QTcF Change Research Articles

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Abstract A194: A QT/QTc and multi-dose pharmacokinetic (PK) study of abiraterone acetate (AA) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Abstract Background: AA is the prodrug of abiraterone (A), an androgen biosynthesis inhibitor that selectively inhibits CYP17, thereby blocking testicular, adrenal, and prostatic intratumoral androgen biosynthesis. In a phase 3 study, AA+P demonstrated survival improvements in post-docetaxel mCRPC pts (De Bono ESMO 2010). ADT with an LHRH analog (LHRHa) has been associated with median QTc interval prolongation of 9–21 msec (Garnick ASCO 2004). Primary objective: effects of AA+P on QT/QTc interval duration in mCRPC pts receiving LHRHa. Secondary objectives: pharmacokinetics (PK) of AA and abiraterone (A) after single/multiple doses of AA. Methods: In this open-label, single-arm phase 1b study (COU-AA-006/NCT00910754), 33 mCRPC pts with disease progression after failure of GnRH hormone therapy, a PSA ≥2 ng/mL and ≤1 course of prior chemotherapy, received AA 1000mg orally QD + P 5mg orally BID. ECGs were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle (C)1 Day (D)-1. Serial ECG recordings and time-matched PK blood samples were collected over 24 hrs on C1D1 and C2D1. Serial PK blood samples were also collected over 24 hrs on C1D8. Results: After AA administration, the upper bound of the 2-sided 90% CI for the mean baseline-adjusted QTcF change was <10 msec; no subjects discontinued due to QTc prolongation or AEs. Most AA plasma concentrations were below the quantification limit; thus AA PK analysis was not performed. A linear mixed-effects model showed no apparent relationship between change in QTcF and A plasma concentrations (estimated slope [90%CI): 0.0031 [−0.0040, 0.0102]). Exposure to A after multiple AA dosing on C1D8 and C2D1 increased versus exposure after single dose on C1D1; accumulation ratios for C1D8 (1.8–2.0) and C2D1 (2.0–2.2) were similar. The most commonly reported treatment-emergent AE (TEAE) was dizziness (12%); all TEAEs were grade 1; except 1 grade 3 AE (increased ALP) with no grade 4 TEAEs. Conclusions: There is no significant effect of AA+P on the cardiac QT/QTc interval in mCRPC pts. No relationship between change in QTcF and A plasma concentration was observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A194.

Abstract C121: A phase 1 QTc study of tivozanib in patients with advanced solid tumors.

Abstract Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Previous preclinical and clinical studies have shown that tivozanib displays strong antiangiogenic and antitumor effects. Preclinical and retrospective electrocardiogram (ECG) analyses did not suggest an effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the proarrhythmogenic potential of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Patients with a repeated baseline QTcF >480 ms were excluded. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20–30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessment of clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received at least one dose of tivozanib were evaluable for the present study. Preliminary adverse event data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib at 1.5 mg daily over a 21-day period does not cause clinically significant prolongation of QT/QTc over baseline. Data from this study suggest that the safety and PK profile of tivozanib was similar to that observed in previous studies, and that the findings are consistent with the ECG evaluation in a monkey telemetry study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C121.

A Supratherapeutic Dose of the Janus Kinase Inhibitor Tasocitinib (CP-690,550) Does Not Prolong QTc Interval in Healthy Participants

Tasocitinib (CP-690,550), a selective inhibitor of the Janus kinase (JAK) family, is being developed for the treatment of several autoimmune diseases and prevention of allograft rejection. The aim of this study was to characterize the effect of tasocitinib on QT interval. Sixty male and female healthy adults were enrolled in a single-dose, randomized, 3-period, crossover study of a supratherapeutic dose of tasocitinib (100 mg), placebo, and moxifloxacin 400 mg. Triplicate electrocardiograms were performed at predose baseline and serially over 24 hours postdose in each treatment period. The upper limits of the 2-sided 90% confidence intervals (CIs) for the difference in QTc interval, corrected using Fridericia correction (QTcF), between tasocitinib and placebo were less than 5 ms at all time points. Concentration-QTcF analysis showed that the predicted mean change (90% CI) in QTcF at the observed mean C(max) was -0.12 (-1.18, 0.94) ms. For moxifloxacin, mean (90% CI) estimates of the change in QTcF from placebo were 11.3 (9.4, 13.1) and 12.5 (10.7, 14.4) ms at 2 and 4 hours, respectively, thereby establishing study sensitivity. A single supratherapeutic dose of tasocitinib 100 mg was well tolerated and not associated with QTc prolongation.

