Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma

Leiomyosarcoma Clinical Trial

— STRASS2  

Official title:

A Randomized Phase III Study of Neoadjuvant Chemotherapy Followed by Surgery Versus Surgery Alone for Patients With High Risk RetroPeritoneal Sarcoma (RPS)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04031677
• Other study ID #: EORTC 1809-STBSG
• Secondary ID: EA7211SR.7ASSG45
• Status: Recruiting
• Phase: Phase 3
• Start date: January 20, 2021
• Est. completion date: April 21, 2028

Study information

• Verified date: April 2024
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: EORTC HQ
• Phone: +3227741611
• Email: 1809[@]eortc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, randomized, open label phase lll trial to assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis of high risk DDLPS (dedifferentiated Liposarcoma) and LMS (Leiomyosarcoma) patients as measured by disease free survival.

After confirmation of eligibility criteria, patients will be randomized to either the standard arm or experimental arm.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: April 21, 2028
• Est. primary completion date: April 21, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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), has no necrosis on the biopsy but clear necrosis on imaging.

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

• Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides must be available at baseline for histological central review.

• Unifocal tumor

• Absence of extension through the sciatic notch or across the diaphragm

• Resectable tumor: 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 patients 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

• Tumor not previously treated (no previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy)

• Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. 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.

• = 18 years old (no upper age limit)

• WHO (World Health Organization) performance status = 2

• Adequate haematological and organ function:

• Haematological: haemoglobin > 9.0 g/dL or 5.6 mmol/L, absolute neutrophils > 1.5 x 109/L, platelets > 100 x 109/L Note: Platelet transfusions is allowed to achieve these baseline values

• Renal: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2; No proteinuria CTCAE = grade 2;

• Hepatic: Bilirubin = 1.0 times upper limit of normal (1.0xULN) of institutional limits, ALT (alanine aminotransferase) and/or AST (aspartate transaminase) =1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved.

• Heart: Clinically normal cardiac function based on left ventricular ejection fraction (LVEF = 50%) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.

• American Society of Anesthesiologist (ASA) score < 3

• Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment or surgery.

Note: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post menopausal unless 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 months of amenorrhea, a single FSH measurement is insufficient..

• Patients of childbearing / reproductive potential should use highly effective birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment or date of surgery. 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. Such methods include:

• Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)

• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

• Intrauterine device (IUD)

• Intrauterine hormone-releasing system (IUS)

• Bilateral tubal occlusion

• Vasectomized partner

• Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)

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

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

Exclusion Criteria:

• Sarcoma originated from bone structure, abdominal or gynecological viscera

• Metastatic disease

• Tumors with extension through the sciatic notch or across the diaphragm

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

• Persistent myelosuppression

• Myocardial infarction within the last 6 months

• Uncontrolled cardiac arrhythmia

• Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin or equivalent 900mg/m² EpiADM) 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 presumably cured prostate cancer.

• Uncontrolled severe illness, infection,medical condition (including, uncontrolled diabetes or hypertension), 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

Related Conditions & MeSH terms

• Leiomyosarcoma
• Liposarcoma
• Retroperitoneal Sarcoma
• Sarcoma

Intervention

Procedure:
• Surgery
Large en-bloc curative-intent surgery

Drug:
• Preoperative chemotherapy
- High grade LPS: ADM 75 mg/m2 (or the equivalent EpiADM 120 mg/m2) + ifosfamide 9 g/m2 Q3 weeks Note: the recommended dose of Ifosfamide can be modified according to national/institutional guidelines, given that the minimum threshold must be 7.5 g/m2 per cycle. - LMS: ADM 75 mg/m2 + DTIC 1g/m2 Q3 weeks

Locations

Country	Name	City	State
Australia	Chris O'Brian Life House - Chris O'Brien Lifehouse	Camperdown
Australia	Peter Maccallum Cancer Institute	Melbourne	Victoria
Australia	Princess Alexandra Hospital - University Of Queensland	Woolloongabba	Queensland
Canada	London Regional Cancer Center	London	Ontario
Canada	Hopital Maisonneuve Rosemont	Montréal	Quebec
Canada	The Research Institute of the McGill University Health Centre	Montréal	Quebec
Canada	The Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	Mount Sinai Hospital	Toronto
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
Cyprus	Bank Of Cyprus Oncology Centre	Stróvolos
Czechia	Masaryk Memorial Cancer Institute	Brno
Denmark	Aarhus University Hospitals - Aarhus University Hospital-Skejby	Aarhus
Denmark	Herlev Hospital - University Copenhagen	Herlev	Copenhagen
France	Centre Leon Berard	Lyon
France	Institut du Cancer de Montpellier	Montpellier
France	Institut Curie- Hopital de Paris	Paris
France	Hopitaux Universitaires de Strasbourg - Hautepierre	Strasbourg
France	Institut Gustave Roussy	Villejuif
Germany	Universitaetsklinikum Carl Gustav Carus	Dresden
Germany	Universitaetsmedizin Goettingen - Georg-August Universitaet	Goettigen	Lower Saxony
Germany	UniversitaetsMedizin Mannheim	Mannheim
Italy	Centro Di Riferimento Oncologico	Aviano
Italy	IRCCS - Fondazione Piemonte Inst di Candiolo	Candiolo
Italy	IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori"	Meldola
Italy	IRCCS - Istituto Nazionale dei Tumori	Milan
Italy	Istituto Clinico Humanitas	Milano
Italy	Istituto Europeo di Oncologia	Milano
Italy	IRCCS - Istituto Oncologico Veneto	Padova
Italy	Policlinico Universitario Campus Bio-Medico- Oncology Center	Roma
Japan	Aichi Cancer Center	Chikusa-ku	Nagoya
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	Osaka International Cancer Institute	Chuo-ku	Osaka
Japan	Kyushu University Hospital	Higashi-ku	Fukuoka
Japan	Okayama University Hospital	Kita-ku	Okayama
Japan	Cancer Institute Hospital of JFCR	Koto-ku	Tokyo
Japan	Niigata University Medical and Dental Hospital	Niigata City	Niigata
Japan	Saitama Medical Center, Jichi Medical University	Saitama
Japan	Tohoku University Hospital	Sendai	Miyagi
Japan	Nagoya University Hospital	Showa-ku	Nagoya
Japan	Kanagawa Cancer Center	Yokohama	Kanagawa
Japan	Yokohama City University Hospital	Yokohama	Kanagawa
Netherlands	The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis	Amsterdam
Netherlands	Leiden University Medical Centre	Leiden
Netherlands	Radboudumc - Radboud University Medical Center Nijmegen	Nijmegen
Poland	Maria Sklodowska-Curie Memorial Cancer Centre - Maria Sklodowska-Curie National Research Institute of Oncology	Warsaw
Slovakia	National Cancer Institute	Bratislava
Spain	Hospital De La Santa Creu I Sant Pau	Barcelona
Spain	Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario San Carlos	Madrid
United Kingdom	University Hospitals Birmingham - Queen Elisabeth Medical Centre	Birmingham
United Kingdom	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	the Royal Marsden Hospital	London
United Kingdom	Newcastle Hospitals - Freeman Hospital, Northern Centre For Cancer Care	Newcastle
United Kingdom	Nottingham University Hospitals NHS Trust - City Hospital	Nottingham
United Kingdom	Oxford University Hospitals NHS Trust - Churchill Hospital	Oxford
United Kingdom	Clatterbridge cancer center	Wirral
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Johns Hopkins Univ/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	LSU Health Baton Rouge-North Clinic	Baton Rouge	Louisiana
United States	Our Lady of The Lake Hospital	Baton Rouge	Louisiana
United States	Our Lady of the Lake Physician Group	Baton Rouge	Louisiana
United States	Nebraska Medicine-Bellevue	Bellevue	Nebraska
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Dana-Farber/Harvard Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Northwestern University	Chicago	Illinois
United States	University of Illinois at Chicago MBCCOP	Chicago	Illinois
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Siteman Cancer Center-West County	Creve Coeur	Missouri
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Smilow Cancer Hospital Care Center at Glastonbury	Glastonbury	Connecticut
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Smilow Cancer Hospital Care Center - Guiford	Guilford	Connecticut
United States	Smilow Cancer Hospital Care Ctr at Saint Francis	Hartford	Connecticut
United States	M D Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Med Ctr/Dartmouth Cancer Ctr	Lebanon	New Hampshire
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	VCU Massey Cancer Center at Hanover Medical Park	Mechanicsville	Virginia
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Marshfield Medical Center	Minocqua	Wisconsin
United States	Yale University	New Haven	Connecticut
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Medicine-Bellevue	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	UC Irvine Health/Chao Family Comprehensive Ca Ctr	Orange	California
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Marshfield Medical Center	Rice Lake	Wisconsin
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth Univ/Massey Cancer Center	Richmond	Virginia
United States	Carilion Roanoke Memorial Hospital	Roanoke	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Siteman Cancer Center-South Country	Saint Louis	Missouri
United States	Washington University School of Medicine - Siteman Cancer Center	Saint Louis	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	VCU Community Memorial Health Center	South Hill	Virginia
United States	Smilow Cancer Hospital Care Center at Long Ridge	Stamford	Connecticut
United States	Marshfield Med Ctr-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Moffitt Cancer Center	Tampa	Florida
United States	Moffitt Cancer Center - McKinley Campus	Tampa	Florida
United States	Moffitt Cancer Center-International Plaza	Tampa	Florida
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	Smilow Cancer Hospital Care Center - Westerly	Westerly	Rhode Island
United States	Marshfield Medical Center	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Ctr	Westwood	Kansas

Sponsors (6)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Anticancer Fund, Belgium, Australia and New Zealand Sarcoma Association, Canadian Cancer Trials Group, ECOG-ACRIN Cancer Research Group, Japan Clinical Oncology Group

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Cyprus,  Czechia,  Denmark,  France,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Slovakia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease free survival	Disease free survival will be measured from the data of randomization (as reference) to the date of recurrence or death, whichever occurs first.	7 years from first patient in
Secondary	Overall survival (OS)	OS will be measured from the date of randomization to the date of death, whatever the cause.	8 years from first patient in
Secondary	Local recurrence free survival	Local recurrence free survival will be measured from the date of randomization to the date of recurrence (local) or death, whichever occurs first.	8 years from first patient in
Secondary	Recurrence free survival	Recurrence free survival will be measured from the date of randomization to the date of recurrence (local or distant) or death, whichever occurs first.	8 years from first patient in
Secondary	Distant metastases free survival	Distant metastases free survival will be measured from the date of randomization to the date of distant metastases or death, whichever occurs first.	8 years from first patient in