This is an open-label, multicenter, Phase Ib dose-escalation study to assess the safety, tolerability, and pharmacokinetics of oral (PO) pictilisib administered with letrozole or intravenous (IV) paclitaxel with and without IV bevacizumab or IV trastuzumab in participants with locally recurrent or metastatic breast cancer. The study consists of three parts. Part 1 (pictilisib will be administered in 21+7 schedule along with paclitaxel and/or bevacizumab), Part 2 (pictilisib will be administered in 5+2 schedule along with paclitaxel and/or bevacizumab or trastuzumab) and Part 3 (pictilisib will be administered in combination with letrozole). Part 1 and Part 2 consists of two stages; a dose escalation stage and a cohort-expansion stage.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
71
Bevacizumab will be administered IV at a dose of 10 mg/kg on Days 1 and 15 of each 28-day cycle.
Pictilisib will be administered PO QD on escalating doses.
Letrozole will be administered PO at a dose of 2.5 mg QD for for each 28-day cycle.
Paclitaxel will be administered IV at a dose of 90 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle.
Trastuzumab will be administered IV at a dose of 2-4 mg/kg on on Days 1, 8, 15, and 22 of each 28-day cycle.
Unnamed facility
Peoria, Illinois, United States
Unnamed facility
Boston, Massachusetts, United States
Unnamed facility
Nashville, Tennessee, United States
Unnamed facility
Leuven, Belgium
Unnamed facility
Milan, Lombardy, Italy
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
Time frame: First treatment cycle (Day 1 up to Day 29)
Maximum Tolerated Dose (MTD) of Pictilisib
Time frame: First treatment cycle (Day 1 up to Day 29)
Recommended Phase II Dose (RP2D) of Pictilisib
Time frame: Baseline up to 54.2 months
Number of Cycles of Each Component of the Treatment Regimen
Time frame: Baseline up to 54.2 months
Dose Intensity of Each Component of the Treatment Regimen
Time frame: Baseline up to 54.2 months
Minimum Observed Plasma Concentration (Cmin) of Pictilisib
Time frame: Parts 1 and 2 (dose escalation): predose (0 hours [h]) on Day (D) 1,3,16, and 17 of Cycle (C) 1. Part 2 (dose expansion): predose (0h) on D3,16,17 of C1; Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Cmin of Paclitaxel
Time frame: Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h) on D2 and D16 of C1. Part 2 (dose expansion): pre-paclitaxel infusion (0 h) on D1 and D16 of C1 (cycle length=28 days)
Cmin of Letrozole
Time frame: Part 3: Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Area Under the Curve From Time Zero to Last Measurable Concentrations (AUClast) of Pictilisib
Parts 1 and 2 (dose escalation): predose (0 h) and 1,2,3,6 h postdose on D1 and D16 of C1, 24h postdose on D1 of C1; predose (0h) on D3,17 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): predose (0h) and 1,2,3,6h postdose on D16 of C1; predose (0h) on D3, D17 of C1; study completion (up to 55.5 months). Part 3: 3h postdose on D1 of C1; 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Time frame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description]
AUClast of Paclitaxel
Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2,4,6,24 h post-paclitaxel infusion on D2 and D16 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 1,2,3,6,24 h post-paclitaxel infusion on D1 of C1; pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2, 4, 6, 24 h post-paclitaxel infusion on D16 of C1; study completion (cycle length=28 days; up to 55.5 months)
Time frame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description]
AUClast of Letrozole
Time frame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Maximum Observed Plasma Concentration (Cmax) of Pictilisib
Parts 1 and 2 (dose escalation): predose (0 h) and 1,2,3,6 h postdose on D1 and D16 of C1, 24h postdose on D1 of C1; predose (0h) on D3,17 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): predose (0h) and 1,2,3,6h postdose on D16 of C1; predose (0h) on D3, D17 of C1; study completion (up to 55.5 months). Part 3: 3h postdose on D1 of C1; 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Time frame: Parts 1 and 2: D1,D3,D16,D17 of C1; study completion. Part 2: D3,D16, D17 of C1; study completion. Part 3: D15 of C1; D1 of C1 to C6, C≥7 (cycle length=28 days; up to 54.5 months) [detailed timeframe is provided in endpoint description]
Cmax of Paclitaxel
Parts 1 and 2 (dose escalation): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2,4,6,24 h post-paclitaxel infusion on D2 and D16 of C1; study completion (up to 55.5 months). Part 2 (dose expansion): pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 1,2,3,6,24 h post-paclitaxel infusion on D1 of C1; pre-paclitaxel infusion (0 h), end of paclitaxel infusion (infusion length = 60 minutes), end of bevacizumab infusion (infusion length = 30 to 90 minutes), 2, 4, 6, 24 h post-paclitaxel infusion on D16 of C1; study completion (cycle length=28 days; up to 55.5 months)
Time frame: Parts 1 and 2 (dose escalation): D2 and D16 of C1; study completion. Part 2 (dose expansion): D1 and D16 of C1; study completion (cycle length=28 days; up to 55.5 months) [detailed timeframe is provided in endpoint description]
Cmax of Letrozole
Time frame: Part 3: 1,2,3,4,8h postdose on D15 of C1; Predose (0h) on D1 of C1, C2-6, C≥7, D15 of C1 (cycle length=28 days; up to 54.5 months)
Percentage of Participants With Objective Response According to Modified Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
Duration of Response According to Modified RECIST
Time frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
Percentage of Participants With Death or Disease Progression According to Modified RECIST
Time frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
Progression-free Survival According to Modified RECIST
Time frame: Screening up to disease progression or death up to approximately 55.5 months (assessed at Screening and at the end [Days 22-28] of Cycles 2, 5, 8, and 11 and every 3 cycles thereafter [cycle length=28 days; up to approximately 55.5 months])
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