talabostat (BXCL701)

In this investigation, PT-100 (also referred to as Talabostat, Val-boroPro, and BXCL701), an orally administered and nonselective dipeptidyl peptidase inhibitor, not only augmented the effectiveness of anti-PD-1 therapy but also significantly improved T immune cell infiltration and reversed the immunosuppressive tumor microenvironment...The results further suggested that PT-100 dramatically reduced the ratio of tumor-associated macrophages. These findings provide a promising combination strategy for immunotherapy in lung cancer.

P2, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.

Major eligibility criteria include: ≥18 years of age, relapsed or refractory AML or relapsed or refractory MDS with ≥10%.refractory to at least 4 cycles of hypomethylating agent, ECOG performance status ≤2, adequate renal function (CrCl ≥30 mL/min), adequate liver function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN), WBC 100 days from allogeneic bone marrow transplant with no active graft versus host disease...There will be a second phase of the study that will evaluate BXCL701 in combination with a hypomethylating agent (decitabine or azacytidine) and venetoclax. The trial is currently open and continuing to enroll.

Additional biomarker analyses are ongoing to build on this finding. It will also be validated in the randomized Phase 2b SCNC trial planned to initiate in 2H 2023.

Talabostat treatment in the co-culture models reverses CAF-induced suppression of T cell proliferation. Conclusions Talabostat reverses stromal-mediated T cell suppression and is a potential therapeutic strategy to elicit a more effective immune response.

P2, N=43, Recruiting, Georgetown University | Not yet recruiting --> Recruiting

P1b/2, N=98, Active, not recruiting, BioXcel Therapeutics Inc | Recruiting --> Active, not recruiting | N=240 --> 98

P2, N=43, Not yet recruiting, Georgetown University | Initiation date: Mar 2023 --> Jul 2023

P2, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Feb 2023 --> Apr 2024 | Trial primary completion date: Feb 2023 --> Apr 2024

P2, N=43, Not yet recruiting, Georgetown University | Initiation date: Dec 2022 --> Mar 2023

P2, N=43, Not yet recruiting, Georgetown University

These findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in 'cold' tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.

Pan-DPP compounds, which inhibit all the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms [2] that are believed to include NLRP1 activation...In summary, this study provides promising data on the efficacy of ARI-4175 in the treatment of early-stage HCC. Targeting the DPP4 family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation [4].

Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation...This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.

P2, N=15, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P2, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=42 --> 15

Here, we show that blocking DPPs using Val-boroPro triggers a lytic form of cell death in primary human CD4 and CD8 T cells, while other prototypical inflammasome stimuli were not active...Interestingly, this CARD8-induced pyroptosis pathway can only be engaged in resting, but not in activated T cells. Altogether, these results broaden the relevance of inflammasome signaling and associated pyroptotic cell death to T cells, central players of the adaptive immune system.

The oral DPP8/9 inhibitor BXCL701 in combination with an anti-PD-1 antibody (aPD-1) [AACR 2017] or in triple combination with aPD-1 and pegylated IL-2 (NKTR-214) [ASCO 2018] has demonstrated inhibition of tumor growth or complete regression respectively in animal models of pancreatic cancer. On the other hand, downregulated gene clusters belonged to functional categories like cell cycle, DNA repair, several genes associated with cancer progression (GPCRs and Olfactory receptors) and extra cellular matrix (ECM) modification (collagen and metalloproteases). In conclusion, BXCL701-treatment induces innate and adaptive immune responses that leads to tumor growth inhibition probably via inducing cell death and reducing ECM modification.

B + PD1 therapy was accompanied by significant tumor infiltration of NK cells by IHC, flow cytometry and Nanostring analysis. A dramatic reduction of tumor stromal fibrosis by Masson’s trichrome staining was found in tumors treated with B alone or B + PD1.  These findings suggest that the combination of BXCL701 with anti-PD1 antibody therapy can exert anti-tumor effects associated with increased intratumoral NK cell content and the loss of fibrosis that may facilitate immunotherapy efficacy.

P2, N=42, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P2, N=42, Not yet recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2022 --> Feb 2023 | Trial primary completion date: Sep 2022 --> Feb 2023

BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.

BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.

P2, N=42, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Apr 2020 --> Jan 2020

Patients with pancreatic cancer should have received at least 1 line of gemcitabine-based therapy and no more than 2 lines of chemotherapy for unresectable or metastatic disease, received no prior anti-PD-1/PD-L1, IL-2 based or other T-cell directed anti-cancer therapy, and have ECOG 0-1... N/A