Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

Abstract

Purpose: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.Experimental Design: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 þ 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies.Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5-to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway ($40%-80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non-small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations.Conclusions: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. Clin Cancer Res; 20(1); 233-45. Ó2013 AACR.

The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models

“…In a single-agent phase I study, robust pharmacodynamic activity across diverse tumors was evident regardless of mutational status. For example, PI3K pathway inhibition was roughly comparable in a tongue squamous cell carcinoma harboring a PIK3CA E545K mutation with that seen in tumors lacking detectable PI3K pathway alterations (24). Moreover, in that study, a partial response was evident in a patient with non-small cell lung cancer, although no mutations affecting the PI3K pathway were detected in archival tumor tissue from the patient (24).…”

“…For example, PI3K pathway inhibition was roughly comparable in a tongue squamous cell carcinoma harboring a PIK3CA E545K mutation with that seen in tumors lacking detectable PI3K pathway alterations (24). Moreover, in that study, a partial response was evident in a patient with non-small cell lung cancer, although no mutations affecting the PI3K pathway were detected in archival tumor tissue from the patient (24). It is also not yet clear whether the presence of PIK3CA mutations or PTEN deficiency will be predictive of greater clinical responsiveness to PI3K pathway inhibitors in general, although an analysis based on combining the results of multiple early-stage trials suggested that PIK3CA H1047R mutations are associated with response (25).…”

“…The plasma concentrations associated with pharmacodynamic activity and antitumor efficacy in mice are comparable with plasma concentrations associated with PI3K pathway inhibition in a single-agent phase I clinical study (compare Supplementary Table S5 with clinical pharmacokinetics summarized in ref. 24). …”

Pharmacodynamic Biomarkers: Falling Short of the Mark?

“…As illustrated in Table 1, PD endpoints may include assessments of protein phosphorylation markers, measures of cellular proliferation/apoptosis, cell-cycle regulation biomarkers, and epigenetic changes (17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

“…63 This molecule has shown good pharmacokinetic properties in animals and humans and is currently in Phase II trials for metastatic estrogen receptor (ER)-positive breast cancer and non-small cell lung cancer. Another agent derived from the heterocyclic compound quinoxalin (benzopyrazine) is XL147, 64 which is being tested in combination with other therapies including chemotherapy and targeted agents such as erlotinib and trastuzumab.…”