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

Abstract

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. Author Manuscript Published OnlineFirst on October 24, 2017; DOI: 10.1158/1078-0432.CCR-17-2260 6 Conclusions Statement of translational relevance (144/150 max)AZD5363 is a potent, selective inhibitor of AKT, a key node in the PI3K/AKT/mTOR pathway that is activated in a wide range of malignancies. In vivo, AZD5363 inhibited tumor growth in xenograft models. Preclinically, sensitivity to AZD5363 has been strongly related to the presence of PIK3CA mutations, which are relatively common in breast and gynecologic cancers. Our study, the first-in-human study of AZD5363, showed that at an identified recommended Phase 2 dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. The study is also the first report of a biomarker-stratified cohort (PIK3CA mutations in breast and gynecologic cancers) of patients treated with an AKT inhibitor. Results suggest that future efforts in developing this class of drugs for the treatment of solid tumors, including PIK3CA-mutated breast and gynecologic cancers, will need to be in combination with other anticancer drugs.

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

“…For FOXO3a, the large decrease in cytoplasmic staining and corresponding large increase in nuclear staining after 4.5 days' exposure seems likely to be a result of redistribution of FOXO3a within the cancer cell as a consequence of upstream changes in AKT signaling pathway activity. This is consistent with the data in paired biopsies from solid tumors in the capivasertib phase I study (13) and validates the preclinical observation of induction of nuclear accumulation of FOXO3a in BT474c breast cancer cells [human epidermal growth factor receptor 2 (HER2)-amplified PIK3CA-mutant] exposed to capivasertib (18). It has been reported that AKT pathway-driven phosphorylation of FOXO3a is arrested by AKT inhibition (18), permitting translocation of FOXO3a to the nucleus; in keeping with this, inverse associations were seen in our study between changes in nuclear FOXO3a and the pathway signaling markers pGSK3b and pS6.…”

“…The secondary biomarkers analyzed (pAKT, pS6, and FOXO3a) also showed significant changes in this study that are consistent with inhibition of the AKT pathway. The observed induction of pAKT is consistent with previous preclinical and clinical data; capivasertib increases phosphorylation of AKT itself, and it has been reported that this is due to the protein being held in a hyperphosphorylated but catalytically inactive form as a consequence of compound binding (8,13,16). Results were obtained from paired biopsies collected during two previous phase I studies (NCT01226316 and NCT01353781), albeit in metastatic solid malignancies (including those with PIK3CA mutation).…”

“…Results were obtained from paired biopsies collected during two previous phase I studies (NCT01226316 and NCT01353781), albeit in metastatic solid malignancies (including those with PIK3CA mutation). These phase I studies also showed downregulation of PD biomarkers (e.g., pPRAS40 and pGSK3b) following capivasertib treatment, increased phosphorylation levels of AKT (consistent with ATP-competitive mechanism of action), and inhibition of FOXO nuclear translocation (13,17). Table 3.…”

“…dose, which, based on initial tolerability, PK, and preliminary efficacy data from a previous phase I study (NCT01226316; ref. 13), was the most likely dose and schedule to be used in clinical studies.…”

Ciliary Neurotrophic Factor (CNTF) Protects Myocardial Cells from Oxygen Glucose Deprivation (OGD)/Re-Oxygenation via Activation of Akt-Nrf2 Signaling

“…To block Akt activation, Akt inhibitors were applied, including MK2206 [30,31], AZD5363 [32,33] and LY294002 [34]. As shown, the Akt inhibitors completely blocked CNTF (25 ng/ mL, 15 min)-induced Akt activation (Fig.…”