total of 45 Gy in 25 fractions and followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of a fixed dose of oxaliplatin (50 mg/m2/week) on Days 1, 8, 22, and 29 and escalated doses of S-1 on Days 1–14 and 22–35. The initial dose of S-1 was 50 mg/m2/day, gradually increasing to 60, 70, and 80 mg/m2/day. Surgery was performed within 6 ± 2 weeks. Results: Twelve patients were enrolled and tolerated up to Dose Level 4 (3 patients at each dose level) without dose-limiting toxicity. An additional 3 patients were enrolled at Dose Level 4, with 1 experiencing a dose-limiting toxicity of Grade 3 diarrhea. Although maximum tolerated dose was not attained, Dose Level 4 (S-1 80 mg/m2/day) was chosen as the recommended dose for further Phase II studies. No Grade 4 toxicity was observed, and Grade 3 toxicities of leukopenia and diarrhea occurred in the same patient (1 of 15, 6.7%). Pathologic complete responses were observed in 2 of 15 patients (13.3%). Conclusions: The recommended dose of S-1 was determined to be 80 mg/m2/day when combined with oxaliplatin in preoperative CRT, and a Phase II trial is now ongoing. [ABSTRACT FROM AUTHOR]

Background: The prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient. Methods: A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–8; (2) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–8; (3) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–10; (4) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7years. Results: None of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3. Conclusion: The recommended phase II dose in children is TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–10 every 28d. The combination was well tolerated and demonstrated antitumour activity. [Copyright &y& Elsevier]

Abstract: The purpose of this phase I/II study is to evaluate a new combination chemotherapy consisting of docetaxel and S-1 as front-line therapy for patients with untreated advanced non-small cell lung cancer (NSCLC). The treatment included docetaxel on day 1 and oral S-1 at a fixed dose of 40mg/m2 administered twice daily on days 1–14 and repeated every 3 weeks. In phase I, docetaxel at escalating doses of 40 (level 0), 50 (level 1) and 60mg/m2 (level 2) was administered starting from level 1. Because only one patient among the 6-patient cohort at level 1 and no patient among the 3-patient cohort at level 2 experienced defined dose-limiting toxicity (DLT), level 2 was determined as the recommended dose. In phase II, 60 patients were treated at the recommended dose for median 3 cycles, and the overall response rate was 30% (95% confidence interval [CI], 18.9–43.2%), and the median overall and progression-free survival times were 15.2 (95% CI: 10.5–17.7) and 4.9 (95% CI: 3.5–5.6) months, respectively. The most frequent toxicities experienced were neutropenia, febrile neutropenia and appetite loss; all toxicities were however well manageable. The present regimen showed a potent activity with mild toxicity in untreated NSCLC. [Copyright &y& Elsevier]

Purpose: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. Patients and methods: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours. Results: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m2. All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1–2, except for the blood and lymphatic system disorders, which were primarily of grades 3–4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m2, with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. Conclusion: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound. [Copyright &y& Elsevier]

Background: Sagopilone (ZK-EPO) is a fully synthetic microtubule-stabilizing agent that has demonstrated high antitumor activity in preclinical models. This first-in-human phase I study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxic effects (DLTs) of 3-weekly sagopilone treatment. [ABSTRACT FROM PUBLISHER]

Abstract: E-3-(4′-Hydroxy-3′-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel oral synthetic adamantyl retinoid derivative, now under early clinical investigation in patients with ovarian cancer. To investigate the pharmacokinetics of this new antitumor agent in human plasma, we developed and validated a high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method based on the addition of ST2222 as internal standard and simple protein precipitation with methanol. The method requires a small volume of sample (100μL); it is rapid and selective, allowing a good resolution of peaks from the plasma matrix in 9min. The method offers high recovery (>90%), it is sensitive, precise and accurate with overall precision expressed as CV% less than 8.2%. We set the lower limit of quantitation at 20.0ng/mL and validated the assay up to the concentration of 1000.0ng/mL. The present method has been successfully applied to study ST1926 pharmacokinetics in patients with advanced ovarian cancer in a Phase I trial, administering the drug orally for five consecutive days. During analysis of the study samples, it became evident the presence of glucuroconjugates of the parent compound, established by LC-Orbitrap MS. Preliminary results show low and variable drug absorption in patients, with extensive glucuroconjugation influencing the bioavailability of ST1926. [Copyright &y& Elsevier]

