Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma

1. STRASS 2 Inclusion Criteria:

• Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.

• LMS:

• Any grade LMS can be included

• Minimum size of LMS tumor should be 5 cm

• LPS:

• Diagnosis should be confirmed based on MDM2 (Mouse double minute 2homolog) and CDK4 (Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while proof of MDM2 amplification is highlyrecommended.

• All grade 3 DDLPS can be included.

• DDLPS with confirmed grade 2 on biopsy can be included when:

• The grade 2 DDLPS has an FNCLCC score=5 (Fédération Nationale desCentres de Lutte Contre Le Cancer), and clear necrosis on imaging (whether or not present on the biopsy).

• The tumors carry a high risk gene profile as determined by theComplexity INdex in SARComas (CINSARC-high)

• Unifocal tumour

• Resectable tumour: resectability is based on pre-operative imaging (CT-abdomen, potentially also with MRI) and has to be defined by the localtreating sarcoma team. A patient is not considered resectable when theexpectation is that only an R2 resection is feasible.

• Criteria for non-resectability are:

• Involvement of the superior mesenteric artery, aorta, coeliac trunk and/orportal vein

• Involvement of bone

• Growth into the spinal canal

• Progression of retro-hepatic inferior vena cava leiomyosarcoma towards theright atrium

• Infiltration of multiple major organs like liver, pancreas and or majorvessels

• Patient must have radiologically measurable disease (RECIST 1.1), asconfirmed by imaging. CT thorax abdomen pelvis with IV contrast is thepreferred imaging modality. In case of any contra-indications (medical orregulatory), it is allowed to perform a non-contrast CT thorax + MRIabdomen & pelvis

• Collection of tumour tissue for central pathology review is mandatory.

• For patients with LMS: if there is not enough tissue for assessing thegrading, this is acceptable.

• If tumour tissue is not available for the central pathology review,patient will not be eligible.

• If the biopsy was not done or the FFPE of the biopsy not available but atleast 10 unstained slides or one pathological block are available for thecentral review, that will be considered as acceptable.

• For the biopsy if fine needle aspiration (FNA) is performed instead ofcore needle biopsy (CNB) recommended by the standard guidelines, pleasecontact the EORTC medical monitors for further evaluation.

• Collection of tumour tissue and blood samples for translational researchis mandatory.

• In case there is not enough tissue for TR, a new biopsy is not requiredand if the patient fulfils all other eligibility criteria, he/she will beeligible.

• If the blood samples are not collected, patient will not be eligible.

• If the patient refuses the collection of biomaterial for TR, patient willnot be eligible even if he/she fulfils all other eligibility criteria

• ≥ 18 years old (no upper age limit)

• WHO performance status ≤ 2

• Adequate haematological and organ function

• American Society of Anaesthesiologist (ASA) score < 3

• Women of childbearing potential (WOCBP) must have a negative serumpregnancy test within 3 days prior to randomization. Note: a woman is considered of childbearing potential, i.e., fertile, if she isfollowing menarche. She remains of childbearing potential until she becomespost-menopausal or permanently sterile.Permanent sterilisation methods includehysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternativemedical cause. A high follicle stimulating hormone (FSH) level in the postmenopausalrange may be used to confirm a post-menopausal state in women not using hormonalcontraception or hormonal replacement therapy. However, in the absence of 12consecutive months without menses, a single FSH measurement is insufficient.

• WOCBP in both arms should use highly effective birth control measures, duringthe study treatment period and for at least 6 months after the last dose ofchemotherapy or date of surgery (except for women receiving chemotherapy withifosfamide who should continue contraception until 1 year after last day oftreatment). A highly effective method of birth control is defined as a methodwhich results in a low failure rate (i.e., less than 1% per year) when usedconsistently and correctly.

• For men in the experimental arm: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive measures, and agreement torefrain from donating sperm.

• Female subjects who are breast feeding should discontinue nursing prior to thefirst day of study treatment and until 6months after the last study treatment.

• Before patient randomization, written informed consent must be given accordingto ICH/GCP, and national/local regulations.

Exclusion criteria:

• Sarcoma originating from bone structure, abdominal or gynecological viscera

• Extension through the sciatic notch or across the diaphragm

• Metastatic disease

• Any previous surgery (excluding diagnostic biopsy), radiotherapy or systemictherapy for the present tumour

• Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of theirmetabolites or to any of their excipients

• Congestive heart failure

• Angina pectoris

• Myocardial infarction within 1 year before randomization

• Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mm Hgdespite optimal medical therapy. Note: in case of high blood pressure: 1) initiation or adjustment ofantihypertensive medication(s) is permitted prior to study entry; 2) blood pressuremust be re-assessed on two occasions that are separated by a minimum of 1 hour. Themean SBP / DBP values from each blood pressure assessment must be ≤ 150/90mmHg inorder for a patient to be eligible for the study.

• Uncontrolled cardiac arrhythmia

• Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin orequivalent 900mg/m² Epirubicin) of doxorubicin, daunorubicin, epirubicin,idarubicin, and/or other anthracyclines and anthracenediones

• Active and uncontrolled infections

• Vaccination with live vaccines within 30 days prior to study entry

• Inflammation of the urinary bladder (interstitial cystitis) and/or obstructionsof the urine flow.

• Other invasive malignancy within 5 years, with the exception of adequatelytreated non-melanoma skin cancer, localized cervical cancer, localized andGleason ≤ 6prostate cancer.

• Uncontrolled severe illness, infection, medical condition (includinguncontrolled diabetes), other than the primary LPS or LMS of theretroperitoneum.

• Female patients who are pregnant or breastfeeding or female and male patientsof reproductive potential who are not willing to employ effective birth controlmethod.

• Any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule; thoseconditions should be discussed with the patient before randomization in thetrial

• Known contraindication to imaging tracer and to MRI

2. Selection criteria for STREXIT 2

• Patients with histologically proven primary resectable localized high-riskDDLPS or LMS of retroperitoneal space or infra-peritoneal spaces of pelvis (asdescribed in the inclusion criteria of STRASS 2) and amenable to receivechemotherapy but for whom the list of eligibility criteria for the study is toorestrictive (tumour grading not available, inadequate organ function,concomitant diseases)

• Patients who meet all eligibility criteria of STRASS 2 but do not consent torandomization or are not enrolled for any other reason.

• Patients enrolled in a Registry collecting data on primary RPS patients in thecentres participating in STRASS 2 (e.g., RESAR) and who satisfy the abovecriteria.

3. Selection criteria for preferences for neoadjuvant chemotherapy in STRASS 2 substudy

All patients recruited to STRASS 2 in participating centres (Australia +/- international sites) that are able to read, comprehend and write in English at a sufficient level to complete study materials.