NCT05116254

Sarcomas and DDR-Inhibition; a Combined Modality Study

Sarcomas and DDR-Inhibition; a Neoadjuvant Phase I Combined Modality Study.

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (actual)
• Sponsor: The Netherlands Cancer Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

To assess the safety and tolerability profile, in the pre- and perioperative period (up to 30 days post-surgery), of combined modality treatment (CMT) by administering AZD1390 with or without durvalumab and RT concurrently treating newly diagnosed, non-metastatic soft tissue sarcoma patients with DDRi-based CMT, in the specific context of systemic toxicities, wound healing post-surgery and in defining the RP2D for the combinations to support further clinical evaluation.

Detailed description

Despite improvements in surgery and radiation for soft tissue sarcoma (STS) patients, local relapses remain an important event for these patients. Most STS subtypes are considered radioresistant and immune cold tumor due to a lack of T-cell infiltration. Investigations into radiosensitization mediated by combining systemic compounds with neoadjuvant radiotherapy (RT) may translate into an increased rate of pathological responses, an increased rate of R0 resections and thus fewer local relapses. RT is highly potent in inducing DNA damage. Normal cells are usually sufficiently able to repair this damage timely before the next fraction because of an intact DNA Damage Response (DDR) pathway. Frequently, tumor cells have (partial or complete) defects in the DDR pathways rendering them more sensitive to radiation than normal tissues. Inhibition of constituents of the DDR pathways may further widen the therapeutic window of fractionated radiotherapy, and combined with radiotherapy may result in increased tumor T-cell infiltration, creating an opportunity for immunotherapy. Clinical studies into radiosensitization of STS by combinations of radiotherapy and DDR inhibitors with or without immunotherapy are warranted. In this study the DDR candidate inhibitor is new drug candidate AZD1390 targeting ATM (Ataxia Telangiectasia Mutated). The immunotherapy candidate of this study is durvalumab (MEDI4736) targeting PD-L1 (programmed death-ligand 1).

Conditions

• Soft Tissue Sarcoma Adult

Interventions

Type	Name	Description
COMBINATION_PRODUCT	AZD1390 + radiotherapy	AZD1390 combined with preoperative radiotherapy
COMBINATION_PRODUCT	AZD1390 + durvlaumab + radiotherapy	AZD1390 combined with durvalumab and preoperative radiotherapy

Timeline

• Start date: 2022-07-18
• Primary completion: 2025-12-09
• Completion: 2025-12-09
• First posted: 2021-11-10
• Last updated: 2026-01-23

Locations

1 site across 1 country: Netherlands