Efficacy and safety of conventional neoadjuvant therapy versus total neoadjuvant therapy in older patients with locally advanced rectal cancer: a multicentre, open-label, randomised pragmatic clinical trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Jules Bordet

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Feb 2024 → ongoing

Decision date (initial)

2024-01-08

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Belgian Health Care Knowledge Centre (KCE)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the trial is to demonstrate that a neoadjuvant treatment strategy of SCRT or LCCRT followed by surgery plus or minus adjuvant chemotherapy is a better trade-off between efficacy and safety than total neoadjuvant therapy (TNT) in an older rectal cancer population.

Secondary objectives 3

1. To assess short- and long-term efficacy of the study treatments
2. To assess safety and quality of life of the study treatments
3. To evaluate the impact of study treatments in terms of use of healthcare resources

Conditions and MedDRA coding

locally advanced rectal cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age ≥ 70 years old
2. ECOG performance status (PS): ≤1 if age > 75 years old, ≤2 if age ≤ 75 years old
3. Histologically or cytologically confirmed adenocarcinoma of the rectum
4. Distal border of the tumour below the peritoneal reflection and within 15 cm of the anal verge
5. Operable stage III or high-risk stage II rectal cancer (high-risk tumours defined as those having ≥1 of the following features: T4, mesorectal fascia (MRF) involvement/threatening [i.e.,tumour within 1 mm of the MRF], extramural venous invasion). Patient with involvement of lateral pelvic lymph nodes are also eligible.
6. Adequate bone marrow function as defined below: - Absolute neutrophil count ≥1,500/µL - Haemoglobin ≥9 g/dL - Platelets ≥100,000/µL
7. Adequate liver function as defined below: - Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert’s syndrome <3xUNL is allowed - AST (SGOT) and ALT (SGPT) ≤2.5 x ULN - Alkaline phosphatase ≤2.5 x ULN
8. Adequate renal function as defined by estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m² (according to the CKD-EPI 2021 equation)
9. Absence of clinical conditions that in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery.
10. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
11. Male subjects with partners of childbearing potential must agree to use condom during the course of this study and for at least 6 months after the last administration of study drugs.

Exclusion criteria 12

1. Extensive growth into cranial part of the sacrum (above S2/3 junction) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is achieved.
2. Complete dihydropyrimidine dehydrogenase (DPD) deficiency.
3. Any previous treatment for rectal cancer
4. Presence of metastatic disease or recurrent rectal tumour.
5. Presence of grade ≥2 peripheral neuropathy according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0.
6. Significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.
7. Any contraindication to pelvic irradiation as evaluated by the investigator.
8. Known hypersensitivity reactions to the study drugs or to any excipients, premedications or non-investigational medicinal products or concomitant medications.
9. Any investigational anti-cancer therapy other than the protocol specified therapies (participation in other prospective studies which do not imply any specific intervention may be allowed after discussion with the Study Chair).
10. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment.
11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (grade III or IV as classified by the New York Heart Association), or serious cardiac arrhythmia requiring medication medication within the past 6 months.
12. Use of brivudine, sorivudine or their chemically related analogues.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is Net Benefit Treatment, according to the following hierarchical outcome measures: 1. Overall survival at 3 years after randomisation 2. Progression-free survival at 3 years after randomisation 3. Increased-grade peripheral sensory neuropathy at 3 years after randomisation 4. Grade ≥3 toxicities during treatment

Secondary endpoints 7

1. Safety of study treatments defined as the frequency of adverse events reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
2. Quality of Life based on EORTC-QLQ-C30, EORTC-QLQ-C29, EORTC-QLQ-CIPN20 and EQ-5Q-5L questionnaires
3. Compliance to treatment
4. Pathological complete response
5. R0 resection
6. Organ preservation
7. Use of healthcare resources

Investigational products

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

Test 3

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Jules Bordet

Sponsor organisation

Institut Jules Bordet

Address

Mijlenmeersstraat 90

City

Brussels

Postcode

1070

Country

Belgium

Scientific contact point

Organisation

Institut Jules Bordet

Contact name

Clinical Trial Support Unit

Public contact point

Organisation

Institut Jules Bordet

Contact name

Clinical Trial Support Unit

Locations

1 EU/EEA country · 26 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 36 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