xevinapant (Debio 1143)

P3, N=730, Terminated, EMD Serono Research & Development Institute, Inc. | Trial completion date: Apr 2027 --> Sep 2024 | Active, not recruiting --> Terminated; Study has crossed the pre-defined futility boundary at the Interim Analysis.

P3, N=166, Terminated, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Terminated; No major safety concerns were identified in XRAY VISION study, but Lack of evidence of efficacy of meaningful clinical benefit.

P3, N=19, Suspended, Groupe Oncologie Radiotherapie Tete et Cou | Trial primary completion date: Jul 2024 --> Oct 2024

P1, N=18, Terminated, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Terminated; No major safety concerns were identified in HyperlynX study, but Lack of evidence of efficacy of meaningful clinical benefit.

Several Survivin inhibitors, including YM-155, Debio1143, EM1421, LQZ-7I, and TL32711, have emerged as potential anticancer drugs awaiting validation in clinical trials. Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.

P2, N=230, Suspended, European Organisation for Research and Treatment of Cancer - EORTC | Recruiting --> Suspended

P2, N=4, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=54 --> 4

Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects...Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased...In vivo, SM-1 combined irradiation showed a good anti-tumor effect. SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

P1, N=12, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Not yet recruiting --> Recruiting

P2, N=0, Withdrawn, ECOG-ACRIN Cancer Research Group | N=180 --> 0 | Not yet recruiting --> Withdrawn

P1, N=18, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=40 --> 18 | Trial completion date: Apr 2025 --> Aug 2024 | Trial primary completion date: Apr 2025 --> Aug 2024

P3, N=166, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting | N=700 --> 166 | Trial completion date: Dec 2030 --> Sep 2024 | Trial primary completion date: Oct 2027 --> Sep 2024

P3, N=19, Suspended, Groupe Oncologie Radiotherapie Tete et Cou | N=538 --> 19 | Recruiting --> Suspended

P1, N=12, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=42, Active, not recruiting, University of Chicago | Not yet recruiting --> Active, not recruiting | Initiation date: Jan 2025 --> Jan 2024

P1, N=42, Not yet recruiting, University of Chicago | Initiation date: Jan 2024 --> Jan 2025

P1, N=40, Recruiting, EMD Serono Research & Development Institute, Inc. | Not yet recruiting --> Recruiting

Xevinapant combined with pembrolizumab was well tolerated with no unexpected adverse events. However, anti-tumor activity was low.

P2, N=180, Not yet recruiting, ECOG-ACRIN Cancer Research Group | Initiation date: Jan 2024 --> Apr 2024

P1, N=42, Not yet recruiting, University of Chicago | Trial primary completion date: Nov 2025 --> Oct 2027

P2, N=54, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=230, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

P2, N=54, Recruiting, Memorial Sloan Kettering Cancer Center

P1, N=40, Not yet recruiting, EMD Serono Research & Development Institute, Inc. | Phase classification: P1b --> P1 | Initiation date: Oct 2023 --> Jan 2024

P1, N=42, Not yet recruiting, University of Chicago

P2, N=180, Not yet recruiting, ECOG-ACRIN Cancer Research Group

Exposure-response relationships were not discernible for 12 of 13 evaluated safety endpoints, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety endpoints, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Obtained biocompatible D@AgNP are stable over six months at room temperature and demonstrated absorbance peak at 406 nm...TEM finding shows that D@AgNP are mostly localized at vesicles such as the endosomes, lysosomes and mitochondria. It is anticipated that the introduced new method serves as the cornerstone for improving the generation of biocompatible hydrophilic carbohydrate-based anticancer drugs.

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.

A phase 3 study, named TrilynX, in a larger group of people, is currently taking place to confirm the results of this study. Clinical Trial Registration: NCT02022098 (Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial) (ClinicalTrials.gov).

ED treat-and-release encounters are common after major gastrointestinal operations, making up nearly half of postdischarge ED encounters. The reasons for ED treat-and-release encounters differ from those for ED encounters with readmissions.

P3, N=538, Not yet recruiting, Groupe Oncologie Radiotherapie Tete et Cou

Xevinapant appears to be a potent new drug for HNSCC therapy, especially in combination with IR. IAP levels could be an indicator for impaired DNA damage repair and increased susceptibility to cellular stress.

Radiotherapy alone for nasopharyngeal carcinoma with an intermediate-risk profile was found to be noninferior to chemoradiotherapy with cisplatin while improving tolerability...In the HNSCC-15-132 trial, sequential application of the PD‑1 inhibitor pembrolizumab to chemoradiotherapy was not significantly, but numerically superior to concomitant application...In addition, new 5‑year overall survival data from the phase II trial of chemoradiotherapy in combination with the inhibitor of apoptosis proteins (IAP) antagonist xevinapant versus placebo were presented. The xevinapant group continued to demonstrate a significant survival advantage and a sustained response to treatment.

Specifically, xevinapant demonstrated superior efficacy in combination with CRT vs placebo + CRT in a randomized, double-blind, phase 2 trial in patients with unresected LA SCCHN. Here, we describe the current treatment landscape in LA SCCHN and provide the rationale for targeting IAPs and the clinical data reported for xevinapant.

