CCX872 / Amgen - LARVOL DELTA

Phase 1b Study of CCX872-B in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1 | N=54 | Completed | Sponsor: Amgen | Phase classification: P1b ➔ P1

Phase classification • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

CC Chemokine Family Members' Modulation as a Novel Approach for Treating Central Nervous System and Peripheral Nervous System Injury-A Review of Clinical and Experimental Findings. (PubMed, Int J Mol Sci) - "Over the past several years, the results of studies in which available pharmacological tools were used indicated that blocking individual receptors, e.g., CCR1 (J113863 and BX513), CCR2 (RS504393, CCX872, INCB3344, and AZ889), CCR3 (SB328437), CCR4 (C021 and AZD-2098), and CCR5 (maraviroc, AZD-5672, and TAK-220), has beneficial effects after damage to both the CNS and PNS...In addition, both single (J113863, RS504393, SB328437, C021, and maraviroc) and dual (cenicriviroc) chemokine receptor antagonists enhanced the analgesic effect of opioid drugs. This review will display the evidence that a multidirectional strategy based on the modulation of neuronal-glial-immune interactions can significantly improve the health of patients after CNS and PNS damage by changing the activity of chemokines belonging to the CC family. Moreover, in the case of pain, the combined administration of such antagonists with opioid drugs could reduce therapeutic doses and minimize the risk of..."

Journal • Review • Immunology • Pain • CCL11 • CCL18 • CCL19 • CCL2 • CCL20 • CCL21 • CCL22 • CCL23 • CCL3 • CCL8 • CCR2 • CCR3 • CCR4

FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. (PubMed, J Hepatol) - "ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCL2 • CCR2 • ETV4 • FGF19 • FGFR4 • HGF • MET • PD-L1

Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: Correlation with blood monocyte counts. (ASCO-SITC 2018) - P1b; "Fifty subjects (ECOG score ≤ 2) were enrolled, receiving FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) once every two weeks (maximum 12 cycles) plus 150 mg CCX872 QD or BID for 12 weeks. CCX872-B plus FOLFIRINOX resulted in an OS of 29% at 18 months with no safety issues. Better OS was associated with lower peripheral blood monocyte counts at baseline."

Clinical • Pancreatic Cancer

Orally administered CCR2 selective inhibitor CCX872-b clinical trial in pancreatic cancer. (ASCO-GI 2017) - P1b; "Patients received FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) q2weeks for up to 24 wks plus 150 mg CCX872-B once or twice daily until disease progression or intolerance to CCX872-B. CCX872-B plus FOLFIRINOX resulted in a TCR of 78% and an ORR of 30 to 37% with no safety issues ascribed to CCX872-B use."

Clinical • Biliary Cancer • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Phase 1b Study of CCX872-B in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1b | N=54 | Completed | Sponsor: ChemoCentryx | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

[VIRTUAL] FGF19-FGFR4 SIGNALING MEDIATED ETV4 OVEREXPRESSION FACILITATES HEPATOCELLULAR CARCINOMA METASTASIS THROUGH UPREGULATING PD-L1 AND CCL2 (AASLD 2021) - "ETV4 facilitated the recruitment and infiltration of TAMs and MDSCs through CCL2-CCR2 pathway, and either knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAMs and MDSCs infiltration and HCC metastasis . Either depletion of TAMs by clodronate liposomes or depletion of MDSCs by anti-Gr-1 attenuated ETV4- mediated HCC metastasis... ETV4 is a prognostic biomarker, and targeting this oncogenic pathway may provide a combinational therapeutic strategy to inhibit HCC metastasis ."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCL2 • CD8 • FGF19 • FGFR4 • PD-L1

[VIRTUAL] Therapeutic Benefit of CCR2 Antagonism in a Model of Diabetic Nephropathy Suggests a Mechanism of Action Distinct from Nrf2 Activation (KIDNEY WEEK 2020) - "We have recently shown that a CCR2 antagonist improved renal structure and reduced proteinuria in the db/db murine model of DN, as well as in the Adriamycin and 5/6 nephrectomy models of CKD. To understand the mechanism we compared CCX872, a small molecule antagonist of CCR2, with Bardoxolone methyl, an investigational drug targeting Nrf2 pathway in the db/db murine model of DN... Treatment with CCR2 antagonist provides rapid renal protection in the db/db mice, as measured by improved UAER. The reduction in UAER was associated with reduction of activated PECs, which are known to contribute to kidney disease. Although Bardoxolone was able to improve GFP, it did not improve UAER or reduce the number of activated PECs."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • CD44

Pre-operative Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma With or Without CCX872-B (clinicaltrials.gov) - P1b; N=20; Not yet recruiting; Sponsor: Alan Katz

Clinical • New P1 trial • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Phase 1b Study of CCX872-B in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1b; N=54; Active, not recruiting; Sponsor: ChemoCentryx; Trial primary completion date: Nov 2017 ➔ Apr 2018

Trial primary completion date • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. (PubMed, Proc Natl Acad Sci U S A) - "The CCR2 antagonist CCX872 increased median survival as a monotherapy in KR158 glioma-bearing animals and further increased median and overall survival when combined with anti-PD-1...Examination of tumor-infiltrating lymphocytes revealed an elevated population, increased IFNγ expression, indicating enhanced cytolytic activity, as well as decreased expression of exhaustion markers in CD4 and CD8 T cells following combination treatment. These data establish that combining CCR2 and PD-1 blockade extends survival in clinically relevant murine glioma models and provides the basis on which to advance this combinatorial treatment toward early-phase human trials."

Checkpoint inhibition • IO Biomarker • Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

Disruption of the CCR2 chemokine receptor pathway overcomes therapeutic resistance to PD-1 blockade in malignant glioma (SNO 2019) - "Examination of tumor infiltrating lymphocytes revealed both increased presence and decreased exhaustion (PD-1+/Tim3+) of CD4+ (P=.029) and CD8+ (P=.011) T-cells following CCX872/anti-PD-1 treatment. CONCLUSION CCX872/anti-PD-1 combination therapy is effective in clinically relevant murine glioma models, providing a basis to progress this novel combinatorial treatment to human clinical trials."

Phase 1b Study of CCX872-B in Patients With Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1b; N=54; Active, not recruiting; Sponsor: ChemoCentryx; Trial completion date: Dec 2019 ➔ Dec 2020; Trial primary completion date: Dec 2018 ➔ Jan 2020

Clinical • Trial completion date • Trial primary completion date

Pre-operative Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma With or Without CCX872-B (clinicaltrials.gov) - P1b; N=0; Withdrawn; Sponsor: Alan Katz; N=20 ➔ 0; Trial completion date: Jan 2024 ➔ Aug 2019; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Jan 2022 ➔ Aug 2019

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal

Pre-operative Stereotactic Body Radiation Therapy for Pancreatic Adenocarcinoma With or Without CCX872-B (clinicaltrials.gov) - P1b; N=20; Not yet recruiting; Sponsor: Alan Katz; Initiation date: Mar 2019 ➔ Jul 2019

Clinical • Trial initiation date