A Phase I Dose‐Escalation Study of the Safety and Pharmacokinetics of Pictilisib in Combination with Erlotinib in Patients with Advanced Solid Tumors
| Autor: | Ruud van der Noll, Jennifer L. Schutzman, Stephen Leong, Daniel W. Bowles, Jill M. Spoerke, Mark R. Lackner, Joseph A. Ware, Jan H.M. Schellens, Geetha Shankar, Rebecca A. Moss, Jing Zhou, Emile E. Voest |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Adult Male Cancer Research medicine.medical_specialty Indazoles Maximum Tolerated Dose Phases of clinical research New Drug Development and Clinical Pharmacology 03 medical and health sciences Erlotinib Hydrochloride Phosphatidylinositol 3-Kinases 0302 clinical medicine Pharmacokinetics Internal medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans heterocyclic compounds Epidermal growth factor receptor Adverse effect neoplasms Protein Kinase Inhibitors Aged Cell Proliferation Neoplasm Staging Phosphoinositide-3 Kinase Inhibitors Sulfonamides biology Dose-Response Relationship Drug business.industry Cancer Middle Aged medicine.disease respiratory tract diseases ErbB Receptors 030104 developmental biology Tolerability 030220 oncology & carcinogenesis biology.protein Female Erlotinib business medicine.drug |
| Popis: | Background Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. Materials and methods A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed. Results Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease. Conclusion Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways. Implications for practice Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition. |
| Databáze: | OpenAIRE |
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