Background: Adenosine, derived from ATP released by dying cancer cells in response to chemotherapy, activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Adenosine receptor blockade may improve the efficacy of chemotherapy, notably anthracycline regimens, by enhancing immunogenicity within the tumor microenvironment. AB928, the first clinical-stage small molecule dual A2aR/A2bR antagonist, is highly potent and well tolerated in combination with chemo/immunotherapy. Novel combinations of AB928 with PLD +/- IPI-549, a PI3Kgamma inhibitor believed to shift tumor associated macrophages toward an anti-tumor phenotype, may offer potential clinical benefit for tumors previously considered immunotherapy-resistant. Methods: ARC-2 (NCT03719326) is an ongoing Phase (Ph) 1/1b, open-label study in patients (pts) with metastatic or locally advanced, unresectable ovarian or triple negative breast (TNBC) cancer. Eligible pts must have ECOG performance status 0-1 and at least one measurable lesion. In dose escalation, AB928 (75 or 150 mg) administered orally once daily was given with standard PLD in a 3+3 design. Once a tolerable doublet regimen was established, escalating doses of oral IPI-549 (30 or 40 mg once daily) were added. Two expansion cohorts, the doublet of AB928 150 mg + standard PLD and the triplet (+ IPI549 40 mg), are ongoing in pts with TNBC. Results: As of 19Jun2020, 29 pts received AB928 as part of the doublet or triplet regimen (Table 1). The number of prior therapies for escalation and expansion range from 0-11 (median=2) and 0-5 (median=1), respectively. Across both regimens, most treatment emergent AEs (TEAEs) were Grade (Gr) 1 or 2. The most common TEAEs (>6 pts) were fatigue, anemia, constipation, stomatitis, cough, and nausea. Four pts reported 6 Gr ≥3 SAEs; none were related to AB928 or IPI-549 and one event (pleural effusion) was at least possibly related to PLD. One pt discontinued study treatment for an AE (Gr 3 peripheral neuropathy) related to the triplet regimen; this pt had a complete response (CR) at the time of discontinuation. Of those pts treated with AB928 + PLD, 16 pts had at least one on-study disease evaluation, 2 pts (1 TNBC, 1 ovarian) achieved a partial response (PR), 8 stable disease (SD) and 6 progressive disease (PD) as best response. The addition of IPI-549 (n=11) resulted in 1 complete response (CR; ovarian), 3 PR (2 ovarian, 1 TNBC), 4 SD, and 3 PD. Nine pts received prior immunotherapy as part of an anticancer regimen; 2/9 achieved a PR on study treatment (1 confirmed, 1 pending). Thirteen pts had prior anthracycline; 6/13 achieved SD as best overall response, including 1 pt who received doublet therapy >1 year. Conclusions: AB928 and PLD +/- IPI-549 is tolerable in pts with advanced ovarian cancer and TNBC. Doublet and triplet combination treatment were associated with clinical benefit, including responses in those with progression after prior immunotherapy. The promising observation that late-line pts, including those previously treated with an anthracycline and/or immunotherapy, can experience clinical benefit with AB928 combination therapy warrants further investigation.

Table 1. ARC-2 Cohort Enrollment and AB928 +/- IPI-549 Dose Received

Study Part:Phase 1Phase 1b
Regimen:DoubletTripletDoubletTriplet
AB928 dose: 75 mg 150 mg 150 mg 150 mg 150 mg 
IPI-549 dose:   30 mg 40 mg  40 mg 
Enrolled, n 
Ovarian – – 
TNBC 
Study Part:Phase 1Phase 1b
Regimen:DoubletTripletDoubletTriplet
AB928 dose: 75 mg 150 mg 150 mg 150 mg 150 mg 
IPI-549 dose:   30 mg 40 mg  40 mg 
Enrolled, n 
Ovarian – – 
TNBC 

Citation Format: Jasgit C. Sachdev, Amy Prawira, Arvind Chaudhry, Vinod Ganju, Caroline Trudeau, Jennifer Scott, Rachel Woloski, Melissa Paoloni, Halle Zhang, Olivia Gardner. Efficacy and safety of AB928 plus pegylated liposomal doxorubicin (PLD) with or without IPI-549 in participants with metastatic ovarian and triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-12.