Study Description

Standard arm:

Large en-bloc curative-intent surgery within 4 weeks following randomization- Experimental arm

Experimental arm:

3 cycles of neoadjuvant chemotherapy starting within 2 weeks following randomization:

High grade LPS: ADM (doxorubicin) 75 mg/m2 (or the equivalent EpiADM 120 mg/m2) + ifosfamide 9 g/m3 Q3 weeks.

LMS: ADM 75 mg/m2 + DTIC (dacarbazine) 1 g/m2 Q3 weeks

re-assessment of operability

curative-intent surgery within 3-6 weeks of last cycle of chemotherapy

Condition or Disease	Intervention/Treatment
Retroperitoneal Sarcoma Liposarcoma Leiomyosarcoma	Procedure: Surgery Drug: Preoperative chemotherapy

Study Design

Study Type	Interventional
Anticipated Enrollment	250 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Official Title	A Randomized Phase III Study of Neoadjuvant Chemotherapy Followed by Surgery Versus Surgery Alone for Patients With High Risk RetroPeritoneal Sarcoma (RPS)
Study Start Date	January 20, 2021
Anticipated Primary Completion Date	April 21, 2027
Anticipated Study Completion Date	April 21, 2028

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
Standard arm Surgery alone	Procedure: Surgery Large en-bloc curative-intent surgery
Experimental arm Preoperative chemotherapy and surgery	Drug: Preoperative chemotherapy

Outcome Measures

Primary Outcome Measures

1. Disease free survival [7 years from first patient in]
   Disease free survival will be measured from the date of randomization (as reference) to the date of recurrence or death, whichever occurs first.

Secondary Outcome Measures

1. Overall survival (OS) [8 years from first patient in]
   OS will be measured from the date of randomization to the date of death, whatever the cause. Alive patients will be censored at the date of last follow-up.
2. Recurrence free survival [8 years from first patient in]
   Recurrence free survival will be measured in patients who were successfully operated (R0/R1 resection) from the date of surgery (as reference) to the date of recurrence (local or distant) or death, whichever occurs first. Patients without one of these events will be censored at the date of last follow-up.
3. Distant metastases free survival [8 years from first patient in]
   Distant metastases free survival will be from the date of randomization (as reference) to the date of distant metastases or death (whatever the cause), whichever occurs first. Patients without any of these events will be censored at the date of last follow-up.
4. Cumulative incidence of local recurrences [8 years from first patient in]
   Cumulative incidence of local recurrences will be measured from the date of randomization (as reference) to the date of local recurrence.
5. Cumulative incidence of distant metastases [8 years from first patient in]
   Cumulative incidence of distant metastases will be measured from the date of randomization to the date of occurrence of distant metastases.
6. Radiological response to neoadjuvant chemotherapy according to RECIST [8 years from first patient in]
   For patients receiving neo-adjuvant chemotherapy, the radiological response will be assessed using RECIST 1.1 by comparison of the baseline and preoperative imaging.
7. Radiological response to neoadjuvant chemotherapy according to CHOI [8 years from first patient in]
   For patients receiving neo-adjuvant chemotherapy, the radiological response will be also assessed using Choi criteria by comparison of the baseline and preoperative imaging.
8. Pathological response [8 years from first patient in]
   Response evaluation will be done according to the EORTC response score.
9. Safety and toxicity of neoadjuvant chemotherapy [8 years from first patient in]
   Safety and toxicity of neoadjuvant chemotherapy will be evaluated and graded using CTCAE V5.0.
10. Perioperative complications [8 years from first patient in]
    Perioperative complications will be evaluated with the Dindo scale for the events related to the surgery and CTCAE V5.0 will be used for all other events.
11. Late complications [8 years from first patient in]
    Late complications (after the 60th day following the surgery) will be evaluated and graded according to the CTCAE version 5.0.
12. Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22) [8 years from first patient in]
    Health-Related Quality of life assessment will be based on the EORTC QLQ C30 questionnaire version 3.0, with additional questions from the QLQ-STO22 module.
13. Health utility, calculated from the collected patient-reported HRQoL data and patient demographics economics. [8 years from first patient in]
    he EORTC QLQ C30 data will be mapped to health utility values using an established indirect mapping approach.

