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M. Steurer et al.
volunteers, single doses of olaptesed pegol mobilized white blood cells into peripheral blood; the mobilization was long-lasting and increased dose-dependently to more than 4 days at the highest dose in a phase I study.1 Further analyzing the mode of action, it could be shown that olaptesed pegol detaches CXCL12 from cell surfaces lead- ing to a disruption of the existing chemokine gradient.3 CXCL12 facilitates homing and retention as well as traf- ficking of hematopoietic and immune cells via CXCR4.4 This feature makes CXCL12 one of the key factors known to support survival of chronic lymphocytic leukemia (CLL) cells in the protective niches of the bone marrow and lymph node microenvironment which is an essential part of the pathogenesis and progression of the disease.5 The CLL dissemination inside tissue microenvironments is actively coordinated by a crosstalk between leukemic cells and stroma, where CXCL12 not only mediates CLL cell chemotaxis, actin polymerization, and migration beneath and underneath CXCL12-secreting stromal cells but also protects CLL cells from spontaneous and drug-induced apoptosis.6 Although surface expression of CXCR7 was not observed on CLL cells,7 CXCR7-dependent angiogenic mononuclear cell trafficking was shown to support bone marrow angiogenesis8 which plays a pathophysiological role in the leukemic microenvironment.9 Interference with CXCL12 signaling by olaptesed pegol was shown to inhibit CLL cell chemotaxis and induce chemosensitiza- tion in vitro using primary CLL cells3 as well as to remove CLL cells from the nurturing and protective microenviron- ment, prevent homing and make them more vulnerable to conventional therapy in vivo in an Eμ-TCL1 transgenic mouse model.10 A similar phenomenon was recently demonstrated preclinically and clinically in multiple myeloma, in which olaptesed pegol was combined with bortezomib and dexamethasone.2,11 In relapsed/refractory CLL patients, disease control becomes increasingly diffi- cult due to increased resistance to therapy. Olaptesed pegol represents a novel paradigm of therapy that moves away from cancer cells to microenvironmental elements as the primary treatment target.
We report here the findings of a phase IIa study, meant to translate the novel concept of combining chemo- immunotherapy and CXCL12 inhibition into the clinic (Online Supplementary Figure S1 delineates the anticipated mode of action), in which we assessed the pharmacoki- netic, pharmacodynamic, safety and first efficacy data of olaptesed pegol in patients with relapsed/refractory CLL. The main objectives of the study were to assess the safety and tolerability of olaptesed pegol alone and in combina- tion with bendamustine and rituximab (BR) in CLL patients, as well as to determine the response rates and remission duration.
Methods
The trial (EudraCT number 2011-004672-11, NCT01486797) was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practices Guidelines. The clinical study protocol and its amendments, informed consent documents, and any other study- related documents were reviewed and approved by the applicable regional review boards or ethics committees. All authors had access to the primary clinical data.
Patients
Twenty-eight patients with relapsed/refractory CLL were enrolled out of 32 patients screened. Patients were eligible for this study if they were bendamustine-sensitive (having achieved at least a partial response lasting at least 6 months) or bendamustine- naïve. Patients were required to present with a World Health Organization (WHO) Performance Status ≤2 and a modified Cumulative Incidence Rating Scale (CIRS) score <7, to have a serum creatinine level ≤1.5 x the upper limit of normal (ULN) and/or calculated creatinine clearance ≥50 mL/min/1.73 m2, and appropriate hematologic (platelet count ≥75x109/L, absolute neu- trophil count >0.75x109/L) and liver parameters (bilirubin ≤1.5 x ULN, aspartate transaminase and/or alanine transaminase ≤2.5 x ULN).
Trial design and treatment
Initially, a single dose of olaptesed pegol was administered intravenously to ten patients in the pilot study phase to study safe- ty, pharmacokinetics and pharmacodynamics of olaptesed pegol alone. Subsequently, olaptesed pegol was administered intra- venously once per cycle in combination with BR as six cycles of 28 days to all 28 eligible patients including the initial ten pilot patients to study safety and efficacy of this novel combination. Details on drug administration are provided in the Online Supplementary Information.
Study assessments
Responses were assessed at the end of cycle 6 according to the 1996 National Cancer Institute-Working Group (NCI-WG) criteria updated in 2008 by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL).12 Adverse events were continu- ously monitored until 30 days after the last olaptesed pegol dose and were graded by National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Olaptesed pegol concentrations were measured in plasma at the indicated time points by a validated assay for pharmacokinetic analyses (see supplement to Vater et al.1). The pharmacodynamic activity of olaptesed pegol was studied by five-color flow cytom- etry analysis using a standard diagnostic panel based on CD5, CD19, CD45, 7-AAD plus beads on peripheral blood samples to study the mobilization of CLL cells. Additionally, CXCR4 expres- sion was assessed on the detected CLL cells. Analyses were per- formed centrally by MLL GmbH (Munich, Germany). Minimal residual disease was not assessed.
A fluorescence in situ hybridization cytogenetics panel was used to investigate CLL cells unless this had been performed within the last 24 weeks prior to screening. Deletions of 11q22-q23, 13q14, 17p13 as well as a marker for trisomy 12 were assessed. IGHV sta- tus and TP53 mutations were not assessed.
Serum for immunogenicity analyses was collected at screening, day -14, before first dosing at cycles 1 and 4 as well as at the final examination and 6 months thereafter. Further details can be found in the Online Supplementary Information.
Statistical analyses
Data management and biostatistics were performed by AMS Advanced Medical Services GmbH (Mannheim, Germany). All statistical analyses are descriptive and exploratory. Efficacy param- eters were analyzed using SAS version 9.1.3 (SAS Institute Inc, Cary, NC, USA). Actuarial survival curves were estimated accord- ing to the Kaplan-Meier method.
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haematologica | 2019; 104(10)