br Study design and procedures br
2.2. Study design and procedures
Patients were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (S1) and stratified by adju-vant treatment, including chemotherapy with radiation (yes versus no), geographic location (Asia versus United States versus European Union) and tumour PTEN sta-tus (H score 0 to 100 versus 101 to 200 versus >200). H score was defined based on cytosolic PTEN staining . Baseline tumour tissues were analysed for presence and type of PIK3CA or AKT mutations and PIK3CA amplification (see Supplementary Material). Crossover from placebo to ipatasertib was not permitted.
Ipatasertib (600 mg) or placebo was administered orally once daily (QD) on day 1 of cycle 1 through day 7 of each 14-day cycle until disease progression (per investigator assessment) or intolerable toxicity. If intolerable toxicity attributed to ipatasertib 600 mg occurred, the dose could be split to 300 mg twice daily or reduced to 400 mg QD or 200 mg QD. Following day 1 administration of ipatasertib or placebo, all patients initiated mFOLFOX6:oxaliplatin (85-mg/m2 intrave-nous [IV] infusion over 2 h on day 1 every 14 days) coadministered with leucovorin 400 mg/m2, then 5-FU 400 mg/m2 administered as Heparin IV infusion, followed by 5-FU 2400-mg/m2 IV continuous infusion over 46e48 h (or 5-FU 1200-mg/m2/d continuous IV infusion over 2 days). After cycle 8, oxaliplatin was discontinued and patients received ipatasertib/placebo followed by chemotherapy with bolus 5-FU, leucovorin, and IV 5-FU, as described previously.
The primary end-point was progression-free survival (PFS), defined as time from randomisation to first occurrence of disease progression per investigator-assessed RECIST v1.1, or death on study 30 days after the last dose of study treatment from any cause in
the intent-to-treat (ITT) population and in patients with PTEN-low tumours. Secondary end-points were overall survival (OS), investigator-assessed objective response rate (ORR) per RECIST v1.1, duration of response (DOR) and time to disease progression in the ITT population and PFS in the patient subgroup with PI3K/ Akteactivated tumours.
Safety assessments included adverse event (AE) inci-dence, description and severity graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and Medical Dictionary for Regulatory Activities (MedRA) version 18.1 terminol-ogy for AEs. All AEs and serious AEs (SAEs) collected until 30 days after the last dose of study treatment or initiation of another therapy were analysed.
2.4. Statistical analysis
This trial was hypothesis generating and was not pow-ered to detect statistically significant differences in PFS across arms. The sample size was determined such that the upper bound of the two-sided 90% CI for a target clinically meaningful hazard ratio (HR) of 0.6 in pa-tients with PTEN-low tumours would be close to 1, which required 48 PFS events. Assuming an estimated 60% of patients had PTEN-low tumours, the target enrolment of 150 patients (75 patients randomised to each arm) included z90 patients with PTEN-low tu-mours. The final PFS analysis was planned when 48 or 80 PFS events had occurred in patients with PTEN-low tumours or in all enrolled patients, respectively.
PFS and OS were evaluated by survival analysis. Primary and secondary efficacy analyses were conducted in all randomised patients and in predefined biomarker subgroups: PTEN-low (tumour samples that were PTEN immunohistochemistry [IHC] in 0 <10% of the tumour cells; see Supplementary Material) and PI3K/ Akteactivated (tumour samples that were PTEN IHC in 0 90% of the tumour cells, samples with PIK3CA mutations or PIK3CA amplification [ratio 1.5]; see Supplementary Material). Patients without post-baseline tumour assessments were considered non-responders. DOR was assessed in all patients with an objective tumour response. Safety analyses were con-ducted in all patients who received any dose of the study treatment.