Sarcomas and DDR-Inhibition; a Combined Modality Study

Inclusion Criteria:

* Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, for which the standard treatment is a combination of RT and surgery (in other words deep seated and/or \> 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition);
* Patients staged by at least a CT scan of the chest (and a CT scan of the abdomen, if deemed indicated according to local practices, e.g. in case of a myxoid liposarcoma). Staging may also be performed by FDG-PET scanning and or total body MRI scans. This staging procedure should not reveal metastatic disease. If, however, a low metastatic burden is detected such that this does not preclude the application of both preoperative RT and definitive surgery, patients are allowed to participate;
* WHO Performance Status ≤ 2;
* Able and willing to undergo preoperative RT;
* Able and willing to undergo definitive surgery;
* Able and willing to comply with regular follow-up visits;
* Able and willing to swallow and retain oral medication;
* Age ≥ 18 years;
* Body weight \>30kg;
* Must have a life expectancy of at least 12 weeks;
* Adequate organ function as defined in Table 5;
* Signed written informed consent prior to any study specific procedures or sampling

Exclusion Criteria:

* Patients with any type soft tissue sarcoma located above the clavicles.
* Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma;
* Patients with recurrent sarcomas who underwent prior RT to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative RT, patients are eligible);
* Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), bone sarcomas;
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;
* Female patients who are pregnant or breast feeding;
* Intention to perform an isolated limb perfusion, instead of a tumor resection;
* Neoadjuvant chemotherapy to be scheduled between end of RT and definitive surgery is not allowed. (neoadjuvant chemotherapy before start of study RT is allowed);
* Concomitant treatment with medicines listed as 'prohibited' or 'excluded';
* Treatment with moderate and strong inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort);

Additional criteria for durvalumab plus AZD1390:

* Past medical history of allogenic organ transplantation;
* Past medical history of leptomeningeal carcinomatosis;
* Past medical history or active autoimmune or inflammatory disorders
* History or presence of primary immunodeficiency
* Presence of active hepatitis infections or HIV
* Treatment with or prior use of immunosuppressive medication within 2 weeks before the start of treatment
* Prior treatment with anti-PD-1, anti PD-L1 or anti CTLA-4 immunotherapy