Abstract 3489: Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia

The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. It has been implicated in the pathogenesis of multiple human diseases. The genetic aberration of JAK2 V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have shown the combination benefits of combining ruxolitinib (Jak1, 2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2 V617F -driven MPN model. This triple combination resulted in ∼99% reduction of total tumor burden and a ∼96% reduction of spleen weight. Furthermore, the triple combination of ruxolitinib, LGH447 and LEE011 reduced JAK2 V617F allele burden by > 80%. To translate this combination from preclinical setting to the clinic, it is critical to evaluate dose to efficacy relationship for each agents and scheduling to efficacy correlation for this combination. Here, the preclinical doses for ruxolitinib, LGH447 and LEE011 were determined, based on their clinically achieved exposure. We then examined “intermittent dosing” of this combination in the same preclinical model. Our data suggest that the combination efficacy of ruxolitinib-LGH447-LEE011 is dependent on continuous administration of the agents. Finally, we examined the effect of dose reduction for each of the three agents on the combination efficacy in the Ba/F3-JAK2 V617F -driven MPN model. By modifying the doses for ruxolitinib, LGH447 and LEE011 separately in the combination, our study reveals that the triple combination efficacy is most sensitive to LEE011 dose reduction, and it is least sensitive to LGH447 dose reduction. In summary, our studies aim to design novel preclinical approaches to inform and the design of clinical dose escalation in novel combination therapies. Citation Format: Maria Pinzon-Ortiz, Xianhui Rong, Gary Vanasse, Z. Alexander Cao. Novel translational pharmacology approaches on dose reduction and alternative scheduling for the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011 in a preclinical model of myeloproliferative neoplasia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3489. doi:10.1158/1538-7445.AM2015-3489