This study has been transitioned to CTIS with ID 2023-505261-84-00 check the CTIS register for the current data. The primary objective of this study is to assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves…
ID
Source
Brief title
Condition
- Soft tissue neoplasms malignant and unspecified
- Soft tissue therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Disease free survival (which includes as events: distant progression on
neoadjuvant treatment, local progression if not followed by R0/R1 surgery,
non-operable tumours, local recurrence and/or distant metastases, R2 and death)
Secondary outcome
• Overall survival
• Recurrence free survival
• Distant metastases free survival
• Cumulative incidence of local recurrences
• Cumulative incidence of distant metastases
• Radiological response to neoadjuvant chemotherapy according to RECIST
• Radiological response to neoadjuvant chemotherapy according to CHOI
• Pathological response
• Safety and toxicity of neoadjuvant chemotherapy
• Perioperative complications
• Late complications
• Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22)
Background summary
High grade dedifferentiated liposarcoma (LPS) and leiomyosarcoma (LMS)
originating from the retroperitoneum have a dismal prognosis, with a risk of
death in excess of 70% at 5 yrs. While WDLPS and G1-G2 DDLPS, the 2 most common
histological subtypes originating at this site, predominantly fail locally, it
has become evident over the past years that high grade DDLPS and LMS are
characterized by a high metastatic risk, which is the leading cause of death.
Systemic chemotherapy has the potential to address the metastatic risk and
improve relapse free survival as well as overall survival. The neoadjuvant
setting is preferable for a study in this disease, as it allows to assess drug
activity as well as efficacy, study tumour biology and response to therapy, and
immediately address the systemic risk which is the cause of death of these
patients. In addition, patients will have to undergo a major abdominal
procedure with a high chance to lose one kidney en bloc with the tumour. It's
therefore easier to perform chemotherapy in the preoperative phase, when
patients have not yet undergone the procedure above.
An attempt to formally study the possible benefit of chemotherapy in these high
risk histologic subtypes has not previously been performed.
Study objective
This study has been transitioned to CTIS with ID 2023-505261-84-00 check the CTIS register for the current data.
The primary objective of this study is to assess whether preoperative
chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis
of patients with high risk de-differentiated liposarcoma (DDLPS) and
leiomyosarcoma (LMS) as measured by disease-free survival.
Secondary objectives:
• To assess whether there is a difference in the overall survival, recurrence
free survival, distant metastases free survival, cumulative incidence of local
recurrences and cumulative incidence of distant metastases between patients
undergoing curative-intent surgery alone and those undergoing preoperative
chemotherapy followed by curative intent surgery
• To assess tumour response in patients undergoing preoperative chemotherapy
• To assess the toxicity profile of preoperative chemotherapy given as
"neoadjuvant" treatment to curative intent surgery in patients with high risk
retroperitoneal (RPS) and of surgery alone
• To assess whether there is a difference in quality of life between patients
undergoing curative-intent surgery alone and those undergoing preoperative
chemotherapy followed by curative intent surgery
Study design
This is a randomized, multicentre, open-label phase III trial of neoadjuvant
chemotherapy followed by surgery versus surgery alone in patients with RPS. The
randomization will be stratified by institution and histology: liposarcoma LPS
or leyomiosarcoma (LMS).
Patients will be randomized to either Standard arm: large en-bloc curative
intent surgery or Experimental arm: 3 cycles of neoadjuvant chemotherapy
followed by curative intent surgery
The primary endpoint of the study is disease free survival which includes as
events: distant progression on neoadjuvant treatment, local progression if not
followed by R0/R1 surgery, non-operable tumours, local recurrence and/or
distant metastases, R2 and death.
Intervention
As part of the study, half of the patients receive chemotherapy pre-treatment,
which consists of three doses that are administered clinically. This means 3
times admission to the hospital for 3-5 days once every 3 weeks, a total of
more than 2 months. The other half of the patients receive surgery alone.
Please note that the current standard of care is often neoadjuvant chemotherapy
as well, but that now depends on certain patient factors. In this study we
randomize patients between chemotherapy and surgery alone, so in the end the
load for the whole group is comparable to the load in the standard of care in
the current practice.
Study burden and risks
The psychological burden caused by taking part of the clinical trial and also
the possibility of more toxicity because of the chemotherapy.
Avenue E. Mounier 83/11
Brussel 1200
BE
Avenue E. Mounier 83/11
Brussel 1200
BE
Listed location countries
Age
Inclusion criteria
• Histologically proven primary high risk leiomyosarcoma (LMS) or
Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal
spaces of pelvis.
- LMS: Any grade and size > 5 cm
- LPS (diagnosis based on MDM2 and CDK4 expression on
IHC; additional proof of MDM2 amplification is highly
recommended but not mandatory):
* Grade 3 DDLPS OR
* Confirmed grade 2 DDLPS on biopsy only if:
FNCLCC score = 5 and clear necrosis on imaging whether or not present on the
biopsy OR
* 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
performed within 28 days before randomization (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
leimyosarcoma 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 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.
• Collection of tumor tissue and blood samples for central pathology
review and translational research are mandatory. If tumor tissue is not
available and/or patient does not consent, patient will not be eligible for
this trial.
• >= 18 years old (no upper age limit)
• WHO performance status <= 2
• Adequate haematological and organ function assessed within 21
days prior to randomization
• American Society of Anesthesiologist (ASA) score < 3
• Women of child bearing potential (WOCBP) must have a negative
serum pregnancy test within 3 days prior to randomization.
• WOCBP in both arms should use higly 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 6 months 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-505261-84-00 |
| EudraCT | EUCTR2019-003543-30-NL |
| ClinicalTrials.gov | NCT04031677 |
| CCMO | NL73078.031.20 |