| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Primary high risk leiomyosarcoma or Liposarcoma of
retroperitoneal space or infra-peritoneal spaces of pelvis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Retroperitoneal sarcoma: a sarcoma developed in the back of the belly, next to the kidneys, in a relatively “hidden” location known as the retroperitoneum. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073135 |
| E.1.2 | Term | Dedifferentiated liposarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10024189 |
| E.1.2 | Term | Leiomyosarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
• 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 LMS of minimum 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 no necrosis on the biopsy but
clear necrosis on imaging. 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.
• ≥ 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, as
defined below:
- With female partners of childbearing potential, men must
remain abstinent* or use a condom plus an additional contraceptive method that together result in a failure rate of 1%
per year during the treatment period and for 6 months after the
last dose of chemotherapy. Men must refrain from donating
sperm during this same period.
- With pregnant female partners, men must remain abstinent* or
use a condom during the treatment period and for 28 days after
the last dose of chemotherapy to avoid exposing the embryo.
• 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. |
|
| E.4 | Principal 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 pateints 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease free survival will be evaluated 4 years after FPI (first interim look for futility), 5 years after FPI (second interim look for futility) and 7 years after FPI (final analysis) |
|
| E.5.2 | Secondary end point(s) |
• 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) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be evaluated at time of the final primary endpoint analysis: 7 years after FPI. A long term overall survival analysis will also be performed at later timepoint after EoT. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Cyprus |
| Czech Republic |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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