ARRY-520 Combined With Pomalidomide Displays Enhanced Anti-Tumor Activity In Preclinical Models Of Multiple Myeloma

Inhibitors of Kinesin Spindle Protein (KSP), a mitosis-specific motor protein, represent a novel class of targeted anti-cancer therapies that have demonstrated clinical activity in hematological cancers. Inhibition of KSP results in the formation of aberrant monopolar spindles, mitotic arrest, and rapid apoptosis through degradation of the survival protein Mcl-1. The majority of KSP-inhibitor sensitive cells are proliferating hematopoietic cells which are dependent on Mcl-1 for survival. ARRY-520, a highly selective KSP inhibitor, is currently in Phase 2 clinical studies in patients with relapsed and refractory multiple myeloma. To date, ARRY-520 has demonstrated a well-tolerated safety profile and clinical activity both alone and in combination with bortezomib, dexamethasone, or carfilzomib in heavily pretreated patients. Updated clinical data will be disclosed at this meeting in separate abstracts. While prior preclinical studies have shown that ARRY-520 is additive or synergistic when combined with bortezomib in several in vivo models of multiple myeloma, the combinability of ARRY-520 with other myeloma standards of care, such as immunomodulatory drugs (IMiD), has not been thoroughly investigated. In the present studies, we have evaluated the combination utility of ARRY-520 and pomalidomide, an IMiD recently approved by the FDA, in preclinical models of multiple myeloma. Our findings show that the combination of ARRY-520 (12.5 mg/kg, IP, D1, 2) with pomalidomide (10 mg/kg, IP, QD) is significantly more active than either monotherapy alone in several in vivo models of multiple myeloma. In particular, complete responses and cures were observed in two models. In the RPMI-8226 model, a 100% cure rate was observed with the combination regimen as compared to a 0% cure rate for either monotherapy (cure is defined as no palpable tumor 100 days from study initiation). Likewise, in the JJN3 model a 100% complete response rate was observed with the combination regimen versus a 0% complete response rate for either monotherapy (complete response is defined as no palpable tumor for 2 consecutive tumor measurements). Notably, similar combination efficacy was also observed in the RPMI-8226 model at full and significantly reduced doses of both ARRY-520 and pomalidomide, supporting a synergistic interaction between these drugs. Characterization of the mechanism underlying the anti-tumor activity of this combination is currently being explored. The combination regimen was well tolerated causing no significant enhancement of body weight loss (not exceeding 10% for any group). Additionally, hematology analysis showed that the combination regimen caused no significant increase in thrombocytopenia or leukopenia. Consistent with clinical findings, both single agent ARRY-520 and pomalidomide caused neutropenia while the combination of these drugs moderately enhanced these effects. Pharmacokinetic studies confirmed that administration of pomalidomide with ARRY-520 does not alter the exposure of either compound, suggesting that the mechanism of enhanced anti-tumor activity is dependent upon pharmacodynamic rather than pharmacokinetic effects. Taken together, these findings show that the novel combination of ARRY-520 and pomalidomide is a well-tolerated and synergistic preclinical regimen that warrants investigation in future clinical trials in patients with multiple myeloma.