TP-3654

P1, N=12, Completed, Sumitomo Pharma America, Inc.

Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  .

P1/2, N=80, Recruiting, Sumitomo Pharma America, Inc.

No abstract available

In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.

In preclinical studies, TP-3654 alone and in combination with ruxolitinib showed spleen size and bone marrow (BM) fibrosis reduction in murine MF models. This preliminary data of TP-3654 in relapsed/refractory MF pts showed early signs of clinical activity including spleen volume reduction, TSS improvement, and correlating cytokine reductions. TP-3654 is well tolerated with limited myelosuppressive adverse events. Enrollment is ongoing as monotherapy and current data support the development of TP-3654 in combination with JAK inhibitors given the preliminary clinical activity and minimal cytopenia.

Preliminary cytokine data showed that TP-3654 monotherapy may prompt early cytokine changes that may correlate with symptoms response. In addition, preliminary data of TP-3654 in relapsed/refractory MF patients showed SVR, TSS improvement, and BM fibrosis reduction. In the dose ranges evaluated to date, TP-3654 has been well tolerated with no myelosuppressive TRAEs.

In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers.

Ruxolitinib and fedratinib, approved JAK inhibitors, have been shown to reduce splenomegaly and improve constitutional symptoms in MF patients, but with a modest reduction of BMF. Informed consent is being obtained for each participant/potential participant in this trial, in accordance with the International Conference on Harmonization-Good Clinical Practice. Results - Conclusion -

Inhibition of pBad was dependent on pretreatment phosphorylation state. These results were confirmed in an automated western blot system.