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Surgery With Our Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma (STRASS2)

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ClinicalTrials.gov Identifier: NCT04031677
Recruitment Status : Recruiting
First Posted : July 24, 2019
Last Update Posted : October 22, 2020
Sponsor:
Collaborators:
Swiss Group for Clinical Cancer Research
Canadian Cancer Trials Group
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Tracking Information
First Submitted Date  ICMJE July 22, 2019
First Posted Date  ICMJE July 24, 2019
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE October 6, 2020
Estimated Primary Completion Date April 21, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
Disease free survival [ Time Frame: 7 years from first patient in ]
Disease free survival will be measured from the data of randomization (as reference) to the date of recurrence or death, whichever occurs first.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
  • Overall survival (OS) [ Time Frame: 8 years from first patient in ]
    OS will be measured from the date of randomization to the date of death, whatever the cause.
  • Local recurrence free survival [ Time Frame: 8 years from first patient in ]
    Local recurrence free survival will be measured from the date of randomization to the date of recurrence (local) or death, whichever occurs first.
  • Recurrence free survival [ Time Frame: 8 years from first patient in ]
    Recurrence free survival will be measured from the date of randomization to the date of recurrence (local or distant) or death, whichever occurs first.
  • Distant metastases free survival [ Time Frame: 8 years from first patient in ]
    Distant metastases free survival will be measured from the date of randomization to the date of distant metastases or death, whichever occurs first.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Surgery With Our Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma
Official Title  ICMJE A Randomized Phase III Study of Neoadjuvant Chemotherapy Followed by Surgery Versus Surgery Alone for Patients With High Risk RetroPeritoneal Sarcoma (RPS)
Brief 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.

Detailed 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Retroperitoneal Sarcoma
  • Liposarcoma
  • Leiomyosarcoma
Intervention  ICMJE
  • 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

    Other Name: neoadjuvant chemotherapy
Study Arms  ICMJE
  • Standard arm
    Surgery alone
    Intervention: Procedure: Surgery
  • Experimental: Experimental arm
    Preoperative chemotherapy and surgery
    Intervention: Drug: Preoperative chemotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 22, 2019)
250
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 21, 2028
Estimated Primary Completion Date April 21, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

    • Grades 2 and 3 of 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: EORTC HQ +3227741611 1809@eortc.org
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04031677
Other Study ID Numbers  ICMJE EORTC 1809-STBSG
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party European Organisation for Research and Treatment of Cancer - EORTC
Study Sponsor  ICMJE European Organisation for Research and Treatment of Cancer - EORTC
Collaborators  ICMJE
  • Swiss Group for Clinical Cancer Research
  • Canadian Cancer Trials Group
Investigators  ICMJE
Study Chair: Alessandro Gronchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Chair: Winan van Houdt The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
PRS Account European Organisation for Research and Treatment of Cancer - EORTC
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP