balixafortide (POL 6326) / Spexis, Fosun Pharma - LARVOL DELTA

Phase I Study of Cosibelimab and Balixafortide in Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Arsen Osipov | Trial completion date: Dec 2027 ➔ Feb 2027 | Initiation date: Sep 2025 ➔ Jan 2026 | Trial primary completion date: Dec 2027 ➔ Feb 2027

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

Targeting the CXCR4/CXCL12 Axis to Overcome Drug Resistance in Triple-Negative Breast Cancer. (PubMed, Cells) - "Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions."

IO biomarker • Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL12 • HER-2

Fat Fraction MRI for Longitudinal Assessment of Bone Marrow Heterogeneity in a Mouse Model of Myelofibrosis. (PubMed, Tomography) - "This study validated our hypothesis that the variance in PDFF in BM decreases with disease progression, indicating pathologic expansion of hematopoietic cells. We can conclude that disease progression can be tracked by a decrease in PDFF values. Analyzing variance in PDFF may improve the assessment of disease progression in pre-clinical models and ultimately patients with MF."

Heterogeneity • Journal • Preclinical • Fibrosis • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Phase I Study of Cosibelimab and Balixafortide in Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Arsen Osipov

New P1 trial • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Intra-operative visualization of metastatic sentinel lymph nodes in early breast cancer: An approach to omission of axillary surgery (AACR 2025) - "1. ICG-POL6326 was successfully synthesized with good stability, biocompatibility with high intensity of NIR-II fluorescent imaging. 2."

Metastases • Surgery • Breast Cancer • Oncology • Solid Tumor • CXCR4

Inhibiting CXCR4 reduces immunosuppressive effects of myeloid cells in breast cancer immunotherapy. (PubMed, Sci Rep) - "MDSCs isolated from mice treated with anti-PD-1 plus balixafortide showed reduced inhibition of T cell proliferation following ex vivo stimulation. These studies demonstrate that combining inhibition of CXCR4 with anti-PD-1 to enhances responses to checkpoint inhibitor immunotherapy in TNBC, supporting future clinical trials."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCR4

Tumor-Targeted-NIR-II Fluorescent Molecular Probes for the Identification of Breast Cancer Tissue and SLN Metastatic Status (clinicaltrials.gov) - P=N/A | N=40 | Recruiting | Sponsor: Yunnan Cancer Hospital

Metastases • New trial • Breast Cancer • Oncology • Solid Tumor • CXCR4

FORTRESS: Pivotal Study in HER2 Negative, Locally Recurrent or Metastatic Breast Cancer (clinicaltrials.gov) - P3 | N=432 | Terminated | Sponsor: Spexis AG | Active, not recruiting ➔ Terminated; The study was halted early due to failure to meet the primary endpoint.

Combination therapy • Metastases • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

Development of a rare earth nanoprobe enables in vivo real-time detection of sentinel lymph node metastasis of breast cancer using NIR-IIb imaging. (PubMed, Cancer Res) - "Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • CXCR4

A CXCR4 inhibitor (balixafortide) enhances docetaxel-mediated antitumor activity in a murine model of prostate cancer bone metastasis. (PubMed, Prostate) - "Our data demonstrate that a combination of BAL and DOC has greater antitumor activity in a model of PCa bone metastases than either drug alone. These data support further evaluation of this combination in metastatic PCa."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3 • CD34 • CXCR4 • IFNG • TRAP

Pharmacological inhibition of CXCR4 increases the anti-tumor activity of conventional and targeted therapies in B cell lymphoma models (AACR 2023) - "Drugs included ibrutinib, copanlisib, idelalisib...These results were confirmed using the clinically available drug candidate balixafortide (SPX6326, POL6326).RNA-Seq in the MCL REC1 model showed a much bigger impact of the SPX5551+ibrutinib on transcriptome than single agents: 2100 transcripts differentially expressed in the combination group vs DMSO (P<0.01), 662 (ibrutinib), 260 (SPX5551)... Results suggest that a combination with the CXCR4 inhibitor SPX5551 adds beneficial effect to BCR inhibitors and might overcome resistance to PI3K/BTK inhibitors. Adding SPX551 to the treatment of patients with B cell lymphoma warrants further exploration."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BIRC3 • CCL3 • CXCL10 • CXCR3 • CXCR4 • MIR17HG • MIR92A1 • RELA

Balixafortide, a CXCR4 inhibitor, synergizes with docetaxel to diminish tumor growth in a prostate cancer model of bone metastasis. (AUA 2023) - "Our data demonstrate that that a combination of BLX and DOC has greater anti-tumor activity in a model of PCa bone metastases than either drug alone. The anti-tumor activity was also associated with decreased tumor-induced bone lesions. The mechanism for the anti-tumor activity is not completely elucidated at this time but does not appear to be through impacting proliferation."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CASP3 • CD34 • CXCR4 • IFNG • TRAP

POLTER: POL6326 (Balixafortide) Plus Nab-paclitaxel or Eribulin in Patients With HER2-negative Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: MedSIR | N=168 ➔ 0 | Not yet recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Metastases • Trial withdrawal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Pharmacology, ADME and selectivity profile of the next generation CXCR4 antagonist balixafortide. (ASCO 2018) - P1; "...Balixafortide in combination with eribulin gave higher response rates than published data for eribulin alone in breast cancer...Receptor occupancy studies with the competitive antibody 12G5 revealed a prolonged binding of Balixafortide to CXCR4 compared to AMD3100. The next-generation CXCR4 antagonist Balixafortide offers a favorable balance between ADME properties, potency and safety which allows high and frequent dosing in cancer patients."

Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor

Anti-angiogenic activity of the CXCR4 antagonist balixafortide (AACR-NCI-EORTC 2019) - P1, P3; "Background: Balixafortide is a potent and selective antagonist of the chemokine receptor CXCR4, and is in PhIII for metastatic HER2-negative breast cancer in combination with eribulin (NCT03786094). Result Balixafortide potently inhibited VEGF alpha-induced migration and permeabilization of an endothelial monolayer in vitro and reduced VEGF alpha levels in both, cultured CXF260 tumor cells in vitro and CXF260 tumors in vivo. Conclusion Balixafortide modulates angiogenic mechanisms in vitro and in vivo and suggests further investigation of balixafortide in anti-angiogenic therapies."

[VIRTUAL] Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX (AACR 2021) - P1, P3 | "Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 in PhIII for metastatic HER2-negative breast cancer (BC) in combination with tubulin-binding eribulin (NCT03786094). There was no decrease in tolerability in balixafortide combination vs paclitaxel alone. This data suggests combination with balixafortide is more efficacious and equally tolerated to paclitaxel single agent treatment."

Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • CD34 • HER-2

Spexis announces promising pre-clinical data with balixafortide in combination with various therapies on the market for treating B-cell lymphomas (GlobeNewswire) - "Spexis AG...announced results from an in vitro study evaluating the effects of combining Spexis’ potent CXCR4 inhibitor balixafortide (BLX) with several conventional or targeted therapies on the market in B-cell lymphoma models....The study results demonstrated that the addition of either BLX or another CXCR4 inhibitor from the Spexis macrocycles platform, SPX5551, to conventional or targeted therapies, including the BCR-ABL tyrosine kinase inhibitor imatinib, the P13K inhibitor copanlisib and the BTK inhibitor ibrutinib, showed an increase in anti-proliferative activity, either additive or synergistic, across all tested B-cell lymphomas. These data suggest that the addition of balixafortide or SPX5551 has the potential to improve the effect of BCR inhibitors and may overcome resistance to BTK and PI3K inhibitors in the treatment of patients with certain types of B-cell lymphoma."

