Phase 1b study of BXCL701, a novel small molecule inhibitor of dipeptidyl peptidases (DPP), combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

e17581 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. In a prior clinical study, BXCL701 at a total daily dose of 0.6mg (as 0.3mg BID) demonstrated single agent activity in 2 pts with Stage IV melanoma (unpublished). Methods: In this multi-center study, eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3X3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated. Results: Six pts were treated at 2 BXCL701 dose levels of 0.4mg qd (n = 3) and 0.6mg qd (n = 3), with 5 pts having adeno, 1 pt having mixed adeno and SC-NEPC. Prior tx included ADT (n = 6), 2nd generation androgen signaling inhibitors (n = 4), chemo (n = 4), RT (n = 5). Among 3 pts at the BXCL701 dose level of 0.6mg, 1 pt had a DLT of Grade 3 syncope (C1D6) and 1 pt had fatal acidosis (C3D8). A dose-dependent increase in pts with low-grade on-target clinical effects was observed. In the 0.4mg qd cohort 1 pt had lower extremity (LE) edema. Whereas in the 0.6mg qd cohort, all pts had events consistent with cytokine release: 3 had hypotension and 2 pts each had dizziness and LE edema. The 0.6mg/day dose level was expanded using a split dose strategy to improve tolerability while maintaining the daily dose previously associated with objective responses. BXCL701 was quantifiable in plasma. Conclusions: BXCL701 0.4 mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days was well tolerated in pts with mCRPC. A dose-dependent increase in on-target clinical effects expected with cytokine upregulation was seen. The final dose expansion using the split dose for the RP2D, plasma drug concentrations and relevant biomarkers will be presented. Clinical trial information: NCT03910660 .

The Association between a Decrease in On-Treatment Neutrophil-to-Eosinophil Ratio (NER) at Week 6 after Ipilimumab Plus Nivolumab Initiation and Improved Clinical Outcomes in Metastatic Renal Cell Carcinoma

“…Our group previously conducted a small retrospective study of 26 patients with solid tumor diagnosis who were concomitantly taking DPP4 inhibitors for diabetes while on ICI treatment [ 43 ]: the objective response rate was 69% (18/26), although the results should be interpreted with caution due to the small sample size and lack of a comparison group. Of note, a phase 1b/2 trial investigating BXCL701, which is an inhibitor of DDP4/DPP8/DPP9, with/without pembrolizumab in mCRPC [ 44 ] (NCT03910660) reported a 26% response rate (6/23) and a disease control rate of 63% in this heavily treated patient population [ 45 ]. Future correlative studies of this trial may provide further translational data for the anti-tumor activity of eosinophils through DPP inhibitions and the possibility to enhance antitumor activity of ICIs.…”

Current Status of Monoclonal Antibodies-Based Therapies in Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials

“…Interim results of ongoing clinical trials on pembrolizumab, avelumab, atezolizumab, pasotuxizumab, and tremelimumab have shown promising results alone or in combination with chemotherapy [51][52][53][54][55][56][57][58].…”

Evolving scenario of big data and Artificial Intelligence (AI) in drug discovery

“…BioXcel Therapeutics ( https://www.bioxceltherapeutics.com/ ) have successfully identified BXCL701, a candidate molecule using AI technology that is effective against schizophrenia and bipolar disorder. BXCL701 is also currently in different phases of clinical trials against pancreatic cancer, for which it has obtained FDA approval [ 172 ]. Thus, conventional drug discovery concepts combined with advanced computational approaches provide an excellent platform for research and development to enhance the drug discovery and development process.…”