Sarcomas and DDR-Inhibition; a neoadjuvant phase I combined modality study - SADDRIN-1

• Histologically confirmed newly diagnosed intermediate to high grade soft
tissue sarcoma localized to the extremities or trunk- and chest wall, for which
the standard treatment is a combination of and RT and surgery (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 4
• Signed written informed consent prior to any study specific procedures or
sampling

Pathological diagnosis
• Patients with any type soft tissue sarcoma located above the clavicles;
• Patients with recurrent sarcomas who underwent prior radiotherapy to the
target lesion (if the primary sarcoma was managed by surgery only and no
perioperative radiotherapy, patients are eligible);
• Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric
and adult), bone sarcomas;

Concurrent therapies
• Neoadjuvant chemotherapy to be scheduled between end of radiotherapy and
definitive surgery is not allowed. (neoadjuvant chemotherapy before start of
study radiotherapy is allowed);
• Intention to perform an isolated limb perfusion, instead of a tumor resection;
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide
field of radiation within 4 weeks of the first dose of study drug;

Medical History
• Prior malignancies; except another malignancy and disease-free for >= 5 years,
or completely resected non-melanomatous skin carcinoma or successfully treated
in situ carcinoma;
• Prior surgical procedure within 28 days prior to the first dose of
durvalumab, excluding minor surgical procedures e.g procedures only recuing
local anesthesia.
• Past medical history of interstitial lung disease (ILD ), drug-induced ILD,
radiation pneumonitis which required steroid treatment, or any evidence of
clinically active interstitial lung disease;
• History or presence of myopathy or raised CK >5 x ULN on 2 occasions at
screening. CK should not be measured following strenuous exercise or in the
presence of a plausible alternative cause of CK increase, which may confound
interpretation of the results. If CK levels are significantly elevated at
baseline (>5 x ULN) a confirmatory test should be carried out within 5 - 7
days. If the repeat test confirms a baseline CK >5 x ULN, treatment should not
be started;
• History and/or presence of COVID-19: (a)Previous severe course of COVID-19
(ie, hospitalisation, extracorporeal membrane oxygenation, mechanically
ventilated), (b) Clinical signs and symptoms consistent with COVID-19, eg,
fever, dry cough, dyspnoea, sore throat, fatigue or confirmed current infection
by appropriate laboratory test within the last 4 weeks prior to screening;

Cardiac function
• Cardiac dysfunction defined as: Myocardial infarction within six months of
study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable
cardiac arrhythmias;
• Any of the following cardiac criteria:
* Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3
electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia*s
formula);
* Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG, e.g., complete left bundle branch block, third degree heart block;
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years-of-age.
Patients stable on concomitant medications known to prolong the QT interval may
be allowed to participate in the study provided that their mean resting
corrected QT interval (QTcF) is < 470 msec at baseline and after discussion
with the Medical Monitor;

Concurrent and prior medication
• Concomitant treatment with medicines listed as *prohibited* or
*excluded* (section 3.1.4);
• 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);
• Known allergy or hypersensitivity to any of the study drugs or any of the
study drug excipients;

Prior and concurrent clinical trials
• Participation in another clinical study with an investigational product
during the last 3 months;
• Concurrent enrolment in another clinical study or, unless it is an
observational (non-interventional) clinical study or during the follow-up
period of an interventional study;

Other
• 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;
• Judgment by the investigator that the patient should not participate in the
study if the patient is unlikely to comply with study procedures, restrictions
and requirements;
• Female patients who are pregnant or breast feeding;
• Male or female patients of reproductive potential who are not willing to
employ effective birth control during treatment;