Cathie Leister

Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer

PURPOSE To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer. PATIENTS AND METHODS Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (I.V.) infusion. RESULTS Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 mg/m(2), dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m(2)). Variability predicted with flat doses appears comparable with data based on body-surface area-normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma. CONCLUSION CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

Population Pharmacokinetics of CCI-779: Correlations to Safety and Pharmacogenomic Responses in Patients with Advanced Renal Cancer

Our objective was to estimate the pharmacokinetic parameters of CCI‐779 and its metabolite, sirolimus, and evaluate associations of exposure parameters with safety and clinical activity. Exposure parameters were also correlated with pharmacogenomic responses in peripheral blood mononuclear cells (PBMCs).

Pharmacokinetic Profile of Temsirolimus With Concomitant Administration of Cytochrome P450‐Inducing Medications1

Temsirolimus is a novel inhibitor of the mammalian target of rapamycin, with antitumor activity in advanced tumors. Because temsirolimus and its metabolite, sirolimus, are cytochrome P450 (CYP) 3A4/5 substrates, the potential exists for interaction with drugs that induce CYP3A activity, including enzyme inducers and rifampin. Cancer patients received once‐weekly intravenous (IV) 220 mg/m2 temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (Cmax) by 36% and increased volume of distribution by 99%. Sirolimus Cmax and area under the concentration‐time curve (AUC) were decreased by 67% and 43%, respectively. In healthy adult subjects, coadministration of 25‐mg intravenous temsirolimus with rifampin had no significant effect on temsirolimus Cmax and AUC but decreased sirolimus Cmax and AUC by 65% and 56%, respectively. Rifampin decreased AUCsum by 41%. Temsirolimus was well tolerated in both studies. If concomitant agents with CYP3A induction potential are used, higher temsirolimus doses may be needed to achieve adequate tumor tissue drug levels.

Effect of Ketoconazole on the Pharmacokinetics of Oral Bosutinib in Healthy Subjects

Bosutinib (SKI‐606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of chronic myelogenous leukemia. The effect of coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib was evaluated in an open‐label, randomized, 2‐period, crossover study. Healthy subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with multiple once‐daily doses of oral ketoconazole 400 mg. PK sampling occurred through 96 hours. The least square geometric mean treatment ratios (90% confidence interval [CI]) of Cmax(bosutinib+ketoconazole)/Cmax(bosutinib alone), AUCT(bosutinib+ketoconazole)/AUCT(bosutinib alone), and AUC(bosutinib+ketoconazole)/AUC(bosutinib alone) were assessed. Compared with bosutinib administered alone, coadministration with ketoconazole increased bosutinib Cmax 5.2‐fold, AUCT 7.6‐fold, and AUC 8.6‐fold. Ketoconazole coadministration decreased the mean apparent clearance of bosutinib approximately 9‐fold and increased the mean (SD) terminal half‐life from 46.2 (16.4) hours to 69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between the 2 treatments. The most common AEs were headache, nausea, and increased blood creatinine. No safety‐related discontinuations or serious AEs occurred. These PK results indicate that bosutinib is susceptible to interaction with potent CYP3A4 inhibitors.

Intravenous temsirolimus in cancer patients: clinical pharmacology and dosing considerations.

