Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan‐Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

Abstract Lessons Learned. A phase I study of the pan‐class I phosphoinositide 3‐kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of pilaralisib tablets was established as 400 mg once daily. Background. A phase I trial of pilaralisib, an oral pan‐class I phosphoinositide 3‐kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated pilaralisib in tablet formulation. Materials and Methods. Patients with advanced solid tumors received pilaralisib tablets (100–600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy. Results. Twenty‐two patients were enrolled. No dose‐limiting toxicities (DLTs) were reported. The most common treatment‐related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose‐proportionally. Steady‐state exposure was higher with pilaralisib tablet formulation at 400 mg than with pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0–24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR). Conclusion. Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for pilaralisib tablets, based on PK data, was 400 mg once daily

MET Genetic Abnormalities Unreliable for Patient Selection for Therapeutic Intervention in Oropharyngeal Squamous Cell Carcinoma

Background: Identification of MET genetic alteration, mutation, or amplification in oropharyngeal squamous cell carcinoma (OPSCC) could lead to development of MET selective kinase inhibitors. The aim of this study was to assess the frequency and prognostic value of MET gene mutation, amplification, and protein expression in primary OPSCC. Methods: A retrospective chart review was conducted of patients treated for single primary OPSCC between January 2007 and December 2009. Pre-treatment OPSCC tissue samples were analyzed for MET mutations, gene amplification, and overexpression using Sanger sequencing, FISH analysis, and immunohistochemistry respectively. Univariate and multivariate analyses were used to analyze correlations between molecular abnormalities and patient survival. Results: 143 patients were included in this study. Six cases (4%) were identified that had a genetic variation, but previously described mutations such as p. Tyr1235Asp (Y1235D) or p.Tyr1230Cys (Y1230C) were not detected. There were 15 high polysomy cases, and only 3 cases met the criteria for true MET amplification, with >= 10% amplified cells per case. Immunohistochemistry evaluation showed 43% of cases were c-MET negative and in 57% c-MET was observed at the tumor cell level. Multivariate analysis showed no significant association between MET mutation, amplification, or expression and survival. Conclusions: Our study shows a low frequency of MET mutations and amplification in this cohort of OPSCC. There was no significant correlation between MET mutations, amplification, or expression and patient survival. These results suggest that patient selection based on these MET genetic abnormalities may not be a reliable strategy for therapeutic intervention in OPSCC

FISH with two color probes: chromosome 7 centromere (green) and <i>MET</i> gene (red).

<p>A) True <i>MET</i> gene amplification in 10% of cells: 4–8 centromere signals and 16–20 <i>MET</i> signals, ratio >2.0. B) High polysomy: the same number of control and <i>MET</i> gene spots were seen in 15% of giant cells, ratio is 1.0. C) Chromosome 7 monosomy: only one control and one <i>MET</i> signal were detected for this case. In some cells there is only one signal (or no signal) due to a nuclei section. D) Normal hybridization pattern: two control spots and two <i>MET</i> gene spots. Again, some cells show only one of two signals due to a nuclei section.</p

IHC staining for c-MET and pYY1234-1235 <i>MET</i> in OPSCC specimens.

<p>Moderate (A) and strong (B) membranous and cytoplasm c-MET immunostaining in tumor cells. No p-MET immunostaining was observed in serial section (C and D). (original magnification ×20).</p

Patient and tumor characteristics.

<p>*American Joint Committee on Cancer</p

The location and predicted effect of each <i>MET</i> variation found, numbered from the reference sequence NM 000245.2.

<p>Mutation Chromatograms include reference sequences and variant description sequence variations described using IUPAC code (<a href="http://www.insdc.org/" target="_blank">http://www.insdc.org/</a>).</p><p>Align-Grantham Variation Grantham Deviation.</p><p>Sorts Intolerant From Tolerant.</p