Phase I safety, pharmacokinetic and pharmacodynamic study of SAR245408 (XL147), a novel oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors
Mené sur 69 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue l'activité antitumorale et la toxicité d'un composé appelé SAR245408, un inhibiteur de la signalisation PI3K
Purpose: SAR245408 is a pan-Class I phosphatidylinositol-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 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair-sheath cells, skin and tumor biopsies. Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600mg; 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 demonstrated a median time to maximum concentration of 8-22 hours, mean terminal elimination half-life of 70-88 hours and 5-13-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 400mg. SAR245408 inhibited the PI3K pathway (~40-80%; reduced phosphorylation of AKT, PRAS40, 4EBP1 and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. 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 was 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 600mg administered orally with CDD.