QT Response after a Test Dose and during Maintenance Therapy with AZD1305 in Patients with Atrial Fibrillation

AZD1305 is an investigational antiarrhythmic agent that prolongs refractoriness through combined potassium and sodium channel inhibition. This study aimed to explore the utility of a test dose in predicting QT interval corrected according to Fridericia's formula (QTcF) during subsequent maintenance treatment with AZD1305. This was a randomized, double-blind, parallel-group, placebo-controlled trial carried out at multiple hospital cardiac facilities in Denmark, Norway, Poland, Slovakia, and Sweden. Patients with documented atrial fibrillation (AF) but currently in stable sinus rhythm for ≥2 hours and ≤90 days were eligible for inclusion. Patients were randomized in a 1 : 1 : 1 ratio to receive AZD1305 extended-release or matching placebo tablets as follows: group A - test dose 250 mg, evening dose 125 mg on day 1, maintenance dose 125 mg twice daily; group B - test dose 500 mg, placebo evening dose, maintenance dose 125 mg twice daily; placebo group - placebo test and maintenance dose. Maintenance dosing was for 9 days. QTcF >550 ms at any time during the in-patient phase or >500 ms after discharge (day 4) were predefined study drug discontinuation criteria. The main outcome measure was the relationship between QTcF following the test dose and during maintenance treatment. Sixty-five patients were randomized (n = 21, 22, and 22 in group A, group B, and the placebo group, respectively). AZD1305 dose-dependently increased QTcF. There was a positive, linear correlation between the change in QTcF during the first 6 hours after the test dose and during the maintenance phase. Three patients, all from group B, discontinued treatment on day 1 due to QTcF >550 ms. All other patients completed the study without events related to QT prolongation. There was a trend for reduced AF recurrence with AZD1305 compared with placebo. In this exploratory study a test dose predicted the QT response during maintenance treatment with AZD1305 and may thus be employed in further studies. [ClinicalTrials.gov Identifier: NCT00643448].

Thorough QT study of the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor, on cardiac repolarization and conduction in healthy volunteers

Objective:This randomized, double-blind study evaluated the effects of vildagliptin, a dipeptidyl peptidase IV inhibitor for treating type 2 diabetes, on cardiac repolarization and conduction.Methods:Healthy volunteers (n = 101) were randomized (1:1:1:1 ratio) to vildagliptin 100 or 400 mg, moxifloxacin 400 mg (active control), or placebo once daily for 5 days. Electrocardiograms were recorded at baseline and day 5 for 24 hours post-dose. Placebo-adjusted mean change from baseline in QT interval, heart-rate-corrected QT intervals by Fridericia's (QTcF) or Bazett's (QTcB) formula, and PR and QRS intervals were compared at each time-point (time-matched analysis) and for values averaged across the dosing period (time-averaged analysis).Results:For time-matched analysis, mean changes in QTcF with vildagliptin were below predefined limits for QTc prolongation (mean increase <5 ms; upper 90% confidence interval [CI] < 10 ms), except for vildagliptin 100 mg at 1 and 8 hours post-dose (upper 90% CI > 10 ms). With moxifloxacin, significant QTcF prolongation occurred at most time-points, demonstrating assay sensitivity. No vildagliptin- or placebo-treated volunteer had QTcF > 450 ms. Incidences of QTcF increases ≥30 ms with vildagliptin (100 and 400 mg) and placebo were similar (4–8%) and were much lower than with moxifloxacin (39%). No QTcF increase ≥60 ms was observed with vildagliptin or placebo (versus one with moxifloxacin). Time-averaged, time-matched, and categorical analyses of QT/QTcF/QTcB showed similar results. Drug exposure analysis showed no correlation between vildagliptin plasma levels and QTc changes. Vildagliptin had no effect on PR or QRS intervals. Although this study, completed before publication of current ICH E14 guidelines, was underpowered for time-matched analysis, the results are consistent with lack of effect of vildagliptin on QTc.Conclusion:Vildagliptin did not prolong QT interval or affect cardiac conduction at the highest daily therapeutic dose or a fourfold higher dose.

Phase II, open-label trial to assess the effect of continuous oral afatinib (BIBW 2992) at a daily dose of 50 mg on QTc, pharmacokinetics, and efficacy in relapsed or refractory solid tumors including brain metastases and glioblastoma that is not amenable to other therapy.

2613^ Background: Afatinib (BIBW 2992) is an oral, irreversible ErbB family blocker. This trial prospectively evaluated the possible proarrhythmic potential of afatinib by assessing QTc interval, as well as its PK and clinical efficacy. Methods: Patients (pts) with tumors known to overexpress EGFR or HER2, including those with brain metastases and GBM were eligible for treatment with daily afatinib 50mg. Pts with a QTcF-interval >470 ms, a PR-interval >230 ms, a QRS-interval >120 ms and ST-segment and T/U-wave abnormalities at screening, as assessed by central cardiology review, were excluded. 60 pts were treated. Time-matched 24-h ECGs were performed prior to drug exposure, after single dose and at steady state. Pharmacokinetic (PK) samples were drawn on days coincident with ECGs. Results: 49 of 60 pts were analyzed for the QTcF. The largest mean time matched QTcF change from baseline to Day 14 was 1.6 ms (90% CI –2.1, 5.2) at 1 h post dosing. The analysis of the relationship between the afatinib concentrations and time-matched QTcF changes from baseline revealed a statistically significant negative slope and a predicted negative QTcF change from baseline (90% CI -2.83, 2.55 ms). No relevant effect of afatinib on other cardiac intervals was detected. The overall AE profile was consistent with the known safety profile of afatinib. The median tmax value for afatinib was approximately 3 h after a single dose (Day 1) and at steady state (Day 14). The gMean accumulation ratio was 2.05 based on Cmax values and 2.67 based on AUC values. Efficacy was assessed in 60 pts including NSCLC (35%), breast cancer (10%), GBM (7%) & GI tumors (32%). Two pts had brain metastases. 42% of the pts received > 4 treatment cycles, 18% > 6 cycles, and one pt 19 cycles. Conclusions: Afatinib at doses of 50 mg daily did not suggest any drug-induced QT/QTcF prolonging effects compared with baseline. Afatinib showed clinical efficacy in this patient population.

