Short-course Radiotherapy Followed by Consolidation Chemotherapy. 2021-001206-29

Phase 2

Active, not recruiting

• Conditions: Locally Advanced Rectal Cancer
• Interventions: Drug: Irinotecan; Drug: Oxaliplatin; Drug: Lederfolin; Drug: 5-Fluorouracil; Radiation: Short-course radiotherapy; Procedure: TME

• Registration Number: NCT05253846
• Lead Sponsor: Gruppo Oncologico del Nord-Ovest

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)

Study Timeline

• Study First Submitted: 2022-01-17
• Study Start: 2022-01-25
• Study First Submitted QC: 2022-02-14
• Study First Posted: 2022-02-24
• Status Verified: 2024-03
• Last Update Submitted: 2024-07-24
• Last Update Posted: 2024-07-25
• Primary Completion: 2024-12-31
• Study Completion: 2028-10-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 63

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
SCRT--> FOLFOXIRI--> SURGERY	Lederfolin	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy
SCRT--> FOLFOXIRI--> SURGERY	Short-course radiotherapy	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy
SCRT--> FOLFOXIRI--> SURGERY	TME	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy
SCRT--> FOLFOXIRI--> SURGERY	Irinotecan	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy
SCRT--> FOLFOXIRI--> SURGERY	Oxaliplatin	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy
SCRT--> FOLFOXIRI--> SURGERY	5-Fluorouracil	SHORT-COURSE RT FOLFOXIRI * IRINOTECAN 165 mg/sqm iv over 60 minutes, day 1 followed by * OXALIPLATIN 85 mg/sqm iv over 2 hours, day 1 in two-way with * LEDERFOLIN 200 mg/sqm iv over 2 hours, day 1 followed by * 5-FLUOROURACIL 3200 mg/sqm 48 h-continuous infusion, starting on day 1. The chemotherapy treatment will be repeated every 2 weeks up to 8 cycles. Surgery with TME should be performed after 4 weeks after the last cycle of chemotherapy

Primary Outcome Measures

Name	Time	Method
complete pathologic response (pCR)	30 months	Pathological complete response rate, defined as the percentage of patients, relative to the total of enrolled subjects, with the absence of residual tumour cells in the resected specimens. pCR will be assessed by tumour regression grade according to Dworak et al, at the histopathological exam

Secondary Outcome Measures

Name	Time	Method
G3/4 toxicity rate	30 months	G3/4 toxicity rate, is defined as the percentage of patients, relative to the total of enrolled subjects, who receive radiotherapy and at least one cycle of chemotherapy, experiencing a specific adverse event of grade 3/4, according the RTOGTC during SCRT, and according to National Cancer Institute Common Toxicity Criteria (version 5.0), during the consolidation chemotherapy.
Overall Survival (OS)	7 years	Overall Survival (OS) is defined as the time from enrolment to death from any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive
Overall toxicity rate	30 months	Overall toxicity rate, defined as the percentage of patients, relative to the total of enrolled subjects, who receive radiotherapy and at least one cycle of chemotherapy, experiencing any adverse event, according the RTOGTC during SCRT, and according to National Cancer Institute Common Toxicity Criteria (version 5.0), during the consolidation chemotherapy
R0 Resection Rate	30 months	R0 Resection Rate is defined as the percentage of patients, relative to the total of enrolled subjects, undergoing R0 resection of primary tumour. R0 surgery is defined as microscopically margin-negative resection at the histopatological exam
Time to distant metastases	7 years	Time to distant metastases, is defined as the time from enrolment to the radiological evidence of distant metastases. The determination of the evidence of distant metastases will be based on investigator-reported measurements. Patients who are died or alive without having distant metastases at the end of the study will be censored at the date of death or their last radiological assessment, respectively
Major pathological response (MPR) rate	30 months	Major pathological response (MPR) rate, defined as the percentage of patients, relative to the total enrolled subjects, achieving TRG1-2 sec Mandard or TRG3-4 sec Dworak at the histopathological exam
Time to locoregional failure	7 years	Time to locoregional failure is defined as the time from the enrolment to non-radical surgery of the primary tumour (non R0/R1 resection) or intrapelvic recurrence after R0/1 resection of the primary tumour. The determination of the intrapelvic recurrence will be based on investigator-reported assessment. Patients who are died or alive without having non-radical surgery or intrapelvic recurrence at the end of the study will be censored at the date of death or at their last radiological assessment
Surgical morbidities	30 months	Surgical morbidities, defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any post-operative complications within 30 days after the surgery
Quality of Life (QoL)	until 1 year after surgery	Quality of Life, (QoL) assessed using the EuroQol EQ-5D questionnaires, will be evaluate at specific time-points (baseline, after radiotherapy, and chemotherapy, after surgery and during follow-up) and will be assessed through descriptive summary statistics
Failure-free survival (FFS)	7 years	Failure-free survival (FFS) is defined as the time from enrollment to one of the following events: non-radical surgery (non R0/R1) of the primary tumour, intrapelvic recurrence after R0/1 resection of the primary tumour, distant relapse, second primary tumour or death from any cause, whichever occurred first. The determination of disease progression will be based on investigator-reported measurements. Patients who are alive without having one of the above events at the end of the study will be censored at their last radiological assessment
Clinical complete response (cCR) rate	30 months	Clinical complete response (cCR) rate, defined as the percentage of patients, relative to the total of enrolled subjects, with the absence of residual tumour (cT0cN0) at the radiological and endoscopic staging after neoadjuvant treatment.
Surgical mortality	30 months	Surgical mortality, defined as the percentage of patients, relative to the total of enrolled subjects, experiencing death within 30 days after the surgery
Rectal Continence	until 180 days after the ileostomy closure surgery	Rectal Continence, assessed using St. Mark Continence scores, will be evaluate at specific time-points (baseline, after radiotherapy, and chemotherapy, after surgery and during follow-up) and will be assessed through descriptive summary statistics

Trial Locations

Locations (1)

U.O. Oncologia Medica 2 Universitaria - Azienda Ospedaliero-Universitaria Pisana Dipartimento di Ricerca Traslazionale e Nuove Tecnologie - University of Pisa; 🇮🇹 Pisa, Italy