Phase I dose escalation study of the oral multi-CDK inhibitor PHA-848125

Tibes, Raoul; Jimeno, Antonio; Hoff, Daniel D. Von; Walker, R.; Pacciarini, M. A.; Scaburri, Angela; Fiorentini, F.; Borad, Mitesh J.; Jameson, Gayle; Hidalgo, María Jesús Cancelo

doi:10.1200/jco.2008.26.15_suppl.3531

Cited by 13 publications

(14 citation statements)

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“…The application of a pharmacokinetic/pharmacodynamic model for predicting TGI in mice also allowed us to estimate expected active doses in man and selection of the schedules that are currently being used in clinical trials. Specifically, we identified a target plasma concentration for tumor eradication of 2.4 μmol/L, which is close to the plasma concentration (1.47 ± 0.51 μmol/L) achieved in patients during a phase I dose escalation study at 150 mg/m 2 for 7 consecutive days in a 2-week cycle, eventually selected as the recommended phase II dose (44).…”

Section: Discussionmentioning

confidence: 67%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC 50 . PHA-848125-treated cells show cell cycle arrest in G 1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243-54. ©2010 AACR.

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Section: Discussionmentioning

confidence: 67%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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“…Interestingly, in a recent phase I study with this compound, a prolonged disease stabilization was observed in one patient with NSCLC (25).…”

Section: Discussionmentioning

confidence: 94%

“…PHA-848125 is a novel CDK inhibitor that just entered phase II clinical development (25) as an oral anticancer treatment for patients with advanced malignancies. It is a CDK2, CDK1, CDK4, and TRKA inhibitor belonging to the pyrazolo [4,3-h]quinazoline chemical class (26).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of PHA-848125, a Cyclin-Dependent Kinase Inhibitor, on the K-RasG12DLA2 Lung Adenocarcinoma Transgenic Mouse Model: Evaluation by Multimodality Imaging

Degrassi

Russo

Nanni

et al. 2010

Molecular Cancer Therapeutics

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K-ras is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), the most common form of lung cancer. Recent studies indicate that NSCLC patients with mutant K-ras do not respond to epidermal growth factor receptor inhibitors. In the attempt to find alternative therapeutic regimes for such patients, we tested PHA-848125, an oral pan cyclin-dependent kinase inhibitor currently under evaluation in phase II clinical trial, on a transgenic mouse model, K-Ras G12D LA2, which develops pulmonary cancerous lesions reminiscent of human lung adenocarcinomas. We used magnetic resonance imaging and positron emission tomography to follow longitudinally disease progression and evaluate therapeutic efficacy in this model. Treatment of K-Ras G12D LA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 induced a significant tumor growth inhibition at the end of treatment (P < 0.005) and this was accompanied by a reduction in the cell membrane turnover, as seen by 11C-Choline-positron emission tomography (P < 0.05). Magnetic resonance imaging data were validated versus histology and the mechanism of action of the compound was verified by immunohistochemistry, using cyclin-dependent kinase-related biomarkers phospho-Retinoblastoma and cyclin A. In this study, multimodality imaging was successfully used for the preclinical assessment of PHA-848125 therapeutic efficacy on a lung adenocarcinoma mouse model. This compound induced a volumetric and metabolic anticancer effect and could represent a valid therapeutic approach for NSCLC patients with mutant K-ras.Mol Cancer Ther; 9(3); 673-81. ©2010 AACR.

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“…PHA-848125 was first evaluated in a multi center phase I study to investigate the safety and pharmacokinetics in patients with advanced/ metastatic solid tumors. Oral administration of PHA-848125 in different treatment schedules showed good tolerability with ataxia and tremors as dose-limiting side-effects and occasional hematological toxicities (BenouaichAmiel et al, 2010;Cresta et al, 2010;Tibes et al, 2008). Similar results were found in a phase I study of PHA-848125 in combination with gemcitabine (Bahleda et al, 2010).…”

Section: Cdk Inhibitors For Cancer Therapymentioning

confidence: 64%