Samuel C. Blackman

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.

BACKGROUND Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. METHODS We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. FINDINGS We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. INTERPRETATION Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. FUNDING GlaxoSmithKline.

Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors

PURPOSE Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752. PATIENTS AND METHODS MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition. RESULTS Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas. CONCLUSION MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

A phase I study was conducted to assess the metabolism and excretion of [14C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation–positive tumors after a single oral dose of 95 mg (80 µCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-high-performance liquid chromatography—tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy- and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18–20 vs. 5–6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned α to an alkyl (ethyl or t-butyl) side chain.

Concomitant Oral and Intravenous Pharmacokinetics of Dabrafenib, a BRAF Inhibitor, in Patients with BRAF V600 Mutation‐Positive Solid Tumors

Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild‐type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single‐center, open‐label study in four patients with BRAF mutation‐positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median Tmax after oral administration was 2.0 hours and the geometric mean terminal half‐life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first‐pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.

Abstract 1752: A phase I/IIa, first time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency

Background: The phosphoinositide 3-kinase (PI3K) pathway is among the most commonly mutated pathways in human cancer. The majority of first-generation PI3K inhibitors currently in clinical trials inhibit multiple PI3K isoforms. The PIK3CB gene encodes p110α isoform, which has been reported to be required for pathway activation in phosphatase and tensin homolog (PTEN) deficient cancer cells [Wee, 2008; Jia 2008]. The observed dependence of PTEN-deficient tumors on p110α provides an opportunity for identification of a novel isoform-selective therapeutic. In addition, as PTEN is commonly mutated, deleted, or epigenetically silenced in a wide range of solid tumors, measurement of PTEN protein expression would provide an identifiable target patient population using a clinically-available biomarker. Methods: GSK2636771 (‘771) is a potent, orally bioavailable, beta isoform-selective inhibitor of PI3K. Study P3B115717 is a Phase I/IIa first-time-in-human dose-escalation study of ‘771. The objectives of the study include the characterization of the safety, tolerability, and pharmacokinetic (PK) profile of ‘771 following single- and repeat-dose administration, evaluation of the pharmacodynamic (PD) effects of ‘771 in tumor and surrogate tissue, and evaluation of the anti-tumor effects of ‘771 in advanced solid tumors with PTEN deficiency. A standard 3+3 dose escalation scheme will be used, however this study incorporates multiple elements designed to accelerate clinical development. These include a single-dose phase for rapid determination of a pharmacokinetically acceptable starting dose, a “backfill” strategy for acquiring parallel samples for PD analyses, mandatory tumor biopsies for select patient cohorts, inclusion of subjects with glioblastoma multiformae, and, importantly, only patients whose tumors lack PTEN expression are eligible for this study, beginning with dose escalation. PD and anti-tumor response will be assessed in-stream to determine biologically effective doses. Anti-tumor efficacy in three tumor types with high prevalence of PTEN loss will be assessed using volumetric imaging in addition to RECIST 1.1, as well as circulating tumor cell enumeration for prostate and breast tumors. Exploratory analyses include evaluation of alterations in tumor growth rates following treatment with ‘771 compared to patient9s prior lines of therapy, correlation of serum markers (e.g., IGFBP-2) with tumor PTEN expression, comparison of anti-tumor response to DNA point mutations detected in circulating tumor DNA, and PD assessment in a surrogate tissue (change in pAKT, pGSK3β, and pS6 in platelets). This study initiated in November 2011 and is currently accruing patients (GSK Study P3B115717 - NCT01458067). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1752. doi:1538-7445.AM2012-1752

Abstract 3773: Absolute bioavailability of BRAF inhibitor GSK2118436: Use of a microtracer study in patients with cancer

Background. Absolute bioavailability (BA) studies in oncology are logistically and technically challenging. Use of an intravenous (IV) microtracer offers an attractive alternative to conventional cross-over design studies. This method involves concomitant administration of a non-labeled oral therapeutic dose with a radiolabeled IV microtracer dose. Advantages include: 1) fewer subjects required as comparisons are within-subject and within-period, yielding reduced variability; 2) easier development of IV formulation for drugs with low solubility (microtracer doses are ≤ 100 μg); 3) radioactivity doses are low and do not require special handling (usually ≤ 270 nCi of 14C) and 4) negligible toxicity, as the contribution of the microtracer dose to overall exposure is typically Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3773. doi:1538-7445.AM2012-3773

