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Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma

PHASE3RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.
  • Any grade LMS can be included
  • Minimum size of LMS tumor should be 5 cm
  • 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.
  • 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.
  • 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.
  • 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 ≤ 6 prostate 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
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2021-01-20

    Primary completion: 2027-04-21

    Study completion finish: 2028-04-21

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE3

    trial

    Trial ID

    NCT04031677

    Intervention or treatment

    PROCEDURE: Surgery

    DRUG: Preoperative chemotherapy

    Conditions

    • • Retroperitoneal Sarcoma
    • • Liposarcoma
    • • Leiomyosarcoma
    Image related to Retroperitoneal Sarcoma

    • Condition: Retroperitoneal Sarcoma, Liposarcoma and more

    • PROCEDURE: Surgery and other drugs

    • Woolloongabba, Queensland, Australia and more

    • Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

    You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

    Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

    Find a site

    Closest Location:

    Princess Alexandra Hospital - University Of Queensland

    Research sites nearby

    Select from list below to view details:

    • Princess Alexandra Hospital - University Of Queensland

      Woolloongabba, Queensland, Australia

    • Peter Maccallum Cancer Institute

      Melbourne, Victoria, Australia

    • Chris O'Brian Life House - Chris O'Brien Lifehouse

      Camperdown, Not Specified, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    OTHER: Standard arm
    • Surgery alone
    PROCEDURE: Surgery
    • Large en-bloc curative-intent surgery
    EXPERIMENTAL: Experimental arm
    • Preoperative chemotherapy and surgery
    DRUG: Preoperative chemotherapy
    • * High grade LPS: ADM 75 mg/m2 (or the equivalent EpiADM 120 mg/m2) + ifosfamide 9 g/m2 Q3 weeks
    • * LMS: ADM 75 mg/m2 + DTIC 1g/m2 Q3 weeks
    • Note: the recommended dose of Doxorubicin (or Epirubicin) can be modified according to national/institutional guidelines, given that the minimal threshold must be Doxorubicin 60 mg/m2 per cycle (or the equivalent Epirubicin 95 mg/m2 per cycle); the recommended dose of Ifosfamide can be modified according to national/institutional guidelines, given that the minimal threshold must be 7.5 g/m2 per cycle; the recommended dose of Dacarbazine can be modified according to national/institutional guidelines, given that the minimal threshold must be 900 mg/m2 per cycle. The schedule of administration of above chemotherapies can be modified according to national/institutional guidelines provided that the minimal threshold of doses, and the treatment periods with chemotherapies remain the same.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Disease free survivalDisease free survival will be measured from the date of randomization (as reference) to the date of recurrence or death, whichever occurs first.7 years from first patient in

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Overall survival (OS)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.8 years from first patient in
    Recurrence free survivalRecurrence 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.8 years from first patient in
    Distant metastases free survivalDistant 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.8 years from first patient in
    Cumulative incidence of local recurrencesCumulative incidence of local recurrences will be measured from the date of randomization (as reference) to the date of local recurrence.8 years from first patient in
    Cumulative incidence of distant metastasesCumulative incidence of distant metastases will be measured from the date of randomization to the date of occurrence of distant metastases.8 years from first patient in
    Radiological response to neoadjuvant chemotherapy according to RECISTFor patients receiving neo-adjuvant chemotherapy, the radiological response will be assessed using RECIST 1.1 by comparison of the baseline and preoperative imaging.8 years from first patient in
    Radiological response to neoadjuvant chemotherapy according to CHOIFor patients receiving neo-adjuvant chemotherapy, the radiological response will be also assessed using Choi criteria by comparison of the baseline and preoperative imaging.8 years from first patient in
    Pathological responseResponse evaluation will be done according to the EORTC response score.8 years from first patient in
    Safety and toxicity of neoadjuvant chemotherapySafety and toxicity of neoadjuvant chemotherapy will be evaluated and graded using CTCAE V5.0.8 years from first patient in
    Perioperative complicationsPerioperative 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.8 years from first patient in
    Late complicationsLate complications (after the 60th day following the surgery) will be evaluated and graded according to the CTCAE version 5.0.8 years from first patient in
    Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22)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.8 years from first patient in
    Health utility, calculated from the collected patient-reported HRQoL data and patient demographics economics.he EORTC QLQ C30 data will be mapped to health utility values using an established indirect mapping approach.8 years from first patient in

    Frequently Asked Questions

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    References

    Clinical Trials Gov: Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma

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