ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data.
Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate.
ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds.
Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu.
Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12).
AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood.
Tunquist:Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.
Asterisk with author names denotes non-ASH members.