This abstract will be presented at a press conference, “Treatment and Resistance to Targeted Therapies,” hosted by Levi Garraway, M.D., Ph.D., assistant professor of medicine in the department of medical oncology at the Dana-Farber Cancer Institute, at 2 p.m. ET on April 7 in Room 153 of the Walter E. Washington Convention Center. Reporters who cannot attend in person can call in using the following information:• U.S./Canada (toll free): 1 (800) 446-2782• International (toll call): 1 (847) 413-3235
Newswise — WASHINGTON, D.C. — The investigational drug AZD5363, which has shown activity in preclinical studies, was well tolerated in humans, and two patients with advanced solid tumors showed partial response, according to data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
“PI3K/AKT signaling is very important in cancer cells,” said Udai Banerji, M.D., Ph.D., clinical senior lecturer at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom. “This signaling pathway is highjacked by abnormalities or mutations in genes that can cause a normal cell to behave like a cancer cell.”
AZD5363 is a new-generation drug inhibiting the three forms of the AKT protein: AKT1, AKT2 and AKT3. It has shown promising results in several tumor cell lines and animal studies. In prior clinical trials, AKT inhibitors have almost always been tested in continuous dosing schedules, resulting in excessive toxicity, according to Banerji.
Banerji and colleagues conducted two phase I studies and administered AZD5363 to the patients in two schedules: continuous dosing seven days a week and intermittent dosing with four days on and three days off.
Among the 92 patients recruited thus far, an intermittent dosing schedule of 480 mg twice a day was generally well tolerated. Side effects included high blood sugar, rash and diarrhea. “But what is important about these side effects, such as raised blood sugar, is that these are known consequences of targeting the AKT pathway,” said Banerji. “This provides proof of principle that the drug is working.”
Using pharmacokinetics studies, the team determined that the dose achieved in the patients’ blood was comparable to the dose used in preclinical studies in which they saw positive outcomes. More than 30 percent reduction was seen in the levels of two proteins, pPRAS40 and pGSK3 beta, in plucked hair and blood samples collected from the patients, suggesting that the drug successfully inhibited AKT.
One patient with ovarian cancer and one with cervical cancer showed partial response to treatment. Both had a mutation in either AKT1 or PIK3CA in their cancers. A third patient with ovarian cancer with a PIK3CA mutation had prolonged stable disease.
“What is very gratifying is that a response like this to a single agent is not something we see very often,” said Banerji. “Also, these data support the growing realization that AKT inhibitors are beneficial when administered intermittently and not continuously.”
Encouraged by these results, AstraZeneca recently initiated two phase Ib studies with patients with prostate and breast cancers. AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics and its collaboration with The Institute of Cancer Research.
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Abstract Number: LB-66
Presenter: Udai Banerji, M.D., Ph.D.
Title: Results of two Phase 1 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
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. Inst. of Cancer Research, Sutton, United Kingdom, Christie Hospital NHS Trust, Manchester, United Kingdom, The Netherlands Cancer Institute, Amsterdam, Netherlands, National Kyushu Cancer Center, Fukuoka, Japan, AstraZeneca R&D, Macclesfield, United Kingdom, The Institute of Cancer Research, Sutton, United Kingdom, National Cancer Center Hospital, Tokyo, Japan
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.
Footnote: AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd).
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