Preclinical • Hematological Malignancies • Lymphoma • Oncology

Balixafortide (a CXCR4 antagonist)+eribulin versus eribulin alone in patients with HER2 negative, locally recurrent or metastatic breast cancer: An international, randomized, phase 3 trial (FORTRESS) (SABCS 2021) - "In this Phase 3 randomized trial, no differences in ORR, CBR, mPFS, or mOS were observed for B + E compared to E alone in any population of HER2‑mBC patients. Efficacy parameters for E alone were similar to those reported previously. The combination was B + E was well-tolerated overall."

Clinical • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Phase I study of the combination of balixafortide (CXCR4 inhibitor) and eribulin in HER2-negative metastatic breast cancer (MBC) patients (pts). (ASCO 2017) - P1; "The therapeutic activity of this treatment regimen appears promising with an ORR of 33% in patients with advanced MBC. B (5.5 mg/kg) can be combined safely with E (1.4 mg/m2) and the safety profile resembles E monotherapy as previously reported. This is the first study of the treatment combination of E with B in relapsed MBC pts."

Biomarker • Clinical • P1 data • Biosimilar • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer

Spexis’ CXCR4 inhibitor balixafortide demonstrates synergistic efficacy in combination with docetaxel in a metastatic prostate cancer preclinical model (GlobeNewswire) - "In vivo study in collaboration with the University of Michigan...Overall, results showed superior synergistic efficacy compared to either drug alone. For measuring tumor burden, PC3-luc tumor cells were assessed by bioluminescence imaging, while bone resorption was analyzed by tartrate-resistant acid phosphatase (TRAcP) serum levels. Animals that received treatment had lower TRAcP levels than the vehicle group (p=0.01). The combination of balixafortide and docetaxel decreased the total tumor burden significantly (p = 0.009)."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Balixafortide-functionalized down-conversion NIR-IIb nanoparticles for lymph node-invaded breast cancer detection (SABCS 2021) - "1. ErNPs @POL6326 was successfully synthesized with good stability and high intensity of NIR-IIb fluorescent. 2."

Breast Cancer • Oncology • Solid Tumor

Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy (AACR 2019) - P1; "E treatment led to a strong, transient increase of plasma IFN-γ levels in breast cancer patients modulated by B. The ANC increase by B may balance possible neutropenic actions of E."

Clinical • Combination therapy

[VIRTUAL] International phase III trial: Balixafortide (a CXCR4 antagonist) + eribulin versus eribulin alone in patients with HER2-negative, locally recurrent or metastatic breast cancer (FORTRESS) (ESMO 2020) - P3 | "Funding: Polyphor Ltd. Clinical trial identification: NCT03786094."

Clinical • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

Balixafortide (a novel CXCR4 inhibitor) and Eribulin in HER2-neg Metastatic Breast Cancer (MBC) patients (pts): a Phase I trial (ESMO 2018) - P1; "This is the first trial to investigate a CXCR4 antagonist in MBC. The tolerability profile and promising anti-tumor activity observed with B + E in this Phase I study warrants further investigation as well as exploration of additional combinations of B with other anti-cancer therapies."

Clinical • P1 data • HER2 Breast Cancer • Triple Negative Breast Cancer

Balixafortide (a CXCR4 antagonist) + eribulin in HER2-negative metastatic breast cancer (MBC): Survival outcomes of the phase I trial. (ASCO 2019) - P1; "Landmark 18 months and 24 months OS data are consistent with the positive trend of all efficacy read-outs observed in this study and safety information is consistent with what was previously reported. Although inter-trial comparisons should be interpreted with caution, these survival rates, especially for the EC, are higher than those reported for eribulin monotherapy in similar MBC populations. These promising results suggest that B + E could potentially provide a new treatment option in heavily pre-treated patients with HER2 negative MBC and this is currently being investigated in a pivotal, randomized trial.The results from the MVA will be presented at the meeting."

IO Biomarker • P1 data