MFOLFOX (neoadjuvant) og XELOX (neoadjuvant) og mFOLFOX (adjuvant) i Endetarmskreft - Klinisk prøveregister

Studieoversikt

Status

Avsluttet

Forhold

Endetarmskreft

Intervensjon / Behandling

Detaljert beskrivelse

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.

Studietype

Intervensjonell

Registrering (Faktiske)

215

Fase

Fase 3

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

Tyskland
- - Mannheim, Tyskland, 68167
    - Unversity Hospital Mannheim

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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:

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.
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).

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

Primært formål: Behandling
Tildeling: Randomisert
Intervensjonsmodell: Parallell tildeling
Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm Deltakergruppe / Arm En gruppe eller undergruppe av deltakere i en klinisk studie som mottar en spesifikk intervensjon/behandling, eller ingen intervensjon, i henhold til studiens protokoll.	Intervensjon / Behandling Intervensjon / Behandling En prosess eller handling som er fokus for en klinisk studie. Intervensjoner inkluderer legemidler, medisinsk utstyr, prosedyrer, vaksiner og andre produkter som enten er undersøkende eller allerede er tilgjengelige. Intervensjoner kan også inkludere ikke-invasive tilnærminger, som utdanning eller modifisering av kosthold og trening.
Eksperimentell: A (experimental arm) 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	Legemiddel: mFOLFOX (neoadjuvant) 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. Andre navn: Folinsyre, oksaliplatin, 5-FU Legemiddel: XELOX (neoadjuvant) 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. Andre navn: Capecitabin, oksaliplatin
Aktiv komparator: B (control arm) 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.	Legemiddel: mFOLFOX (adjuvant) 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. Andre navn: Folinsyre, oksaliplatin, 5-FU Legemiddel: XELOX (adjuvant) 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. Andre navn: Capecitabin, oksaliplatin Legemiddel: Capecitabine (adjuvant) 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. Andre navn: Capecitabin Legemiddel: infusional 5-FU/FA "AIO" regimen (adjuvant) 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. Andre navn: 5-FU, folinsyre Legemiddel: infusional 5-FU/FA "de Gramont" (adjuvant) 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. Andre navn: 5-FU, folinsyre

Deltakergruppe / Arm

Intervensjon / Behandling

Eksperimentell: A (experimental arm)

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

Legemiddel: mFOLFOX (neoadjuvant)

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.

Andre navn:

Folinsyre, oksaliplatin, 5-FU

Legemiddel: XELOX (neoadjuvant)

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.

Andre navn:

Capecitabin, oksaliplatin

Aktiv komparator: B (control arm)

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.

Legemiddel: mFOLFOX (adjuvant)

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.

Andre navn:

Folinsyre, oksaliplatin, 5-FU

Legemiddel: XELOX (adjuvant)

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.

Andre navn:

Capecitabin, oksaliplatin

Legemiddel: Capecitabine (adjuvant)

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.

Andre navn:

Capecitabin

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

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.

Andre navn:

5-FU, folinsyre

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

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.

Andre navn:

5-FU, folinsyre

Hva måler studien?

Primære resultatmål

Resultatmål	Tiltaksbeskrivelse	Tidsramme
disease-free survival Tidsramme: up to 3 years	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

Sekundære resultatmål

Resultatmål	Tiltaksbeskrivelse	Tidsramme
Acute and late toxicity Tidsramme: From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment	assessment of acute and late toxicity according to NCI CTCAE version 5.0	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 Tidsramme: From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization	Rate of completion of administered 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 Tidsramme: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization	Surgical morbidity and complications if surgery is performed and events occur	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Pathological UICC-staging, including pCR (ypT0N0) rate Tidsramme: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization	Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
R0 resection rate, Negative circumferential resection rate (CRM > 1mm) Tidsramme: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization	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	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Tumor regression grading according to Dworak in the experimental arm Tidsramme: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization	Grading of tumor regression according to Dworak in the experimental arm	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Rate of sphincter-sparing surgery Tidsramme: After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization	Rate of sphincter-sparing surgery if surgery is performed	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Rate of W&W with or without local regrowth Tidsramme: Up to 5 years after end of treatment	Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery	Up to 5 years after end of treatment
Cumulative incidence of local and distant recurrences Tidsramme: Up to 5 years after end of treatment	Total number of local and distant recurrences, if they occur	Up to 5 years after end of treatment
Overall survival Tidsramme: Up to at least 3 years and until 5 years	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	Up to at least 3 years and until 5 years
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30 Tidsramme: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months	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.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29 Tidsramme: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months	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.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
Patient reported outcome: Functional outcome according to Wexner score Tidsramme: From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months	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.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Ralf Hofheinz

Samarbeidspartnere

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Deutsche Krebshilfe e.V., Bonn (Germany)

German Rectal Cancer Study Group

Etterforskere

Hovedetterforsker: Ralf-Dieter Hofheinz, Prof. Dr., Universitätsmedizin Mannheim

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

30. september 2020

Primær fullføring (Faktiske)

31. juli 2026

Studiet fullført (Faktiske)

31. juli 2026

Datoer for studieregistrering

Først innsendt

28. juli 2020

Først innsendt som oppfylte QC-kriteriene

28. juli 2020

Først lagt ut (Faktiske)

31. juli 2020

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

2. oktober 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

29. september 2026

Sist bekreftet

1. september 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Endetarmskreft

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

ACO/ARO/AIO-18.2
2018 (U.S. NIH-stipend/kontrakt)
2018-001356-35 (EudraCT-nummer)

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

NEI

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

Denne informasjonen ble hentet direkte fra nettstedet clinicaltrials.gov uten noen endringer. Hvis du har noen forespørsler om å endre, fjerne eller oppdatere studiedetaljene dine, vennligst kontakt register@clinicaltrials.gov. Så snart en endring er implementert på clinicaltrials.gov, vil denne også bli oppdatert automatisk på nettstedet vårt. .

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Studieoversikt

Status

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Studietype

Registrering (Faktiske)

Fase

Kontakter og plasseringer

Studiesteder

Deltakelseskriterier

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

Tar imot friske frivillige

Kjønn som er kvalifisert for studier

Beskrivelse

Studieplan

Hvordan er studiet utformet?

Designdetaljer

Antall våpen

Våpen og intervensjoner

Deltakergruppe / Arm

Intervensjon / Behandling

Hva måler studien?

Primære resultatmål

Resultatmål

Tiltaksbeskrivelse

Tidsramme

Sekundære resultatmål

Resultatmål

Tiltaksbeskrivelse

Tidsramme

Samarbeidspartnere og etterforskere

Sponsor

Samarbeidspartnere

Etterforskere

Studierekorddatoer

Studer hoveddatoer

Studiestart (Faktiske)

Primær fullføring (Faktiske)

Studiet fullført (Faktiske)

Datoer for studieregistrering

Først innsendt

Først innsendt som oppfylte QC-kriteriene

Først lagt ut (Faktiske)

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

Siste oppdatering sendt inn som oppfylte QC-kriteriene

Sist bekreftet

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Studerer et amerikansk FDA-regulert enhetsprodukt