P1/2, N=230, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Oct 2024 --> Dec 2025

P1, N=42, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Nov 2024 --> Aug 2025

P1, N=33, Not yet recruiting, National Cancer Institute (NCI)

P1/2, N=132, Active, not recruiting, Astex Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

P1, N=10, Recruiting, Emory University | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=78, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Not yet recruiting --> Recruiting

P1, N=84, Not yet recruiting, Roswell Park Cancer Institute

Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely.

We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer.

P1b, N=78, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris

Therefore, future work will explore these pathways under hypoxic conditions. Additionally changes in cell proliferation and protein expression of IAPs will be measured following exposure of cervical cancer cell lines to different hypoxic conditions in combination with irradiation, cisplatin and tolinapant.

While there are limited studies using decitabine as a hypomethylating agent (HMA) in PTCL, a recent guadecitabine prospective study showed 40% ORR (Wong et al., Leukemia, 2022)...Subjects with CD30-positive disease must have received or be ineligible for brentuximab vedotin... The Study opened in June 2022 with primary completion estimated to be December 2025. Pharmacokinetic, Oral, Peripheral T-cell lymphoma

Subjects with CD30-positive disease must have received, be ineligible for, or intolerant to brentuximab vedotin. In Phase 2, there will be efficacy analysis for every 34 subjects, without a pause in enrollment. Study initiated in May 2022.

In addition, re-expression of RIPK3 in CT26 cells increased lytic cell death on treatment with tolinapant indicating its essential role in the necroptosis pathway.Objectives: 1) Characterize the single-agent activity of tolinapant in a range of TCL lines; 2) Determine the synergy of tolinapant in combination with drugs active against PTCL (romidepsin, pralatrexate) and HMAs (azacytidine-AZA; decitabine-DAC), and 3) Define the role of necroptosis in the mechanism of synergy. Thus, activation of the necroptosis pathway, is a possible mechanism for the high degree of synergy displayed when HMAs are used in combination with tolinapant in the TCL lines in vitro. These data provided the rationale for a phase 1-2 study of the combination of tolinapant and oral decitabine/cedazuridine treatment in relapsed/refractory PTCL (NCT05403450).

These results support the continued development of tolinapant for the treatment of R/R PTCL and CTCL. A drug combination study using tolinapant in R/R PTCL is being developed.

Methods On-target effects of decitabine and tolinapant were measured by analysing levels of DNMT1 and cIAP1, respectively, by Western blotting in mouse and human cell lines. In addition, modulation of cytokine response and cancer/testis antigen expression could enhance anti-tumour response. These findings provide a strong rationale to explore this combination clinically.

Aims We explored the sensitivity of a range of TCL lines to tolinapant, established the synergy coefficient and interrogated the role of necroptosis in the mechanism of synergy between tolinapant and drugs active against PTCL, the HMAs; azacytidine and decitabine Methods A panel of 10 human TCL lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10 ng/ml of TNFa. Thus, activation of the necroptosis pathway, is a possible mechanism for the high degree of synergism displayed when HMAs are used in combination with tolinapant in the TCL lines in vitro . These data provide the rationale to initiate clinical trials with the combination of tolinapant and decitabine.

Our study highlights that ASTX660 can overcome the limitation of apoptosis induction via triggering necroptosis in BC cells. Therefore, our findings may provide some important clues for the design of a novel treatment strategy for BC.

Tolinapant synergizes with the anti-leukemic activity of ABT199 and DEX, establishing a therapeutic rationale for IAP antagonist in T-ALL.

Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha.

A Phase 1 clinical study investigating the combination of tolinapant and ASTX727 (oral decitabine) in AML is currently in progress (NCT04155580). Conclusion : These data demonstrate that decitabine enhances immunogenic cell death induced by tolinapant through the re-expression of genes in the necroptotic pathway. This finding provides strong rationale to explore this combination clinically.