FAKTION; Phase 1b/2 randomised placebo controlled trial of fulvestrant +/- AZD5363 in postmenopausal women with advanced breast cancer previously treated with a 3rd generation aromatase inhibibitor


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Robert Jones1,Sacha Howell2,Paul Rugman3,Angela Casbard4,Emily Bongard4
1Velindre,2Manchester University,3Astra-Zeneca,4Cardiff University

Abstract

Background

Endocrine therapy targeting the ER is effective in controlling advanced ER+ breast cancers but eventually all tumours develop resistance. The PI3K/AKT pathway is frequently mutated in ER+BC and preclinical evidence suggests that Akt inhibition may be effective at overcoming resistance. We report findings from the phase 1b portion of the AZ/NCRN Alliance FAKTION trial investigating the addition of pan-Akt inhibitor AZD5363 to fulvestrant.

Method

Eligible patients were recruited in cohorts of 3 patients and treated with fulvestrant 500mg according to its licensed schedule. AZD5363 was initiated on C1D15 at 400mg po bd in an intermittent schedule (4 days on/ 3 days off) and if tolerated escalate the next patient cohort to AZD5363 480mg po bd. Patients were eligible for toxicity review if 80% planned dose was taken or DLT was observed.

Results

Five patients were recruited into cohort 1 (400mg po bd), in 3 evaluable patients no DLTs were observed (2 ended treatment before the DLT evaluation period). Due to toxicity related withdrawals the SRC recommended cohort expansion. Two of four additional patients were evaluable with no DLTs. Of 8 patients who received AZD5363 400mg bd the toxicity profile was consistent with prior AZD5363 studies: diarrhoea (n=8) and grade 3 rash (n=3). Rash responded in all patients to AZD5363 dose interruption and 2 of 3 patients tolerated reintroduction with dose reduction (320mg bd). Median duration of treatment was 8.1 weeks in the ITT population and 9.7 weeks in evaluable patients. Although no DLTs were observed the SRC concluded 480mg bd would unlikely be tolerated for long-term dosing combined with fulvestrant in this patient population. AZD5363 400mg bd po was declared the MTD and recommended Phase 2 combination dose (RP2CD) with fulvestrant.

Conclusion

The randomised phase 2 FAKTION trial is actively recruiting in multiple UK sites using the RP2D for AZD5363 of 400mg bd.