Abstract CT247: A phase 1/2 study of GB1275, a first-in-class CD11b modulator, as monotherapy and with an anti-PD-1 antibody in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36)
Authors: Wang-Gillam Andrea , Rasco Drew W. , Park Wungki , O'Reilly Eileen , Messersmith Wells , DeNardo David G. , Gupta Vineet , Zhou Lei , Galkin Anna , Slee Debbie , Carter Laura L. , Nickle David , Tran Rebecca , Li Jack , Ferguson Beatrice , Chaney Marya F. , Salter-Cid Luisa , Dupont Jakob , Bendell Johanna C. 
Published: September 2020

Abstract
Background: Tumor influx of CD11b-expressing myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) creates an immunosuppressive tumor microenvironment associated with resistance to anti-PD-1 antibody therapy. GB1275 is a novel, first-in-class, CD11b modulator that, in vivo, reduced MDSCs and TAMs at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells. In combination with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models. We hypothesize that GB1275-based therapy can alleviate myeloid cell-mediated immunosuppression and improve cancer treatment outcomes. Methods: This is an open-label, first-in-human study comprising phase 1 dose escalation of GB1275 monotherapy (Regimen A) and GB1275 plus pembrolizumab (Regimen B) in patients with previously treated, locally advanced or metastatic PDA, esophageal, gastric/GEJ, triple negative breast, castration-resistant prostate, or microsatellite-stable colorectal cancer (MSS CRC), and GB1275 plus nab-paclitaxel and gemcitabine (Nab-P+Gem) (Regimen C) in mPDAC. This is followed by phase 2 expansion in three disease cohorts: 1) newly diagnosed stage IV mPDAC (GB1275+Nab-P+Gem), 2) MSS CRC (GB1275+pembrolizumab), and 3) PD-L1+ gastric/GEJ cancer (GB1275+pembrolizumab). Patients are enrolled in Regimen A initially, with Regimen B commencing after completion of the first few cohorts of Regimen A. Regimen C will initiate when Regimen A is completed. Eligible patients are ≥18 years of age, with histologically confirmed locally advanced/metastatic tumor specified and ECOG 0-1 PS; prior immunotherapy is permissible during Regimen A and B dose escalation, but not Regimen C or during the expansion phase. Patients are excluded for untreated or symptomatic CNS metastasis, prior myeloid targeting treatment or other prohibited medications, or a history of clinically significant cardiovascular disease. Patients with active autoimmune disease requiring systemic therapy will be excluded from Regimen B and from expansion cohorts 2 and 3. Primary objectives for phase 1 are to determine the maximum tolerated dose/recommended phase dose and pharmacokinetic profile of GB1275 alone and combination with pembrolizumab, and safety in combination with Nab-P+Gem, and for phase 2, to assess efficacy.Statistical Considerations: A 3+3 design is used for the dose escalation phase and Simon's 2-stage design for the expansion phase. Adverse events are graded per CTCAE v5.0, responses per RECIST v1.1. This study is open for recruitment (NCT04060342).
Citation Format: Andrea Wang-Gillam, Drew W. Rasco, Wungki Park, Eileen O'Reilly, Wells Messersmith, David G. DeNardo, Vineet Gupta, Lei Zhou, Anna Galkin, Debbie Slee, Laura L. Carter, David Nickle, Rebecca Tran, Jack Li, Beatrice Ferguson, Marya F. Chaney, Luisa Salter-Cid, Jakob Dupont, Johanna C. Bendell. A phase 1/2 study of GB1275, a first-in-class CD11b modulator, as monotherapy and with an anti-PD-1 antibody in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT247.