Abstract: Purpose: This study was performed to assess the toxicities, the maximum-tolerated dose (MTD), the pharmacokinetics and the anti-tumour activity of gemcitabine given by 24-h hepatic arterial infusion (HAI). Patients and methods: Patients with liver malignancies received gemcitabine by 24-h HAI, weekly×3, every 4weeks. On day 1 or day 8 of the first cycle, patients received one administration by 24-h intravenous infusion for pharmacokinetic comparison and to determine hepatic extraction. Results: Thirteen patients received gemcitabine at the dose levels of 75, 135 and 180mg/m2. The MTD was 180mg/m2 with thrombocytopaenia as the dose-limiting toxicity. Pharmacokinetic analysis showed a significantly lower maximum gemcitabine plasma concentration (C max: HAI, 26, 80 and 128nM, respectively; IV, 229, 264 and 293nM, respectively) and area under the plasma-concentration-versus-time curve (AUC0–24h: HAI, 386, 1247 and 2033nmol×h/L, respectively; IV, 3526, 4818 and 5363nmol×h/L, respectively) during HAI, compared with intravenous infusion (both P <0.001). Additionally, the mean hepatic extraction ratios of gemcitabine at the 75, 135 and 180mg/m2 dose level were 0.89, 0.75 and 0.55, respectively. Hepatic extraction decreased linearly with increasing dose. The C max and AUC0–24h of 2′,2′-difluoro-2′-deoxyuridine, the deaminated product of gemcitabine, were similar for HAI and intravenous infusion. Seven patients had stable disease for a median duration of 9months (range: 2–11months). Conclusions: Gemcitabine given by 24-h HAI was well tolerated and resulted in significantly lower systemic gemcitabine plasma concentrations than intravenous infusion due to a relatively high hepatic extraction. [Copyright &y& Elsevier]

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non–small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m−2/day−1]/cisplatin [mg/m−2/day−1]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to a total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed ≥Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC. [Copyright &y& Elsevier]

Abstract: The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m2, which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m2 (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified. [Copyright &y& Elsevier]

Recombinant human albumin (rHA) is an alternative to human serum albumin (HSA) for treating ascites in cirrhosis patients. This study was to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics/pharmacodynamics (PK/PD) of rHA in healthy subjects to guide the design for further clinical trials. Healthy subjects aged 18–55 years were enrolled in this double-blinded, first-in-human, placebo-controlled single ascending dose (SAD) (1.25, 5, 10, 20, or 30g) and positive-controlled multiple-dose study (3-day treatment of 10g/day for three cycles every three weeks). The safety was assessed by adverse events (AEs). Antibodies (IgE and IgD) and cytokines were analyzed for immunogenicity. Serum albumin levels and changes in plasma colloid osmotic pressure (PCOP) and hematocrit (HCT) were measured for PK/PD analysis. rHA was well tolerated as all AEs were assessed as mild or moderate. No severe allergy or difference in the incidence of AEs was observed among the different cohorts in the SAD study or in the different cycles in the multiple-dose study. The incidence of AEs was similar for the rHA and HSA cohort. Antibodies or cytokines showed no changes after drug administration. As expected, serum albumin levels and PCOP increases, and HCT ratio decreases were dose-related with significant differences (p < 0.01). No differences were observed between rHA and HSA. rHA is safe and well-tolerated in healthy Chinese subjects. rHA and HSA exhibited similar safety, tolerability, and PK/PD profiles. The results support further evaluation of rHA treatment in cirrhotic patients with ascites. The clinical trial registration numbers are CTR20191221 (http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml). [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: Background: Irinotecan and cisplatin with concurrent radiotherapy is a powerful treatment combination for patients with limited-disease small-cell lung cancer (LD-SCLC). The objective was to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of irinotecan and cisplatin with concurrent thoracic radiotherapy (TRT) as a once-every-three-weeks schedule. Patients and methods: Patients with LD-SCLC received a fixed-dose of irinotecan (340mg) and cisplatin (135mg) at day 1 in cycles 1 and 4. During cycles 2 and 3, irinotecan and cisplatin were given in a dose-escalation schedule with concurrent TRT (once daily, total dose 45Gray). Results: No DLT was observed at first two levels (irinotecan 100mg or 120mg and cisplatin 100mg at day 1 of cycles 2 and 3). In the first five patients, four episodes of grade III diarrhoea/dehydration were observed at cycles 1 and 4. Therefore, from the sixth patient on, fixed-dose irinotecan at cycles 1 and 4 was reduced to 250mg. At the subsequent level of irinotecan 140mg and cisplatin 100mg in cycles 2 and 3, two DLTs (severe oesophagitis and late vertebral radiation toxicity) were observed in one patient. Conclusion: Irinotecan 140mg and cisplatin 100mg with concurrent TRT was considered the MTD. Irinotecan and cisplatin in a once-every-three-weeks schedule is not recommended due to severe toxicity. Irinotecan may be more suited for intermittent weekly administration. [Copyright &y& Elsevier]

