A study to test the effect of chemotherapy before surgery compared to surgery alone in patients with high risk retroperitoneal sarcoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

European Organisation For Research And Treatment Of Cancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Oct 2020 → ongoing

Decision date (initial)

2023-08-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Horizon Europe funding program (project 101103843) · Anticancer fund · INCA · Novo Nordisk Foundation · European Organisation for the Research and Treatment of Cancer

External identifiers

EU CT number

2023-505261-84-00

EudraCT number

2019-003543-30

ClinicalTrials.gov

NCT04031677

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

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 6

1. 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
2. To assess tumour response in patients undergoing preoperative chemotherapy
3. 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
4. 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
5. To transform self-reported quality of life data into health utility values, ready to be used in subsequent health economic analyses. To compare the outcome of these patients with the outcome of an observational cohort of patients (STREXIT 2) eligible for but not randomized into STRASS 2 to see how the outcome of the randomized patients compares with real-life, clinical practice data.
6. If feasible, to augment the analysis of STRASS 2 with patients from the STREXIT 2 cohort to compare the outcome of patients treated with preoperative chemotherapy followed by surgery versus surgery alone in the pooled patient populations, as well as in the LPS and LMS subgroups separately.

Conditions and MedDRA coding

Primary high risk leiomyosarcoma or liposarcoma of retroperitoneal space or infra-peritoneal spaces of pelvis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. STRASS 2: Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.
2. STRASS 2: 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.
3. STRASS 2: ≥ 18 years old (no upper age limit)
4. STRASS 2: WHO performance status ≤ 2
5. STRASS 2: Adequate haematological and organ function
6. STRASS 2: American Society of Anaesthesiologist (ASA) score < 3
7. STRASS 2: 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.
8. STREXIT 2: Patients with histologically proven primary resectable localized high-risk DDLPS or LMS of retroperitoneal space or infra-peritoneal spaces of pelvis (as described in the inclusion criteria of STRASS 2) but for whom the list of eligibility criteria for the study is too restrictive.
9. STREXIT 2: Patients who meet all eligibility criteria of STRASS 2 but do not consent to randomization or are not enrolled for any other reason.
10. STREXIT 2: Patients enrolled in a Registry collecting data on primary RPS patients in the centres participating in STRASS 2 (e.g., RESAR) and who satisfy the above criteria.
11. Preferences for neoadjuvant chemotherapy in STRASS 2 substudy: All patients recruited to STRASS 2 in participating centres (Australia +/- international sites) that are able to read, comprehend and write in English at a sufficient level to complete study materials.
12. STRASS 2: Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to randomization. Note: a woman is considered of childbearing potential, i.e. fertile, if she is following menarche. She remains of childbearing potential until she becomes post-menopausal or 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 consecutive months without menses, a single FSH measurement is insufficient.
13. STRASS 2: 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.
14. STRASS 2: 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.
15. STRASS 2: 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.
16. STRASS 2: Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
17. STRASS 2: Unifocal tumour
18. STRASS 2: 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.
19. STRASS 2: 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.
20. STREXIT 2: Retrospectively all the patients observed and treated since the site activation for STRASS 2 to the opening of STREXIT2 can be included provided they consented before enrolment and the clinical data and/or CT/MRI images can be accessed.

Exclusion criteria 16

1. Sarcoma originating from bone structure, abdominal or gynecological viscera
2. 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.
3. 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
4. Active and uncontrolled infections
5. Vaccination with live vaccines within 30 days prior to study entry
6. Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
7. Other invasive malignancy within 5 years, with the exception of adequately treated non-melanoma skin cancer, localized cervical cancer, localized and Gleason ≤ 6prostate cancer.
8. Uncontrolled severe illness, infection, medical condition (including but not limited to uncontrolled diabetes and recent thromboembolic event in dose adjustments of the anticoagulation), other than the primary LPS or LMS of the retroperitoneum.
9. 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
10. Known contraindication to imaging tracer and to MRI
11. Tumour grading not assessable from biopsy (except for LMS)
12. Extension through the sciatic notch or across the diaphragm
13. Metastatic disease
14. Any previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy for the present tumour
15. Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites or to any of their excipients
16. Cardiac disorders: 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 13

1. Overall survival
2. Recurrence free survival
3. Distant metastases free survival
4. Cumulative incidence of local recurrences
5. Cumulative incidence of distant metastases
6. Radiological response to neoadjuvant chemotherapy according to RECIST
7. Radiological response to neoadjuvant chemotherapy according to CHOI
8. Pathological response
9. Safety and toxicity of neoadjuvant chemotherapy
10. Perioperative complications
11. Late complications
12. Health-Related Quality of life (EORTC QLQ-C30 + Item list from QLQ-STO22)
13. Health utility, calculated from the collected patient-reported HRQoL data and patient demographics economics.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 13

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

European Organisation For Research And Treatment Of Cancer

Sponsor organisation

European Organisation For Research And Treatment Of Cancer

Address

Emmanuel Mounierlaan 83 Bus 11

City

Sint-Lambrechts-Woluwe

Postcode

1200

Country

Belgium

Scientific contact point

Organisation

European Organisation For Research And Treatment Of Cancer

Contact name

Stéphanie Kromar

Public contact point

Organisation

European Organisation For Research And Treatment Of Cancer

Contact name

Vassilis Golfinopoulos

Third parties 12

Locations

10 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 2 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 98 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications