Stewart, A., Coker, E.A., Pölsterl, S., Georgiou, A., Minchom, A.R., Carreira, S., Cunningham, D., O'Brien, M.E., Raynaud, F.I., de Bono, J.S., et al.
(2019). Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers. Molecular cancer therapeutics,
Banerji, U., van Herpen, C.M., Saura, C., Thistlethwaite, F., Lord, S., Moreno, V., Macpherson, I.R., Boni, V., Rolfo, C., de Vries, E.G., et al.
(2019). Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. The lancet oncology,
Banerji, U., Dean, E., Pérez-Fidalgo, J.A., Batist, G., Bedard, P.L., You, B., Westin, S.N., Kabos, P., Garrett, M.D., Tall, M., et al.
(2017). A Phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. Clinical cancer research,
Purpose: This Phase 1, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity. Experimental design: Patients were aged ≥18 years with WHO performance status 0-1. Dose escalation was conducted within separate continuous and intermittent (4 days/week [4/7] or 2 days/week [2/7]) schedules with safety, pharmacokinetic and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers. Results: Maximum tolerated doses were 320 mg, 480 mg and 640 mg for continuous (n=47), 4/7 (n=21) and 2/7 (n=22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for CTCAE grade ≥3 events, hyperglycemia (20%). The recommended Phase 2 dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the pre-specified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA cohort were met. Conclusions: At the recommended Phase 2 dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363..