Neoplasms

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Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Durvalumab

The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy. Drug will be taken at same day as radiotherapy for 5 weeks at weekdays.

When starting dose of 20 mg is proven safe the next cohort will be 100 and thereafter 200, 400 mg

The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy and durvalumab (fixed dose 1500 mg Q4W, until surgery). Drug will be taken at same day as radiotherapy for 5 weeks at weekdays. The dose of AZD1390 in the AZD1390 plus durvalumab cohort will follow the dosing of the AZD1390 only cohort. When starting dose of 20 mg and the next dose of AZD1390 only has been proven safe, the next cohort will be 100 and thereafter 200, 400 mg.

AZD1390 combined with preoperative radiotherapy

AZD1390 + radiotherapy

AZD1390 combined with durvalumab and preoperative radiotherapy

AZD1390 + durvlaumab + radiotherapy

Rick Haas, MD Prof

Neeltje Steeghs, MD PhD

Rick Haas, MD, PhD

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.

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Sarcomas and DDR-Inhibition; a Combined Modality Study	NCT05116254	Soft Tissue Sar...	AZD1390 + radio... AZD1390 + durvl...	18 Years -	The Netherlands Cancer Institute
Sarcomas and DDR-Inhibition; a Combined Modality Study	NCT05116254	Soft Tissue Sar...	AZD1390 + radio... AZD1390 + durvl...	18 Years -	The Netherlands Cancer Institute

Spots Global Cancer Trial Database for azd1390 + radiotherapy