Dawn Colburn

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations. Clin Cancer Res; 17(17); 5774–82. ©2011 AACR.

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

Biomarker Analyses from a Randomized, Placebo-Controlled, Phase IIIb Trial Comparing Bevacizumab with or without Erlotinib as Maintenance Therapy for the Treatment of Advanced Non-Small-Cell Lung Cancer (ATLAS)

Introduction: ATLAS compared bevacizumab plus erlotinib (B+E) with bevacizumab plus placebo (B+P) as maintenance therapy after first-line bevacizumab plus chemotherapy (B+C) for advanced non-small-cell lung cancer (NSCLC). Prespecified biomarkers were prospectively evaluated. Methods: Tumor samples were analyzed for: epidermal growth factor receptor (EGFR) expression (immunohistochemistry [IHC]); EGFR gene copy number (fluorescence in-situ hybridization [FISH]); EGFR mutations (exon 19 deletions/L858R mutations); and KRAS mutations (exons 2/3). Progression-free survival (PFS) and overall survival (OS) were estimated. Results: Of 743 patients randomized to receive maintenance treatment (after four cycles of B+C without progression), 190 (B+E) and 177 (B+P) were evaluable for biomarker status. Median PFS (from randomization) was 4.4 months (B+E) versus 3.7 months (B+P; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57–0.99), which was numerically similar to the intent-to-treat PFS. PFS benefit of B+E was observed across most biomarker subgroups. EGFR IHC, EGFR FISH, and EGFR/KRAS mutation status were not predictive of outcome. B+E-treated patients with EGFR mutation-positive NSCLC had longer PFS compared with B+P-treated patients (HR, 0.44; 95% CI, 0.22–0.86; p = 0.0139). Patients with KRAS wild-type disease had significant PFS improvements with B+E, compared with B+P (HR, 0.66; 95% CI, 0.485–0.914; p = 0.0105). No OS benefit of B+E was observed. Conclusions: Patients with KRAS wild-type or EGFR mutation-positive NSCLC derived PFS benefits from B+E. However, EGFR IHC, EGFR FISH, and EGFR or KRAS mutation status were not strongly predictive of survival. A larger sample size would be needed to confirm the initial trends observed in this study.

Abstract B188: Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.

Vismodegib is a first-in-class small molecule Hedgehog pathway inhibitor that is being developed for the treatment of advanced basal cell carcinoma. In a previous phase I study for patients with advanced malignancies, vismodegib was well tolerated and tumor regressions were seen in patients with advanced basal cell carcinoma and medulloblastoma. In vitro, vismodegib inhibits CYP2C8 with a Ki of 6.0 μM, which was the most potent relative to other CYP isoforms. With the average steady-state plasma concentration of total vismodegib being approximately 20 μM, inhibition of CYP2C8 by vismodegib may be important when patients are taking drugs known to be metabolized by CYP2C8. Furthermore, while vismodegib was not shown to induce CYP enzymes in vitro, it is a known teratogen. A DDI assessment with combined oral contraceptive (OC) was therefore conducted to ensure efficacious levels of OC would be maintained in patients taking vismodegib and OC in combination. This single-arm study consisted of two cohorts; 24 patients took 4 mg rosiglitazone (a known CYP2C8 substrate) and 27 patients took OC (norethindrone 1 mg/ethinyl estradiol 35 mcg, Ortho-Novum 1/35®). On Day 1 patients took rosiglitazone or OC followed by extensive PK sampling for 24 hrs. From Day 2 to Day 7 patients took 150 mg vismodegib once per day. On Day 8 patients took either vismodegib and rosiglitazone or vismodegib and OC followed by extensive PK sampling for 24 hrs. From Day 9 onward patients took vismodegib until disease progression or lack of benefit. The primary objective of this study was to evaluate the relative effect of vismodegib on AUC and Cmax for rosiglitazone and OC (ethinyl estradiol and norethindrone). The average steady state plasma concentration of total vismodegib (N=51) was 20.6 μM (range, 7.93 − 62.4 μM). There was no clinically meaningful difference in rosiglitazone PK parameters between Day 1 (without vismodegib) and Day 8 (with vismodegib) with a less than 10% difference in AUCinf and Cmax, on average. The geometric mean ratios (GMRs) for rosiglitazone AUC0−inf and Cmax were 93.1 and 93.4 with corresponding 90% confidence intervals (CIs) of (85.0, 102) and (89.4, 97.6), respectively. Concomitant administration of vismodegib with OC did not strongly impact the plasma concentrations of ethinyl estradiol or norethindrone, as evidenced by a less than 20% change in AUCinf and Cmax, on average, for both components. The GMRs for ethinyl estradiol AUC0−inf and Cmax were 99.3 and 106 with corresponding 90% CIs of (91.9, 107) and (94.8, 117), respectively while the GMRs for norethindrone AUC0−inf and Cmax were 124 and 112 with corresponding 90% CIs of (116, 132) and (101, 124), respectively. In the current study, the steady state plasma concentration of total vismodegib was above the in vitro Ki for CYP2C8. In addition, daily dosing of 150 mg vismodegib for 7 days should have been adequate to result in enzyme induction, if applicable. Overall, results from this study indicate that there was no clinically meaningful difference in AUC0−inf and Cmax for rosiglitazone, ethinyl estradiol, or norethindrone when co-administered with vismodegib. Taken together these results suggest that vismodegib can be co-administered with CYP substrates and combined oral contraceptive without the risk of a pharmacokinetic DDI. 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 B188.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Digoxin in Patients With BRAFV600 Mutation–Positive Metastatic Malignancy

The primary objective of this phase 1, open‐label, multicenter, 3‐period, fixed‐sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P‐glycoprotein (P‐gp) substrate, in patients with BRAFV600 mutation‐positive metastatic malignancy. Following a 28‐day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8‐28), and a single oral dose of digoxin 0.25 mg on day 29 and vemurafenib 960 mg twice a day for 7 days (days 29‐35) in period C. Log‐transformed area under the concentration‐time curve and peak concentration values for digoxin were compared between periods A (digoxin alone) and C (digoxin + vemurafenib) using an analysis of variance model. Twenty‐six patients were evaluated for the primary pharmacokinetic analysis. The geometric mean ratio (period C/period A) of area under the curve to the last measurable concentration for digoxin was 1.82 (90%CI 1.63 to 2.02), and the geometric mean ratio of peak concentrations was 1.47 (90%CI 1.30 to 1.65); the 90%CIs were outside of the equivalence limits of 0.82 to 1.22, indicating an effect of vemurafenib on digoxin. Multiple oral doses of vemurafenib were generally well tolerated, with an adverse event profile similar to that previously seen in phase 2 and 3 studies of vemurafenib monotherapy. This study confirmed vemurafenib as an inhibitor of P‐gp in vivo with a statistically significant drug‐drug interaction with digoxin. Caution should be exercised when dosing vemurafenib concurrently with P‐gp substrates.

Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial

lymphoma kinase positive anaplastic large cell lymphoma with extranodal involvement: an analysis of 1306 cases from the US National Cancer Database. British Journal of Haematology, 181, 196–204. Su, C., Nguyen, K.A., Bai, H.X., Cao, Y., Tao, Y., Karakousis, G., Zhang, P.J., Zhang, G. & Xiao, R. (2017) Disease site as a determinant of survival outcome in patients with primary cutaneous peripheral T-cell lymphoma, unspecified: an analysis of 4057 cases from the US National Cancer Database. Leukemia & Lymphoma, 59, 2105–2112. Wilson, L.D., Hinds, G.A. & Yu, J.B. (2012) Age, race, sex, stage, and incidence of cutaneous lymphoma. Clinical Lymphoma, Myeloma & Leukemia, 12, 291–296.