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
Inclusion Criteria	riteria: 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 2 homolog) and CDK4 (Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while proof of MDM2 amplification is highly recommended. 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 des Centres 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 the Complexity 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 local treating sarcoma team. A patient is not considered resectable when the expectation is that only an R2 resection is feasible. Criteria for non-resectability are: Involvement of the superior mesenteric artery, aorta, coeliac trunk and/or portal vein Involvement of bone Growth into the spinal canal Progression of retro-hepatic inferior vena cava leiomyosarcoma towards the right atrium Infiltration of multiple major organs like liver, pancreas and or major vessels Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging. CT thorax abdomen pelvis with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT thorax + MRI abdomen & pelvis Collection of tumour tissue for central pathology review is mandatory. For patients with LMS: if there is not enough tissue for assessing the grading, 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 at least 10 unstained slides or one pathological block are available for the central review, that will be considered as acceptable. For the biopsy if fine needle aspiration (FNA) is performed instead of core needle biopsy (CNB) recommended by the standard guidelines, please contact the EORTC medical monitors for further evaluation. Collection of tumour tissue and blood samples for translational research is mandatory. In case there is not enough tissue for TR, a new biopsy is not required and if the patient fulfils all other eligibility criteria, he/she will be eligible. If the blood samples are not collected, patient will not be eligible. If the patient refuses the collection of biomaterial for TR, patient will not 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 serum pregnancy test within 3 days prior to randomization. Note: a woman is considered of childbearing potential, i.e., fertile, if she is following menarche. She remains of childbearing potential until she becomes post-menopausal or permanently sterile.Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 consecutive months without menses, a single FSH measurement is insufficient. WOCBP in both arms should use highly effective birth control measures, during the study treatment period and for at least 6 months after the last dose of chemotherapy or date of surgery (except for women receiving chemotherapy with ifosfamide who should continue contraception until 1 year after last day of treatment). A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. For men in the experimental arm: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm. Female subjects who are breast feeding should discontinue nursing prior to the first day of study treatment and until 6months after the last study treatment. Before patient randomization, written informed consent must be given according to 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 systemic therapy for the present tumour Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites 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 Hg despite optimal medical therapy. Note: in case of high blood pressure: 1) initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; 2) blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The mean SBP / DBP values from each blood pressure assessment must be ≤ 150/90mmHg in order for a patient to be eligible for the study. Uncontrolled cardiac arrhythmia Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin or equivalent 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 obstructions of the urine flow. Other invasive malignancy within 5 years, with the exception of adequately treated non-melanoma skin cancer, localized cervical cancer, localized and Gleason ≤ 6prostate cancer. Uncontrolled severe illness, infection, medical condition (including uncontrolled diabetes), other than the primary LPS or LMS of the retroperitoneum. Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control method. 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 randomization in the trial Known contraindication to imaging tracer and to MRI Selection criteria for STREXIT 2 Patients with histologically proven primary resectable localized high-risk DDLPS or LMS of retroperitoneal space or infra-peritoneal spaces of pelvis (as described in the inclusion criteria of STRASS 2) and amenable to receive chemotherapy but for whom the list of eligibility criteria for the study is too restrictive (tumour grading not available, inadequate organ function, concomitant diseases) Patients who meet all eligibility criteria of STRASS 2 but do not consent to randomization or are not enrolled for any other reason. Patients enrolled in a Registry collecting data on primary RPS patients in the centres participating in STRASS 2 (e.g., RESAR) and who satisfy the above criteria. 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.

