Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer.
ABSTRACT: Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval.The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8.After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)].There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.
Project description:The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8?h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2?:?1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ? 480?ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ? 60?ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125?mg palbociclib were less than 10?ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
Project description:The aims of this study were (i) to evaluate the effect of talazoparib (1?mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6?h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15?min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from -3.5 to 6.9?ms, with the greatest change 1?h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1?mg once daily) had no clinically relevant effects on cardiac repolarization.
Project description:Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets ?-spending function was used for OS. Adverse events were summarised descriptively.With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (?-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ?24 mo.Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.
Project description:BACKGROUND:Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern. METHODS:Male and non-pregnant females aged 1-65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4-5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation?>?500, change in QTc interval (?QTc)?>?60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively. RESULTS:A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals?>?500 ms on day 5 by both formulae. Patients with ?QTc?>?60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ?QTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p?=?0.010) and 13.4 ms (95% CI 5.3-21.5, p?=?0.001), for QTcB and QTcF, respectively. CONCLUSION:The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed in the intervention arm underscore the importance of further monitoring of QTc parameters in extended artemether-lumefantrine treatment. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017. https://clinicaltrials.gov/show/NCT03241901.
Project description:This dedicated QTc study was designed to evaluate the effect of the mammalian target of rapamycin inhibitor, ridaforolimus, on the QTc interval in patients with advanced malignancies.We conducted a fixed-sequence, single-blind, placebo-controlled study. Patients (n = 23) received placebo on day 1 and a single 100-mg oral dose of ridaforolimus on day 2 in the fasted state. Holter electrocardiogram (ECG) monitoring was performed for 24 h after each treatment, and blood ridaforolimus concentrations were measured for 24 h after dosing. The ECGs were interpreted in a blinded fashion, and the QT interval was corrected using Fridericia's formula (QTcF). After a washout of at least 5 days, 22 patients went on to receive a therapeutic regimen of ridaforolimus (40 mg orally once daily for 5 days per week).The upper limit of the two-sided 90 % confidence interval for the placebo-adjusted mean change from baseline in QTcF was <10 ms at each time point. No patient had a QTcF change from baseline >30 ms or QTcF interval >480 ms. Geometric mean exposure to ridaforolimus after the single 100-mg dose was comparable to previous experience with the therapeutic regimen. There appeared to be no clear relationship between individual QTcF change from baseline and ridaforolimus blood concentrations. Ridaforolimus was generally well tolerated, with adverse events consistent with prior studies.Administration of the single 100-mg dose of ridaforolimus did not cause a clinically meaningful prolongation of QTcF, suggesting that patients treated with ridaforolimus have a low likelihood of delayed ventricular repolarization.
Project description:The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters.Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) and after (0-15 and 60-75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia's correction was applied to QT measurements (QTcF) and change from baseline (?QTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (??QTcF). Linear mixed-effects modeling evaluated potential exposure-response relationships between ?QTcF and observed pertuzumab concentrations.Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ??QTcF (90 % CI) values at 0-15 min, 60-75 min, and 72 h post-infusion were -6.96 (-13.69, -0.23), -6.35 (-13.57, 0.88), and -4.08 (-12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ??QTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration-QTc modeling showed no apparent relationship between ?QTcF and pertuzumab concentrations.Cardiac monitoring and concentration-QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters.
Project description:Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial.Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals.Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship.Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.
Project description:Abiraterone acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate is the oral prodrug of abiraterone, a specific CYP17 inhibitor that blocks androgen biosynthesis within the adrenal glands, testes and tumor microenvironment. In a phase III trial of men with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC, treatment with oral abiraterone acetate plus prednisone led to a statistically significant improvement in the co-primary endpoints of overall survival and radiographic progression-free survival when compared with placebo plus prednisone. In long-term follow-up of phase III trials, the incidence of corticosteroid-associated adverse events was 25.5% in the abiraterone acetate plus prednisone arm compared with 23.3% in the placebo plus prednisone arm. The need for regular patient monitoring and appropriate management of symptoms during long-term use of prednisone must be placed in context with the improvement in survival seen with abiraterone plus prednisone. Within the multidisciplinary environment that is emerging to meet quality and cost imperatives, abiraterone acetate plus prednisone is suitable for use in the chemotherapy-naïve population with minimal symptoms as well as in patients who have been treated with docetaxel and may have symptomatic disease. Ongoing trials are evaluating the role of abiraterone acetate plus prednisone in patients with nonmetastatic CRPC and metastatic hormone-sensitive prostate cancer, while further trials in the mCRPC setting are evaluating its use in combination regimens.
Project description:Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs.The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer.Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia's formula (QTcF) in patients with advanced cancer.Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline.Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline.Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF.
Project description:We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients.COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression.A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels.Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.