Furthermore, we evaluated the impact of these potential SCAFs on cell death by making use of the small molecule inhibitors embelin (targets XIAP), AT406 (targets c-IAP1 > XIAP), BV6 (targets c-IAP1, c-IAP2 and marginal XIAP) and Venetoclax (targets Bcl-2) and performed COMBENEFIT analysis for synergy. We conclude that the upregulation of the antiapoptotic fac- tors c-IAP1, c-IAP2 and Bcl-2 during TMZ-induced senescence is a key event in the protection from cell death, and inhibition of these factors effectively kills senescent glioblastoma cells. Indication of source: 1 Schwarzenbach, C.; Tatsch, L.; Brandstetter Vilar, J.; Rasenberger, B.; Beltzig, L.; Kaina, B.; Tomicic, M.T.; Christmann, M. Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment. Cancers 2021, 13, 3585.

IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy.

Xevinapant has demonstrated promising activity in combination with CRT in LA-SCCHN. The outcome of the exploratory PD analyses indicates that XVT modulates NF-kB signaling, leading to serum increases in MCP1 and TNFα while further augmenting CRT-induced apoptotic marker CKM30. Our findings further characterize the mechanism of action of XVT and how it may ultimately result in enhanced clinical responses to CRT.

At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

Therapy of malignant glioma depends on the induction of O-methylguanine by the methylating agent temozolomide (TMZ). In contrast to BV6 and venetoclax, AT406, embelin, and TMZ itself, teniposide and the PARP inhibitor pamiparib did not increase cell death in senescent cells. Based on these data, we suggest that BV6 and venetoclax act as senolytic agents in glioblastoma cells upon TMZ exposure.

Risk factors (e.g., tobacco/alcohol consumption, exposure to environmental pollutants) for the development of head and neck cancer Diagnosis, screening and prevention strategies in SCCHN; molecular biomarkers and key pathways in the development and progression of SCCHN Clinical factors (e.g., pre-existing comorbidities, performance status and pathologic features) to consider when designing a therapeutic plan for patients with SCCHN Role of the human papillomavirus (HPV) in the development of head and neck cancers; impact of HPV status on the use of immune checkpoint inhibitors in SCCHN Factors guiding the selection of therapy for patients with SCCHN; influence of prior treatment, time since completion of definitive treatment, age, symptomatology, extent of metastases and PD-L1 expression status in the choice of treatment regimen Clinical role of concurrent and/or induction chemotherapy with radiation therapy for patients presenting with locoregional SCCHN Published research data with and current clinical role of cetuximab for patients with localized, recurrent or metastatic SCCHN; role of EGFR targeted therapies in the era of immunotherapy Prevalence and clinical implications of EGFR mutations in progressive SCCHN; recent FDA approval of a new dosage regimen for cetuximab Spectrum, frequency and severity of toxicities observed with cetuximab in combination with platinum-based chemotherapy; strategies to mitigate the associated side-effects Clinical utility of microsatellite instability (MSI) testing and PD-L1 status determinations using the tumor proportion score (TPS) and/or the combined positive score (CPS) for patients with SCCHN; similarities and differences in the available PD-L1 assay platforms Key efficacy and safety results supporting the FDA approval of pembrolizumab as first-line therapy in the Phase III KEYNOTE-048 trial for recurrent or metastatic SCCHN Optimal management of disease that progresses on pembrolizumab when administered as first-line therapy either alone or in combination with chemotherapy for patients with PD-L1-positive SCCHN Research databases supporting the use of immune checkpoint inhibitors for patients SCCHN; identification of patients with SCCHN who are ineligible for immune checkpoint inhibitor therapy Mechanism of action of and emerging results with camrelizumab alone or in combination with chemotherapy for recurrent or metastatic head and neck cancers Results from the Phase III KESTREL and EAGLE trials of the anti-PD-L1 antibody durvalumab with or without tremelimumab versus standard of care treatment for patients with recurrent or metastatic SCCHN Biologic rationale for the investigation of bempegaldesleukin in combination with pembrolizumab in a Phase II/III trial for patients with head and neck cancer whose tumors express PD-L1 CPS or 1 or more Updated results from the Phase III JAVELIN Head and Neck 100 study of avelumab in addition to chemoradiotherapy (CRT) versus CRT alone for untreated locally advanced SCCHN; recommendations for study termination Recognition, incidence, monitoring and optimal management of immune-related adverse events in patients receiving immune checkpoint inhibitor therapy Mechanisms of resistance to EGFR inhibition and immune checkpoint inhibition in SCCHN Mechanism of action of tipifarnib and published data with this agent in the Phase II RUN-HN trial in the cohort of patients with HRAS-mutant recurrent and/or metastatic SCCHN after disease progression on platinum-based chemotherapy; recent FDA breakthrough therapy designation Role of entrectinib and Larotrectinib in patients with NTRK gene fusion-positive salivary gland carcinomas Mechanism of action and rationale for the ongoing investigation of xevinapant in the Phase III TrilynX study for previously untreated high-risk locally advanced SCCHN

Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day D1-15 +/-2); Debio 1143 (200 mg/day D1-15 +/-2) plus cisplatin (40 mg/m D-1 and 8); cisplatin alone (40 mg/m D-1 and 8) (EudraCT: 2014-004655-31). Debio 1143 penetrated SCCHN tumors, engaged cIAP-1 and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.