Contacts and Locations

Sponsors and Collaborators	European Organisation for Research and Treatment of Cancer - EORTC, Canadian Cancer Trials Group, ECOG-ACRIN Cancer Research Group, Anticancer Fund, Belgium, Australia and New Zealand Sarcoma Association, Japan Clinical Oncology Group
	Canadian Cancer Trials Group, ECOG-ACRIN Cancer Research Group, Anticancer Fund, Belgium, Australia and New Zealand Sarcoma Association, Japan Clinical Oncology Group
Locations	Mayo Clinic Hospital in Arizona | Phoenix, Arizona, United States, 85054 City of Hope Comprehensive Cancer Center | Duarte, California, United States, 91010 UC Irvine Health/Chao Family Comprehensive Ca Ctr | Orange, California, United States, 92668 UCHealth University of Colorado Hospital | Aurora, Colorado, United States, 80045 Smilow Cancer Hospital-Derby Care Center | Derby, Connecticut, United States, 06418 Smilow Cancer Hospital Care Center-Fairfield | Fairfield, Connecticut, United States, 06824 Smilow Cancer Hospital Care Center at Glastonbury | Glastonbury, Connecticut, United States, 06033 Smilow Cancer Hospital Care Center at Greenwich | Greenwich, Connecticut, United States, 06830 Smilow Cancer Hospital Care Center - Guiford | Guilford, Connecticut, United States, 06437 Smilow Cancer Hospital Care Ctr at Saint Francis | Hartford, Connecticut, United States, 06105 Yale University | New Haven, Connecticut, United States, 06520 Yale-New Haven Hospital North Haven Medical Center | North Haven, Connecticut, United States, 06385 Smilow Cancer Hospital Care Center at Long Ridge | Stamford, Connecticut, United States, 06902 Smilow Cancer Hospital Care Center-Trumbull | Trumbull, Connecticut, United States, 06611 Smilow Cancer Hospital-Waterbury Care Center | Waterbury, Connecticut, United States, 06708 Smilow Cancer Hospital Care Center - Waterford | Waterford, Connecticut, United States, 06385 Mayo Clinic in Florida | Jacksonville, Florida, United States, 32224 Moffitt Cancer Center-International Plaza | Tampa, Florida, United States, 33607 Moffitt Cancer Center - McKinley Campus | Tampa, Florida, United States, 33612 Moffitt Cancer Center | Tampa, Florida, United States, 33612 Emory University Hospital Midtown | Atlanta, Georgia, United States, 30308 Northwestern University | Chicago, Illinois, United States, 60611 University of Illinois at Chicago MBCCOP | Chicago, Illinois, United States, 60612 Indiana Univ/Melvin and Bren Simon Cancer Center | Indianapolis, Indiana, United States, 46202 University of Kansas Cancer Center | Kansas City, Kansas, United States, 66160 University of Kansas Cancer Center-Overland Park | Overland Park, Kansas, United States, 66210 University of Kansas Hospital-Westwood Cancer Ctr | Westwood, Kansas, United States, 66205 James Graham Brown Ca Ctr at Univ of Louisville | Louisville, Kentucky, United States, 40202 LSU Health Baton Rouge-North Clinic | Baton Rouge, Louisiana, United States, 70805 Our Lady of The Lake Hospital | Baton Rouge, Louisiana, United States, 70808 Our Lady of the Lake Physician Group | Baton Rouge, Louisiana, United States, 70808 Johns Hopkins Univ/Sidney Kimmel Cancer Center | Baltimore, Maryland, United States, 21205 Dana-Farber/Harvard Cancer Center | Boston, Massachusetts, United States, 02215 University of Michigan Comprehensive Cancer Center | Ann Arbor, Michigan, United States, 48109 Sanford Joe Lueken Cancer Center | Bemidji, Minnesota, United States, 56601 Mayo Clinic | Rochester, Minnesota, United States, 55905 Siteman Cancer Center-West County | Creve Coeur, Missouri, United States, 63141 Washington University School of Medicine - Siteman Cancer Center | Saint Louis, Missouri, United States, 63110 Siteman Cancer Center-South Country | Saint Louis, Missouri, United States, 63129 Nebraska Medicine-Bellevue | Bellevue, Nebraska, United States, 68123 Nebraska Medicine-Bellevue | Omaha, Nebraska, United States, 68118 University of Nebraska Medical Center | Omaha, Nebraska, United States, 68198 Dartmouth