P3, N=31, Active, not recruiting, X4 Pharmaceuticals | Trial primary completion date: Oct 2022 --> Dec 2024

CTCE-9908 significantly inhibited melanoma cell survival at a concentration 10 times lower than the IC50 in B16 F10 cells but not RAW 264.7 cells. However, CTCE-9908 did not affect CXCR4 phosphorylation, apoptosis, or cell cycle distribution in either cell line.

P2, N=40, Recruiting, GPCR Therapeutics, Inc. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Patients who had far less therapy before apheresis were more likely to mobilize successfully. Our study provides a detailed practice approach including complications during APSCA aiming to increase the success rates of apheresis in transplantation centers.

Chemotactic gradients to induce cell migration across the hydrogel width are assessed using the chemokine CXCL12, and its inhibition by AMD3100 is validated. This open-top hydrogel-based fluidic system to deliver chemoattractant cues over square-centimeter-scale areas and millimeter-scale depths can potentially serve as a robust screening platform to assess emerging glioma models and chemotherapeutic agents to eradicate them.

This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

P3, N=9, Terminated, Chimerix | Active, not recruiting --> Terminated; Study enrollment was terminated on 16 May 2022 due to slow recruitment.

The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.

P1/2, N=43, Active, not recruiting, X4 Pharmaceuticals | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

The second generation D-peptide AlF-NOTA-2xDV1(c11sc12s) showed high affinity for human CXCR4 and the corresponding radiotracer was produced in good radiochemical yields. However, [18F]AlF-NOTA-2xDV1(c11sc12s) is not specific for CXCR4 and is also a substrate for OATP1B1 and/or OATP1B3, known to mediate hepatic uptake. Therefore, D-amino acid peptides, based on the viral macrophage inflammatory protein II, are not the prefered vector molecule for the development of CXCR4 targeting molecular imaging tools.

P2, N=10, Not yet recruiting, MedRegen LLC

Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.

Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.

The significantly higher amount of CD34+ cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.

P2, N=60, Not yet recruiting, MedRegen LLC

P2, N=32, Not yet recruiting, MedRegen LLC

In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.

The clinicians are actively seeking the optimal use of plerixafor to improve the success rate of PBSC collection and reduce the cost. This article reviews the latest research progress related to plerixafor application, in order to summarize the optimal use of plerixafor in autologous hematopoietic stem cell transplantation (auto-HSCT).

Initially PLER was investigated in placebo-controlled trials with the granulocyte colony-stimulating factor (G-CSF) filgrastim. This also appears to be the case in patients receiving plerixafor for poor or suboptimal mobilization of CD34+ cells. In practice, PLER is safe and has not been shown to increase tumor cell mobilization.

P1, N=12, Recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Sep 2024

P=N/A, N=300, Completed, Fondazione EMN Italy Onlus | Active, not recruiting --> Completed | Trial completion date: Apr 2022 --> Jan 2024

P1, N=5, Recruiting, Washington University School of Medicine | Trial completion date: Jan 2024 --> Dec 2024 | Trial primary completion date: Jan 2024 --> Dec 2024

P3, N=180, Active, not recruiting, BioLineRx, Ltd. | Trial completion date: Dec 2025 --> Sep 2029

Herein, we developed an iRGD ligand-modified polymeric nanoplatform for the co-delivery of CXCR4 antagonist AMD3100 and the small-molecule immune checkpoint inhibitor BMS-1...Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.

P1, N=8, Completed, AdAlta Limited | Not yet recruiting --> Completed | N=16 --> 8 | Trial completion date: Jul 2024 --> Feb 2024 | Trial primary completion date: Jul 2024 --> Feb 2024

Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes...In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies.

Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57 CD8 T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57 CD8 T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

The combination of on-demand PXF with HD-Cy and PEG G-CSF offers a cost-effective approach with a high mobilization success rate, manageable side effects, and the convenience of fewer injections. It stands as a promising mobilization strategy for MM patients.

Adequately selected plerixafor administration reduces "mobilization-related-failure" rate and assure a high-level cell dose for SC transplants, with superior "therapeutic-potential" and safety profile. The mobilization strategy that incorporates "just-in-time" plerixafor administration, also leads to a reduction of hospitalization days and healthcare resource utilization. For definitive conclusions, further controlled/larger clinical trials concerning correlation of CD34 cell count/yield, with hematopoietic reconstitution are required.

OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor...Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.

XN-HPC is a sufficient quantitative marker for stem cell assessment of harvest yield in allogeneic but not autologous HSCT.

P2, N=28, Active, not recruiting, The First Hospital of Jilin University

P2, N=18, Completed, M.D. Anderson Cancer Center | Phase classification: P2b --> P2

P1, N=0, Withdrawn, Mainline Biosciences, Inc. | Not yet recruiting --> Withdrawn

Because failure to achieve sufficient CD34 cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34 mobilization in PM patients...Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs.

With the use of plerixafor in addition to growth factor for peripheral blood stem cell mobilization, the yield of autologous stem cell harvest has been higher while the length of apheresis days has become shorter...In conclusion, stem cell collection efficacy in ASCT is more frequent in MM than lymphoma patients, but is not predictive of faster engraftment. On the other hand, 1-year OS was 100% in the super-mobilizers group versus 93% in the other group.

On 11 September 2023, motixafortide was approved in the USA for use in combination with filgrastim [granulocyte colony stimulating factor (G-CSF)] to mobilize HSCs to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. Clinical development is ongoing for the mobilization of CD34 HSCs for gene therapy in patients with sickle cell disease. This article summarizes the milestones in the development of motixafortide leading to this first approval.

Furthermore, IS4 and IS4-FAM inhibited both CXCL12-stimulated cancer cell migration and Ca release in both adherent and suspension cell lines with similar or improved potency as compared to two literature CXCR4 antagonists. Our results highlight the potential of IS4 and IS4-FAM as research tools and as potent CXCR4 antagonists for the prevention of metastasis.

HPC mobilization typically uses G-CSF with or without the CXCR4 antagonist Plerixafor (P)...Prior to October 2017, patients were initiated on P if any 1 of the following criteria were met: age>60 years, prior treatment with melphalan or other alkylating therapy, prior treatment with lenalidomide >2 cycles, extensive bone marrow disease, or platelet count <100K... Changes to our institutional HPC mobilization algorithm led to a substantial decrease in the use of preemptive P prior to day 1 of collection by design. The resulting decrease in total doses of P per patient was smaller than expected, although still statistically significant. However, this was offset by a concomitant significant increase in the number of apheresis sessions required per patient despite a lower collection target.

Key secondary objectives include: assessment of safety and tolerability of GPC-100 and propranolol with and without G-CSF, evaluation of the pharmacodynamics by determining levels of circulating CD34 + cell counts and levels of the chemokine CXCL12 in peripheral blood, and assessment of mean time to ANC and platelet count recovery after ASCT. Exploratory objectives are also included to discover key biomarkers for patient selection, to evaluate cancer/stem/immune cell profiles, and to evaluate treatment impact on patient quality of life.