Supra-therapeutic doses of roflumilast have no effect on cardiac repolarization in healthy subjects

Objective: This study assesses the potential of the phosphodiesterase 4 inhibitor roflumilast to affect cardiac repolarization.Methods: In this randomized, placebo-controlled study (n = 80), 40 healthy subjects received moxifloxacin 400 mg p.o. (positive control for prolongation of QT/heart-rate corrected QT [QTc]) and another 40 received placebo. After a 1-day washout, subjects received placebo or ascending doses of roflumilast 500 (therapeutic dose), 750 or 1000 μg/day p.o., for 14, 7 and 14 days, respectively. QT intervals were measured and corrected for heart rate with a Fridericia algorithm (QTcF). The primary endpoint was the largest mean time-matched change in QTcF from baseline (day 1). Safety and tolerability were monitored.Results: Moxifloxacin gave a maximum time-matched change in QTcF versus baseline of 6.79 ms. Repeated administration of roflumilast 500 and 1000 μg resulted in maximum QTcF changes from baseline of -3.23 and -4.81 ms, respectively, confirming the absence of any QT/QTc prolongation at therapeutic and supra-therapeutic dosing. There were no changes in other electrocardiographic variables or time intervals, and roflumilast was well tolerated.Conclusions: Repeated administration of roflumilast at doses ≤ 1000 μg/day had no effect on cardiac repolarization or overall cardiac safety evaluations in healthy subjects.Clinical trial registration number: ISRCTN63818313

Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations.

There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown. This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett's (QTcB) and Fredericia's (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group. Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P < 0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P < 0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P < 0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P < 0.01). Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.

A Phase I Study of Midostaurin (PKC412) Investigating Cardiac Interval Effects In Healthy Subjects

AbstractAbstract 4362Midostaurin (PKC412) is a multi-targeted tyrosine kinase inhibitor (TKI) of several receptors, including wild-type and mutant variants of KIT and the FMS-like tyrosine kinase 3 (FLT3) receptor, and has known roles in hematopoiesis and leukemia. Midostaurin has demonstrated activity in acute myeloid leukemia (AML) and myelodysplastic syndrome in phase 1 and 2 trials, and is currently under investigation in a randomized phase 3 AML study at 50mg twice daily (bid) in combination with chemotherapy and a phase 2 monotherapy study of aggressive systemic mastocytosis (ASM) at 100mg bid. Despite the absence of specific midostaurin-related cardiac toxicity issues, we conducted a dedicated phase 1 study to directly investigate the effect of midostaurin on QTc interval. Healthy subjects were randomized to 3 treatment arms: placebo; midostaurin administered orally at 75mg bid on days 1 and 2 and once daily (od) on day 3; or an active control arm of moxifloxacin administered orally at 400mg od on day 3. The primary variable was QTcF interval on day 3 corrected for baseline and placebo in the midostaurin and moxifloxacin treatment arms. Drug exposure levels at each time point were confirmed for moxifloxacin, midostaurin, and its two metabolites – CGP62221 and CGP52421. Of 192 subjects enrolled, 166 completed the study. 24 of 80 subjects discontinued in the midostaurin arm: 19 (23%) due to adverse events (AEs), 17 of which encompassed expected gastrointestinal events. No patients were discontinued for AEs in the other 2 treatment groups. Discontinued patients were not included in the ECG analysis. In time-matched analysis of QTcF interval change, the maximum mean change in the midostaurin arm corrected for baseline and placebo was 0.72ms with a 90% confidence interval (CI) upper bound of 4.71ms, which excluded 10ms. At each nominal time point, the mean change from baseline placebo-corrected for midostaurin was <0ms. The QTcF change point estimate corrected for time-averaged baseline and placebo also showed a lack of QTc prolongation for midostaurin. Moxifloxacin had a maximum mean change corrected for baseline and placebo of 10.7ms with a lower unadjusted 90% CI of 6.4ms 1 hour post-dose on day 3. Plasma concentration vs QTcF change from baseline analysis confirmed a negative or lack of QT effect by midostaurin but a positive correlation for moxifloxacin. No symptomatic, clinically significant new post-baseline morphological abnormalities were identified in the study. 3 patients in the midostaurin group at a single time point or evaluation experienced new post-baseline T-wave abnormalities, as did 1 and 4 patients in the placebo and moxifloxacin groups, respectively, some at multiple time points. No subject had a new >30ms or >480ms change from baseline for QTcF or QTcI. For QTcB the only occurrences of change were in the 30–60ms category: 1 (1.3%) of the subjects on midostaurin met this non-specific outlier criterion; 7 (15.9%) on moxifloxacin; and 1 (1.5%) on placebo. 1 new U-wave abnormality was noted in the moxifloxacin group. The peak plasma concentration of midostaurin achieved in the present study (mean 2273ng/mL) covered the peak and trough plasma exposure observed at 50mg bid (2220ng/mL and 1005ng/mL, respectively) in AML patients. The peak level achieved for midostaurin was also above the steady-state trough level of 1060ng/mL, but below the peak concentration of 3500ng/mL, for the 100mg bid dose. Midostaurin was safe and generally well tolerated: 97% of the AEs noted in subjects while on study drug (n=61; 40%) were reported as grade 1. No grade 3/4 AEs were reported. While some TKIs exert pharmacologic effects on QTc interval, this carefully conducted trial demonstrates that midostaurin at 75mg bid has no effect on heart rate, AV conduction, or cardiac depolarization. The midostaurin exposure achieved in this study exceeds the peak and trough levels for the 50mg bid dose regimen under investigation in the AML phase 3 trial. The midostaurin exposure achieved also exceeds the steady state trough level, but not the peak level, of the 100mg bid dose regimen under investigation in the phase 2 ASM trial. Further, the effects of the long-acting metabolite CGP52421 cannot be fully addressed by this short study. Due to the lack of QT prolongation observed in this trial, we recommend reduced but continued ECG monitoring and omission of QT-related exclusion criteria in future midostaurin clinical trials. Disclosures:del Corral:Novartis Pharmaceuticals Corporation: Employment. Dutreix:Novartis Pharmaceuticals Corporation: Employment. Huntsman Labed:Novartis Pharmaceuticals Corporation: Employment. Rai:Novartis Pharmaceuticals Corporation: Employment. Grosch:Novartis Pharmaceuticals Corporation: Employment. Morganroth:eResearchTechnology Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Cardiac Safety Profile of Imatinib and Nilotinib In Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Results From ENESTnd

