ShorTrip study - Phase II study of Short-course radiotherapy followed by consolidation chemotherapy with the Triplet FOLFOXIRI as total neoadjuvant therapy for locally advanced rectal cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Jan 2022 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-513297-21-00

EudraCT number

2021-001206-29

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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

Secondary objectives 1

1. Secondary objectives of this study are to evaluate: Safety profile;R0 resection rate;Failure-free survival (FFS);Overall survival (OS);Distant relapse;Locoregional failure;Clinical complete response after neoadjuvant treatment;Major pathological response (MPR);Post-operative morbidity and mortality;Quality of life (QoL);Rectal Continence.

Conditions and MedDRA coding

Locally advanced rectal cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. Written informed consent to study procedures and to translational analyses;
2. Age 18-70 years
3. Histologically proven diagnosis of rectal adenocarcinoma
4. Patients with locally advanced rectal cancer defined by the presence of at least one of the following features: o cN2 (defined as at least 4 positive lymphnodes at pelvic MRI) o cT4 o tumor extending to within 1 mm of or beyond mesorectal fascia (i.e., circumferential radial margin threatened or involved) o cT3, N1
5. Distal border of the tumour located between 5 and 12 cm from the anal verge (as measured by pelvic MRI)
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1
7. No evidence of metastatic disease by total body CT-scan
8. Available tumour samples at baseline (archival biopsy)
9. Tumour amenable to curative resection (including pelvic exenteration)
10. No history of invasive rectal malignancy, regardless of disease-free interval
11. No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma) or synchronous colon cancer
12. No clear involvement of the pelvic side walls by imaging
13. Life expectancy of at least 5 years (excluding diagnosis of cancer)
14. Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count ≥100,000/mm3; haemoglobin level ≥ 9 g/dL
15. Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST ≤ 2 times ULN
16. 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
17. 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
18. 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
19. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
20. Will and ability to comply with the protocol

Exclusion criteria 16

1. 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
2. Patients with radiological evidence of distant metastases
3. Previous pelvic radiation therapy
4. Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria
5. Previous treatment with fluoropyrimidine and/or oxaliplatin and/or irinotecan
6. Patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT)
7. Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
8. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
9. 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
10. Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic)
11. Partial or total colectomy
12. 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
13. Known hypersensitivity to fluorouracil, oxaliplatin or irinotecan
14. Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation
15. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
16. Withdrawal of the consent to take part to the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathological complete response (pCR) 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 endpoints 12

1. 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
2. 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.
3. 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
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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
10. Surgical mortality, defined as the percentage of patients, relative to the total of enrolled subjects, experiencing death within 30 days after the surgery
11. 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
12. Quality of Life, (QoL) assessed using the EORTC QLQ-C30, the EORTC QLQ-CR29 and the EuroQol EQ-5D questionnaires, and Rectal Continence, assessed using LARS and 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications