quemliclustat (AB680) / Arcus Biosci, Gilead, Otsuka - LARVOL DELTA

Quemliclustat and chemotherapy in previously untreated patients with metastatic pancreatic ductal adenocarcinoma: PRISM-1, a randomized, placebo-controlled, phase III trial (ESMO-GI 2025) - P3 | "In a previous phase 1b study (ARC-8), quemliclustat combined with nab-paclitaxel (nP) plus gemcitabine (Gem) demonstrated a promising signal in median OS without a significant increase in toxicity.Trial design: PRISM-1 is a randomized, placebo-controlled, double-blind, global, multicenter, phase 3 trial evaluating the efficacy and safety of quemliclustat in treatment-naive patients with metastatic PDAC. The safety and tolerability of quemliclustat in combination with nP-Gem will be assessed; adverse events will be graded according to NCI CTCAE 5.0. Recruitment is planned across Asia, Australia, Europe, and North America."

Clinical • Metastases • P3 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD73 • NT5E

Arcus Biosciences’ Quemliclustat Receives Orphan Drug Designation for Pancreatic Cancer (Businesswire) - "Arcus Biosciences...announced that quemliclustat, an investigational small molecule CD73 inhibitor, was granted orphan drug designation by the U.S. Food and Drug Administration for the treatment of pancreatic cancer....The company initiated PRISM-1, a registrational Phase 3 study to evaluate quemliclustat plus gemcitabine/nab-paclitaxel chemotherapy versus gemcitabine/nab-paclitaxel chemotherapy alone in approximately 610 patients with pancreatic ductal adenocarcinoma (PDAC) that have not been previously treated in the metastatic setting. The study is expected to be fully enrolled this year."

Enrollment status • Orphan drug • Pancreatic Ductal Adenocarcinoma

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12+ microglia transformation. (PubMed, Acta Pharmacol Sin) - "Overall, this study demonstrates that targeting CD73 with AB680 alters purine metabolism in the GBM microenvironment, promotes the transformation of P2RY12+ microglia, and triggers robust anti-tumor immune responses. These results support the rationale for AB680-based therapeutic clinical trials for GBM."

Journal • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD73 • NT5E

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12+ microglia transformation (Nature, Acta Pharmacol Sin) - "Administration of AB680 significantly prolonged survival in G422TN-GBM-bearing mice, reduced tumor size, cell proliferation, angiogenesis, and enhanced microglia activation and anti-tumor immune responses....Furthermore, AB680 combined with RT/TMZ exhibited synergistic therapeutic effects by reversing RT/TMZ-induced increases in adenosine levels and promoting the transformation of P2RY12+ microglia."

Preclinical • Glioblastoma

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12+ microglia transformation (Nature, Acta Pharmacol Sin) - "Administration of AB680 significantly prolonged survival in G422TN-GBM-bearing mice, reduced tumor size, cell proliferation, angiogenesis, and enhanced microglia activation and anti-tumor immune responses....Furthermore, AB680 combined with RT/TMZ exhibited synergistic therapeutic effects by reversing RT/TMZ-induced increases in adenosine levels and promoting the transformation of P2RY12+ microglia."

Preclinical • Glioblastoma

EDGE-Gastric: A Safety and Efficacy Study of Treatment Combinations With and Without Chemotherapy in Adult Participants With Advanced Upper Gastrointestinal Tract Malignancies (clinicaltrials.gov) - P2 | N=332 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Trial primary completion date: Sep 2026 ➔ Jan 2027

IO biomarker • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Disorder • Oncology • PD-L1

SBRT-AMICO: Adenosine Signaling Modulation and Immune Checkpoint Inhibition With Hormone Sensitive Oligometastatic Prostate Cancer (clinicaltrials.gov) - P2 | N=23 | Recruiting | Sponsor: Catherine Spina | Trial primary completion date: Dec 2025 ➔ Dec 2026

Checkpoint inhibition • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

ARC-8: A Study to Evaluate the Safety and Tolerability of AB680 in Participants With Gastrointestinal Malignancies (clinicaltrials.gov) - P1 | N=195 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Arcus Biosciences Reports First-Quarter 2025 Financial Results and Provides a Pipeline Update (Businesswire) - "Pipeline Highlights:...Quemliclustat: In the fourth quarter of 2024, Arcus initiated PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in first-line treatment of metastatic pancreatic cancer. PRISM-1 is recruiting rapidly, with enrollment completion expected by the end of 2025."

