Citations

63 Background: A novel vaccine strategy may prevent recurrence in high-risk melanoma patients (pts). The TLPLDC vaccine uses yeast cell wall particles (YCWP) to load tumor lysate into autologous dendritic cells (DC). In this phase IIb trial of TLPLDC vs. placebo in resected stage III/IV pts, TLPLDC increased 24 month (mo) disease free survival (DFS) in the per treatment (PT) population. Here, we present a 24mo DFS subgroup analysis and estimated overall 36mo DFS. Methods: Disease-free pts were randomized 2:1 to the TLPLDC vaccine vs. unloaded YCWP+DC at 0, 1, 2, 6, 12, and 18mo. The protocol was amended to allow concurrent adjuvant checkpoint inhibitor (CPI) therapy once approved. The pre-specified PT population included only pts completing the primary vaccine/placebo series (PVS) at 6 mo. Kaplan-Meier estimates of DFS were used to compare treatment arms by stage (III or IV) and CPI therapy (yes/no) in the ITT and PT populations. Results: 144 pts were randomized (103 TLPLDC, 41 placebo); 98 pts (66 TLPLDC, 32 placebo) completed the PVS. There were no clinicopathologic differences between treatment groups. There was no difference in 24mo DFS in stage III pts (n = 112), but in stage IV pts (n = 32), the 24mo DFS was 44% vs 0% (TLPLDC vs placebo) (p = 0.41) in ITT and 73.3% vs. 0% (HR 0.14, p = 0.002) in PT. Stage IV pts were more likely to receive CPI than stage III pts (50% vs. 30%, p = 0.003). There was no difference in 24mo DFS for pts who did not receive CPI (n = 102), but in pts who received CPI (n = 42), the 24mo DFS was 49.3% vs. 31.3% (p = 0.71) in ITT and 68.8% vs. 41.7% (HR 0.46, p = 0.28) in PT, showing a trend toward improved DFS in pts who completed the PVS and received CPI (n = 31). Overall, the 36mo estimated DFS was 34.2% vs. 21.6% (p = 0.89) for ITT and 56.9% vs. 27.9% (p = 0.021) for PT. Conclusions: The TLPLDC vaccine improved DFS in patients completing the PVS at 24 and 36 mos, particularly in the resected stage IV subset. The apparent synergistic effect with TLPLDC + CPI will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI vs. CPI alone in resected stage IV melanoma pts. Clinical trial information: NCT02301611.

Abstract Myeloproliferative diseases (MPDs) are a subset of myeloid malignancies that are characterized by the expansion of a multipotent hematopoietic stem cell. Chronic MPDs can be classified into two categories, those harboring the BCR-ABL oncogene and those that are negative. This later category of neoplasms encompasses polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent discovery of activating mutations in the tyrosine kinase gene, JAK2 and constitutive activation of JAK2-STAT pathway, in large number of MPD patients has ignited considerable interest in MPD and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts. However, high-sequence homology with other JAK family members has posed a major challenge to design selective JAK2 inhibitors. Given that other JAK family members are involved in the regulation of immune function, it is important to maintain selectivity for JAK2 over these family members in order to mitigate the risks associated with undesired immunosuppression. Several JAK2 inhibitors with varying selectivity profiles are currently being evaluated in preclinical testing as well as in clinical trials for the treatment of MPD. Additionally, emerging genetic and pharmacologic evidence suggest that inhibition of the JAK2-STAT pathway may be an important therapeutic intervention point in other hematological malignancies as well as in certain solid tumors. We report here the discovery and characterization of BMS-911543, a functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a potent and reversible inhibitor of JAK2 with a biochemical Ki of 0.48 nM. It has over 65-, 74- and 350-fold selectivity against the other JAK family members, TYK2, JAK3 and JAK1, respectively. Importantly, examination of > 450 other kinases in competition binding assays and in selected biochemical kinase assays did not reveal significant inhibitory activity for this JAK2 inhibitor, highlighting its high degree of biochemical selectivity for JAK2. Functionally, BMS-911543 displayed potent antiproliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. Further, single agent antiproliferative activity was not observed for BMS-911543 in a variety of solid tumor cell lines dependent upon other signaling pathways. In contrast, BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased antiproliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species with durable and potent pathway suppression observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. To test the hypothesis that a JAK2 selective inhibitor would have less effect on immune system function, BMS-911543 was compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production for BMS-911543 whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive and resistant cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors in clinical testing, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other malignancies reliant upon constitutively active JAK2 signaling. References: Levine, R.L., et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders (2007). Nature Rev. Cancer, 7, 673-683. Atallah, E. and Verstovsek, S. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. (2009). Expert Rev. Anticancer Ther. 9, 663-670. Ghoreschi, K., et al. Janus kinases in immune cell signaling. (2009). Immunol. Rev.,228, 273-287. Mesa, R.A. and Tefferi, A. Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis (2009). Expert Opin. Emerging Drugs, 14, 1-9. Roll, J.D. and Reuther, G.W. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. (2010) Cancer Res, 70, 7347-7352. Rui et al., Cooperative epigenetic modulation by cancer amplicon genes (2010). Cancer Cell, 18, 590-605. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2011-DDT01-03