FOLFOX before surgey compared to risk-adapted chemotherapy after surgery in patients with locally advanced rectal cancer and low risk for local failure

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Heidelberg University

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Sep 2020 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

German Cancer Aid

External identifiers

EU CT number

2024-518077-34-00

EudraCT number

2018-001356-35

ClinicalTrials.gov

NCT04495088

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The primary endpoint of this trial is disease-free survival, defined as the time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.
We hypothesize that the 3-year DFS probability would improve from 76% in the standard arm to 85% in the investigational arm (hazard ratio of 0.60). With a power of 90% at a two-sided significance level of 5%, the sample size required to obtain a statistically significant difference is 550 patients (161 events) in total.

Secondary objectives 11

1. Acute and late toxicity assessment according to NCI CTCAE version 5.0
2. Compliance (completion rate) of chemotherapy
3. Surgical morbidity and complications
4. Pathological UICC-staging, including pCR (ypT0N0) rate
5. R0 resection rate; negative circumferential resection rate (CRM > 1mm)
6. Tumor regression grading according to Dworak in the experimental arm
7. Rate of sphincter-sparing surgery
8. Rate of W&W with or without local regrowth
9. Cumulative incidence of local and distant recurrences
10. Overall survival
11. Quality of life and functional outcome based on treatment arm, and surgical procedures

Conditions and MedDRA coding

locally advanced rectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Male and female patients* with histologically confirmed diagnosis of rectal adenocarcinoma localized 0 – 16 cm from the anal verge as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below). *Thera are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
2. Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
3. Transrectal endoscopic ultrasound (EUS) is mandatory and used to help discriminate between T1/2 and early T3 tumors.
4. 4. MRI-defined inclusion criteria: - Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria and cT3a-b (i.e. infiltration up to 5mm into the perirectal fat) (see SOP in chapter 12.3 of the appendix), provided CRM >2mm and EMVI-** (defined as MRI-EMVI score 0-3; see SOP in chapter 12 of the appendix) - Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3 irrespective of the depths of infiltration into the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM > 2 mm), N0 or N1, EMVI-** - Upper third (≥ 12-16 cm): cT1/2 with clear cN+, irrespective of CRM and EMVI; any cT3-4 irrespective of nodal status, CRM and EMVI.
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 hematological, hepatic, renal and metabolic function parameters:
9. Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl
10. Serum creatinine ≤ 1.5 x upper limit of normal
11. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.
12. QTc interval (Bazett***) ≤ 440 ms Formula for QTc interval calculation (Bazett): 𝑄𝑇𝑐=𝑄𝑇̅̅̅̅(ms)√ (𝑠𝑒𝑐)=𝑄𝑇̅̅̅̅(ms)√60𝐹𝑒𝑞𝑢𝑒𝑧 (1𝑚𝑖)
13. Informed consent of the patient.

Exclusion criteria 20

1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).
2. Prior antineoplastic therapy for rectal cancer.
3. Prior radiotherapy of the pelvic region.
4. Major surgery within the last 4 weeks prior to inclusion.
5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
6. Subject (male or female) is not willing to use highly effective**** methods of contraception during treatment and for 6 months (male or female) after the end of treatment. Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure. ****highly effective (i.e. failure rate of <1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).
7. On-treatment participation in a clinical study in the period 30 days prior to inclusion.
8. Previous or current drug abuse.
9. Other concomitant antineoplastic therapy.
10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
11. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
12. Chronic diarrhea (> grade 1 according NCI CTCAE).
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 or hypersensitivity on study medication or to any of the other excipients.
15. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0 (see appendix).
16. Severe kidney dysfunction (creatinine clearance < 30 ml/min).
17. Recent or concurrent treatment with brivudine.
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
19. Known dihydropyrimidine dehydrogenase deficiency (activity score < 1,5 after genetic testing of DPYD variants).† † For adjustments of chemotherapy for patients with DPYD activity score = 1,5 see Protocol section 4.2.4.3
20. 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 is disease-free survival, defined as the time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.

Secondary endpoints 11

1. Acute and late toxicity assessment according to NCI CTCAE version 5.0
2. Compliance (completion rate) of chemotherapy
3. Surgical morbidity and complications
4. Pathological UICC-staging, including pCR (ypT0N0) rate
5. R0 resection rate; negative circumferential resection rate (CRM > 1mm)
6. Tumor regression grading according to Dworak in the experimental arm
7. Rate of sphincter-sparing surgery
8. Rate of W&W with or without local regrowth
9. Cumulative incidence of local and distant recurrences
10. Overall survival
11. Quality of life and functional outcome based on treatment arm, and surgical procedures

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Heidelberg University

Sponsor organisation

Heidelberg University

Address

Seminarstrasse 2, Altstadt Altstadt

City

Heidelberg

Postcode

69117

Country

Germany

Scientific contact point

Organisation

Heidelberg University

Contact name

Prof. Dr. Ralf-Dieter Hofheinz

Public contact point

Organisation

Heidelberg University

Contact name

Prof. Dr. Ralf-Dieter Hofheinz

Third parties 1

Locations

1 EU/EEA country · 71 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 12 files

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

Application history

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