Abstract 2291 Background: Nilotinib is a potent and the most selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy vs imatinib with higher and faster molecular responses and a significantly lower rate of progression on treatment to accelerated or blast phases of CML. Nilotinib has been previously shown to prolong the QT interval. The cardiac safety profile of nilotinib was previously described in pts with imatinib-resistant and -intolerant CML-CP enrolled in phase 2 clinical trials. Here, we report cardiac safety data on nilotinib 300 and 400 mg twice daily (bid), and imatinib, in pts with newly diagnosed CML-CP from the ENESTnd trial. Methods: A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. Pts were excluded from study participation if they had known uncontrolled or medically significant cardiac disease, left ventricular ejection fraction (LVEF) 450 msec. Prospective cardiac monitoring was conducted throughout the study for QT prolongation (via electrocardiogram) and LVEF (via echocardiogram) at regular intervals. Results: QTcF increases of > 30 msec from baseline occurred in 26% of pts in each nilotinib arm and in 18% of pts in the imatinib arm. QTcF increases of > 60 msec from baseline were uncommon, occurring in 500 msec. Analysis was conducted to identify any potential case of clinically symptomatic QT prolongation. Only events of syncope were identified (1 pt in each arm with drug-related events) by this analysis and none of these could be attributed to QT prolongation; there were no episodes of torsades de pointes in any treatment arm. Additionally, there was no decrease from baseline in mean LVEF observed anytime on treatment in any arm (Table). No patient in any treatment arm had a LVEF of 15%. Importantly, no pt discontinued therapy due to QT prolongation or LVEF change. An analysis of grouped adverse event terms was performed to identify cases consistent with ischemic heart disease (IHD) or left ventricular dysfunction. A total of 11 pts in all treatment arms experienced IHD events after median treatment duration of 18 months: 3 (1%) on nilotinib 300 mg bid, 6 (2%) on nilotinib 400 mg bid, and 2 ( Conclusions: Overall, QT prolongation, changes in LVEF, and clinical cardiac events were uncommon in all arms and seldom led to discontinuation. There was no cumulative effect of nilotinib exposure on cardiac safety with a median of 18 months follow-up. Nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Lopez: Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gallagher: Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp: Novartis: Employment. Ortmann: Novartis: Employment. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib

Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib

Pharmacokinetics and Pharmacodynamics of Three Moxifloxacin Dosage Forms: Implications for Blinding in Active‐Controlled Cardiac Repolarization Studies

