P1, N=25, Not yet recruiting, St. Jude Children's Research Hospital | Trial completion date: Dec 2031 --> Dec 2032 | Trial primary completion date: Dec 2028 --> Dec 2029

[18F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an 18F-alternative to [68Ga]PentixaFor.

P=N/A, N=40, Recruiting, Yunnan Cancer Hospital

The rate of engraftment was 10 days for neutrophils > 0.5 × 10e9/L and 13 days for platelets > 20 × 10e9/L. In conclusion, the addition of PLX to salvage therapy in patients with R/R DLBCL is effective and may be routinely used in the future to increase the number of CD34 + cells collected and minimize the risk of poor mobilization.

P1/2, N=50, Recruiting, TCM Biotech International Corp. | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Aug 2024 --> Aug 2026

Thank to their particular pharmacokinetics, the use of small organic molecules can be a very promising alternative to macromolecular targeting biomolecules (i.e. antibodies, peptides…) for specific imaging of tumours. Herein, the potential of two AMD070-like inhibitors as CXCR4-targeting units for specific imaging of cancer cells, and the influence of chromophore-grafting on their recognition properties has been investigated.

The primary endpoint was a less than 15% difference in successful stem cell collection ( ≥ 5.0 × 106 CD34+ cells/kg b.w. in a single day collection procedure without additional stimulation with plerixafor) with the G regimen...Our data indicate that G-CSF only is inferior to chemotherapy with G-CSF for peripheral CD34+ stem cell mobilization. Trial registration SNCTP #: SNCTP000002952; Trials.gov #: NCT03442673.

P1/2, N=32, Completed, X4 Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Aug 2024 | Trial primary completion date: Jun 2025 --> Aug 2024

PMs were re-mobilized with plerixafor (n = 24, 39.3%) or non-plerixafor-based regimens (n = 37, 60.7%)...The median OS was 41.1 months for PM and 41.2 months for non-PM patients (p = 0.86). These data suggest that salvage mobilization is effective and does not affect overall outcomes after a second auto-HCT.

P1, N=20, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

Methods Patients diagnosed with myeloma and concomitant dialysis-dependent renal dysfunction were admitted for ASCT after achieving at least partial response with bortezomib-based induction therapy. For both patients, mobilization consisted of granulocyte colony stimulating factor for 5 days and CD34 directed Plerixafor on Day 1...Use of reduced dose melphalan, pre-emptive dialysis after 24 hours and monitoring for acidosis and symptoms of uraemia to identify acidosis at an early stage allows safe administration of high dose chemotherapy. A major proportion of patients can potentially achieve reduction or freedom from dialysis support post-transplant.

MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers...Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively...74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.

The generic plerixafor produced comparable cumulative collection yields and early engraftment outcomes as Mozobil, but fewer doses and collection days were needed to reach collection goal.

Ara-C is a nonselective chemotherapeutic agent against AML...LipoAraN-E5 effectively prevented the infiltration of leukemia cells in peripheral blood, bone marrow, spleen, and liver, prolonged the mice survival, and showed outstanding antineoplastic efficacy with negligible toxicity, which were attributed to the ingenious design of AraN, the use of a liposomal delivery carrier, and the introduction of E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate against AML.

P1, N=5, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=12 --> 5 | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.

P1, N=15, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

Preemptive plerixafor in GCT patients undergoing PBSC collection allows relatively poor mobilizers to collect in fewer days and with lower overall cost. Fewer apheresis procedures result in less risk to the patient, increased patient satisfaction, and the ability to schedule more patients within the constraints of staffing.

P2, N=42, Completed, BioLineRx, Ltd. | Phase classification: P2a --> P2

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives...Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.

The surface modification with Plerixafor enhances the targeting ability of the nanoparticles, performing more significant efficacy and biocompatibility in the 4T1 cancer cell model. The study demonstrates that CuFeSe2@PA is a promising multifunctional theranostic platform with clinical application potential.

Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.

Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic...Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.

X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics.

