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

Primary Purpose

Rectal Cancer

Status

Recruiting

Phase

Phase 3

Locations

Germany

Study Type

Interventional

Intervention

mFOLFOX (neoadjuvant)

XELOX (neoadjuvant)

mFOLFOX (adjuvant)

XELOX (adjuvant)

Capecitabine (adjuvant)

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

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

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring Rectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below).
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.
MRI-defined inclusion criteria:
- Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria (see SOP in chapter 13.3 of the appendix), provided CRM- and EMVI- (defined as MRI-EMVI score 0-3; see SOP in chapter 13.3 of the appendix)
- Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3a/b, i.e. evidence of extramural tumor spread into the mesorectal fat of ≤ 5 mm provided N-, CRM-, and EMVI-
- Upper third (≥ 12-16 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; any cT3-4 irrespective of nodal status.
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.
QTc interval (Bazett**) ≤ 440 ms
Informed consent of the patient.

"**" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))= ((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion Criteria:

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.
Major surgery within the last 4 weeks prior to inclusion.
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.
On-treatment participation in a clinical study in the period 30 days prior to inclusion.
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.
Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
Known dihydropyrimidine dehydrogenase deficiency.
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).

"***"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).

Sites / Locations

Unversity Hospital MannheimRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

A (experimental arm)

B (control arm)

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Acute and late toxicity

assessment of acute and late toxicity according to NCI CTCAE version 5.0

Compliance (completion rate) of chemotherapy

Rate of completion of administered chemotherapy

Surgical morbidity and complications

Surgical morbidity and complications if surgery is performed and events occur

Pathological UICC-staging, including pCR (ypT0N0) rate

Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)

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

defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist

Tumor regression grading according to Dworak in the experimental arm

Grading of tumor regression according to Dworak in the experimental arm

Rate of sphincter-sparing surgery

Rate of sphincter-sparing surgery if surgery is performed

Rate of W&W with or without local regrowth

Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery

Cumulative incidence of local and distant recurrences

Total number of local and distant recurrences, if they occur

Overall survival

Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up

Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30

Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.

Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29

Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.

Patient reported outcome: Functional outcome according to Wexner score

Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from "never" to "1 per day or more often". The more often the worse the outcome.

Full Information

NCT ID

NCT04495088

First Posted

July 28, 2020

Last Updated

August 12, 2022

Sponsor

Ralf Hofheinz

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT04495088

Brief Title

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

Official Title

Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer and Low Risk for Local Failure: A Randomized Phase III Trial of the German Rectal Cancer Study Group

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Recruiting

Study Start Date

September 30, 2020 (Actual)

Primary Completion Date

August 2030 (Anticipated)

Study Completion Date

August 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Ralf Hofheinz

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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

Detailed Description

Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in order to decrease the rate of local failure. In patients with low risk for local failure in the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant radiotherapy may be omitted. However, distant failure rate is still substantial in the range of 20-25% in these patients highlighting the need for more effective systemic treatment. The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1) patient selection relies on strict and quality controlled MRI features and therefore identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy and surgery is changed in a way that chemotherapy is administered preoperatively to increase the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative treatment in order to administer effective doses of the presumably most effective perioperative treatment at an early time point during the course of disease. Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third) will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer

Keywords

Rectal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

multicenter, randomized, two-armed

Masking

None (Open Label)

Masking Description

open-label

Allocation

Randomized

Enrollment

818 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

A (experimental arm)

Arm Type

Experimental

Arm Description

Arm Title

B (control arm)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

mFOLFOX (neoadjuvant)

Other Intervention Name(s)

Folinic acid, Oxaliplatin, 5-FU

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

XELOX (neoadjuvant)

Other Intervention Name(s)

Capecitabine, Oxaliplatin

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

mFOLFOX (adjuvant)

Other Intervention Name(s)

Folinic acid, Oxaliplatin, 5-FU

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

XELOX (adjuvant)

Other Intervention Name(s)

Capecitabine, Oxaliplatin

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Capecitabine (adjuvant)

Other Intervention Name(s)

Capecitabine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

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

Other Intervention Name(s)

5-FU, Folinic acid

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

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

Other Intervention Name(s)

5-FU, Folinic acid

Intervention Description

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.

Primary Outcome Measure Information:

Title

disease-free survival

Description

Time Frame

up to 3 years

Secondary Outcome Measure Information:

Title

Acute and late toxicity

Description

assessment of acute and late toxicity according to NCI CTCAE version 5.0

Time Frame

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

Title

Compliance (completion rate) of chemotherapy

Description

Rate of completion of administered chemotherapy

Time Frame

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

Title

Surgical morbidity and complications

Description

Surgical morbidity and complications if surgery is performed and events occur

Time Frame