Trial status • Pancreatic Cancer

Zimberelimab and Quemliclustat in Combination With Chemotherapy for the Treatment of Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Jonsson Comprehensive Cancer Center | Trial completion date: Sep 2026 ➔ Mar 2026 | Trial primary completion date: Sep 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Adenosine production suppression and PD-1 immune check point inhibitor for treatment of malignant pleural mesothelioma. (MPM) (AACR 2025) - "After three weeks we started monitoring tumor growth and the animals were randomized into five groups of three mice each for treatment with PBS 100 μl (control), Pembro (anti murine PD-1; MCE ) 4.4 mg/Kg, TT-4 (ADORA2 Inhibitor Portage), 3 mg/Kg, Pembro+TT-4, AB-680 (CD73 inhibitor, MCE, HY-125286) 20 mg kg) and Pembro+AB-680 were injected every two days for three weeks. Inhibition of the purinergic pathway exerts a significant immune-mediated MPM growth inhibition"

IO biomarker • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • ADORA2A • ADORA2B • CD73 • CD8 • ENTPD1

Zimberelimab and Quemliclustat in Combination With Chemotherapy for the Treatment of Patients With Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Jonsson Comprehensive Cancer Center | Trial completion date: May 2026 ➔ Sep 2026 | Trial primary completion date: May 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

The adenosine pathway is an actionable multitarget for mesothelioma (MMe) (ELCC 2025) - "Inhibition of the purinergic pathway exerts significant immune-mediated growth inhibition vs MPM."

IO biomarker • Lung Cancer • Oncology • Solid Tumor • ADORA2B • CD73 • ENTPD1

EDGE-Gastric: A Safety and Efficacy Study of Treatment Combinations With and Without Chemotherapy in Adult Participants With Advanced Upper Gastrointestinal Tract Malignancies (clinicaltrials.gov) - P2 | N=333 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • PD-L1

Arcus Biosciences Reports Fourth-Quarter and Full-Year 2024 Financial Results and Provides a Pipeline Update (Businesswire) - "Pipeline Highlights:...CD73-Adenosine Axis:...(i) Quemliclustat: In the fourth quarter of 2024, Arcus initiated PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in pancreatic cancer. In February 2025, Arcus’s partner, Taiho, dosed their first patient in Japan for PRISM-1; (ii) Etrumadenant: Arcus plans to meet with the FDA in the first half of 2025 to clarify next steps for ARC-9, evaluating etrumadenant plus zimberelimab, FOLFOX, chemotherapy and bevacizumab (EZFB) versus regorafenib in third-line metastatic colorectal cancer (mCRC)."

FDA event • Trial status • Colorectal Cancer • Pancreatic Ductal Adenocarcinoma

Study of Gemcitabine, Cisplatin, AB680 and AB122 During First Line Treatment of Advanced Biliary Tract Cancers (QUIC) (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: Nataliya Uboha | Trial completion date: Jul 2025 ➔ Jul 2027 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Hepatology • Oncology • Solid Tumor

PRISM-1: Study of Quemliclustat and Chemotherapy Versus Placebo and Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P3 | N=610 | Recruiting | Sponsor: Arcus Biosciences, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

ARC-9: An Open Label Study Evaluating the Efficacy and Safety of Etrumadenant (AB928) Based Treatment Combinations in Participants With Metastatic Colorectal Cancer. (clinicaltrials.gov) - P1/2 | N=227 | Active, not recruiting | Sponsor: Arcus Biosciences, Inc. | Trial completion date: Oct 2024 ➔ Jul 2025 | Trial primary completion date: Oct 2024 ➔ Jul 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

