Short course radiotherapy versus chemoradiotherapy, followed by consolidation chemotherapy, and selective organ preservation for MRI-defined intermediate and high-risk rectal cancer patients, A randomized phase III trial of the German Rectal Cancer Study Group

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Goethe University Frankfurt

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Mar 2020 → ongoing

Decision date (initial)

2024-09-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

German Cancer Aid

External identifiers

EU CT number

2024-511577-29-01

EudraCT number

2018-000876-14

ClinicalTrials.gov

NCT04246684

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-cCR, or for any locoregional regrowth after initial cCR requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). With a power of 90% and a two-sided type I error of 5%, the sample size required to obtain a statistically significant difference is 702 patients (564 events) in total.

Secondary objectives 18

1. Disease-free survival
2. Rate of clinical complete response after TNT
3. Rate of immediate TME after TNT
4. Cumulative incidence of locoregional regrowth after cCR
5. Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth
6. Cumulative incidence of local recurrence after (salvage) surgery
7. Postoperative complications of (salvage) surgery
8. Rate of sphincter-sparing (salvage) surgery
9. Pathological TNM-staging
10. R0 resection rate; negative circumferential resection rate
11. Tumor regression grading according to Dworak
12. Neoadjuvant rectal score
13. Quality of TME according to MERCURY
14. Acute and late toxicity assessment according to NCI CTCAE V.5.0)
15. Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation
16. Cumulative incidence of distant metastase
17. Overall survival
18. Translational / biomarker studies

Conditions and MedDRA coding

intermediate and high-risk rectal cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 – 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum).
2. Staging requirements: High-resolution, thin-sliced (i.e. 3 mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
3. MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions: any cT3 if the distal extent of the tumor is < 6 cm from the anocutaneous line, or cT3c/d in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or cT3 with clear cN+ based on strict MRI-criteria (see appendix) cT4 tumors, or Tany middle/low third of rectum with clear MRI criteria for N+, mrCRM+ (≤1mm), or Extramural venous invasion (EMVI+).
4. Transrectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum.
5. Spiral-CT of the abdomen and chest to exclude distant metastases.
6. Aged at least 18 years. No upper age limit.
7. WHO/ECOG Performance Status ≤1.
8. Adequate haematological, hepatic, renal and metabolic function parameters: Leukocytes ≥ 3.000/mm3 , ANC ≥ 1.500/mm3 , platelets ≥ 100.000/mm3 , Hb > 9 g/dl. Serum creatinine ≤ 1.5 x upper limit of normal. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.
9. Informed consent of the patient.

Exclusion criteria 16

1. Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy.
2. Distant metastases (to be excluded by CT scan of the thorax and abdomen).
3. Prior antineoplastic therapy for rectal cancer.
4. Prior radiotherapy of the pelvic region.
5. Major surgery within the last 4 weeks prior to inclusion.
6. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
7. Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
8. On-treatment participation in a clinical study in the period 30 days prior to inclusion.
9. Previous or current drug abuse.
10. Other concomitant antineoplastic therapy.
11. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
12. Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
13. Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non- melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free.
14. Known allergic reactions on study medication.
15. Known dihydropyrimidine dehydrogenase deficiency (activity score < 1,5 after genetic testing of DPYD variants)
16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma.

Secondary endpoints 18

1. Disease-free survival
2. Rate of clinical complete response after TNT
3. Rate of immediate TME after TNT
4. Cumulative incidence of locoregional regrowth after cCR
5. Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth
6. Cumulative incidence of local recurrence after (salvage) surgery
7. Postoperative complications of (salvage) surgery
8. Rate of sphincter-sparing (salvage) surgery
9. Pathological TNM-staging
10. R0 resection rate; negative circumferential resection rate
11. Tumor regression grading according to Dworak
12. Neoadjuvant rectal score
13. Quality of TME according to MERCURY
14. Acute and late toxicity assessment according to NCI CTCAE V.5.0)
15. Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation
16. Cumulative incidence of distant metastases
17. Overall survival
18. Translational / biomarker studies

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Goethe University Frankfurt

Sponsor organisation

Goethe University Frankfurt

Address

Theodor-Stern-Kai 7

City

Frankfurt Am Main

Postcode

60590

Country

Germany

Scientific contact point

Organisation

Goethe University Frankfurt

Contact name

Atefeh Nateghian

Public contact point

Organisation

Goethe University Frankfurt

Contact name

Atefeh Nateghian

Third parties 1

Locations

1 EU/EEA country · 67 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 13 files

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

Application history

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