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

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