Dataset Information

Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors.

ABSTRACT:

Purpose

TAS-102 is a novel oral agent combining the antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil (molar ratio 1:0.5). TAS-102 has shown good activity in refractory metastatic colorectal cancer with acceptable safety. No QT prolongation was seen in clinical studies. This study aimed to investigate TAS-102 cardiac safety for regulatory requirements.

Methods

This was a phase 1, non-randomized study in adults with advanced solid tumors. Intensive QT assessments were conducted at baseline, placebo, and following single and multiple doses of TAS-102 during a 28-day cycle.

Results

Following single- and multiple-dose administration (N = 30), the upper bounds of the one-sided 95 % confidence intervals for the difference between TAS-102 and placebo in time-matched baseline-subtracted 12-lead Holter QT intervals did not exceed 20 ms at any prespecified time point. One patient had a change from baseline in QTcI interval ≥60 ms, and one patient had a QTcI interval >500 ms following multiple-dose TAS-102 administration. No patient had an uncorrected QT, QTcF, or QTcB interval >500 ms. Based on the exposure-response analysis between TAS-102 plasma concentrations and the placebo-adjusted QTc intervals, none of the upper bounds of the one-sided 95 % prediction intervals exceeded 20 ms. There were no significant morphological changes for T or U waves. No cardiovascular AEs were reported in cycle 1. Across all cycles, no patient experienced an AE of ventricular tachycardia, ventricular fibrillation, syncope, or seizure.

Conclusions

There was no clinically relevant relationship between TAS-102 plasma concentrations and QTc interval; TAS-102 had no clinically relevant effects on cardiac repolarization.

Clinical trials

ClinicalTrials.gov study number: NCT01867879.

SUBMITTER: Bendell JC

PROVIDER: S-EPMC4882359 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors.

Bendell Johanna C JC Patel Manish R MR Yoshida Kenichiro K Seraj Jabed J Weaver Racquel R Lemech Charlotte C Todaro Thomas G TG Pant Shubham S Arkenau Hendrik-Tobias HT

Cancer chemotherapy and pharmacology 20160505 6

<h4>Purpose</h4>TAS-102 is a novel oral agent combining the antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil (molar ratio 1:0.5). TAS-102 has shown good activity in refractory metastatic colorectal cancer with acceptable safety. No QT prolongation was seen in clinical studies. This study aimed to investigate TAS-102 cardiac safety for regulatory requirements.<h4>Methods</h4>This was a phase 1, non-randomized study in adults wi ...[more]

PMID: 27151157

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Project description:PurposeCopanlisib in combination with immune checkpoint inhibitors demonstrated synergy and favorable antitumor immune responses in preclinical models. This study evaluated copanlisib plus nivolumab in adults with advanced solid tumors.Patients and methodsIn this phase Ib, nonrandomized, open-label, dose-escalation study, patients received intravenous nivolumab 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles) plus intravenous copanlisib (45 or 60 mg on days 1, 8, and 15 of each cycle) in 28-day cycles. The primary objective was to determine the MTD and/or recommended phase II dose of copanlisib plus nivolumab. Secondary objectives were safety, tolerability, and efficacy. Exploratory objectives included evaluation of potentially predictive biomarkers.ResultsOverall, 16 patients were treated [copanlisib: 45 mg (n = 5); 60 mg (n = 11)]. The most common cancer types at baseline were bladder (25.0%) and oropharyngeal (18.8%) cancers. No dose-limiting toxicities were observed; copanlisib 60 mg was deemed the recommended phase II dose in combination with nivolumab 240 mg. Grade 3 and 4 treatment-emergent adverse events were reported in 56.3% and 12.5% of patients, respectively; one grade 5 event was reported (unrelated to treatment). Overall, 18.8% of patients achieved a partial response. Evaluations of potential biomarkers did not correlate with response, but copanlisib-modulated biomarker changes were observed before nivolumab administration and were consistent and dose-dependent.ConclusionsNo new safety concerns were identified with this combination, and preliminary efficacy indicated an antitumor effect. Data supported an immunomodulatory effect of copanlisib, suggesting that this combination may enhance the efficacy of immune checkpoint inhibitors.SignificanceThe combination of copanlisib and nivolumab was well tolerated and showed antitumor effects in patients with advanced solid tumors. The number of circulating myeloid-derived suppressive cells decreased 24 to 48 hours after treatment with copanlisib. Further investigation of copanlisib and nivolumab is warranted as a novel strategy to enhance the efficacy of checkpoint inhibitors.

Dataset Information

Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors.

Purpose

Methods

Results

Conclusions

Clinical trials

Publications

Phase 1 study of cardiac safety of TAS-102 in patients with advanced solid tumors.

Similar Datasets

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