Purpose: The primary objective of this study was to determine the maximum-tolerated dose (MTD) of S-1, an oral fluoropyrimidine derivative, with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day from Day 1 to 14 and 22 to 35 at escalating doses from 60 to 80 mg/m2/day. Results: Sixteen patients were enrolled in this study. Three patients received S-1 at 60 mg/m2/day, 3 at 70 mg/m2/day, and 10 at 80 mg/m2/day. Though 1 patient at the final dose level (80 mg/m2/day) experienced a dose limiting toxicity (biliary infection with Grade 3 neutropenia), the MTD was not reached in this study. The most common toxicities were anorexia and leukocytopenia, with Grade 3 toxicity occurring in 31% and 6.3% of the patients, respectively. Conclusions: The recommended dose of S-1 with concurrent radiotherapy was determined to be 80 mg/m2/day from Day 1 to 14 and 22 to 35 in patients with locally advanced pancreatic cancer. Oral S-1 and radiotherapy is well tolerated and feasible and should be further investigated. [Copyright &y& Elsevier]

Abstract: Aim of the study: Adecatumumab (also known as MT201) is a human recombinant IgG1 monoclonal antibody binding with low affinity to epithelial cell adhesion molecule (EpCAM). To explore safety, pharmacokinetics and pharmacodynamics of adecatumumab, a phase I trial in patients with hormone refractory prostate cancer (HRPC) was performed. Methods: Twenty patients were treated with two adecatumumab infusions on days 0 and 14 in cohorts with doses of ten up to 262mg/m2. Results: Adecatumumab was well tolerated at all doses tested, and no maximum tolerated dose reached. Most adverse events were mild or moderate with pyrexia and nausea being most frequent. The highest dose of adecatumumab induced shortly after infusion robust and transient increases of TNF-alpha serum levels. At all doses, significant transient declines of peripheral natural killer cells were observed shortly after antibody infusions. Adecatumumab had a serum half-life of 15 days, and immune responses to the antibody were not detected. Conclusions: A benign safety profile, long serum half-life and low immunogenicity do warrant further exploration of adecatumumab for treatment of EpCAM-expressing neoplasia. [Copyright &y& Elsevier]

Abstract: Purpose: Perifosine is an orally applicable, membrane-targeted alkylphosphocholine analogue with antitumour activity and radiosensitising properties in preclinical models. The purpose of this phase I study was to determine the feasibility and tolerability of concurrent daily perifosine and radiation in patients with advanced cancer. Patients and methods: Starting dose of perifosine was 50mg/day; dose escalation was in steps of 50mg. Daily administration commenced 2 days before radiotherapy and was continued throughout the radiation treatment. At least three patients were entered at each dose level; at the 150mg/day level 10 patients were included. Pharmacokinetic sampling was performed weekly pre-dosing. Twenty-one patients were entered. Tumour types included NSCLC (n =17), prostate, oesophageal, colon and bladder cancer. Most patients (16/21) had received prior chemotherapy; none radiotherapy. Median number of daily perifosine administrations was 31 (range 24–53). Mean radiation dose (BED10) was 59.8Gy (range 50.7–87.5Gy in 13–28 fractions). Results: Major drug-related toxicities according to CTC criteria were nausea in 57%, fatigue in 48%, vomiting in 38%, diarrhoea in 38% and anorexia in 19%. No bone marrow toxicity was observed. DLT (nausea/vomiting) was encountered in two of five patients at the 200mg/day dose level. Dose-dependent steady-state plasma levels were reached after 1 week. Major radiotherapy-related acute toxicity consisted of dysphagia in 38% and pneumonitis in 29%. Conclusion: Perifosine can be safely combined with fractionated radiotherapy. A dosage of 150mg/day, to be started at least 1 week prior to radiotherapy, is recommended for phase II evaluation. [Copyright &y& Elsevier]

Abstract: The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n =24), metastatic (n =17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30mg/m2 and the 5FU dosage 150mg/m2/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80mg/m2, 5FU 225mg/m2/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60mg/m2) combined with 5FU continuous infusion (225mg/m2) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies. [Copyright &y& Elsevier]