Moxifloxacin is used in thorough QT studies to assess sensitivity for detection of an increase in QTc. Moxifloxacin is usually over-encapsulated for blinding. However, there is concern that over-encapsulation alters its pharmacokinetics. In a 4-arm, randomized crossover study, 22 volunteers received over-encapsulated moxifloxacin, over-encapsulated placebo, bare moxifloxacin, and intravenous (IV) moxifloxacin. Placebo capsules and IV infusions were administered so that treatments in each arm, except for bare moxifloxacin, were indistinguishable. Pharmacokinetics of the oral treatments were found to be nearly identical and to meet Food and Drug Administration criteria for bioequivalency. Relative to the IV infusion administered over 1 hour, the tablet formulation was bioequivalent to total exposure but not peak exposure maximum plasma concentration, which was lower by 22%. Median time to maximum plasma concentration of the IV infusion was 1.00 hour. A 2-compartment model with oral absorption and linear elimination adequately described the observed moxifloxacin data. Changes in QTcF mirrored the pharmacokinetic changes, and there was a linear relationship between plasma concentration of moxifloxacin and change in QTcF. A 2-stage infusion scheme for IV moxifloxacin mimics the oral plasma concentration versus time curve. Over-encapsulation of moxifloxacin did not alter its peak or total systemic exposures or pharmacodynamics after oral administration.

The safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of BMS-708163 in young and elderly subjects

BMS-708163, in Phase II development for Alzheimer's Disease, selectively inhibits Aβ synthesis relative to Notch, and is a potent and orally active γ-secretase inhibitor. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of BMS-708163 in young and elderly subjects in this randomized, double-blind, placebo-controlled, ascending-dose study. Healthy young men (n = 72) were randomized to single doses of BMS-708163 0.3-800 mg or placebo (sequential panels) and elderly men and women (n = 44) to BMS-708163 50 mg or placebo. 115 of 116 enrolled subjects completed the study. A maximal tolerated dose was not identified. One young male discontinued due to positive occult blood test (mild). Three serious adverse events (SAEs) occurred in 3 elderly subjects (all unrelated to study drug). Most adverse events (AEs) were mild to moderate in severity. Most common AEs were procedural pain, oropharyngeal pain, back pain, dizziness, headache, abnormal dreams, and rash. There were no dose-related effects on mean QTcF, change in QTcF, HPA, thyroid function, renal function, immunophenotyping, or liver function tests. There were no effects on WBC and differential except up to 35% increases of leukocytes in the 800-mg panel and up to 37% increases of lymphocytes in the 400-mg and 800-mg panels. There were no clinically significant effects on exploratory safety biomarkers (plasma TFF3, and whole blood HES1, DUSP6, BIRC3 mRNA gene expression). BMS-708163 was quickly absorbed (median Tmax, 1-2h); plasma profiles were biphasic; mean terminal T1/2 was ∼40h. Plasma AUC was dose proportional in the range 1.5-200 mg and was ∼60% (90% CI: 10% to 127%) higher in subjects > = 75 years of age. BMS-708163 was safe and well tolerated at single doses of up to 800 mg, with no evidence of Notch-related dose-limiting toxicities. BMS-708163 produced dose-dependent decreases in plasma Aβ1-40 levels. Single-dose pharmacokinetics were linear up to 200 mg, with no gender-related differences. Pharmacokinetics were similar across all age groups except for higher AUC in subjects aged > = 75 years.

Thorough QT study of the effect of fesoterodine on cardiac repolarization

Fesoterodine 4 mg and 8 mg once daily are indicated for the treatment of overactive bladder. A thorough QT study was conducted to investigate the effects of fesoterodine on cardiac repolarization. In this parallel-group study, subjects were randomly assigned to receive double-blind fesoterodine 4 mg, fesoterodine 28 mg, or placebo or open-label moxifloxacin 400 mg (positive control) for 3 days. Electrocardiograms (ECGs) were obtained on Days -1 (baseline), 1, and 3. The primary analysis was the time-averaged changes from baseline for Fridericia's-corrected QT interval (QTcF) on Day 3. Among 261 subjects randomized to fesoterodine 4 mg (n = 64), fesoterodine 28 mg (n = 68), placebo (n = 65), or moxifloxacin 400 mg (n = 64), 256 completed the trial. The least squares mean changes in QTcF from baseline were 21.1, 20.5, 18.5, and 31.3 ms (maximum), and -5.1, -4.2, -5.2, and 7.6 ms (time-averaged at Day 3) for placebo, fesoterodine 4 mg, fesoterodine 28 mg, and moxifloxacin, respectively. The lower limit of the 95% confidence interval exceeded 5 ms for moxifloxacin. The results indicate that fesoterodine is not associated with QTc prolongation or other ECG abnormalities at either therapeutic or supratherapeutic doses.

