cabiralizumab (BMS-986227)

P2, N=4, Completed, University of Michigan Rogel Cancer Center | Active, not recruiting --> Completed

Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.

LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy (including pexidartinib, cabiralizumab, or vimseltinib) were enrolled and treated with vimseltinib 30 mg twice weekly (recommended phase 2 dose). Longer follow-up demonstrated that vimseltinib continued to be well tolerated with a manageable safety profile in pts with TGCT not amenable to surgery who received prior anti-CSF1/CSF1R therapy. Antitumor activity continued to improve in this pretreated population, with an increased ORR. At week 25, all responders experienced ≥30% reductions in worst and average pain.

P2, N=206, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Jun 2023 | Trial primary completion date: Oct 2023 --> Jun 2023

Pexidartinib is the first CSF-1 receptor inhibitor approved for the treatment of TGCT. Here, we discuss various available treatment strategies and ongoing investigations and trials targeting diffuse TGCT, which include nilotinib, lacnotuzumab, cabiralizumab, vimseltinib, and emactuzumab.

P1/2, N=15, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting | N=31 --> 15 | Trial completion date: Jun 2027 --> May 2026 | Trial primary completion date: Apr 2024 --> Mar 2023

P1, N=60, Completed, University of Chicago | Active, not recruiting --> Completed

P2, N=4, Active, not recruiting, Ryan Wilcox | Trial completion date: Aug 2024 --> Jul 2023

P1/2, N=31, Recruiting, Washington University School of Medicine | N=50 --> 31 | Trial completion date: Jun 2029 --> Jun 2027

P1, N=42, Active, not recruiting, Yale University | Recruiting --> Active, not recruiting | N=120 --> 42 | Trial completion date: Oct 2024 --> Oct 2027 | Trial primary completion date: May 2022 --> Nov 2022

P1/2, N=50, Recruiting, Washington University School of Medicine | Trial completion date: Feb 2024 --> Jun 2029 | Trial primary completion date: Dec 2022 --> Apr 2024

P1, N=60, Active, not recruiting, University of Chicago | Trial completion date: Feb 2022 --> Jul 2022

To test the importance of myeloid attraction and signaling to CTC survival in the portal blood, humanized monoclonal blocking antibodies to CSF1R (BMS-986227, Cabralizumab), IL-8 (BMS-986253), and mouse monoclonal antibodies to IL-34 (1D12, Abcam) were used to inhibit CTC/M-FB signaling pathways. Blocking IL-8 signaling from CTC allowed myeloid cells to produce their own IL-8 and avoid being drawn to CTC and their CSF1/IL-34/CSF2 influence on myeloid differentiation. Without myeloid cell attraction and differentiation, clusters don’t form, leaving CTC unaided by M-FB, and myeloid cells differentiating away from immunosuppressive, pro-tumor phenotypes. Such treatments could lead to enhanced anti-tumor myeloid cell responses and suppression of CTC survival.

P2, N=4, Active, not recruiting, Ryan Wilcox | N=33 --> 4 | Trial completion date: May 2025 --> Aug 2024

This first in-human study of patients with anti-PD-1/PD-L1-resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

P1/2, N=50, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P1a/1b, N=295, Completed, Five Prime Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Mar 2020 --> Nov 2019

P1/2, N=50, Not yet recruiting, Washington University School of Medicine | Trial completion date: Sep 2023 --> Jan 2024 | Initiation date: Jun 2020 --> Oct 2020 | Trial primary completion date: Jul 2022 --> Nov 2022

P1/2, N=50, Not yet recruiting, Washington University School of Medicine

Clinical trial information: NCT04050462. Research Funding: Bristol-Myers Squibb