Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer

Abstract

Daily oral administration of PF-04691502 was tolerable at 8 mg orally once daily, with a safety profile similar to other PI3K/mTOR inhibitors. PF-04691502 demonstrated PI3K pathway inhibition by changing glucose homeostasis, and by decreasing phosphorylation of downstream molecules in tumor tissue.

The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

“…34 In this study, we showed that in primary CLL cells, PF-04691502 induced caspase-dependent apoptosis. In contrast, little effect on the viability of normal B and T lymphocytes was evident.…”

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…Several dual PI3K/ mTOR inhibitors, such as XL765 (voxtalisib; IC 50 of 157, 39, 113, 9, and 43 nM for mTOR, p110-α, -β, -γ, and -δ, respectively), GDC-0980 (apitolisib; IC 50 of 17, 5, 27, 7, and 4 nM for mTOR, p110-α, -β, -γ, and -δ, respectively), BEZ235 (dactolisib; IC 50 of 6, 4, 5, 7, and 75 nM for mTOR, p110-α, -β, -γ, and -δ, respectively), and PF04691502 (IC 50 of 16, 1.8, 2.1, 1.6, and 1.9 nM for mTOR, p110-α, -β, -γ, and -δ, respectively), are now in clinical development. [63][64][65][66] However, although some objective tumor responses have been observed, the activity of these agents thus far has been modest, and no clinical trial with either a pan-class I PI3K inhibitor or dual PI3K/mTOR inhibitor has reported robust clinical activity, even in tumors with known genetic alterations. 67 Possible reasons for this include (1) uncertainty as to the extent of downstream phosphoprotein biomarker modulation required to result in efficacy in patients; (2) insufficient target inhibition; (3) inappropriate biomarker selection; or (4) inappropriate patient selection.…”

“…Furthermore, it is conceivable that continuous inhibition of PI3K/mTOR may result in an adaptation favoring cell growth. 64 For certain conditions harboring driver mutations, such as BCR-ABL in chronic myeloid leukemia, the continued inhibition of kinase activity provided by higher trough concentrations of targeted therapy results in more favorable clinical outcomes. 68,69 However, in other malignancies, models of drug resistance are challenging the requirement for continuous inhibition.…”

“…64 The analyses were performed on paired tumor biopsies, paired hair follicle samples, and blood. Posttreatment tumor biopsies and hair follicle samples demonstrated reductions in phosphorylation of AKT S473 , AKT T308 , FKHR T24 /FKHRL1 T32 , and STAT3 Y705 or AKT S473 , PRAS40 T246 , and STAT3 Y705 on day 21 of treatment cycle 1.…”

Le rôle des cohortes d’expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase I

“…Néanmoins, l'objectif et le plan d'expérience sont rarement détaillés et la taille des cohortes d'expansion est rarement justifiée par une approche statistique rigoureuse, ce qui limite le contrôle du risque d'erreur et la robustesse des conclusions. À titre d'exemple, l'étude publiée par Britten et al n'est pas basée sur des hypothèses statistiques mais sur des considérations pratiques afin d'obtenir un minimum de 5 patients avec une biopsie disponible avant et après le traitement pour l'étude d'un biomarqueur [3]. Penel et al ont proposé une approche pour justifier la taille de ces cohortes à l'aide d'une analyse rétrospective basée sur la probabilité d'observer la TLD à la dose à recommander [4].…”