Abstract Background:: Urinary tract infections (UTIs) account for 5 to 6 million medical consultations in the United States each year. Worldwide, an estimated 20% to 30% of women aged 20 to 40 years have at least 1 episode of the most common type of UTI (uncomplicated cystitis) in their lifetime, with Escherichia coli being the causative pathogen in 80% of cases. Antibacterial activity in urine has been shownto be correlated with outcomes of uncomplicated cystitis. Objective:: The objectives of this study were to determine urinary concentrations and ex vivo bactericidal activity of sustained-release (SR) amoxicillin/clavulanic acid 2000/125 mg against intermediately resistant and resistant strains of E coli over 72 hours and compare them with those of a susceptible strain. This study also investigated whether urinary concentrations obtained after dosing cover E coli strains categorized as intermediately resistant and resistant based on current Clinical and Laboratory Standards Institute (formerly NCCLS) breakpoints in uncomplicated cystitis. Methods:: This Phase I, open-label, noncomparative study in healthy male volunteers was conducted at the Pharmacology Unit, Aut ónoma University, Madrid, Spain. Subjects received a single oral dose of amoxicillin/clavulanic acid 2000/125 mg SR. The amoxicillin/clavulanic acid MICs were 8/4 g/mL (susceptible), 16/8 g/mL (intermediately resistant), and 32/16 and 64/32 g/mL (resistant). Urine samples were collected before (baseline; time 0) and at the following intervals: 0–2, 2–4, 4–8, 8–12, 12–16, 16–24, 24–36, 36–48, 48–60, and 60–72hours after dosing. Killing curves with urine samples were performed with initial inocula of ∼107 colony-forming units (CFU)/mL, and bactericidal activity (defined as >3 log10 CFU/mL and >99.9% reduction in bacterial counts) was calculated as the difference between log10 initial inoculum and log10 CFU/mL after 4 hours of incubation of each sample. Results:: Twelve volunteers were included (mean [SD] age, 24.83[5.64] years; mean [SD] height, 175.75 [7.56] cm; and mean [SD] weight, 73.55 [9.19] kg). No statistically significant differences between the activities in the 12–16-hour interval compared with baseline were found in any of the strains tested. Bactericidal activity against the susceptible and intermediately resistant strains (MICs 8/4 and 16/8 g/mL, respectively) was obtained up to 8 hours after dosing. Bactericidal activity against the resistant strains (MICs 32/16 and 64/32 g/mL) was obtained in the 2–4-hour interval. Conclusions:: In this Phase I study in healthy volunteers, urinary concentrations after dosing with amoxicillin/clavulanic acid 2000/125 mg SRshowed bactericidal activity against the amoxicillin-susceptible and intermediately resistant strains of E coli. [Copyright &y& Elsevier]

Abstract: Aviscumine is a ribosome-inactivating protein with potent antitumour activity in vitro and in vivo and is an Escherichia coli-derived recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a prolonged infusion of aviscumine in cancer patients. Aviscumine was given once weekly as a 24h central intravenous infusion in patients with advanced, refractory progressive solid malignant tumours. Fourteen fully eligible patients (11 male, 3 female) with a median age 58 yrs (range 41–77) were enrolled. They had histologically verified disease, were ⩾18 yrs old, had an ECOG PS ⩽2 and adequate bone marrow, liver and renal function. DLT was defined as any non-haematological grade 3–4 toxicity (Common Toxicity Criteria [CTC] version 2.0), neutrophil count &#60;500/μl for ⩾7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose level below the dose at which ⩾2 patients per dose level experienced a DLT during the first treatment cycle. Colorectal cancer, soft tissue sarcoma and pancreatic cancer were the most common tumour types. Dose levels of aviscumine ranged from 4 to 6μg/kg. The median number of cycles was 2.8 (range, 2–8). Common side effects in cycle 1 were fatigue, fever, nocturia, urticaria, erythema and pruritus. DLTs occurred in 2/3 patients on the 6μg/kg dose level and consisted of increases in ASAT grade 3, ALAT grade 3, γGT grade 3/4, hypokalemia grade 3 and fatigue grade 3. No DLTs were observed on dose levels 4 and 5μg/kg. The best response (RECIST) was stable disease in 4 pts, lasting for 4–8 cycles. Pharmacokinetics indicated that potentially active plasma levels of the compound were maintained during the entire infusion. We conclude that the recommended dose for weekly 24h infusions of Aviscumine should be 5μg/kg. [Copyright &y& Elsevier]

