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Background: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib., Methods: We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50-800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited., Findings: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration., Interpretation: Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment., Funding: Bayer AG., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors., Methods: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker)., Results: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease)., Conclusions: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients., Trial Registration: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

Purpose: This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator., Methods: The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored., Results: 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy., Conclusion: Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.

Purpose: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors., Patients and Methods: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry., Results: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient., Conclusion: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.

Introduction IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro , IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent. Methods This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose–escalation cohorts (33, 100, 300, 600, and 1000 mg/m 2 ) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the primary objectives; secondary objectives included assessment of the IMAB362 pharmacokinetic profile, immunogenicity, and antitumour activity (assessed by Response Evaluation Criteria in Solid Tumors v1.0). Results IMAB362 was generally well tolerated at all doses, with gastrointestinal toxicities being the most commonly observed treatment-related adverse events. As dose-limiting toxicity was not observed within 4 weeks of treatment, a maximum tolerated dose was not established. The pharmacokinetic profile of IMAB362 appeared to be proportional across the dose range; and mean half-life ranged from 13 to 24 d. While most patients showed progressive disease at weeks 4–5 after a single intravenous IMAB362 infusion, one patient in the 600 mg/m 2 dose group achieved and maintained stable disease for approximately 2 months postinfusion. Conclusions Findings from this study demonstrate that IMAB362 is generally well tolerated and support further evaluation in patients with gastric/gastro-oesophageal junction cancer. Clinical trial registry ClinicalTrials.gov, Identifier NCT00909025 . [ABSTRACT FROM AUTHOR]