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.
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.
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.
- 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
- 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 ≤ 6prostate 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
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE3
Study ID
NCT04031677
Intervention or treatment
PROCEDURE: Surgery
DRUG: Preoperative chemotherapy
Conditions
- Retroperitoneal Sarcoma
- Liposarcoma
- Leiomyosarcoma
You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.
Research sites nearby
Closest Location:
Princess Alexandra Hospital - University Of Queensland
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, Australia
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Who is running the clinical trial?
EOfRaToC-E
European Organisation for Research and Treatment of Cancer - EORTC
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/Arm | Intervention/Treatment |
|---|---|
OTHER: Standard arm
| Procedure: Surgery |
EXPERIMENTAL: Experimental arm
| Drug: Preoperative chemotherapy |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Disease free survival | Disease 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
| Measure | Description | 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 survival | Recurrence 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 survival | Distant 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 recurrences | Cumulative 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 metastases | Cumulative 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 RECIST | For 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 CHOI | For 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 response | Response evaluation will be done according to the EORTC response score. | 8 years from first patient in |
| Safety and toxicity of neoadjuvant chemotherapy | Safety and toxicity of neoadjuvant chemotherapy will be evaluated and graded using CTCAE V5.0. | 8 years from first patient in |
| Perioperative complications | Perioperative 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 complications | Late 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 |
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References
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