Summary: A phase I study combining a fixed dose of gemcitabine with differing doses of CPT-11 every two weeks for previously treated non-small cell lung cancer (NSCLC) patients. Patients and methods:: A total of 21 patients with previously treated non-small cell lung cancer were treated every two weeks with CPT-11 followed by gemcitabine. The gemcitabine dose was fixed at 1000mg/m2. The starting dose of CPT-11 (50mg/m2) was then escalated different patients in 25mg/m2 increments until 150mg/m2 (level 5), the recommended dose as a single agent in Japan. Results:: Dose-limiting toxicity was only observed at level 5, in three of nine patients receiving the highest dose of CPT-11. One patient had grade 3 diarrhea, and two could not continue chemotherapy with grade 1 diarrhea or grade 1 neutropenia on day 15. Hematologic toxicity with this combination regimen, however, was generally mild. No grade 4 neutropenia, and only one case of grade 3 leukopenia was noted at level 5. Compliance with the combination regimen was good and there was no cumulative toxicity with the subsequent courses. Twenty-five courses of therapy were given at level 5 and the percentage of actual delivered doses/planned doses was 82%. Conclusions:: The combination chemotherapy has only very mild toxicity and dose which can be recommended with this regimen are 1000mg/m2 for gemcitabine and 150mg/m2 for CPT-11 every two weeks. [Copyright &y& Elsevier]

Summary: Based on our previous preclinical data, a phase I study was designed to investigate the tolerability of a novel sequence, docetaxel (DOC)–gemcitabine (GEM), in the treatment of non small cell lung cancer (NSCLC). Preclinical study: We evaluated the cytotoxicity of DOC and GEM on NSCLC cell lines and assessed the type of interaction between drug activities following different treatment schemes. Clinical study: Fifteen patients with stage IIIB–IV NSCLC received DOC (day 1) and GEM (days 3 and 8) every 21 days. Dose escalation of both agents was used to identify the maximum tolerated dose. The study was closed at the fifth dose level due to the occurrence of three dose-limiting toxicities: grade 4 febrile neutropoenia, persistent grade 2 fever and grade 3 diarrhoea. The most frequent toxicity was neutropoenia. Non haematological toxicities were diarrhoea, nausea and vomiting, mucositis and alopoecia. Of the 14 evaluable patients, 1 complete response, 4 partial responses, 4 stable diseases and 5 disease progressions were observed. Based on the results of the present study, a phase II trial is ongoing using the fourth dose levels. [Copyright &y& Elsevier]

The tolerability and immunogenicity of the hepatitis C virus E1 protein as a candidate vaccine was examined in a Phase I, single-arm study. Twenty healthy male volunteers were injected in the deltoid muscle at weeks 0, 3 and 6 with 20 μg recombinant E1 adsorbed on alum. A fourth (booster) dose was administered to 19 subjects at week 26. The candidate therapeutic vaccine was well tolerated. Three vaccine doses induced a clear humoral anti-E1 response that was boosted by a fourth dose. A strong, specific cellular immune response towards E1 was elicited in all vaccine recipients, which included a clear Th1 type response in all but one of the subjects. [Copyright &y& Elsevier]

Purpose: To determine the maximum-tolerated dose (MTD) of irinotecan and paclitaxel in this two-drug combination, and to investigate a sequence-dependent effect in the pharmacokinetics of these drugs, we conducted a phase I study in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Patients with stage IIIB/IV NSCLC were enrolled in this study. Both irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3 weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially administered and followed by paclitaxel infusion, while the sequence of drug administration was reversed in the second cycle. Blood samples for pharmacokinetic analysis were obtained on day 1 of the first and second cycles. Results: Nine patients received a total of 12 cycles, which were evaluated for toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3 or more neutropenia was observed in 67% of cycles at dose level 2. The main non-hematological toxicities were grade 3 febrile neutropenia, supraventricular arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum concentration of paclitaxel was elevated in a dose-dependent manner. There was a trend toward elevation of the area under the plasma concentration–time curve (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan (r=0.894,P<0.0001). The objective response was not observed in the nine patients. Conclusion: The combination of irinotecan and paclitaxel with this schedule produced considerable toxicities without any antitumor effect for advanced NSCLC. The different schedule of administration or other combinations should be investigated. [Copyright &y& Elsevier]

