Alterations in the gene encoding fibroblast growth factor receptor (
) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine ...kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with
alterations.
In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified
alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival.
A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths.
The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with
alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).
Background
Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of ...efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib.
Methods
Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors.
Results
Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 95% CI 0.46–0.72 per mg/dL of PO4;
p
= 0.01), PFS (hazard ratio 0.80 0.67–0.94 per mg/dL of PO4;
p
= 0.01), and ORR (odds ratio 1.38 1.02–1.86 per mg/dL of PO4;
p
= 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4.
Conclusions
The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio.
Clinical trial registration number
NCT02365597.
A population pharmacokinetic (PK)–pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK‐PD model evaluated the effect of erdafitinib total and free ...plasma concentrations on serum phosphate concentrations after once‐daily oral continuous (0.5–12 mg) and intermittent (10–12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib‐related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23–mediated signaling. PK‐PD model‐based simulations were performed to assess the approved PD‐guided dosing algorithm of erdafitinib (8 mg once‐daily continuous dosing, with up‐titration to 9 mg based on phosphate levels <5.5 mg/dl and tolerability at 14–21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8‐fold increase in drug‐related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak‐to‐trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68–5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate–parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8‐mg with up‐titration to 9‐mg on Days 14–21 maximized the number of patients within the target serum phosphate concentrations (5.5–7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK‐PD model provided a detailed understanding of the erdafitinib concentration‐related phosphate changes over time, which supports erdafitinib's dosing algorithm.
The p53 gene family, comprising p53, p63, and p73, has overlapping and distinctive functional roles. These members share structural similarities allowing for dynamic interplay in the activation of ...genes that are important in development and key cellular functions, such as the induction of apoptosis. Whereas p53 is a classical tumor suppressor gene, p63 and p73 do not share this feature in cancer formation and progression. The compensation in the expression level of these members in a background that is deficient for one of them has not been examined previously. Given the importance of p63 in the development and differentiation of oral-esophageal stratified squamous epithelia and the absence of oral-esophageal tumors in p53-null mice, we postulated and describe herein that p63 expression is associated with the loss of p53 in a p53-deficient background. Both full-length and amino-truncated forms of p63 are expressed and increased in oral-esophageal epithelia of p53-null mice when compared with wild-type mice, and the induction of p21 may potentially be preserved through the increase of p63.
9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged ...administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 microg/m(2)/h over 120 hours (3000 microg/m(2) over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6-4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer.
Abstract
Objectives This article observes the mean daily dose of fentanyl required for adequate sedation in critically ill, mechanically ventilated children randomized to receive dexmedetomidine or ...placebo.
Methods We conducted Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multicenter, double-blind, randomized, placebo-controlled, dose-escalating trial. We enrolled children aged 35 weeks postmenstrual to 17 years (inclusive) admitted across 13 pediatric multidisciplinary and cardiac intensive care units. Adequate sedation was based on a State Behavioral Score and Richmond Agitation-Sedation Scale of –1 or lower. Only the first two dexmedetomidine dosing cohorts opened for enrollment, due to early trial closure during the coronavirus 2019 pandemic. Thirty children were randomized over 13 months and included in the analyses.
Results Demographic and baseline characteristics were not different between dexmedetomidine and placebo cohorts. Similarly, mean daily fentanyl use was not different, using an unadjusted mixed regression model that considered treatment, time, and a treatment-by-time interaction. Adverse events and safety events of special interest were not different between cohorts.
Conclusion The DOSE trial revealed that dexmedetomidine added to fentanyl does not impact safety and may not spare fentanyl use in critically ill children, although the trial did not meet its recruitment goals, due to early closure during the coronavirus 2019 pandemic. More rigorous inpatient pediatric trials like DOSE that study critically ill, mechanically ventilated children are needed. Despite the many obstacles faced, the DOSE trial presents challenges from which the greater research community can learn and use to optimize future therapeutic trials in children.
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