AKT inhibitor AZD5363 well tolerated, yielded partial response in some patients with advanced solid tumours

An observation that AKT inhibitors are beneficial when administered intermittently and not continuously

The investigational drug AZD5363, which has shown activity in preclinical studies, was well tolerated in two phase I studies, and patients with advanced solid tumours showed partial response and stable disease, according to data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

AZD5363 inhibits AKT and it is effective against tumour cells with mutations in the PI3K pathway

The PI3K/AKT signalling pathway is often involved in cancer development and drug resistance. 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 tumour 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 Udai Banerji, MD, PhD, clinical senior lecturer at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, United Kingdom.

Two phase I studies showed the drug was well tolerated; partial response and stable disease were achieved

Dr 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 hyperglycemia, rash and diarrhoea. But what is important about side effects, such as hyperglycemia, is that these are known consequences of targeting the AKT pathway. Actually, it provides a proof of principle that the drug is working.

Using pharmacokinetic 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% 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.

According to Dr Banerji a response like this to a single agent is not something the oncologists see very often. Also, these data support the growing evidence 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.