Background: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly mutated in cancer. Tas is a selective β-isoform-sparing PI3K inhibitor with improved therapeutic index compared to pan-PI3K inhibitors. Palb is a CDK4/6 inhibitor now standard of care in combination with endocrine therapy (ET) in hormone receptor positive breast cancer. Combination of Tas, Palb and ET is synergistic in preclinical models. Methods: This investigator-initiated study investigated safety and tolerability, pharmacokinetics (PK), PD and antitumor activity of Tas+Palb, with addition of ET in dose expansion. Pts were enrolled in 3+3 dose escalation design. Tas was given continuously or 3-weeks-on, 1-week-off (3/1), Palb was given on 3/1 schedule. PD studies included analyses of platelet-rich plasma (PRP) (n = 20) and paired tumor biopsies (n = 5). Serial circulating tumor DNA was monitored in pts with PIK3CA mutations. Results: 24 pts were treated, 22 with Tas+Palb, 2 with Tas+Palb+fulvestrant(ful); M/F 11/13, median lines prior therapy 4. Treatment was well tolerated with mainly G1-2 toxicities. Most frequent G3 toxicities were neutropenia (5/24), thrombocytopenia (5/24) and rash (5/24), with no G4/5 toxicities. Two pts had dose-limiting toxicities (DLT) at DL2. No DLTs were observed at DL4, although pts experienced delayed neutrophil recovery. PK was linear and comparable with monotherapy. At 125mg Palb, significant decreases in pAKT and pGSK3β in PRP confirmed PI3K target inhibition. Two pts with PI3KCA H1047R mutant breast cancers have ongoing RECIST partial response; 1 pt with PIK3CA E542K colorectal cancer had stable disease for 20 weeks. Conclusions: Tas+Palb is well tolerated with evidence of PD and antitumor activity. Dose expansion including recruitment to triplet Tas+Palb+ful and Tas+Palb+letrozole is ongoing with continuous Tas 2mg QD, and Palb 100mg QD on 3/1 schedule, increasing to 125mg after cycle 1 in absence of myelosuppression. Clinical trial information: NCT02389842