Abstract B212: QTc study of picoplatin with emphasis on pharmacodynamics of cardiac repolarization

Abstract Introduction: Clinical studies have demonstrated that picoplatin (Pico), a new-generation platinum analogue designed to overcome platinum resistance, has activity when administered IV in solid tumors patients (pts); over 1,100 pts have received pico. The primary toxicity is hematological. Clinically significant nephro-, oto-, or neurotoxicity has rarely been observed (&amp;lt;1% grade 3 and 0% grade 4), even in platinum-pretreated patients. Pico (150 mg/m2) Q3W is currently being studied in a Phase 3 trial as 2nd-line monotherapy for SCLC. Pico is also being studied in Phase 2 trials in combination with other chemotherapy drugs for colorectal and prostate cancers. In preclinical studies in dogs, pico had no effect on cardiovascular function, including the QT interval. In clinical trials to date, drug-related serious ventricular arrhythmias have not been observed. The purpose of this study was to assess cardiac effects of Pico in patients with advanced solid tumors. Methods: The effect of pico on the QT/QTc interval as measured by the ECG was evaluated. The correlation between the QTcF interval and platinum concentration in plasma and plasma ultrafiltrate (PUF) was evaluated. ECG was recorded continuously with a Holter monitor. Triplicate 20 second ECG readings were extracted at 3 times before (baseline reference) and at 8 times in the 24 hrs after pico administration in Cycle 1. Triplicate 12-lead ECGs were obtained at the end of the pico infusion in subsequent cycles. Blood samples were collected before study drug administration and immediately after each ECG timepoint in Cycle 1 for pharmacokinetic analysis. The primary endpoint was the Fredericia corrected QT (QTcF). Time-averaged and time point analyses for QTcF were performed. Heart rate, PR, QRS, QT, QTcB (Bazett's) and morphological changes were also evaluated. Results: 45 pts (28 women and 17 men), age 44–79 years (median = 60) received 150 mg/m2 pico as a 1-hr IV infusion. The time-averaged mean change from baseline of QTcF duration during Cycle 1 was +2.2 ms, which is considered a nonsignificant increase. At each time point in Cycle 1 and in subsequent cycles, there were only minimal changes from baseline in QTcF duration. Other ECG changes from baseline were unremarkable: ST depression was noted in 9% of pts at baseline and new T-wave changes in 7% of pts in Cycle 1. Mean ± SD Cmax in plasma and PUF were 5566 ± 1079 ng/mL and 4034 ± 674 ng/mL, respectively. The change in QTcF vs. platinum concentration in plasma or PUF showed a Cmax effect of 5–6 ms with an upper confidence interval of 8–9 ms, suggesting no clear effect of picoplatin on QTcF. Conclusions: Pico had no effect on the QTcF interval or any other ECG parameter, supporting the clinical data showing that Pico does not increase the risk of serious ventricular arrhythmias. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B212.

Absence of Effect of Telbivudine on Cardiac Repolarization: Results of a Thorough QT/QTc Study in Healthy Participants

The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive calibrator, and telbivudine 600 and 1800 mg/d for 7 days. Intensive time-matched electrocardiogram measurements and pharmacokinetic sampling were performed at baseline and on day 7 over 24 hours. For telbivudine and moxifloxacin, time-matched, placebo-adjusted change from baseline in QT was calculated and corrected using Fridericia's formula (QTcF). While moxifloxacin produced the expected significant changes in QTcF, none of the changes in QTcF for either doses of telbivudine exceeded 5 ms, and none of the associated upper 1-sided 95% confidence intervals (CI) exceeded the limit of 10 ms. There was no increase in QTcF with increasing plasma telbivudine. The supratherapeutic dose of telbivudine was well tolerated with a safety profile similar to the clinical dose despite a 3-fold increase in plasma exposure. This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin.

QT Interval Measurements in Patients with Hematologic Malignancies and Solid Tumors Treated with Oral Panobinostat (LBH589).

