Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer

NCT04495088 | Recruiting Phase 3 DMC

• 2 other identifiers: ACO/ARO/AIO-18.22018-001356-35
• Study Type: interventional
• Target: 550
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multicenter, prospective, randomized, stratified, controlled, open-label study comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with locally advanced rectal cancer and low risk for local failure

Conditions

Rectal Cancer

Keywords

Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• disease-free survival

  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.

  up to 3 years

Secondary Outcomes (13)

• Acute and late toxicity

  From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment

• Compliance (completion rate) of chemotherapy

  From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization

• Surgical morbidity and complications

  After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization

• Pathological UICC-staging, including pCR (ypT0N0) rate

  After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization

• R0 resection rate, Negative circumferential resection rate (CRM > 1mm)

  After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization

Study Arms (2)

A (experimental arm)

EXPERIMENTAL

The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned

Drug: mFOLFOX (neoadjuvant); Drug: XELOX (neoadjuvant)

B (control arm)

ACTIVE COMPARATOR

In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol.

Drug: mFOLFOX (adjuvant); Drug: XELOX (adjuvant); Drug: Capecitabine (adjuvant); Drug: infusional 5-FU/FA "AIO" regimen (adjuvant); Drug: infusional 5-FU/FA "de Gramont" (adjuvant)

Interventions

mFOLFOX (neoadjuvant) DRUG

neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.

Also known as: Folinic acid, Oxaliplatin, 5-FU

A (experimental arm)

XELOX (neoadjuvant) DRUG

neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.

Also known as: Capecitabine, Oxaliplatin

A (experimental arm)

mFOLFOX (adjuvant) DRUG

adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.

Also known as: Folinic acid, Oxaliplatin, 5-FU

B (control arm)

XELOX (adjuvant) DRUG

adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.

Also known as: Capecitabine, Oxaliplatin

B (control arm)

Capecitabine (adjuvant) DRUG

adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.

Also known as: Capecitabine

B (control arm)

infusional 5-FU/FA "AIO" regimen (adjuvant) DRUG

adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.

Also known as: 5-FU, Folinic acid

B (control arm)

infusional 5-FU/FA "de Gramont" (adjuvant) DRUG

adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.

Also known as: 5-FU, Folinic acid

B (control arm)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
• Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors.
• i. Lower third (0-6 cm):
• cT1/2 with clear cN+ based on defined MRI criteria or T3a-b (i.e. maximum infiltration into the perirectal fat of 5mm), provided CRM \> 2mm and EMVI-\*\* ii. Middle third (≥ 6-12 cm):
• cT1/2 with clear cN+ provided CRM- and EMVI-\*\*
• cT3 irrespective of the depth of invasion 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-\*\* iii. 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.
• Spiral-CT of the abdomen and chest to exclude distant metastases.
• Aged at least 18 years. No upper age limit.
• WHO/ECOG Performance Status ≤1.
• Adequate haematological, hepatic, renal and metabolic function parameters:
• Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/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.

You may not qualify if:

• Distant metastases (to be excluded by CT scan of the thorax and abdomen).
• Prior antineoplastic therapy for rectal cancer.
• Prior radiotherapy of the pelvic region.
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
• 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.
• Previous or current drug abuse.
• Other concomitant antineoplastic therapy.
• Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
• Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
• Chronic diarrhea (\> grade 1 according NCI CTCAE).
• 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.
• Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
• Evidence of peripheral sensory neuropathy \> grade 1 according to CTCAE version 5.0 (see appendix).
• Severe kidney dysfunction (creatinine clearance \< 30 ml/min).
• Recent or concurrent treatment with brivudine.

Sponsors & Collaborators

• Ralf Hofheinz: lead
• Deutsche Krebshilfe e.V., Bonn (Germany): collaborator
• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: collaborator
• German Rectal Cancer Study Group: collaborator

Study Sites (1)

Unversity Hospital Mannheim

Mannheim, 68167, Germany

RECRUITING

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Neoadjuvant Therapy; Leucovorin; Oxaliplatin; Fluorouracil; XELOX; Adjuvants, Pharmaceutic; Capecitabine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Pharmaceutic Aids; Pharmaceutical Preparations; Specialty Uses of Chemicals; Chemical Actions and Uses; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Ralf-Dieter Hofheinz, Prof. Dr.

  Universitätsmedizin Mannheim

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ralf-Dieter Hofheinz, Prof. Dr.

CONTACT

+49 621 383; ralf.hofheinz@umm.de

Michelle Tez

CONTACT

+49 69 5899 787; tez.michelle@ikf-khnw.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: open-label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: multicenter, randomized, two-armed

Study Record Dates

• First Submitted: July 28, 2020
• First Posted: July 31, 2020
• Study Start: September 30, 2020
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2030
• Last Updated: February 2, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)