Olaptesed pegol, an anti-CXCL12/SDF-1 Spiegelmer, alone and with bortezomib–dexamethasone in relapsed/refractory multiple myeloma: a Phase IIa Study
| Autor: | Stephanie Vauléon, Katja Weisel, D Zboralski, Xavier Leleu, C. Leitgeb, Richard Greil, A. M. Cafro, M.T. Petrucci, Anna Kruschinski, Ibrahim Yakoub-Agha, Thomas Dümmler, Robert Foa, Matthias Baumann, Kai Riecke, Heinz Ludwig, Diana Beyer, Monika Engelhardt, Laurent Garderet |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Oncology Male medicine.medical_specialty Proteasome Endopeptidase Complex Cancer Research Pharmacology Dexamethasone Bortezomib 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Refractory Hematology Anesthesiology and Pain Medicine Internal medicine Antineoplastic Combined Chemotherapy Protocols Medicine Humans Letter to the Editor Multiple myeloma Aged Oligoribonucleotides business.industry Middle Aged medicine.disease Chemokine CXCL12 Leukemia 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Female Bone marrow business Multiple Myeloma medicine.drug |
| Zdroj: | Leukemia |
| Popis: | Olaptesed pegol (olaptesed, NOX-A12) is a pegylated l-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine which signals through CXCR4 and CXCR7 regulating a variety of processes during multiple myeloma (MM) development.1 CXCL12 inhibition reduces the myeloma-supportive activity of the bone marrow microenvironment and mobilizes myeloma cells to the circulation.2 In addition, CXCL12α levels were reported to correlate with osteolytic bone lesions and with increased bone marrow angiogenesis.3 Targeting CXCL12, therefore, is a promising strategy for disrupting myeloma-stroma interactions and inhibiting myeloma growth and survival. Here, we report pharmacokinetic, pharmacodynamic, safety and efficacy data of olaptesed in patients with relapsed/refractory MM and present data on baseline CXCL12α levels in this patient cohort. This first-in-patient Phase IIa study aims to translate the novel concept of combining proteasome and CXCL12 inhibition into the clinic and builds on a preclinical proof-of-concept regarding the significance of CXCL12 blockade in MM2 and on Phase I data in healthy subjects.4 Combining CXCL12 inhibition with bortezomib and dexamethasone (VD) was investigated in 28 patients with relapsed/refractory MM, who were either bortezomib-naive or considered not refractory to bortezomib. The median number of prior lines of therapy was 2 (range: 1–5), 39 and 14% of the patients presented with 3 or 4 prior lines, respectively. Cytogenetics were tested in 21 patients and high risk features were found in 36% of them. 54% of patients had prior treatment with bortezomib, 39% had a prior stem cell transplant and 57% were refractory to prior treatment. Further details on patient characteristics (Supplementary Table S1) and inclusion and exclusion criteria are available in the Supplementary Information. In the pilot phase, three cohorts of three patients each (four patients in the 1 mg/kg cohort due to patient replacement) were administered single doses of 1, 2 or 4 mg/kg of olaptesed alone by slow intravenous bolus injection 2 weeks prior to starting the combination treatment. Combination treatment was administered for eight cycles of 21 days. An intra-patient escalation was applied for safety reasons as olaptesed was combined for the first time with VD in cancer patients. Olaptesed was given 1–2 h prior to bortezomib at doses of 1 mg/kg in cycle 1, 2 mg/kg in cycle 2 and 4 mg/kg in cycles 3–8. Bortezomib was given on days 1, 4, 8 and 11 of each 21-day treatment cycle as intravenous injection of 1.3 mg/m2. Oral dexamethasone (20 mg) was added on the day of and the day after bortezomib administration. An outline of the study and details of patients’ flow are given in Supplementary Figures S1 and S2. |
| Databáze: | OpenAIRE |
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