A Phase II, Open-Label Pilot Study to Evaluate the Hematopoietic Stem Cell Mobilization of TG-0054 Combined with G-CSF in 12 Patients with Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Lymphoma - an Interim Analysis

Abstract

Background: TG-0054 (burixafor) is a potent and selective antagonist of human chemokine receptor CXCR4 that inhibits the binding of stromal-derived factor 1 (SDF-1). Interruption of the CXCR4/SDF-1 interaction prevents sequestration of CD34+ stem cells to the bone marrow and subsequently mobilizes these cells into the peripheral blood within 1 to 3 hours of drug administration. Materials and Methods: An open-label, phase II pilot trial was conducted in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), or Hodgkin's lymphoma (HL) to evaluate the safety and stem cell mobilization of TG-0054 in combination with G-CSF. We planned to treat twelve patients with subcutaneous injections of 10 µg/kg/day G-CSF in the afternoon for 4 days. On the morning of Day 5, patients received 3.14 mg/kg TG-0054 and underwent large volume (18-24L) leukapheresis approximately 2 hours post-drug infusion. Patients were allowed by protocol to undergo leukapheresis for 1-5 days to obtain the predetermined target of ≥5.0 x 106 CD34+ cells/kg. 9 of 12 patients have been treated thus far with a plan to treat 3 additional patients. Results: A planned interim analysis revealed that6 of the 9 patients treated thus far collected more than 10 x 106 CD34+ cells/kg in 1 leukapheresis session. 2 patients required 2 days to achieve the study endpoint, and 1 outlier patient who had received Revlimid only 1 week prior to peripheral blood CD34 analysis failed to mobilize stem cells until he was allowed 2 more weeks to recover from his Revlimid treatment. Burixafor was well tolerated, and there were no adverse events that were attributed to the drug. All of the patients engrafted promptly after melphalan (7 patients) or BEAM (2 patients) conditioning regimens. Conclusion: Burixafor in combination with G-CSF is a potent and well-tolerated mobilizer of stem cells into the peripheral blood, and with the exception of 1 outlier, was able to mobilize >5.0 x 106 CD34+ cells/kg in 1-2 leukapheresis sessions in all patients treated thus far (median 1 day). This contrasts with our historical controls that required a median of 2-3 days to achieve a collection of ≥5.0 x 106 CD34+ cells/kg. A total of 12 patients will be treated on this pilot study. These encouraging results warrant the further testing of this drug in a larger randomized clinical trial. Disclosures Hsu: Taigen Biotechnology: Employment. Chang:Taigen Biotechnology: Employment. Schuster:Taigen Biotechnology: Research Funding.

Microtiter plate-based antibody-competition assay to determine binding affinities and plasma/blood stability of CXCR4 ligands

“…The fluorescence-based antibody competition assay allows for a rapid and quantitative determination of the half-maximal inhibitory concentration (IC 50 ) and the inhibitory constants (K i ) for each CXCR4 ligand analyzed, allowing a direct comparison of pharmacological parameters. The lowest K i (~ 0.1 nM) was observed for Burixafor (TG-0054), an orally bioavailable stem cell mobilizing agent currently in phase I trials 23 , followed by IT1t (K i ~ 0.6 nM), an allosteric inhibitor that is currently not in clinical development. AMD3100, the only marketed CXCR4 antagonist approved to mobilize hematopoietic stem cells in cancer patients 62 and currently also in advanced clinical trials for therapy of other CXCR4-associated diseases, showed a high nanomolar K i with 221 nM.…”

“…Another orally available small molecule is MSX-122 that was described as a partial antagonist of CXCR4 and is currently investigated in a phase II clinical trial as an oral drug for hot flashes in breast cancer-positive post-menopausal women 20 , 22 . Two other orally available small drug candidates are Burixafor (TG-0054) that is a monocyclic CXCR4 antagonist und currently tested in a phase II study for stem cell mobilization 20 , 23 , and the isothiourea compound IT1t that was used for crystallization of the CXCR4 receptor thereby revealing a distinct binding mode from AMD3100 within the receptor binding pocket 24 – 26 .…”

The Biological and Clinical Relevance of G Protein-Coupled Receptors to the Outcomes of Hematopoietic Stem Cell Transplantation: A Systematized Review

“…Examining these varied studies, an extension of plerixafor indications is to be expected in the coming years, as are new pharmacological alternatives. Indeed, new compounds targeting CXCR4 are in development: small molecules (TG-0054 [60,61,62]) such as plerixafor, but also peptides (BL-8040 [63], (BK)T140 [64], POL6326 [65], LY2510924 [66]), or oligonucleotides (NOX-A12 [67]). All have already been tested in humans as part of phase I or early phase II clinical trials.…”

Microtiter plate-based antibody-competition assay to determine binding affinities and plasma/blood stability of CXCR4 ligands

“…The fluorescence-based antibody competition assay allows for a rapid and quantitative determination of the half-maximal inhibitory concentration (IC50) and the inhibitory constants (Ki) for each CXCR4 ligand analyzed, allowing a direct comparison of pharmacological parameters. The lowest Ki, (~ 0.1 nM) was observed for Burixafor (TG-0054), an orally bioavailable stem cell mobilizing agent currently in phase I trials 23 , followed by IT1t (Ki ~ 0.6 nM), an allosteric inhibitor that is currently not in clinical development. AMD3100, the only marketed CXCR4 antagonist approved to mobilize hematopoietic stem cells in cancer patients 60 and currently also in advanced clinical trials for therapy of other CXCR4associated diseases, showed a high nanomolar Ki with 221 nM.…”

“…Another orally available small molecule is MSX-122 that was described as a partial antagonist of CXCR4 and is currently investigated in a phase II clinical trial as an oral drug for hot flashes in breast cancer-positive post-menopausal women 20,21 . Two other orally available small drug candidates are Burixafor (TG-0054) that is a monocyclic CXCR4 antagonist und currently tested in a phase II study for stem cell mobilization 23,21 , and the isothiourea compound IT1t that was used for crystallization of the CXCR4 receptor thereby revealing a distinct binding mode from AMD3100 within the receptor binding pocket 24,25,26 . Besides small molecules, several peptide-based CXCR4 antagonist are also being tested for multiple applications.…”