Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit or progress after an initial response. Our group and others have shown that loss of the tumor suppressor protein PTEN occurs in multiple cancers, up to 30% of MM pts, activates the PI3K pathway, and correlates with decreased MM response rates to CPI and decreased T cell infiltrates. In PTEN-null MM preclinical models, inhibition of the PI3Kβ-subunit with GSK2636771 (G) was superior to pan-PI3K inhibitors, increased intratumoral T cell infiltration and the activity of CPI. To test our hypothesis that PI3Kβi reverses resistance to CPI, we are conducting a Phase I/II study (NCT03131908) combining G with P in PD-1 refractory pts with PTEN loss. Methods: The primary objective of Ph I portion is to determine the Maximum-Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of G with P in PD-1 refractory pts (including melanoma, endometrial, TNBC, and prostate cancers) with PTEN loss. Pts receive P at 200mg IV q 3 wks. G starting dose level (DL1) was 300 mg PO qd for 21 days and escalated to 400 mg PO qd (DL2) using a 3+3 design. A dose level -1 (DL-1) (200 mg PO qd) was also included in the event of unacceptable toxicities at higher doses. Ph II will accrue 35 pts at the RP2D. This study is continuously monitored for toxicity and futility. The primary objectives of Ph II are safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1. Secondary Objectives include the PKs of G and PD effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Results: 13 pts have been treated, 6 at the 300mg (DL1), 5 at 400mg (DL2), and 2 at 200 mg (DL-1). One DLT (grade 3 hypocalcemia) was observed at the 300mg dose. Two DLTs were observed in the 400mg cohort, one of which was AKI requiring dialysis and the other was a Gr 3 rash. Based on this experience and additional safety data from GSK regarding renal toxicity, DL-1 was declared RP2D at 200mg. 2 pts at the RP2D have passed the DLT evaluation period without toxicities. Conclusions: The combination of G and P is being explored at the RP2D of 200 mg. Renal toxicity precluded higher doses. No objective responses have been observed although 2 pts have experienced prolonged clinical benefit including a MM pt with 27% decrease in tumor burden. Through longitudinal biopsies, we aim to better understand the role PTEN loss plays when targeted in combination with CPI. Clinical trial information: NCT03131908