Abstract 3781Poster Board III-717 IntroductionPanobinostat (LBH589), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor (DACi) with broad anti-tumor activity in preclinical models and promising clinical activity in Phase I/II studies. Prolongation of the QT interval has been reported with DACis, and data on file indicate this is a class effect associated with inhibition of maturation of hERG – a component of potassium ion channels. This analysis represents the first extended evaluation of the incidence of QT prolongation in patients treated with oral, single-agent panobinostat at different doses and schedules. Patients and methodsAn analysis was performed on pooled data from eight completed or ongoing Phase I and II studies of single-agent oral panobinostat in patients with advanced hematologic malignancies or solid tumors. The following doses and 28-day cycle dosing schedules were analyzed: doses of 20 to 60 mg/dose administered TIW (Days 1, 3 and 5) weekly (QW), or doses of 30 to 60 mg/dose administered TIW every other week (QOW). Twelve-lead electrocardiograms (ECGs) were performed in triplicate pre- and 3 hours post-dose on Days 1, 5 and 26 in Cycle 1, and as a single reading pre-dose on Days 8 and 15. In subsequent cycles, a single ECG was performed on Day 1 pre-dose. All ECGs were evaluated centrally. QT intervals were corrected individually for heart rate using Fridericia's formula and were reported as absolute QTcF and mean QTcF change from baseline. In addition, a mixed effect model was used to explore the relationships between QTcF change and baseline characteristics within the pooled data of oral, single-agent panobinostat with two schedules – QW and QOW. ResultsAnalysis of oral TIW QW dosing is available based on ECGs from 392 patients (241 female/151 male), with a median age of 60 years (range: 16–88), receiving oral panobinostat at 20 mg/dose (n=282), 30 mg/dose (n=22), 40 mg/dose (n=34), or 60 mg/dose (n=54). At panobinostat doses of ≤40 mg/dose, QTcF >500 ms and mean QTcF change from baseline >60 ms on at least one ECG were reported in <1% and 3.5% of patients, respectively. Across these dose levels, 30–50% of patients experienced a clinically non-significant QTcF change of 30 to 60 ms from baseline. At the 60 mg dose level, QTcF >500 ms and mean QTcF change from baseline >60 ms were reported in 5.6% and 9.3% of patients, respectively. Most QT prolongation events occurred in a single ECG and were not persistent over time. No cases of Torsade de pointes were observed with oral panobinostat. A separate analysis of QTcF change from baseline across two schedules was performed on 436 treated patients (178 female/258 male), with a median age of 58 years (range: 16–88), receiving oral panobinostat (20, 30 or 40 mg/dose TIW QW [n=384], and 30 or 60 mg/dose TIW QOW [n=52]). This analysis showed that the greatest mean QTcF changes from baseline were observed on Days 1 and 5 of Cycle 1. Later in the cycle, a trend was noted of QTcF values to return to baseline, with QW dosing. ConclusionsAbsolute QTcF prolongation >500 ms and changes >60 ms from baseline were infrequently reported with weekly administration of oral panobinostat up to 40 mg/dose TIW. These data support a significant reduction of the ECG monitoring schedule in future studies investigating oral panobinostat at doses up to 40 mg/dose on a TIW schedule. ECG monitoring based on the original schedule is ongoing in a clinical trial investigating the oral dose of 60 mg/dose TIW at QW schedule in patients with refractory AML to better characterize the QTcF interval at this dose level. Disclosures:Weber:Novartis Pharma AG: Employment. Tai:Novartis: Employment. Paul:Novartis: Employment. Schindler:Novartis: Employment. Woo:Novartis: Employment. Spence:Novartis: Employment. Marlowe:Novartis: Employment. Lin:Novartis: Employment.

Systematic Assessment of Potential Cardiac Effects of the Novel Histone Deacetylase (HDAC) Inhibitor Romidepsin.

Abstract 3709Poster Board III-645 BackgroundRomidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in cutaneous T-cell lymphoma (CTCL) in 2 studies (GPI-04-0001 and NCI 1312). In the GPI study the overall response rate (ORR) was 34% including 6 complete clinical responses (CCRs) in 96 pts with CTCL and the median duration of response (DOR) was 14.9 months (mo). In the NCI study, the ORR was 35% including 4 CCR in 71 pts and the median DOR was 11 mo. NCI 1312 has also reported single-agent activity in patients with peripheral T-cell lymphoma with an ORR of 31% including 4 CRs in the 48 pts analyzed. HDAC inhibitors have variably been reported to have cardiovascular effects, in particular, QTc prolongation. To systemically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA Division of Oncology Drug Products. Subsequently, a romidepsin QTc Clinical/Statisitcal Analysis Plan was developed following the ICH E14 Guidelines, to provide a comprehensive evaluation of the cardiac effects of romidepsin. MethodsAn analysis of romidepsin cardiac safety, including review and analysis of ECG findings, was performed. The primary objective of these analyses was to evaluate the effect of romidepsin on the change from baseline on the corrected QT interval of the ECG using the Fridericia QT correction method (QTcF) during Cycle 1 Day 1 exposure to study drug. A total of 4909 ECGs from 110 patients in 3 clinical studies, GPI study, NCI study, and Study GPI-06-0005 (a Phase 1 PK study) were evaluated. The 110 patients comprised 103 patients with T-cell lymphoma and 7 patients with advanced cancer treated with romidepsin at 14 mg/m2 as a 4-hour infusion on Days 1, 8, and 15 of a 28-day cycle. Using a nonlinear mixed effects model the pharmacodynamics of romidepsin was characterized for exposure-QTc effects. ResultsIn an analysis of ECG data, a mean increase of 5.0 msec (90% CI upper bound 7.7 msec) in QTcF interval was measured following infusion of romidepsin; this value includes a contribution to QTc prolongation by pre-dose antiemetics. Data from the NCI study showed that the QTcF change persisted to 24 hours, with a return to baseline by 48 hours, whereas in the smaller GPI-06-0005 study, QTcF peaked 2 hours post infusion and there was no QTcF effect seen at 24 hours. Categorical analyses showed no patients with a change from baseline >60 msec or an absolute QTcF >480 msec. No cardiac events of Torsade de Pointes were reported. Per the ICH E14 guidance,56 a threshold for regulatory concern for mean QTc prolongation is 5 msec with an upper bound of the 95% CI of 10 msec. Prolongations of >60 msec over baseline or a value >500 msec are also considered cautionary. Treatment-emergent morphological changes on ECG (minor ST-segment depression, T-wave flattening, biphasic T-waves, and T-wave inversion) have been observed during treatment with romidepsin; however the overall frequency of these minor, asymptomatic changes was similar to the frequency of pre-exposure abnormalities on each dosing day, suggesting a high degree of background noise in these data. Furthermore, there was no association between these ECG findings and any clinical, functional, or laboratory findings of cardiac abnormalities.Categorical Analysis of QTc Change on Cycle 1, Day 1CategoryStudyGPI Study N=87 n (%)NCI Study N=41 n (%)GPI-06-0005 N=7 n (%)Total N=135 n (%)QTcF change from baseline1No increase31 (36)10 (24)2 (29)43 (32)1-29 msec increase46 (53)27 (66)4 (57)77 (57)30-60 msec increase2 (2)4 (10)1 (14)7 (5)>60 msec increase0000QTcF not available8 (9)008 (6)QTcF absolute value:>450 msec2 (2)2 (5)04 (3)>480 msec0000>500 msec00001For GPI studies, baseline values are those post co-med, or if missing post co-med, then pre-comed baseline is used. ConclusionsThe findings from the romidepsin studies show that the observed QTc changes were below the threshold levels of concern outlined in ICH E14. Pharmacodynamic modeling showed no evidence of a relationship between the plasma concentration of romidepsin and changes in the QTc interval. Since hypokalemia and hypomagnesemia are associated with ECG abnormalities, supplementation with potassium and magnesium to achieve normal levels prior to romidepsin administration is recommended. Disclosures:Cabell:Gloucester Pharmaceuticals: Consultancy. Whittaker:Gloucester Pharmaceuticals: Research Funding. Nichols:Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix:Gloucester Pharmaceuticals: Employment. Burris:Gloucester Pharmaceutcals: Research Funding.