Purpose: Oxaliplatin (OHP) is a new platinum antineoplastic, while gemcitabine (GEM) is one of the most active drugs against non-small cell carcinoma (NSCLC). The OHP/GEM combination is interesting because the drugs have different mechanisms of action and toxicity profiles. The primary endpoint of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of OHP/GEM combination in non-small cell carcinoma of the lung. Methods: Patients with relapsed NSCLC were treated with fixed dose i.v. GEM (1250 mg/m2) on days 1 and 8; followed on day 1 by i.v. OHP over 3 h, starting from 70 mg/m2 with 20 mg/m2 increments, up to 130 mg/m2. We enrolled 19 patients with eastern cooperative oncology group (ECOG) status 0/1=13/6; male/female=13/6. All had received first-line and four second-line chemotherapy. Results: Four patients dropped out. At dose level 2, one patient died of pulmonary embolism; at level 3, two patients died of disease progression. One patient at level 3, refused to continue treatment after allergic reaction (high fever episode) during infusion of third cycle. Fifteen patients were evaluable for toxicity and response. According to a priori statistical considerations, three patients in each of the first three treatment levels and six in the last level were evaluable. No G3–4 toxicity was observed at levels 1 and 2. G3 neutropenia and anemia occurred in 8% of cycles at level 3. Six patients entered level 4 (OHP 130 mg/m2) with 22 courses delivered: G3–4 neutropenia occurred in 9%, G1–2 thrombocytopenia in 18%; other toxicities were mainly limited to G1–2 flu-like syndrome in about one third of patients and G1–2 nausea and vomiting in 5% of courses. There was no myelo-DLT at the highest dose level. There was no neurotoxicity at any level. Treatment was delayed in 12% and dose reduced in 26% of courses. There were 2/15 PR. Conclusions: MTD was not reached. OHP and GEM can probably be administered safely at 130 and 1250 mg/m2, respectively, as first-line therapy. The schedule is being used in a phase II trial. [Copyright &y& Elsevier]

We previously observed that a detoxified Escherichia coli O111, Rc chemotype J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) vaccine protected animals from experimental lethal sepsis when immune antibodies were given passively as treatment at the onset of fever or when vaccine was given actively as prophylaxis. To test the safety and immunogenicity of this vaccine, we administered doses of 5, 10 and 25 μg (based on dLPS) of vaccine at days 0, 28 and 56 to 24 human subjects (8 per group). Temperatures of 100.3, 99.5 and 99.4 °F occurred in three subjects. At 24 h, pain at the injection site was moderate in 38%, mild in 44% and not present in 18%, while at 48 h, it was 1, 25 and 73%, respectively. No alterations in baseline renal, hepatic or hematologic functions occurred. There were two to three times mean-fold increases in anti-J5dLPS IgG (range: 1.9–5.1) and IgM (range: 1.2–9.2) levels in subjects receiving the 10 and 25 μg doses. At 12-month follow-up, three of the original responders had continued elevation of antibody levels. A 25 μg booster dose of vaccine did not increase antibody levels among those responders and did not elicit antibodies among three subjects with no previous antibody response. The plasma from the six volunteers inhibited LPS-induced cytokine generation in human whole blood ex vivo. We conclude that this J5dLPS/OMP vaccine was safe and well-tolerated with transient, local pain at the injection site. Vaccine formulations with different adjuvants are currently under investigation. [Copyright &y& Elsevier]

A dose-escalation study was conducted for patients with metastatic gastric cancer to determine the recommended dose of weekly intravenous (i.v.) cisplatin combined with a fixed dose of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1, on an outpatient basis. Secondary endpoints were to define the toxicity profile and to determine tumour responses. S-1 was fixed at a dose of 70 mg/m2/day and was administered for 2 weeks followed by a 1-week rest. Three dose levels of cisplatin (10, 15 and 20 mg/m2) were studied. Cisplatin was infused over 30 min on days 1 and 8. 20 patients were enrolled. No dose-limiting toxicities (DLTs) were recorded during the administration of cisplatin up to 20 mg/m2, except for grade 3 diarrhoea and stomatitis in one patient at dose level 3. No grade 4 adverse events occurred. However, grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in 7 of 13 patients at dose level 3 within the first two treatment cycles. This was determined to be the maximum acceptable level that would not negate the advantages observed with use of an oral drug such as S-1. An objective tumour response was seen at all dose levels, and the overall response rate in the 18 patients evaluated was 61%. A higher response rate of 78% was observed in 9 patients who had received no prior chemotherapy. Oral S-1 with weekly cisplatin is a feasible and promising combination regimen that is appropriate for an outpatient setting. A randomised phase II study comparing this combination with S-1 alone in chemo-naı¨ve patients is warranted. [Copyright &y& Elsevier]

Yondelis™ (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 μg/m2, initially as a 1-h infusion, and later at doses between 1000 and 1800 μg/m2 as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 μg/m2 for the 1-h infusion schedule and 1800 μg/m2 when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3–4 increase in transaminases (not considered DLT) and grades 3–4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 μg/m2 given as a 3-h infusion. [Copyright &y& Elsevier]

