Reference Detail

Ref Type

PMID

Authors

Udai Banerji; Malcolm Ranson; Jan HM Schellens; Taito Esaki; Emma Dean; Andrea Zivi; Ruud van der Noll; Paul K. Stockman; Marcelo Marotti; Michelle D. Garrett; Barry R. Davies; Paul Elvin; Andrew Hastie; Peter Lawrence; SY Amy Cheung; Christine Stephens; Kenji Tamura

Title

Abstract LB-66: Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors .

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Res	73	8 Suppl	2013		Cancer Res

URL

https://aacrjournals.org/cancerres/article/73/8_Supplement/LB-66/592409/Abstract-LB-66-Results-of-two-phase-I-multicenter

Abstract Text

Background: AZD5363 is an oral, potent, and selective inhibitor of AKT1, 2 and 3, with activity in a wide range of tumor cell lines and xenografts dependent upon PI3K/AKT signaling. Methods: Two phase I studies (NCT01226316 [West], NCT01353781 [Japan]) were initiated to define the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profile of AZD5363. Two schedules, continuous bid dosing (7/7) and an intermittent schedule bid dosing 4 days on 3 days off (4/7), were investigated. PD biomarkers of AKT signaling were assessed (using pre- and on-treatment samples) in plasma (pPRAS40, pGSK3β, pAKT, glucose, insulin), plucked hair (pPRAS40) and tumor tissue (pPRAS40, pGSK3β, pAKT). Results: At data cut-off (January 2013), 92 patients had been treated in the dose-escalation phases of both studies. In the Western study, the maximum tolerated dose (MTD) for each schedule was 320 mg bid (7/7) and 480 mg bid intermittent dosing (4/7). In the Japanese study, 320 mg bid (7/7) was not tolerated; the MTD for intermittent dosing (4/7) was 480 mg bid. The most commonly reported adverse events, of note, were hyperglycemia, rash, and diarrhea. The PK profile suggests a dose proportional increase in Cmax and AUC. Exposures achieved at doses of 320 mg bid (7/7) and 480 mg bid (4/7) and above are consistent with activity seen in xenograft models. At the doses described, target engagement was seen as evidenced by PD changes in normal tissue (>50% reduction in pPRAS40 in 7/10 patients on AZD5363 480 mg bid (4/7) in plucked hair samples and 30-50% reduction in pPRAS40 and >30% reduction in pGSK3β in platelet rich plasma). Importantly, 7/9 paired biopsies showed an increase in pAKT consistent with the non allosteric inhibition of AKT. Investigation of another intermittent schedule of AZD5363 bid, 2 days on/5 days off treatment, is ongoing. Exploratory mutation analyses of plasma samples are ongoing. Two partial responses were observed, one endometrioid cancer of the ovary and one cervical cancer, in patients on AZD5363 at 480 mg bid (4/7) and 400 mg bid (7/7), respectively. Mutation of either AKT1 or PIK3CA was identified in tumor tissue from both patients. A further patient, with endometrioid cancer of ovary (PIK3CA mutation), had stable disease (SD) for 156 days. Conclusions: AZD5363 administered at 480 mg bid (4/7) was generally well tolerated and showed a PK and PD profile consistent with activity in preclinical models. Partial responses were noted in patients with mutations driving the PI3K pathway.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA mutant	endometrioid ovary carcinoma	sensitive	Capivasertib	Case Reports/Case Series	Actionable	In a Phase I clinical trial, Truqap (capivasertib) demonstrated safety and efficacy in patients with advanced solid tumors, including prolonged stable disease (156 days) in one patient with a PIK3CA-mutant endometrioid ovarian cancer (Cancer Res 2013;73(8 Suppl):Abstract nr LB-66; NCT01226316, NCT01353781).	detail...