Nilotinib-Associated Molecular Responses Achieved in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients with a Suboptimal Molecular Response to Imatinib.

Abstract 2206Poster Board II-183 BackgroundNilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to imatinib. The achievement of a major molecular response (MMR), defined as a 3 log reduction of the Bcr-Abl transcript level from the baseline mean, is a favorable prognostic factor for the disease at any time point. This multi-center, open-label study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in patients who have achieved complete cytogenetic response but have demonstrated a suboptimal molecular response to imatinib. MethodsThis study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP patients (n=160) who achieve CCyR but have a suboptimal molecular response to imatinib defined either as: (Group 1) treated > 1 year with imatinib, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1 log increase in Bcr-Abl transcript levels regardless of the imatinib treatment duration. At study entry, patients are treated with nilotinib 300 mg b.i.d. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 months on treatment with nilotinib. Since there is a paucity of efficacy data published for suboptimal responders to imatinib, this preliminary analysis was performed on a small cohort of patients enrolled as of the data cut-off date of July 21, 2009. Results11 CML-CP suboptimal molecular responding patients have been treated with a median of 2.6 months on nilotinib. One patient entered the study as a Group 2 patient and ten entered into Group 1. 1 patient was deemed ineligible due to lack of evidence of CCyR at baseline. The remaining 10 entered the trial with a baseline CCyR. Prior to enrollment, patients were treated with at least 400mg QD imatinib; the mean dose of prior imatinib treatment was 463 mg/day (range 377 – 573 mg/day). The median duration of prior imatinib treatment was 39.5 months (range 14.0-106.4 mo). 1 patient was previously treated with interferon.8 patients have been treated for >3 months. Out of these 8 patients, 2 have been treated for > 6 months and 1 patient has been treated for > 9 months. Aside from these 8 patients, another 3 did not yet reach end of Month 3 at the time of analysis. Six out of 8 evaluable patients (75%) achieved MMR; 4 patients after three months on nilotinib, 1 patient after 4.5 months on nilotinib (measured at end of study), and 1 patient after 9 months on nilotinib. Overall, patients achieved a median log reduction of PCR transcript levels of 3.1 (range 2.1-4.5) from the standardized baseline (based on the IS) at the end of Month 3.4 out of 11 patients were dose reduced for nilotinib related adverse events (AEs). No grade 4 AEs were reported. 1 patient experienced a grade 3 headache and two cases of grade 3 elevated ALT were reported. Brief dose interruptions were sufficient to manage most AEs. The median dose intensity was 600 (range 400-600 mg/day). No patients discontinued from the study due to an AE as of the data cut-off date. No patients who experienced QTcF changes had differences >34 msec from baseline. No QTcF prolongation >500 msec was observed. ConclusionsNilotinib treatment results in high rates of molecular response in CML-CP patients with suboptimal molecular responses to imatinib. 75% of the evaluable patients who switched to nilotinib achieved MMR at the time of analysis, and all evaluable patients achieved a median > 3 log reduction of PCR transcripts from the standardized baseline within 3 months of starting therapy. No patients were discontinued due to AEs. Outcomes for additional patients enrolled and longer term follow-up will become available. [Display omitted] Disclosures:Yang:Bristol Myers Squibb: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Esai: Speakers Bureau; Therepi: Equity Ownership. Off Label Use: Nilotinib for suboptimal responders to imatinib therapy. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Akard:Novartis: Consultancy, Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Speakers Bureau. Goldberg:Novartis Pharmaceuticals: Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.