: PurposeChemoradiation based on cisplatin, most commonly weekly, is the standard treatment of locally advanced cervical cancer; however, the nephrotoxic potential and the requirement for hydration of cisplatin somewhat restrains its use. The objective of this study was to determine the recommended dose of carboplatin when administered weekly during pelvic radiation (RT).: Methods and materialsTwenty-four histologically proven, International Federation of Gynecology and Obstetrics Stage IIIB patients were treated with standard pelvic RT concurrently with six weekly applications of carboplatin at the following dose levels: 100 mg/m2, 116 mg/m2, 133 mg/m2, and 150 mg/m2. Six patients per level were treated. Acute toxicity was assessed according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. The recommended dose was defined as the one that was one level below the level at which dose-limiting toxicity was present in more than one-third of patients.: ResultsBetween September 2001 and July 2002, 24 patients were accrued. All but two completed external beam radiotherapy and intracavitary treatment. The treatment was well tolerated. The median number of weekly applications of carboplatin was six, and the mean dose to points A and B was 85.6 Gy (range 75.2–91.6) and 62.9 Gy (range 58.2–74.6), respectively. RT was delivered within 41.7 days (range 33–70). Dose-limiting toxicity (leukopenia and/or neutropenia) was present in 50% of patients treated at the higher dose level (150 mg/m2). At the recommended dose of 133 mg/m2, 33% of patients presented with Grade 3 leukopenia. At treatment completion, 75% of patients had a complete clinical response.: ConclusionCarboplatin at 133 mg/m2, weekly for 6 weeks, is a well tolerated and effective radiosensitizer in cervical cancer patients. [Copyright &y& Elsevier]

Purpose: Maximal therapeutic gain in xenograft sarcoma and toxicity for jejunal mucosa is time dependent for concurrent gemcitabine and radiotherapy (RT). We used a time-dependent schedule to determine the maximal-tolerated dose and dose-limiting toxicities (DLTs; Grade 4 hematologic or Grade 3 other toxicity).Methods and Materials: Patients with pancreatic cancer (n = 33), periampullary carcinoma (n = 1), or bile duct cancer (n = 2) were treated with 3-day conformal RT with 50.4 Gy (tumor, lymphatics) plus a 5.4-Gy boost. Concurrent cisplatin (20 mg/m2/d on Days 1–5 and 29–33) and gemcitabine (initially 600 mg/m2, weekly on Fridays 68 h before RT) were administered. Because of DLT, the doses were reduced to 500 mg/m2 weekly and then 500, 400, or 300 mg/m2 on Days 2, 5, 26, 33.Results: DLT occurred at all dose levels of gemcitabine >300 mg/m2. Fourteen patients were treated at the recommended Phase II dose of gemcitabine (300 mg/m2) without DLT. The response to chemoradiation allowed 10 of 30 initially unresectable patients with primary pancreatic carcinoma to undergo radical surgery, including a complete response in 2 cases.Conclusions: At the recommended Phase II dose, chemoradiation with gemcitabine and cisplatin can be administered safely in pancreatic carcinoma. However, at higher dose levels, toxicity is severe and frequent. Patients with a chance for conversion to resection could benefit from this schedule. [Copyright &y& Elsevier]

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m2), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47–75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4–59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m2 of gemcitabine and 100 mg/m2 of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study. [Copyright &y& Elsevier]

Objective: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. Methods: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks’ visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks’ visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. Results: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. Conclusion: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study. [Copyright &y& Elsevier]

The aim of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of a weekly administration of paclitaxel and pegylated liposomal doxorubicin (Caelyx; Schering Plough Pharmaceutical) in patients with advanced solid tumours. 19 pretreated patients with solid tumours received escalated doses of pegylated liposomal doxorubicin (6–12 mg/m2) as a 1-h intravenous (i.v.) infusion followed by a fixed dose of paclitaxel (80 mg/m2) weekly for 4 consecutive weeks in cycles of 6 weeks. DLT was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during cycle 1. The MTD was reached at the dose of pegylated liposomal doxorubicin of 10 mg/m2/week and paclitaxel of 80 mg/m2/week. The DLTs were treatment delay due to grade 3 neutropenia and grade 3 diarrhoea. A total of 55 chemotherapy cycles were administered, and grades 3–4 neutropenia occurred in seven cycles (13%); the non-haematological toxicity was mild with grades 2/3 diarrhoea occurring in 4 (7%), grades 2–4 asthenia in 11 (20%) and grade 2 mucositis in 7 (13%) cycles. There was no case with more than a 10% LVEF decrease after a median of 3 (range 2–6) administered cycles/patients. One patient with breast cancer and 1 with ovarian cancer experienced a major partial response. The weekly administration of pegylated liposomal doxorubicin at the dose of 10 mg/m2 in combination with paclitaxel at the dose of 80 mg/m2 for 4 consecutive weeks, in cycles of 6 weeks which represent the recommended doses for further phase II studies, is a well tolerated regimen, which merits further evaluation in tumours known to be sensitive to taxanes and/or anthracyclines. [Copyright &y& Elsevier]