Temsirolimus, a highly specific inhibitor of mammalian target of rapamycin (mTOR), is a novel anticancer targeted therapy with a new mechanism of action. The prototype mTOR inhibitor, oral rapamycin, is poorly soluble and undergoes extensive first-pass metabolism, leading to low and potentially variable absorption and exposure. For some tumors, maximizing the bioavailability and dose intensity via intravenous (IV) administration may provide optimal clinical benefit. Temsirolimus is an ester analog of rapamycin that retains its potent intrinsic mTOR inhibitory activity while exhibiting better solubility for IV formulation. In the treatment of advanced renal cell carcinoma, temsirolimus is administered as a 30- to 60-minute IV infusion once weekly at a flat dose of 25 mg. This dosage results in high peak temsirolimus concentrations and limited immunosuppressive activity. Because temsirolimus is active and well tolerated, different dosages and schedules are being explored for other solid and hematologic malignancies, including mantle cell lymphoma. Temsirolimus exhibits a high volume of distribution that, together with IV administration, leads to extensive distribution into peripheral tissues. In addition, significant and protracted exposures are attained with sirolimus (rapamycin), the major equipotent metabolite of temsirolimus. Whereas temsirolimus and sirolimus are both metabolized by cytochrome P450 (CYP) 3A4, drug interaction studies with agents that induce or inhibit CYP3A4 activity indicate that exposure to the sirolimus metabolite is somewhat sensitive to pharmacokinetic (PK) drug interaction. Therefore, temsirolimus dose adjustments are warranted if coadministration cannot be avoided. Despite its complexity, the PK profile of IV temsirolimus is well characterized in cancer patients and provides a strong basis for its future study as a monotherapy or in combination with other anticancer agents.

Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects.

AIM The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. METHODS This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed. RESULTS Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). CONCLUSION Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.

A randomized, crossover, placebo‐ and moxifloxacin‐controlled study to evaluate the effects of bosutinib (SKI‐606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH‐E14 guidelines, in this 2‐part, randomized, single‐dose, double‐blind, crossover, placebo‐ and open‐label moxifloxacin‐controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline‐adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population‐specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericias formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (Cmax, 114 ng/mL; AUC, 2,330 ng·h/mL) and mean supratherapeutic exposures (Cmax, 326 ng/mL; AUC, 15,200 ng·h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered With Ketoconazole to Healthy Adult Subjects

BACKGROUND Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. OBJECTIVE This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. METHODS This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days -1 and 1 through 4. RESULTS Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18-50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C(max) and 2980 (802) to 23,000 (4020) ng·h/mL for AUC(0-∞); mean AUC(0-24) and AUC(0-last) ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C(max) and AUC were linear and dose proportional. Mean C(max) at 600 mg was 2.1-fold higher than the steady-state C(max) previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. CONCLUSIONS Single doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.

Abstract PR06: Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors

Background: Combined inhibition of the MAPK pathway and CDK4/6 is an emerging treatment strategy for cancer. Dual inhibition of MEK, a key mediator of the MAPK pathway, and CDK4/6 showed synergy in cellular growth and survival assays in preclinical models, particularly in the setting of activating Ras mutations. Trametinib (Tram) is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2 that is non-competitive towards adenosine triphosphate (ATP) and inhibits both MEK activation and kinase activity. Palbociclib (Palbo) is a highly selective reversible oral inhibitor of CDK4/6. This phase 1b study (NCT02065063) evaluated trametinib once daily combined with palbociclib 21 days-on / 7 days-off (21/7) in patients (pts) with advanced solid malignancies. Methods: The primary objectives were to determine the safety, tolerability, recommended combination regimen (RCR). Secondary objectives were to characterize the pharmacokinetics (PK) and describe anti-cancer activity. Pts were accrued to dose escalating cohorts and treated with Tram at 1.5 or 2.0 mg once-daily (QD) co-administered with Palbo at 75, 100, or 125 mg 21/7 in 28-day cycles. Results: As of 24 August 2015, 28 pts were enrolled [18 M, 10 F; median age 59 yr (range 31 to 77)]. Systemic exposure to trametinib or palbociclib in combination was similar to that observed with single agents. The RCRs were determined to be Tram 2.0 mg QD plus Palbo 75 mg 21/7 (RCR1) and Tram 1.5 mg QD plus Palbo 100 mg 21/7 (RCR2). DLTs were observed in 1 (Gr 3 mucocitis) out of 7 (14.3%) and 1 (Gr 3 left ventricular ejection fraction decrease) out of 6 (16.7%) evaluable pts at RCR1 and RCR2, respectively. Two higher dose levels above RCR1 and RCR2 were deemed intolerable with DLTs observed in 2 out of 7 evaluable pts at Tram 2.0 mg QD plus Palbo 100 mg 21/7 (Gr 3 fatigue, and Gr 3 LVEF decrease); and in 2 out of 4 evaluable pts at Tram 1.5 mg QD and Palbo 125 mg 21/7 (Gr3 hypertension and vitreous hemorrhage, and Gr 4 thrombocytopenia, respectively). Common adverse events (AEs), regardless of study drug relationship, were diarrhea (67.9%), acneiform rash (64.3%), and fatigue (53.6%). Grade 3 AEs and Grade 4 AEs occurred in 21 (75%) and 6 (21.4%) individual patients, respectively. Two patients with melanoma and CRC treated at RCR1 experienced partial responses that are ongoing, with duration of drug exposure of 13.6 and 10.8 months respectively at time of data cut-off. The patient with melanoma does not have any known BRAF or RAS mutations, while the patient with CRC has a known NRAS mutation Q61K 181C->A but no known BRAF mutation. Conclusions: Two RCRs for trametinib and palbociclib combination were determined together with the preliminary safety and PK/PD profile, as well as clinical activity. (This study is funded by GlaxoSmithKline and Pfizer, Inc.) Citation Format: Ryan J. Sullivan, Rodabe N. Amaria, Donald P. Lawrence, John Brennan, Cathie Leister, Rajendra Singh, Jeff Legos, Holger Thurm, Li Yan, Keith T. Flaherty, Michael A. Davies, Jeffrey Sosman. Phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR06.