IS4-FAM directly labels CXCR4 in several cell lines including high CXCR4 expressing SK-MEL-28 (malignant melanoma) and PC3 (metastatic prostate cancer) and lower CXCR4 expressing THP-1 (acute monocytic leukemia) and was competitive with the established CXCR4 antagonist, AMD3100. This highlights the potential of IS4-FAM as a pharmacological tool for drug discovery in native cells lines and tissues.

In this review, we discuss the roles CXCR4 and VLA4 play in bone marrow homing and retention and will summarize more recent development of small-molecule CXCR4 and VLA4 inhibitors that, when combined, can synergistically improve the magnitude, quality and convenience of HSPC mobilization for stem cell transplantation and ex vivo gene therapy after the administration of just a single dose. This optimized regimen has the potential to afford a superior alternative to G-CSF for HSPC mobilization.

P1/2, N=20, Recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Jun 2025 --> Apr 2026 | Trial primary completion date: Jun 2025 --> Dec 2025

The administration of AMD3100, an inhibitor of CXCR4, reversed the entire phenomenon. Our results strongly suggest that targeting this signaling axis in CRC is a feasible approach to attenuating tumor progression, and it may, therefore, serve as an alternative treatment method to improve the prognosis of patients with CRC, especially those with advanced, recurrent, or metastatic CRC following standard therapy.

P2, N=80, Completed, BioLineRx, Ltd. | Phase classification: P2a --> P2

P1, N=16, Completed, X4 Pharmaceuticals | Phase classification: P1b --> P1

P2, N=60, Not yet recruiting, MedRegen LLC | Initiation date: Jul 2024 --> Dec 2024

P2, N=10, Not yet recruiting, MedRegen LLC | Trial completion date: Dec 2024 --> Mar 2026 | Initiation date: Jul 2024 --> Jul 2025 | Trial primary completion date: Nov 2024 --> Jan 2026

Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect...Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR-ABL1-transformed cells even at a lower dose of Imatinib...This suggests that the inhibitory effect of JM#170 is specific for BCR-ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL.

P1, N=20, Not yet recruiting, Washington University School of Medicine

P2, N=10, Recruiting, MedRegen LLC | Trial primary completion date: Jul 2024 --> Oct 2024

Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

Moreover, multiple antagonistic nanobodies targeting CXCR4 displayed similar or better potencies as compared to the CXCR4-targeting molecule AMD3100 (Plerixafor), which was further enhanced through avid binding of bivalent derivatives...Of these, C-terminal fusion, especially to human Fc, was most advantageous with a 2-log-fold and 3-log-fold increased potency in inhibiting CXCL12-mediated Gαi- or β-arrestin recruitment, respectively. Overall, we describe strategies for generating multivalent and high-potency CXCR4 antagonistic nanobodies able to induce receptor clustering and conclude that fusion to an Fc-tail results in the highest avidity effect irrespective of the hinge linker.

Since we adopted the plerixafor protocol guided by CD34 counts, the number of patients with harvest failure has decreased. In conclusion, the rational and standardized use of plerixafor favors satisfactory harvest in patients who require autologous transplantation in South-American patients.

In light of these discoveries, scientific investigations and clinical trials have underscored the therapeutic promise found in small-molecule antagonists like plerixafor, peptides/peptidomimetics such as BKT140, monoclonal antibodies like PF-06747143 and ulocuplumab, as well as microRNAs. The information collectively emphasizes the potential of CXCR4 antagonists as a therapeutic strategy for hematologic malignancies, showcasing advancements in preclinical and clinical studies. As these therapeutic strategies progress through clinical trials, their potential to reshape the prognosis of hematologic malignancies will become increasingly apparent.

Additionally, the plerixafor group showed a significantly better toxicity profile and lower adverse event rate than patients treated with G-CSF alone (p = 0.0028) or chemomobilization (p < 0.0001), with a trend toward reduced survival in chemomobilization patients. Taken together, these data support the routine use of plerixafor-based mobilization to increase apheresis efficiency and reduce toxicity in myeloma patients undergoing transplant.

P3, N=60, Not yet recruiting, Guangzhou Gloria Biosciences Co., Ltd.

P1/2, N=22, Completed, University of Alberta | Active, not recruiting --> Completed | N=60 --> 22 | Trial completion date: Dec 2025 --> Jul 2024