Background: Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of OC and TNBC. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. BET inhibition may also play a role in immune modulation via downregulation of CD47 and PD-L1. We hypothesized that RO may enhance the clinical potential of A. We report results of a phase 1b study of RO in combination with A in advanced OC and TNBC (NCT03292172). Methods: Patients with advanced OC or TNBC were eligible. In the dose escalation part, pts received subcutaneous escalating doses of RO (0.30, 0.45, 0.65 mg/kg) on days 1 - 14 of 21-day cycles in combination with A at 1200 mg IV on Day 1 of each cycle. In the expansion part, pts received RO at 0.45 mg/kg. Primary objectives were safety, tolerability and preliminary clinical activity of the combination. Results: Between Nov 2017 and Dec 2018, a total of 36 pts were enrolled, 27 pts in the dose escalation and 9 pts in the expansion part at 6 sites in the US, Canada, Denmark and Australia. The median age was 53 (34 - 72) years. 99 total cycles were completed, with a median of 2 (1-14) cycles per pt. During dose escalation, one pt at 0.65 mg/kg + A experienced a DLT of Grade 3 febrile neutropenia. Grade ≥ 3 treatment emergent AEs in ≥ 5% of all pts were immune-related AEs (irAEs) associated with laboratory findings suggestive of secondary hemophagocytic lymphohistiocytosis (HLH), anemia and hyponatremia (11.1% each), abdominal pain, fatigue and small intestinal obstruction (8.3% each), thrombocytopenia, ALT increased and hyperglycemia (5.6% each). Organ toxicities associated with the 4 cases of suspected HLH included fever and febrile neutropenia, myocarditis, encephalitis and pneumonitis; there was no clear correlation between RO exposure and these events. irAEs were observed in an additional 4 pts. AEs leading to treatment discontinuation were reported in 22.2% of pts, with suspected HLH being the most common AE (11.1%). A total of 15 deaths were reported in the study: 9 deaths due to progressive disease, and 6 deaths reported during long-term follow-up where the cause of death was reported as unknown. Two PRs were noted; one each at 0.30 mg/kg + A and at 0.45 mg/kg + A. 15 pts had SD and 14 pts had PD as best response. Median duration of disease control was 93 (95% CI 51-178) days. Response assessment of 5 pts was missing. Conclusions: While suspected HLH/HLH is rare for RO or A given as monotherapy, the safety profile of the combination was considered unacceptable as noted by the high frequency and severity of irAEs including suspected HLH. A limited anti-tumor activity was observed with PR as best overall response in 2 pts. The trial was terminated early due to the unfavorable risk-benefit profile.
Citation Format: Stephanie Lheureux, Iben Spangaard, Erika Hamilton, George Au-Yeung, Debra Richardson, Mark DeMario, Emily Labriola-Tompkins, Barbara Brennan, Eveline Nueesch, Evelyne Chesne, Izolda Franjkovic, Katharina Lechner, Martin Kornacker, Geoffrey I. Shapiro. Dose-Finding/Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB104.