Abstract B215: Ascending single‐dose study of safety, tolerability, and pharmacokinetics of bosutinib (SKI‐606) in healthy subjects

Introduction: Bosutinib (SKI‐606), a dual inhibitor of Src and Abl tyrosine kinases, is being developed for the treatment of patients with chronic myelogenous leukemia. An oral dose of 500 mg daily shows evidence of clinical efficacy in patients with Philadelphia chromosome‐positive chronic myelogenous leukemia (Cortes et al. Blood 112:1098, 2008). To support the clinical pharmacology assessment of bosutinib, a single‐ascending‐dose safety and pharmacokinetic (PK) evaluation was performed in healthy subjects. Methods: This was a randomized, double‐blind, placebo‐controlled, single‐ascending dose, sequential‐group study of oral bosutinib in healthy subjects. Subjects were originally to receive doses of 200, 400, 600, 800, 1000 and 1200 mg of bosutinib in the fasting state. However, subjects who received 400 mg bosutinib had multiple adverse events and then 200 mg, 400 mg, 600 mg, and 800 mg bosutinib was administered with food. Each cohort included 6 subjects who received one dose of bosutinib and 2 who received placebo. Plasma samples, collected through 96 h post‐dose, were analyzed by using a liquid chromatography/tandem mass spectrometry assay for bosutinib concentrations. PK analyses were performed using a noncompartmental method and dose linearity was assessed using a power model. Results: A total of 55 subjects (41 bosutinib, 14 placebo) were enrolled (47 males, 8 females, median age [range] 28 [18–50] y, 87%White). Thirty‐three (81%) subjects had adverse events (AEs) after receiving bosutinib. The most common AEs for all subjects receiving bosutinib included diarrhea (39% subjects), nausea (29%), headache (22%), postural dizziness (22%) catheter site‐related reaction and fatigue (10% each). The frequency and severity of gastrointestinal AEs appeared to be dose related. Doses up to 600 (fed) were well tolerated. After administration of single ascending doses of 200–800 mg bosutinib with food, absorption of bosutinib was relatively slow with a median tmax of 6 h, and both Cmax and AUC increased with increasing dose in a linear fashion. The apparent volume of distribution (Vz/F) was large (131–214 L/kg), mean clearance (CL/F) was 2.25–3.81 L/h/kg, and mean half‐life was 32–39 h. Food increased bosutinib exposure (Cmax and AUC) by ∼2‐fold and 1.5‐fold after administration of the 200‐mg and 400‐mg doses, respectively. Conclusions: Bosutinib was generally safe and well tolerated in healthy subjects after administration of single oral doses up to 600 mg (fed). The PK of bosutinib was linear when given with food, and the half‐life supports a once‐daily dosing regimen. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B215.