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BackgroundBDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a Phase I trial. Here, we report on the safety and efficacy of BDB001 in combination with atezolizumab in a Phase I dose escalation/expansion trial in advanced solid tumors (NCT04196530).MethodsBDB001-102 is a Phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with an anti-PD-L1 antibody, atezolizumab (IV, Q3W), in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation.ResultsForty-one subjects with 17 different tumor types were enrolled across 4 dose levels. Fifty-nine percent were female, median age was 67 years (range, 32–80), median number of prior therapies was 3 (range, 0–8), and 63% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with atezolizumab was well tolerated and 13 (31.7%) subjects did not experience any treatment related adverse events (TRAEs). No dose-limiting toxicities were observed. Common TRAEs were transient Grade 1 or 2 fatigue (31.7%), fever (26.8%) and chills/rigor (26.8%). Only 3 (7.3%) subjects experienced Grade 3 TRAEs of fatigue and nausea. There were no Grade 4 or 5 TRAEs and no new safety concerns. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 4. IP-10 induction was associated with clinical responses. Preliminary efficacy evaluation of the 19 subjects at Dose Level 4 showed durable and deep clinical responses in 3 (16%) subjects, 2 with urothelial carcinoma and 1 with anti-PD-1 mAb refractory NSCLC. All responders remain on treatment, with a duration of response ranging from 7.1+ to 34.1+ weeks. Ten (53%) subjects had stable disease (DCR 68%), 3 of whom had a reduction in tumor burden and were on treatment for over 18 weeks (up to 56 weeks).ConclusionsIntravenous BDB001 in combination with atezolizumab is well tolerated. Deep and durable clinical responses were observed in PD-1 refractory and naive patients, supported by robust systemic immune activation. BDB001 in combination with atezolizumab is a promising therapeutic option for patients with advanced solid tumors. A phase 2 trial (NCT03915678) of BDB001 in combination with atezolizumab and radiotherapy is currently enrolling patients.Ethics ApprovalThis study was approved by the institutional review boards at the five participating institutions. All subjects signed informed consent before enrolling in the clinical trial.

Background GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342) Methods This study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis. Results As of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing. Conclusions Dose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging. Ethics Approval This ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust. Reference Panni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).