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Supplementary material from A Phase I 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

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posted on 2023-03-31, 19:43 authored by Udai Banerji, Emma J. Dean, J. Alejandro Pérez-Fidalgo, Gerald Batist, Philippe L. Bedard, Benoit You, Shannon N. Westin, Peter Kabos, Michelle D. Garrett, Mathew Tall, Helen Ambrose, J. Carl Barrett, T. Hedley Carr, S.Y. Amy Cheung, Claire Corcoran, Marie Cullberg, Barry R. Davies, Elza C. de Bruin, Paul Elvin, Andrew Foxley, Peter Lawrence, Justin P.O. Lindemann, Rhiannon Maudsley, Martin Pass, Vicky Rowlands, Paul Rugman, Gaia Schiavon, James Yates, Jan H.M. Schellens

Supplementary methods and results Supplementary Figure 1. Study 1 (NCT01226316) design Supplementary Figure 2. Dose escalation and DLTs in Part A, with MTDs of the continuous, 4/7, and 2/7 schedules being 320, 480, and 640 mg bid, respectively Supplementary Figure 3. Exploratory mutation analyses (ddPCR) in archival tissue and plasma (ctDNA) samples from a breast cancer patient who had progressive disease as best response (Cb cohort) Supplementary Figure 4. A) Tumour growth inhibition in preclinical tumor xenograft models (BT474c, HGC-27, HCC1954 and 786.0) treated with AZD5363 bid po at the indicated doses. B) AZD5363 PD in BT474c tumor xenografts. C) AZD5363 PD at steady state in BT474c xenograft tumors. D) Time course of pPRAS40 and pAkt S473 in BT474c tumor xenograft tissue following the final dose of AZD5363 after 3 weeks' continuous (100 mg/kg bid) or intermittent dosing (130 mg/kg bid 4/7 and 170 mg/kg bid 2/7) Supplementary Figure 5. Glucose (non-fasting/random) values over time after 480 mg single-dose AZD5363 (all dosing schedules) Supplementary Table 1. Percentage change from baseline for PoM biomarkers for 12 evaluable patients Supplementary Table 2. Antibodies and conditions for IHC analysis Supplementary Table 3. ddPCR primers and probes Supplementary Table 4. Tables with results of molecular analyses of Part C patients (PIK3CA and ESR1 mutation status in tissue and ctDNA, PTEN status in archival tissue) Supplementary Table 5. AEs of CTCAE grade {greater than or equal to}3 (irrespective of causality) in Parts A and B (frequency >3% total) and Part C (frequency >5% total)

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ARTICLE ABSTRACT

Purpose: This phase I, 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 World Health Organization (WHO) performance status of 0 to 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: MTDs were 320, 480, 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 Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II 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 prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II 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. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR.See related commentary by Costa and Bosch, p. 2029

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