Abstract CT308: Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction

Background: Vismodegib is an inhibitor of the hedgehog signaling pathway approved for treatment of advanced basal cell carcinoma. Pharmacokinetics (PK) and safety of vismodegib in patients (pts) with hepatic dysfunction are unknown. Methods: Pts with advanced solid malignancies and hepatic impairment (HI) were enrolled into 4 cohorts as defined by NCI Organ Dysfunction Working Group Criteria: normal (bilirubin [bili] Results: The average concentration of vismodegib in semen on Day 8 was 1.16 μM, approximately 7% of the average C ss observed in plasma from these same male patients of the normal cohort (n = 3) (Table 1). Best response among the 21 patients with HCC was 38% stable disease, 19% disease progression, and 43% not assessed. Conclusion: HI does not appear to impact vismodegib PK. However, the study is influenced by the high number of patients with HCC with advanced cirrhosis, rendering it difficult to draw any causality relationships between DLT and SAE, and vismodegib. This is confirmed by inability to deduce any correlation between C ss values and AST or total bilirubin concentrations. Stable disease is reported in 38% of patients with HCC. Further study of vismodegib in pts with severe HI and HCC should be carefully considered within the context of the DLT and SAE events reported herein. Citation Format: Ghassan K. Abou-Alfa, Lionel D. Lewis, Patricia LoRusso, Michael Maitland, Sravanthi Cheeti, Dawn Colburn, Sarah Williams, Brian Simmons, Richard A. Graham, Priya Chandra. Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT308. doi:10.1158/1538-7445.AM2015-CT308

Abstract 1310: Evaluation of optimal dosing schedule on steady-state pharmacokinetics of orally administered hedgehog pathway inhibitor GDC-0449 in cancer patients

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: GDC-0449 is being developed for treatment of advanced basal cell carcinoma and other solid cancers. In a previous phase I trial in healthy volunteers who were administered a single 150-mg oral dose of GDC-0449, the half-life was determined to be 10 to 14 days (Ding et al., JCB, 878:785-790, ‘10). The primary objectives of the study described here were to evaluate the effects of dosing schedule on safety/tolerability and total and unbound GDC-0449 pharmacokinetics (PK) at steady state (SS). Methods: This study was a two-stage (loading and maintenance), open-label, Phase Ib study designed to evaluate the PK of daily (QD), three times weekly (TIW), or once weekly (QW) dosing of GDC-0449 in patients with advanced solid tumors refractory to treatment or for whom no standard therapy exists. All patients received a daily 150-mg loading dose for 11 days (loading phase), followed by a maintenance phase during which GDC-0449 was administered by randomized assignment at 150-mg QD (n=20 pts), TIW (n=21 pts), or QW (n=22 pts), for up to an additional 42 days. Total and unbound GDC-0449 plasma concentrations were measured frequently through day 15 and then weekly through day 56 using a validated LC-MS/MS assay. A mechanism-based PK model was previously developed and used to prospectively simulate the impact of dosing schedule on GDC-0449 PK. Results: The most frequently reported adverse events were consistent with those reported in other GDC-0449 monotherapy clinical trials, with similar incidence regardless of dosing schedule. A time-dependent change in protein binding was observed when comparing single dose to SS GDC-0449 fraction unbound (fu). On average, the single dose fu was 0.002 (+ 0.001), increasing to 0.007 (+0.003) at SS: a 3.5-fold increase (range, 1.5-8.4-fold). Compared with QD dosing, average total and unbound GDC-0449 concentrations at SS were lower for TIW and QW dosing; the extent of the decrease from initial levels was markedly greater for unbound. During the maintenance stage, unbound SS GDC-0449 levels decreased by more than 50% in over half of the TIW patients (up to 76% decrease) and in all of the QW patients (up to 89% decrease). The mechanism-based PK model simulations accurately described the key PK results in a prospective manner. Conclusions: Overall, the results provide important mechanistic insight into the PK of GDC-0449 and validate the mechanism-based PK model. Importantly, results from this study suggest that patients receiving GDC-0449 TIW or QW would be at risk of not achieving unbound plasma concentrations previously associated with efficacy in advanced BCC. In spite of the long single dose half-life of GDC-0449, the 150-mg QD regimen is most appropriate for ongoing and future clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1310. doi:10.1158/1538-7445.AM2011-1310