Background: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). Methods: At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m2 on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5–7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m2 (level 7). Twenty-nine patients were entered into this phase I study. Results: At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). Conclusion: The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m2, the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m2. [Copyright &y& Elsevier]

• Sensitive clinical determination of finerenone in human plasma samples by HPLC–MS/MS. • Quantification of finerenone concentrations in plasma volumes as low as 10 µL. • Application of HPLC–MS/MS to pharmacokinetics in venous and capillary human plasma. • Similar area under the concentration vs time curve in venous and capillary plasma. • Subtle differences in the absorption phase with higher capillary concentrations. A straightforward and rapid high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) assay allowing the sensitive and selective quantitation of finerenone (BAY 94–8862) in lithium heparin human plasma is described. Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that is in phase III clinical trials for the treatment of chronic kidney disease. Finerenone quantitation is performed after addition of its stable isotope-labelled internal standard (ISTD) by protein precipitation with acidified acetonitrile followed by HPLC–MS/MS separation and detection. The determination of finerenone concentrations was validated for a plasma volume of 0.100 mL and subsequently also for a lower plasma volume of 0.010 mL, collected e.g. in paediatric studies. The analytical range was from 0.100 µg/L (lower limit of quantification) to 200 µg/L (upper limit of quantification). Inter-day accuracy was 99.7–105.0% for the plasma volume of 0.100 mL and 101.1–104.5% for the plasma volume of 0.010 mL. Inter-day precision was ≤ 7.0%, independent of the extracted plasma volume. A moderate, concentration-independent matrix effect on ionisation was observed for both finerenone and its ISTD of 0.535–0.617, which is fully compensated by the ISTD (ISTD-normalised matrix factors were 0.98–1.03). The assay was successfully applied with both validated plasma volumes to a clinical phase I study in which the pharmacokinetics of 20 mg finerenone were compared in capillary plasma (0.010 mL) and venous plasma (0.100 mL) in a concentration range from the lower limit of quantification to 310 µg/L (capillary plasma) and 252 µg/L (venous plasma). The area under the plasma concentration versus time curve was similar in both matrices, while maximum concentrations were 37% higher in capillary plasma. In conclusion, capillary sampling should not bias pharmacokinetic exposure estimates compared with venous plasma values, if limited to sampling times in the distribution and elimination phases of finerenone. [ABSTRACT FROM AUTHOR]

Neuromuscular blockers (NMBs) selectively block neuromuscular transmission at the N2-nicotinic receptor on motor neurons to paralyze skeletal muscles, and are mainly used to facilitate tracheal intubation and surgical procedures. Rapid reversal is necessary in clinical practice to avoid profound block and reduce recovery time. Adamgammadex sodium is a modified γ-cyclodextrin derivative consisting of a lipophilic core and a hydrophilic outer end that forms an inactive tight inclusion complex with free molecules of rocuronium and vecuronium. In preclinical study, adamgammadex produced a concentration-dependent reversion effect of neuromuscular blockade induced by rocuronium in beagle dogs. Furthermore, adamgammadex had a less potential side effects than sugammadex and other clinical used neuromuscular block antagonists. In this study, the objective was to assess the safety, tolerability, and pharmacokinetics of single intravenous injection of adamgammadex in healthy volunteers. Approved by the China Food and Drug Administration, 52 healthy volunteers (half male and half female) were enrolled in this single-center, randomized, double-blind placebo-controlled study. No serious adverse effects were happened in this study. The overall frequency of adverse effects in adamgammadex was similar for that in placebo, and there was no specific adverse effect in adamgammadex. All of the volunteers bearing the adverse effects were recovered to normal without any treatment or intervention. In pharmacokinetic study, the value of half-time, T max , and clearance were not changed significantly, and the C max and AUC 0–∞ increased with a similar ratio of the escalating doses. For dose proportionality analysis of adamgammadex, the estimate of slope was close to 1, and it was not significantly different from 1 after doses (AUC 0-∞ , 0.9965 [90%CI, 0.9468, 1.046]; C max , 0.9462 [90%CI, 0.8800, 1.012]). Therefore, adamgammadex exposure in plasma increased in a dose- proportional manner. The urinary route is a significant excretory pathway for adamgammadex, and it is mostly completed at 8 h. All the results in this study showed that adamgammadex may be a novel safe neuromuscular blockade reversal agent. Image, graphical abstract [ABSTRACT FROM AUTHOR]