Abstract CT124: A phase Ib/II study of BMS-813160, a CC chemokine receptor (CCR) 2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients (pts) with advanced pancreatic or colorectal cancer
Bibliographic record
Abstract
Abstract Background: During cancer progression, immunosuppressive cells, such as those of myeloid and lymphoid origin, are recruited to the tumor microenvironment (TME) through interactions between chemokines and chemokine receptors (CKRs). CCR2 and CCR5 are CKRs expressed on both myeloid and T-cell infiltrates in the TME and have been shown to mediate the migration of monocyte/myeloid-derived suppressor cells (MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), respectively, from bone marrow to the blood and TME. CCR5 can also recruit regulatory T cells to the TME, potentiate PMN-MDSC immunosuppressive function via arginase-1, and polarize tumor-associated macrophages into an immunosuppressive M2 phenotype. Engagement of CCR2 or CCR5 promotes an immunosuppressive environment and prevents antitumor immunity; this has been preclinically validated in multiple tumor types, including pancreatic and colorectal. Preliminary data also support the utility of combination with PD-(L)1 inhibition. Clinically, CCR2- and CCR5-selective antagonists have separately shown proof of mechanism in combination with chemotherapy in pts with pancreatic and colorectal cancers, respectively (1, 2). These encouraging studies support further investigation of CCR2/5 dual antagonism in providing greater benefit to pts than CCR2- or CCR5-selective inhibition when combined with chemotherapy. Here we describe the design of a phase 1b/2, nonrandomized, open-label study of BMS-813160 (small-molecule CCR2/5 dual antagonist) as monotherapy or in combination with chemotherapy or nivolumab in pts with advanced pancreatic or colorectal cancer (NCT03184870). Methods: Approximately 260 pts aged ≥ 18 years with an ECOG PS of ≤ 1, adequate marrow and organ function, and the ability to undergo pre- and on-treatment biopsies will be enrolled. Exclusion criteria include prior treatment with CCR2 and/or CCR5 inhibitors, requirement for corticosteroids/other immunosuppressive medications, CNS metastases, autoimmune diseases, and symptomatic interstitial lung disease. In part 1, pts will receive BMS-813160 monotherapy safety lead-in for 2 weeks followed by combination with chemotherapy (5-fluorouracil + leucovorin + irinotecan [colorectal cancer] or nab-paclitaxel + gemcitabine [pancreatic cancer]) or nivolumab. In part 2, pts will receive either the same regimens (without a monotherapy lead-in) or BMS-813160 monotherapy. Primary outcomes are safety, tolerability, objective response rate, median duration of response, and progression-free survival rate at 24 weeks. Secondary outcomes are pharmacokinetics and pharmacodynamics of BMS-813160 and immunogenicity of nivolumab. References 1. Nywening TM, et al. Lancet Oncol 2016;17:651-662. 2. Halama N, et al. Cancer Cell 2016;29:587-601. Citation Format: Dung Le, Martin E. Gutierrez, Mansoor Saleh, Eric Chen, Atrayee Basu Mallick, Michael J. Pishvaian, Jürgen Krauss, Peter O'Dwyer, Ignacio Garrido-Laguna, Qihong Zhao, Anke Kippel, Xiaoli Wang, Yali Liu, Allyson Pollack, Ashwin Sama, Heinz-Josef Lenz. A phase Ib/II study of BMS-813160, a CC chemokine receptor (CCR) 2/5 dual antagonist, in combination with chemotherapy or nivolumab in patients (pts) with advanced pancreatic or colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT124.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".