Hitchcock Med Ctr/Dartmouth Cancer Ctr | Lebanon, New Hampshire, United States, 03756 Rutgers Cancer Institute of New Jersey | New Brunswick, New Jersey, United States, 08903 Roswell Park Cancer Institute | Buffalo, New York, United States, 14263 University of Rochester | Rochester, New York, United States, 14642 Stony Brook University Medical Center | Stony Brook, New York, United States, 11794 Duke University Medical Center | Durham, North Carolina, United States, 27710 Sanford Bismarck Medical Center | Bismarck, North Dakota, United States, 58501 Sanford Broadway Medical Center | Fargo, North Dakota, United States, 58122 Sanford Roger Maris Cancer Center | Fargo, North Dakota, United States, 58122 Ohio State University Comprehensive Cancer Center | Columbus, Ohio, United States, 43210 University of Oklahoma Health Sciences Center | Oklahoma City, Oklahoma, United States, 73104 Oregon Health and Science University | Portland, Oregon, United States, 97239 Saint Vincent Hospital | Erie, Pennsylvania, United States, 16544 Jefferson Hospital | Jefferson Hills, Pennsylvania, United States, 15025 Forbes Hospital | Monroeville, Pennsylvania, United States, 15146 Allegheny Valley Hospital | Natrona Heights, Pennsylvania, United States, 15065 University of Pennsylvania/Abramson Cancer Center | Philadelphia, Pennsylvania, United States, 19104 Pennsylvania Hospital | Philadelphia, Pennsylvania, United States, 19107 Thomas Jefferson University Hospital | Philadelphia, Pennsylvania, United States, 19107 Fox Chase Cancer Center | Philadelphia, Pennsylvania, United States, 19111 Allegheny General Hospital | Pittsburgh, Pennsylvania, United States, 15212 West Penn Hospital | Pittsburgh, Pennsylvania, United States, 15224 UPMC Hillman Cancer Center | Pittsburgh, Pennsylvania, United States, 15232 Wexford Health and Wellness Pavilion | Wexford, Pennsylvania, United States, 15090 Smilow Cancer Hospital Care Center - Westerly | Westerly, Rhode Island, United States, 02891 Sanford Cancer Center Oncology Clinic | Sioux Falls, South Dakota, United States, 57104 Sanford USD Medical Center - Sioux Falls | Sioux Falls, South Dakota, United States, 57117 Vanderbilt University/Ingram Cancer Center | Nashville, Tennessee, United States, 37232 M D Anderson Cancer Center | Houston, Texas, United States, 77030 Huntsman Cancer Institute/University of Utah | Salt Lake City, Utah, United States, 84132 VCU Massey Cancer Center at Hanover Medical Park | Mechanicsville, Virginia, United States, 23116 VCU Massey Cancer Center at Stony Point | Richmond, Virginia, United States, 23235 Virginia Commonwealth Univ/Massey Cancer Center | Richmond, Virginia, United States, 23298 Carilion Roanoke Memorial Hospital | Roanoke, Virginia, United States, 24014 VCU Community Memorial Health Center | South Hill, Virginia, United States, 23970 FHCC South Lake Union | Seattle, Washington, United States, 98109 Fred Hutchinson Cancer Center | Seattle, Washington, United States, 98109 University of Washington Medical Center - Montlake | Seattle, Washington, United States, 98195 Marshfield Medical Center-EC Cancer Center | Eau Claire, Wisconsin, United States, 54701 Marshfield Medical Center | Marshfield, Wisconsin, United States, 54449 Medical College of Wisconsin | Milwaukee, Wisconsin, United States, 53226 Marshfield Medical Center | Minocqua, Wisconsin, United States, 54548 Marshfield Medical Center | Rice Lake, Wisconsin, United States, 54868 Marshfield Med Ctr-River Region at Stevens Point | Stevens Point, Wisconsin, United States, 54482 Marshfield Medical Center | Weston, Wisconsin, United States, 54476 Princess Alexandra Hospital - University Of Queensland | Woolloongabba, Queensland, Australia, QLD 4102 Peter Maccallum Cancer Institute | Melbourne, Victoria, Australia, 3000 Chris O'Brian Life House - Chris O'Brien Lifehouse | Camperdown, Australia, 2050 BCCA - Vancouver Cancer Centre | Vancouver, British Columbia, Canada, V5Z 4E6 London Regional Cancer Center | London, Ontario, Canada, N6A 4L6 The Ottawa Hospital - General Campus | Ottawa, Ontario, Canada, Hopital Maisonneuve Rosemont | Montréal, Quebec, Canada, H1T 2M4 The Research Institute of the McGill University Health Centre | Montréal, Quebec, Canada, H4A3J1 Mount Sinai Hospital | Toronto, Canada, Bank Of Cyprus Oncology Centre | Stróvolos, Cyprus, 2006 Masaryk Memorial Cancer Institute | Brno, Czechia, 656 53 Herlev Hospital - University Copenhagen | Herlev, Copenhagen, Denmark, 2730 Aarhus University Hospitals - Aarhus University Hospital-Skejby | Aarhus, Denmark, 8250 Centre Leon Berard | Lyon, France, 69008 Institut du Cancer de Montpellier | Montpellier, France, 34298 Institut Curie- Hopital de Paris | Paris, France, 75248 Hopitaux Universitaires de Strasbourg - Hautepierre | Strasbourg, France, 67098 Institut Gustave Roussy | Villejuif, France, 94805 Universitaetsmedizin Goettingen - Georg-August Universitaet | Goettigen, Lower Saxony, Germany, 37075 Universitaetsklinikum Carl Gustav Carus | Dresden, Germany, 01307 UniversitaetsMedizin Mannheim | Mannheim, Germany, 68167 Centro Di Riferimento Oncologico | Aviano, Italy, 33081 IRCCS - Fondazione Piemonte Inst di Candiolo | Candiolo, Italy, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori" | Meldola, Italy, Istituto Clinico Humanitas | Milano, Italy, Istituto Europeo di Oncologia | Milano, Italy, IRCCS - Istituto Nazionale dei Tumori | Milan, Italy, 20133 IRCCS - Istituto Oncologico Veneto | Padova, Italy, Policlinico Universitario Campus Bio-Medico- Oncology Center | Roma, Italy, Kyushu University Hospital | Higashi-ku, Fukuoka, Japan, 812-8582 Yokohama City University Hospital | Yokohama, Kanagawa, Japan, 236-0004 Kanagawa Cancer Center | Yokohama, Kanagawa, Japan, 241-8515 Tohoku University Hospital | Sendai, Miyagi, Japan, 780-8574 Aichi Cancer Center | Chikusa-ku, Nagoya, Japan, 464-8681 Nagoya University Hospital | Showa-ku, Nagoya, Japan, 466-8550 Niigata University Medical and Dental Hospital | Niigata City, Niigata, Japan, 951-8520 Okayama University Hospital | Kita-ku, Okayama, Japan, 700-8558 Osaka International Cancer Institute | Chuo-ku, Osaka, Japan, 541-8567 National Cancer Center Hospital | Chuo-ku, Tokyo, Japan, 104-0045 Cancer Institute Hospital of JFCR | Koto-ku, Tokyo, Japan, 135-8550 Saitama Medical Center, Jichi Medical University | Saitama, Japan, 330-8503 The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis | Amsterdam, Netherlands, 1066 Leiden University Medical Centre | Leiden, Netherlands, 2300 RC Radboudumc - Radboud University Medical Center Nijmegen | Nijmegen, Netherlands, 6525 Maria Sklodowska-Curie Memorial Cancer Centre - Maria Sklodowska-Curie National Research Institute of Oncology | Warsaw, Poland, National Cancer Institute | Bratislava, Slovakia, SK 833 10 Hospital De La Santa Creu I Sant Pau | Barcelona, Spain, 08041 Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol | Barcelona, Spain, Hospital General Universitario Gregorio Maranon | Madrid, Spain, 28007 Hospital Universitario San Carlos | Madrid, Spain, 28040 University Hospitals Birmingham - Queen Elisabeth Medical Centre | Birmingham, United Kingdom, B15 2TH NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital | Glasgow, United Kingdom, Leeds Teaching Hospitals NHS Trust - St. James's University Hospital | Leeds, United Kingdom, LS9 7TF the Royal Marsden Hospital | London, United Kingdom, Newcastle Hospitals - Freeman Hospital, Northern Centre For Cancer Care | Newcastle, United Kingdom, NE7 7DN Nottingham University Hospitals NHS Trust - City Hospital | Nottingham, United Kingdom, NG5 1PB Oxford University Hospitals NHS Trust - Churchill Hospital | Oxford, United Kingdom, OX3 7LE Clatterbridge cancer center | Wirral, United Kingdom, CH63 4JY

More Information

Additional Relevant MeSH Terms

• Sarcoma
• Leiomyosarcoma
• Liposarcoma
• Neoplasms, Connective and Soft Tissue
• Neoplasms by Histologic Type
• Neoplasms
• Neoplasms, Muscle Tissue
• Neoplasms, Adipose Tissue