Abstract 3766: Effects of a high-fat meal on the pharmacokinetics of orally administered GSK2118436 in patients with BRAF mutation-positive tumors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL GSK2118436 is a potent and selective small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF mutation-positive tumors. This study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of a single 150 mg oral dose of GSK2118436 administered to patients with BRAF-mutant solid tumors. This was an open-label, randomized, two-period crossover study. In a cohort of 14 patients, GSK2118436 was administered under fasted state or with a high-fat meal, with a 1-week washout between periods. Blood samples were collected up to 96 hours post-dose to characterize the PK of GSK2118436 and its circulating metabolites. PK parameters were calculated by non-compartmental methods (WinNonlin 5.2). Geometric mean ratios (fed/fasted) for the point estimate and 90% CIs were calculated for Cmax and AUC0-α, and median difference (90% CI) was calculated for tmax using the Hodges-Lehmann non-parametric method. The absence of a food effect can be concluded if the 90% CIs are contained between 0.8 and 1.25 for Cmax and AUC0-α. Following administration of a high-fat meal, median Cmax concentrations were delayed by 3.7 h (90% CI: 2.4-5.0) compared with the fasted state. A high-fat meal decreased the exposure to GSK2118436, with geometric mean ratios (90% CI) for Cmax and AUC0-α of 0.49 (0.35-0.69) and 0.69 (0.57-0.85), respectively. Metabolite exposures were decreased to a similar extent. Based on the data generated in this study, it appears that there is a food effect for GSK2118436, as the 90% CI are not contained within the acceptable boundaries of 0.8 and 1.25. In clinical studies GSK2118436 has been administered on an empty stomach, and results from this study are consistent with these recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3766. doi:1538-7445.AM2012-3766

Abstract B155: A phase I study of the MEK inhibitor GSK1120212 (GSK212) in combination with PI3K/mTOR inhibitor GSK2126458 (GSK458) in patients with advanced solid tumors.

Background: This is a Phase I, open-label, dose escalation, pharmacokinetic (PK), pharmacodynamic (PD) and safety study in patients (pts) with advanced solid tumors exploring the combination of the investigational drugs GSK458 and GSK212. GSK212 is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2). GSK458 is a potent, reversible, ATP-competitive, pan-phosphoinositide-3 kinase (PI3K) inhibitor, which also inhibits the mammalian target of rapamycin (mTOR), and the common activating mutations of catalytic isoform p110α. The MTD for daily, continuous dosing of monotherapy GSK458 is 2.5mg and GSK212 is 2.0mg. Methods: The study consists of two parts: dose escalation in Part 1 (ongoing) uses a zone design (3+3 rules) to study safety, tolerability, PK, PD and clinical activity, and to establish the maximum tolerated doses (MTDs) and schedules for the combination. Adult pts with relapsed or refractory solid tumors are receiving oral doses of GSK458+GSK 212 once daily until disease progression or toxicity. Efficacy is assessed using RECIST 1.1. Part 2 will examine safe dose combinations from Part 1 in patients with tumors likely to respond to MEK/PI3K pathway inhibition. Genetic and protein profiles collected from blood and tumor samples will be used to explore relationships between predictive biomarkers of response and efficacy. Results: 34 pts(45% female) with a mean age of 58y (range 37–82y) have enrolled. Safety data includes31 subjects who have received ≥1 dose of GSK458+GSK212. Most commonly reported drug-related AEs >10%, n=31) include rash (68%; G3/4, 3%), diarrhea (42%; G3/4, 6%), nausea (29%; G3/4, 0%), vomiting (23%; G3/4, 3%), decreased appetite (19%; G3/4, 0%), stomatitis (13%; G3/4, 3%) and fatigue (13%; G3/4; 3%). Of 21 serious adverse events (SAEs) reported in 14 pts, 3 were considered related to study drug. Stable disease has been observed in several patients with the longest being at 6 months (renal cell carcinoma and colorectal cancer). The combination of GSK458 0.5 mg + GSK212 2.0 mg exceeded the MTD. However, once daily and continuous combination dosing of GSK458 (0.5, 1.0 or 1.5mg) + GSK212 ≤ 2.0 mg were well tolerated. Conclusions: The preliminary safety profile and anti-tumor activity of this combination warrants further investigation in continued dose escalation and planned expansion cohorts. 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 B155.