Identification and Analysis of Anticancer Therapeutic Targets from the Polysaccharide Krestin (PSK) and Polysaccharopeptide (PSP) Using Inverse Docking. (PubMed, Molecules) - "This led to the identification interactions and similarities of PSK and the AB680 inhibitor in the active site of CD73. With the isoform of the K-RAS protein, PSK bonded to the TYR32 amino acid at switch 1, while with BAK it bonded to the region of the α1 helix, while PSP bonded to the activation site and the C-terminal and N-terminal ends of that helix. In Bcl-2, PSK interacted at the binding site of the Venetoclax inhibitor, showing similarities with the amino acids ASP111, VAL133, LEU137, MET115, PHE112, and TYR108, while PSP had similarities with THR132, VAL133, LEU137, GLN118, MET115, APS111, PHE112, and PHE104."

Journal • Oncology • BCL2 • CD59 • CD73 • KRAS

CD73-Adenosine Axis: Quemliclustat (small-molecule CD73 inhibitor) and Etrumadenant (A2a/A2b receptor antagonist) (Businesswire) - "Quemliclustat: Arcus has initiated PRISM-1, a Phase 3 trial of quemliclustat combined with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in pancreatic cancer....Etrumadenant: Biomarker data from cohort B of ARC-9, a randomized Phase 1b/2 study evaluating etrumadenant plus zimberelimab, FOLFOX chemotherapy and bevacizumab (EZFB) versus regorafenib in third-line metastatic colorectal cancer (mCRC), are being presented at SITC in November."

Biomarker • P1/2 data • Trial status • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Quemliclustat (CD73 Inhibitor) reduces adenosine-regulated NR4A gene expression and increases mPDAC inflammation in patients from the ARC-8 trial (AACRPanCa 2024) - P1, P1b/2 | "Quemli, in combination with gemcitabine/nab-paclitaxel (G/nP) ± anti-PD-1 antibody zimberelimab (zim), demonstrated encouraging clinical activity in the first line (1L) mPDAC study ARC-8 (NCT04104672), with median OS ranging from 14.6-19.4 months...Analysis of a published transcriptional dataset from the nivolumab + G/nP control arm of the PRINCE trial in front-line mPDAC (NCT03214250) indicated that high levels of tumor NR4A1, 2, and 3 expression portend significantly worse clinical outcomes in patients treated with this IO/chemotherapy regimen, highlighting a potential opportunity for quemli to provide clinical benefit by reversing adenosine-mediated immunosuppression in mPDAC...Quemli + G/nP treatment was associated with a reduction in tumor expression levels of adenosine-regulated NR4A gene family and was accompanied by an increase in tumor inflammation. Given the adenosine-modulating MoA, patients with mPDACs expressing high levels of NR4A in..."

Clinical • IO biomarker • Gastrointestinal Cancer • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD73 • NR4A1 • NR4A2 • NR4A3

ARC-6: Adenosine Receptor Antagonist Combination Therapy for Metastatic Castrate Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=173 | Completed | Sponsor: Arcus Biosciences, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

The first small molecule CD73 inhibitor entered Phase III stage [Google translation] (bydrug.pharmcube.com) - "On September 23, the United States clinical trial website clinicaltrials showed that the small molecule CD73 inhibitor Quemliclustat (AB680) started phase III clinical trial (PRISM-1), becoming the first small molecule CD73 inhibitor to enter the phase III stage...The study is a multicenter, randomized, double-blind, placebo-controlled clinical trial (n=610) to evaluate the efficacy and safety of Quemliclustat in combination with chemotherapy (nab-paclitaxel + gemcitabine) versus placebo plus chemotherapy in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The primary endpoint of the study was overall survival (OS)."

Trial status • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Zimberelimab and Quemliclustat in Combination with Chemotherapy for the Treatment of Patients with Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=56 | Recruiting | Sponsor: Jonsson Comprehensive Cancer Center | Suspended ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

PRISM-1: Study of Quemliclustat and Chemotherapy Versus Placebo and Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P3 | N=610 | Not yet recruiting | Sponsor: Arcus Biosciences, Inc.

New P3 trial • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma