Clinical Trials /

Surgery With Our Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma

NCT04031677

Description:

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.

Related Conditions:
  • Leiomyosarcoma
  • Liposarcoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Surgery With Our Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma
  • 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 IDs

  • ORG STUDY ID: EORTC 1809-STBSG
  • NCT ID: NCT04031677

Conditions

  • Retroperitoneal Sarcoma
  • Liposarcoma
  • Leiomyosarcoma

Interventions

DrugSynonymsArms
Preoperative chemotherapyneoadjuvant chemotherapyExperimental arm

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Standard armOtherSurgery alone
    Experimental armExperimentalPreoperative chemotherapy and surgery
    • Preoperative chemotherapy

    Eligibility Criteria

            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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease free survival
    Time Frame:7 years from first patient in
    Safety Issue:
    Description:Disease free survival will be measured from the data of randomization (as reference) to the date of recurrence or death, whichever occurs first.

    Secondary Outcome Measures

    Measure:Overall survival (OS)
    Time Frame:8 years from first patient in
    Safety Issue:
    Description:OS will be measured from the date of randomization to the date of death, whatever the cause.
    Measure:Local recurrence free survival
    Time Frame:8 years from first patient in
    Safety Issue:
    Description:Local recurrence free survival will be measured from the date of randomization to the date of recurrence (local) or death, whichever occurs first.
    Measure:Recurrence free survival
    Time Frame:8 years from first patient in
    Safety Issue:
    Description:Recurrence free survival will be measured from the date of randomization to the date of recurrence (local or distant) or death, whichever occurs first.
    Measure:Distant metastases free survival
    Time Frame:8 years from first patient in
    Safety Issue:
    Description:Distant metastases free survival will be measured from the date of randomization to the date of distant metastases or death, whichever occurs first.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

    Last Updated

    July 20, 2021