Effects of Rovalpituzumab Tesirine on Ventricular Repolarization in Patients With Small‐Cell Lung Cancer

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova‐T) is an antibody‐drug conjugate that targets delta‐like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova‐T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova‐T in patients with previously treated extensive‐stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova‐T over 30 minutes, administered 6 weeks apart. Forty‐six patients received at least one dose of Rova‐T. At the geometric mean Rova‐T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia‐corrected QT (QTcF) interval; the upper limit of the 2‐sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova‐T administration. All patients experienced a treatment‐emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac‐related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova‐T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ There currently are no clinical data regarding the electrocardiographic (ECG) effects of rovalpituzumab tesirine (Rova‐T).

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study was conducted to address questions regarding cardiac safety of this agent during its clinical drug development cycle to meet the US Food and Drug Administration (FDA) requirements.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study confirmed that targeting delta‐like 3 using Rova‐T at the 0.3 mg/kg dose that was utilized in the phase II/III studies did not result in any clinically significant changes in the ECG throughout several time points.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This knowledge will facilitate future development of tesirine‐containing antibody‐drug conjugates by ameliorating concerns of potential ECG effect, even if Rova‐T itself did not meet efficacy end points for drug approval.

Lung cancer is one of the most common and deadly cancers, with 228,000 new diagnoses per year and 143,000 deaths per year in the United States. ¹ Small cell lung cancer (SCLC) accounts for 10% to 15% of lung cancers ¹ and is a leading cause of cancer death worldwide. ² , ³ The prognosis of patients with SCLC is poor, with a 5‐year survival rate of < 5%. ⁴ , ⁵ SCLC is categorized into limited‐stage and extensive‐stage (ES) disease based on the extent of the disease, with ES disease accounting for 65% of cases. ⁶ Treatment options are limited for ES disease, with platinum doublet chemotherapy along with anti‐PD‐L1 checkpoint blockade (atezolizumab or durvalumab) as the preferred first‐line treatment. There are few effective therapies approved for second‐line treatment of ES SCLC ⁷ ; median overall survival in patients treated with topotecan is only 26 weeks. ⁸ Recent studies of single‐agent cytotoxic agents and immunotherapy have yielded only modest improvements. ⁷ The Notch‐family ligand delta‐like 3 (DLL3) is highly expressed on SCLC cells but not expressed in most normal tissue, making it a tractable drug target for SCLC. ⁹ Rovalpituzumab tesirine (Rova‐T) is a first‐in‐class antibody‐drug conjugate (ADC) that targets DLL3 to deliver a cytotoxic agent directly to SCLC cells. Rova‐T is composed of a monoclonal DLL3 antibody linked to a DNA‐intercalating payload (pyrrolobenzodiazepine (PBD)) via a protease‐cleavable linker. The safety and efficacy of Rova‐T were initially evaluated in 82 patients in the first‐in‐human phase I study SCRX16‐001 (74 patients with SCLC and 8 patients with large‐cell neuroendocrine carcinoma). Treatment‐related cardiac adverse events (AEs) were uncommon. ¹⁰ The change in Fredericia‐corrected QT interval (QTcF) remained below a 10‐msec increase relative to baseline at 30 minutes after the end of infusion, when maximum Rova‐T serum concentrations were observed (unpublished data). Effects on QTcF at later time points have not been evaluated. In the phase 2 TRINITY study of patients with DLL3‐expressing relapsed/refractory SCLC, 12% of patients had a confirmed objective response to Rova‐T, and a manageable safety profile was observed. ¹¹ Further development of Rova‐T has since been halted because two phase III studies showed a lack of clinical benefit of Rova‐T in the frontline maintenance and second‐line settings. ¹² , ¹³ Determining cardiovascular safety is a key part of drug characterization. A delay in cardiac repolarization results in an electrophysiological environment that may lead to development of potentially fatal cardiac arrythmias. Typically, a thorough QT/corrected QT (QTc) study is conducted after the initial clinical study to determine whether an investigational agent meets a threshold level of effect on cardiac repolarization as detected by QT/QTc prolongation. ¹⁴ The cytotoxic component of Rova‐T precluded a thorough conventional QT/QTc study, which usually includes a crossover with the therapeutic dose, a supratherapeutic dose, a placebo, and a positive control in healthy volunteers. Additionally, because patients with SCLC require active treatment, the use of a placebo and/or a positive control would not be ethical. ¹⁵ Therefore, an alternative, intensive QT/QTc study design was determined to be appropriate, with the primary objective of determining the effect of Rova‐T on QTcF in patients with SCLC during the first two cycles of Rova‐T administration.     

The characteristics of the action of mildronate (dihydrate 3-(2,2,2-trimethylhydrazine)propionate) on the red blood parameters in heart failure]

Mildronat potentiates the therapeutic effect of the combined treatment of heart failure, which includes the use of nitro drugs. It also decreases the level of methemoglobin in the patients' blood and improves the phosphate balance, especially that of 2,3-diphosphoglycerate to control oxygen transport by hemoglobin, which is of paramount importance in hypoxia caused by coronary heart disease.     

Silver resistance in Escherichia coli R1

Escherichia coli strain R1, originally isolated from a patient whose burns were treated with silver sulphadiazine, contained two large plasmids of 83 kb (pJT1) and 77 kb (pJT2), and was resistant to 1 mM AgNO3. A silver-sensitive derivative, E. coli S1, cured of the 83-kb plasmid pJT1, was obtained by growth at 46 degrees C. Studies with an Ag+-specific ion electrode showed no significant differences in Ag+ binding by washed resting cell suspensions of strains R1 and S1, with and without glucose. However, transmission electronmicroscopy and energy dispersive X-ray analysis of whole cell mounts from actively growing cultures showed that the Ag+-resistant strain did not accumulate Ag+, whereas the sensitive strain contained dense silver particles. Both strains produced H2S, detected by blackening of lead acetate paper above inoculated broth, and reducing substances (possibly H2S) were detected only around E. coli R1 colonies when methylene blue was used as a indicator in LB agar, which may be a less sensitive assay. The mechanism of silver resistance is not known, but actively growing cells of E. coli R1 did not accumulate silver.     

Effect of oxygen concentration on denitrification in freshwater sediment

The effect of different O₂ concentrations on denitrification in freshwater sediment was studied using the acetylene blockage technique. Denitrification occurred over a wide range of O₂ concentrations ranging from 10.1 to 0.33 μmol ml^?1 in nitrate amended sediment. However, denitrifying activity was not observed in sediment incubated under similar conditions when NO₃-was absent. These observations suggested that an anoxic environment or low O₂ concentrations were not required for denitrification to occur, if NO₃- was initially present in the sediment. Denitrification gradually decreased as the dissolved O₂ concentration in sediment increased to 0.25 μmol ml^?1. However, between 0.25 and 0.35 μmol ml^?1 dissolved O₂, denitrifying activity was higher than at the lower dissolved O₂ concentration (0.25 μmol ml^?1).     

Galanin suppresses calcium conductance and activates inwardly rectifying potassium channels in myenteric neurones from guinea-pig small intestine

Whole-cell patch-clamp recording methods were used to investigate the ionic mechanisms underlying the hyperpolarizing action of galanin in enteric neurones. Galanin suppressed calcium current (ICa) and activated inwardly rectifying potassium current (IK,ir) in AH-type myenteric neurones of guinea-pig small intestine. Both suppression of ICa and activation of IK,ir were concentration-dependent, with an EC50 of 1.4 nmol L-1 and 55 nmol L-1, respectively. Pretreatment with pertussis toxin eliminated both actions of galanin, suggesting that both galanin-induced inhibition of ICa and galanin-induced activation of IK,ir involved activation of Gi/Go proteins. Both suppression of ICa and activation of IK,ir by galanin were mimicked by the N-terminal fragment of galanin, galanin-(1-16) suggesting that the first 16 amino acids of the peptide were sufficient for both actions. The galanin receptor antagonist galantide suppressed the galanin-induced activation of IK,ir with an EC50 of 16 nmol L-1. However, galantide alone suppressed ICa. The results suggest two mechanisms of action for galanin: one is opening of inwardly rectifying potassium channels and the second is blockade of voltage-activated calcium channels.     

Association of serum lactate and survival outcomes in patients undergoing therapeutic hypothermia after cardiac arrest

Introduction

Recent studies have suggested that serum lactate may serve as a marker to predict mortality after resuscitation from cardiac arrest (CA). The relationship between serum lactate and CA outcomes requires further characterization, especially among patients treated with therapeutic hypothermia (TH) and aggressive post-arrest care.

Methods

A retrospective analysis of patients resuscitated from non-traumatic CA at three urban U.S. hospitals was performed using an established internet-based post-arrest registry. Adult (≥18 years) patients resuscitated from CA and receiving TH treatment were included. Logistic regression analysis was used to adjust for potential confounders to survival outcomes. Survival to discharge served as the primary endpoint.

Results

A total of 199 post-CA patients treated with TH between 5/2005 and 11/2011 were included in this analysis. The mean age was 56.9 ± 16.5 years, 85/199 (42.7%) patients were female, and survival to discharge was attained in 84/199 (42.2%). While lower initial post-CA serum lactate levels were not associated with increased survival to discharge, subsequent lactate measurements were significantly associated with outcomes (24-h serum lactate levels in survivors vs. non-survivors, 2.7 ± 0.5 vs. 4.2 ± 0.4 mmol/L, p < 0.01). Multivariable logistic regression confirmed this relationship with survival to discharge (p < 0.01).

Conclusion

Lower serum lactate levels at 12 h and 24 h, but not initially following cardiac arrest, are associated with survival to hospital discharge after resuscitation from CA and TH treatment. Prospective investigation of serum lactate as a potential prognostic tool in CA is needed.