plerixafor

P=N/A, N=60, Completed, University of Liverpool | Unknown status --> Completed

[111In]In-DOTAGA-VUN400-C demonstrated nearly identical plasma stability (41.08 ± 5.45%, n = 4) but showed high and specific uptake in the CXCR4-expressing xenografted tumor (SUVU87.CD4.CXCR4 3.75 ± 1.08 vs SUVU87.CD4 = 0.64 ± 0.19, n = 5, 60 min p.i.), which could be blocked by coinjection of AMD3100 (5 mg/kg) (SUVU87.CD4.CXCR4 0.55 ± 0.32 vs SUVU87.CD4 = 0.39 ± 0.07, n = 2, 60 min p.i.). In conclusion, all six sdAbs exhibited high in vitro affinity against hCXCR4. Among these, [111In]In-DOTAGA-VUN400-C showed high CXCR4-specific tumor uptake and favorable pharmacokinetic properties, indicating VUN400-C's potential as a promising vector for future CXCR4 PET imaging applications with fluorine-18.

Plerixafor significantly improved mobilisation regimens' yield and cost-effectiveness by greatly increasing mobilisation success rates, particularly in heavily pre-treated lymphoma patients.

P1/2, N=40, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Recruiting --> Active, not recruiting | N=90 --> 40 | Trial completion date: Nov 2033 --> Jan 2027 | Trial primary completion date: Nov 2032 --> Jan 2026

AMD3100 (CXCR4 antagonist) and CPI-444 (adenosine 2A receptor inhibitor) were formulated into micelles, denoted as AMD@iNPDBCO and CPI@iNPN3, respectively. Furthermore, the nanoplatform remarkably amplifies immuno-radiotherapy by potently evoking cytotoxic CD8+ T cell priming, and synergized with immune checkpoint blockade by delaying CD8+ T cell exhaustion. Our work highlights the potential of the in situ assembly nanoplatform tailored for delivery of extracellular-targeted therapeutic agents for boosting GBM immunotherapy.

Both methods may additionally include Plerixafor...We compared G-CSF only, cyclophosphamide plus G-CSF (Cyclo-G) and G-CSF plus alternative chemotherapy (Chemo+G) mobilization...In MM, G-CSF only resulted in yields sufficient for at least one transplant. In HL, our data show no evidence to support the use of Cyclo-G over G-CSF only.

P1/2, N=18, Not yet recruiting, National Institute of Allergy and Infectious Diseases (NIAID)

In in vivo pharmacodynamic studies, combination therapy exhibits a superior therapeutical effect over monotherapy in MASLD models. These results constitute an siRNA therapeutical approach combined with a small molecule drug against inflammation and liver injury in MASLD, offering a promising therapeutic intervention for MASLD.

Knockdown of CXCR4 expression using short hairpin RNA, inhibition of CXCR4 signaling with AMD3100, and targeting of STAT3, a downstream effector of CXCR4, with WP1066 in DTC cells significantly diminished their self-renewal ability, tumorigenic potential, IR resistance, and Sox2 expression. Furthermore, DTC cells infected with shCXCR4 exhibited substantial tumor suppression, and the combination of IR and AMD3100 significantly reduced DTC tumor growth in a mouse xenograft model. These findings underscore the functional significance of CXCR4 as a CSC marker, highlighting its potential as a therapeutic target for malignant chordomas.

P1/2, N=10, Suspended, National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting --> Suspended

Our results demonstrated that there were no statistically significant differences in achieving the patient-specific minimally required CD34+ cell yield after the first mobilization attempt between patients in the daratumumab-containing arm and those in the non-daratumumab-containing arm (P = 0.28).However, patients who received the quadruplet induction regimen with daratumumab experienced a statistically significant longer duration of apheresis collection (median of 2 days in the daratumumab-containing arm vs. 1 day in the non-daratumumab-containing arm, P = 0.011) than those who received traditional three-drug induction.Our findings reinforce the importance of incorporating both granulocyte-colony stimulating factors and plerixafor upfront into mobilization practices. Furthermore, the findings of this study may have implications for the judicious use of apheresis machines and further inform the optimal delivery of daratumumab-containing induction therapies for newly diagnosed multiple myeloma.

Plerixafor was administered as a just-in-time approach with granulocyte-colony stimulating factor (G-CSF) alone or with cyclophosphamide (Cy) + G-CSF mobilization...There was no statistically significant difference between the two groups in terms of age, gender, RT history, previous lines of treatment, pretransplant lenalidomide cycles (p = 0.778, 0.165, 0.520, 0.094, 0.530, respectively)...This study demonstrates the comparable efficacy of generic plerixafor in myeloma patients, suggesting that it can be a cost-effective alternative with a similar safety profile. These findings contribute to the body of evidence on the use of generic plerixafor in specific patient cohorts, emphasizing its efficacy and safety for ASCT in a sole multiple myeloma patient cohort.

GDP and cytarabine-based regimen have better mobilization success compared to ifosfamide-based regimen or G-CSF (±plerixafor) in lymphoma patients. It may be best to avoid ifosfamide-based regimens in patients who have received radiation to mediastinum, spine or pelvis due to high rates of mobilization failure.

No plerixafor-related increase in tumor cells was observed in apheresis products. In conclusion, our comprehensive study supports the use of plerixafor and furthermore demonstrates the potential of patient-friendly PEG-G-CSF for mobilization of pediatric patients.

P1, N=25, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

P2, N=21, Completed, Fred Hutchinson Cancer Center | Active, not recruiting --> Completed

P1, N=5, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P1, N=5, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Rats received intrathecal Walker 256 tumor cell implantations and were treated with morphine combined with the intrathecal injection of AM1241 or the CB2 receptor antagonists AM630 and AM1241, or a CXCL12-neutralizing antibody, exogenous CXCL12, or the CXCR4 antagonist AMD3100. CXCR4 colocalized with MOR and CB2. Therefore, a non-analgesic dose of AM1241 attenuated morphine tolerance via CXCL12/CXCR4 signaling, whereas CXCL12/CXCR4 signaling participated in the development of morphine tolerance, potentially by modulating MOR expression in Walker 256 tumor-bearing rats.

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.

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.

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.

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.

P2, N=59, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P1/2, N=265, Recruiting, National Cancer Institute (NCI) | Suspended --> 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.

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.

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.

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.

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=40, Suspended, St. Jude Children's Research Hospital | Trial completion date: Jul 2025 --> Aug 2027 | Trial primary completion date: Jul 2024 --> Aug 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.