PIPA: Combination of PI3 Kinase Inhibitors and PAlbociclib

This is a phase Ib trial of palbociclib in combination with either taselisib or pictilisib. The study will include a dose escalation phase (Part A), and an MTD dose expansion phase (Part B). Part A: will investigate escalating doses of palbociclib with either pictilisib or taselisib administered orally, continuously for 21 days out of a 28 day cycle in patients with advanced solid tumours recruited simultaneously into two parallel arms (up to 24 patients in each arm with a maximum of 48 patients in Part A). Once the MTD is determined the combination with the optimum safety and PK/PD profile as determined by the SRC will be taken forward to the dose expansion phase (Part B). Part B: The MTD dose expansion phase will be conducted using the optimal combination from Part A in two parallel arms as follows: B1: Patients (n=25) with PIK3CA mutant ER + HER2-ve advanced breast cancers will be treated with a triplet combination of palbociclib and either taselisib or pictilisib along with fulvestrant. Part B1 will require at least two of the first 15 patients to respond to progress to recruit the full 25 patients. B2: Patients (n=20) with PIK3CA mutant advanced solid tumours including at least 8 patients with PIK3CA mutant ER negative and/or HER2 positive breast cancers will be treated with the doublet combination of palbociclib and either taselisib or pictilisib. Other cancers with relevant genetic aberrations (e.g. KRAS mutations) may be considered, depending on emerging preclinical and clinical data on these novel antitumour agents. In total, it is expected that a minimum of 70 and up to a maximum of 93 patients will be enrolled into the trial, the final number will depend on the number of dose escalations required to reach DLT. If \< 48 patients are enrolled in Part A, investigators will be permitted to enrol \> 45 patients in Part B, providing the maximum number of patients remains ≤93 patients across the study. The anticipated accrual rate during the dose escalation phase is estimated at 2 patients per month. Accrual in the expansion phase is estimated at 4 patients per month across 2 centres. It is expected that the trial will have a duration of recruitment of 12 to 24 months.