A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T‐cell lymphomas

Abstract

The transcription factor GATA-3, highly expressed in many cutaneous and peripheral T-cell lymphomas, confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed pre-clinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our pre-clinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.

Combinatorial ixazomib and belinostat therapy induces NFE2L2‐dependent apoptosis in Hodgkin and T‐cell lymphoma

“…We demonstrated in the present study that the synergistic activity of ixazomib and belinostat involve blocking compensatory proteasomal recovery responses, following proteasomal inhibition by ixazomib. Considering that ixazomib clinical trials in PTCL or other solid tumours showed only modest benefits (Assouline et al , ; Boonstra et al , ), our observations pertaining to compensatory proteasomal recovery response occurring with ixazomib (or increased proteasomal gene expression with ixazomib resistance) indicate that such responses could be the limiting factors responsible for reduced effectiveness observed with ixazomib. Furthermore, superior pharmacokinetic/pharmacodynamic activity and tolerability of ixazomib compared to bortezomib, make ixazomib an ideal choice for proteasomal targeted therapy and overcoming the adaptive proteasomal responses could be necessary to enhance the therapeutic activity of ixazomib in lymphoma.…”

“…(O'Connor et al , ) Ixazomib was reported as well tolerated among patients with PTCL and other lymphomas, however the response rates were, overall, suboptimal. (Assouline et al , ; Boonstra et al , ) We also previously established that HDACi (PCI24781/abexinostat) and bortezomib combination therapy acts synergistically to promote cell death in HL and non‐Hodgkin lymphoma (Bhalla et al , ).…”

Targeting DNA binding proteins for cancer therapy

“…Several inhibitors of DNA binding proteins have been evaluated in clinical trials (Table 2). 34‐38 Signal transducer and activator of transcription 3 plays key roles in multiple cancer‐related signaling pathways and is aberrantly expressed in various human cancers 39 . Activation of STAT3 is associated with cancer stem cell properties such as tumor seeding ability and drug resistance 40,41 .…”

GATA‐3 in T‐cell lymphoproliferative disorders

“…36 Proteasomal inhibition indirectly inhibits NF-κB by impairing IkBα degradation, and was observed to impair GATA-3 expression in preclinical studies and in an exceptional responder (with PTCL, NOS) in a small phase II study. 70 Engagement of the TCR unleashes a signaling barrage that activates a number of pathways providing therapeutic opportunities, many of which are the subject of ongoing or planned clinical trials.…”