Clinical trial NCT05253846: Short-course Radiotherapy Followed by Consolidation Chemotherapy. 2021-001206-29
Official title: Phase II Study of Short-course Radiotherapy Followed by Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: the ShorTrip Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Locally Advanced Rectal Cancer
Keywords: FOLFOXIRI
Locally advanced rectal cancer
Short-course radiotherapy
Total neoadjuvant strategy
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
First posted: 2022-02-24
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of the ShorTrip trail is to evaluate the activity and the safety of total neoadjuvant strategy with FOLFOXIRI as consolidation therapy preceded by short-course radiotherapy and followed by surgery in LARC patients.

Detailed description: This is a prospective, open-label, multicentre, phase II single arm trial. Eligible patients with middle-high LARC will receive short-course radiotherapy followed by consolidation chemotherapy with FOLFOXIRI and surgery.

The primary objective of this trial is to evaluate the rate of complete pathologic response (pCR)

Eligibility criteria: Inclusion Criteria:

* Written informed consent to study procedures and to translational analyses;
* Age 18-70 years;
* Histologically proven diagnosis of rectal adenocarcinoma;
* Patients with locally advanced rectal cancer defined by the presence of at least one of the following features:

  * cN2 (defined as at least 4 positive lymphnodes at pelvic MRI)
  * cT4
  * tumor extending to within 1 mm of or beyond mesorectal fascia (i.e., circumferential radial margin threatened or involved)
  * cT3, N1
* Distal border of the tumour located between 5 and 12 cm from the anal verge (as measured by pelvic MRI);
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1;
* No evidence of metastatic disease by total body CT-scan;
* Available tumour samples at baseline (archival biopsy);
* Tumour amenable to curative resection (including pelvic exenteration);
* No history of invasive rectal malignancy, regardless of disease-free interval;
* No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma) or synchronous colon cancer;
* No clear involvement of the pelvic side walls by imaging;
* Life expectancy of at least 5 years (excluding diagnosis of cancer);
* Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count

  ≥100,000/mm3; haemoglobin level ≥ 9 g/dL;
* Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST ≤ 2 times ULN;
* Renal function: creatinine clearance \> 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up;
* Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.

However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient; - Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception.

Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;

- Will and ability to comply with the protocol.

Exclusion Criteria:

* Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
* Patients with radiological evidence of distant metastases;
* Previous pelvic radiation therapy;
* Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria;
* Previous treatment with fluoropyrimidine and/or oxaliplatin and/or irinotecan;
* Patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
* Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration;
* Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication;
* Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic);
* Partial or total colectomy;
* Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment;
* Known hypersensitivity to fluorouracil, oxaliplatin or irinotecan;
* Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation;
* Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration;
* Withdrawal of the consent to take part to the study.

Primary outcomes:
measure: complete pathologic response (pCR)
timeFrame: 30 months
Secondary outcomes:
measure: Overall toxicity rate
timeFrame: 30 months
measure: G3/4 toxicity rate
timeFrame: 30 months
measure: R0 Resection Rate
timeFrame: 30 months
measure: Failure-free survival (FFS)
timeFrame: 7 years
measure: Overall Survival (OS)
timeFrame: 7 years
measure: Time to distant metastases
timeFrame: 7 years
measure: Time to locoregional failure
timeFrame: 7 years
measure: Clinical complete response (cCR) rate
timeFrame: 30 months
measure: Major pathological response (MPR) rate
timeFrame: 30 months
measure: Surgical mortality
timeFrame: 30 months
measure: Surgical morbidities
timeFrame: 30 months
measure: Quality of Life (QoL)
timeFrame: until 1 year after surgery
measure: Quality of Life (QoL)
timeFrame: until 1 year after surgery
measure: Quality of Life (QoL)
timeFrame: until 1 year after surgery
measure: Rectal Continence
timeFrame: until 180 days after the ileostomy closure surgery
measure: Rectal Continence
timeFrame: until 180 days after the ileostomy closure surgery
Other outcomes:
measure: Correlation of FFS and pCR with ctDNA status
timeFrame: 7 years
Locations:
city: Pisa
country: Italy
facility: U.O. Oncologia Medica 2 Universitaria - Azienda Ospedaliero-Universitaria Pisana Dipartimento di Ricerca Traslazionale e Nuove Tecnologie - University of Pisa
Study officials:
affiliation: Azienda Ospedaliero, Universitaria Pisana
name: Roberto Moretto, MD
role: PRINCIPAL_INVESTIGATOR
References: