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Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Oxaliplatin

Fluorouracil

Capecitabine

Neoadjuvant radiation therapy : 5Gyx5 Neoadjuvant chemo therapy : CAPOX (Oxaliplatin 130mg/m2, Capecitabine2000mg/m2/day, d1-14, 3week)x6cycles Operation: Total methorectum excision wiht radical lymph node dissection

Radiation

CAPOX (Oxaliplatin 130mg/m2, Capecitabine2000mg/m2/day, d1-14, 3week)x6cycles

Chemotherapy

Operation: Total methorectum excision wiht radical lymph node dissection

Surgery

Mamoru Uemura, MD, PhD

Yoshinori Kagawa, MD, PhD

Yoshinori Kagawa

Mamoru Uemura

A multicenter single-arm phase 2 study to evaluate safety and efficacy of the total neoadjuvant therapy of short course radiation therapy followed by neoadjuvant oxaliplatin/fluorouracil-based chemotherapy (CAPOX) for cT2 rectal cancer

To evaluate the efficacy and safety of preoperative radiation therapy followed by preoperative chemotherapy and surgery for T2 advanced rectal cancer.

A Multicenter Single-arm P2 to Evaluate Safety and Efficacy of the Total Neoadjuvant Therapy for cT2 Rectal Cancer

A Multicenter Single-arm Phase 2 Study to Evaluate Safety and Efficacy of the Total Neoadjuvant Therapy of Short Course Radiation Therapy Followed by Neoadjuvant Oxaliplatin/Fluorouracil-based Chemotherapy (CAPOX) for cT2 Rectal Cancer.

pCR is evaluated by using the grading scale according to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma

Osaka University

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine

Antibodies

Immunomodulating Agents

Immunoglobulins

Antimetabolites

Participants will receive 5\*5Gy node-sparing short-course radiation (radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes) concurrently with total neoadjuvant CAPOX and sintilimab regimens: Oxaliplatin, 130mg/m2, intravenous infusion,d1 of each cycle; Capecitabine, 1000mg/m2, PO, BID, d1-14 and sintilimab, 200mg intravenous infusion d1 of each cycle. CAPOX and sintilimab are repeated every 3 weeks for 8 cycles. Patients with cCR will be managed with a WW strategy, and patients who did not achieve cCR will receive TME surgery.

Interventions:

* Radiation: node-sparing short-course radiation
* Drug: PD-1 antibody (Sintilimab)
* Drug: Capecitabine
* Drug: Oxaliplatin

5Gy\*5d, radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes

node-sparing short-course radiotherapy

200mg intravenous infusion d1 of each cycle\*8cycles

Sintilimab

1000mg/m2, PO, BID, d1-14 of each cycle\*8cycles

130mg/m2, intravenous infusion,d1 of each cycle\*8cycles

laparoscopic or robotic TME surgery for non-cCR patients

TME surgery

watch and wait

jinlin du, master

cheng cai, master

Cheng Cai, master

Jinlin Du, master

phase II clinical trial to evaluate node-sparing short-course radiation combined with total neoadjuvant CAPOX and Sintilimab for MSS locally advanced rectal cancers.

This is an open-label, prospective, single-center phase II clinical trial to evaluate node-sparing short-course radiation (Radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes) combined with total neoadjuvant CAPOX and PD-1 Inhibitor (Sintilimab) for patients with MSS locally advanced of middle and low rectal cancer. A total of 47 patients will be enrolled in this trial. The primary endpoint is the complete response(CR) rate, which includes cCR and pCR. The organ preservation rate, tumor regression grade, 3-year DFS, 3-year OS, and adverse effects will also be analyzed.

Radiation: node-sparing short-course radiotherapy (5Gy\*5d) Drug: PD-1 antibody (Sintilimab) Drug: Capecitabine Drug: Oxaliplatin

Node-sparing Radiotherapy Combined With Total Neoadjuvant CAPOX and Sintilimab for MSS Middle and Low Rectal Cancer

Total Neoadjuvant CAPOX And PD-1 Inhibitor（Sintilimab） Combined With Node-sparing Short-course Radiotherapy For MSS Locally Advanced Of Middle And Low Rectal Cancer(CASINOs): An Open Label, Single-arm, Prospective Clinical Trial

JinhuaCH will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.

Pathological complete response (pCR) ：absence of residual tumour on resected specimen. Clinical complete response（cCR）: no residual tumour visible on imaging or colonoscopy and biopsy.

TRG is evaluated according to the AJCC system. TRG0-1 is defined as good response, TRG2 as moderate response, and TRG3 as poor response.

Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology.

the time from randomization to recurrence of tumor or death

Rate of radiotherapy, chemotherapy and immunotherapy related adverse events

Rectal specific quality of life according to European Organization for Research and Treatment of Cancer ( EORTC) Quality of life questionnaire QLQ-CR29. scale from 0 to 100, A higher scale represents better function and a higher quality of life.

Quality of life according to EORTC Quality of life Questionnaire QLQ-C30 version 3.0. Score range from 0 to 100 points. A higher score represents better function and a higher quality of life.

The change of severity of fecal incontinence assessment according to Wexner score. a score from 0-20, where 0 is perfect continence and 20 is complete incontinence.

Jinhua Central Hospital

Clinical Professor

The experimental strategy is the omission of radical surgery if complete or almost complete response after neoadjuvant treatment for locally advanced rectal cancer

Patients with a complete response or a almost complete response after neoadjuvant treatment will be offered an organ preservation strategy

Organ Preservation

Javier Gallego, PhD

Silvia Fernández, MS

Antonio Arroyo, PhD

Francisco J Sola-Vera, PhD

PRONAR trial aims to assess if treatment with organ preservation in stage II and III rectal cancer after a complete or almost complete response to neoadjuvant treatment is feasible and safe in our environment.

The main objective of this project is to implement the organ preservation strategy in the treatment of rectal cancer in our environment within a clinical study that allows the analysis of its results in terms of survival.

The secondary objective is to assess local relapse, distant relapse and quality of life.

After pathology confirmed rectal cancer patients with stage II and III (MRI, CT and endoscopy) will be identified in the first visit to Medical Oncology Department. Patients will receive the most appropriate neoadjuvant treatment according to clinical guidelines.

Response to neoadjuvant treatment will be assessed by MRI. Those patients with a complete response in MRI, confirmed by endoscopy, will be offered a "watch and wait" strategy. Patients with a complete response in MRI, with an almost complete response in endoscopy, will be offered transanal endoscopic microsurgery. All patients with complete or near complete response will sign an informed consent before study entry.

Radical surgery will be performed in patients without complete or almost complete response criteria after neoadjuvant treatment.

Patients in organ preserving strategy will be subjected to a more intensive follow up schedule, including MRI and endoscopy, compared to patients with radical surgery.

As the complete histopathologic response rate after neoadjuvant treatment in locally advanced rectal cancer is approximately 15-20%, considering that approximately 40 patients with locally advanced rectal cancer are diagnosed annually in our setting, approximately 6-8 patients per year could be potentially recruited for this project, until reaching an initial sample of 30 patients for evaluation.

The following results will be analyzed:

* Percentage of complete and almost complete responses.
* Percentage of watch and wait and transanal endoscopic microsurgery.
* Disease free survival.
* Overall survival.
* Local relapse rate.
* Distant relapse rate.
* Treatment and outcomes of relapses.
* Colostomy free survival.
* Quality of life.

All data will be obtained from patient's medical records

Organ Preservation in Locally Advanced Rectal Cancer

ORGAN PRESERVATION AFTER NEOADJUVANT TREATMENT FOR LOCALLY ADVANCED RECTAL CANCER

It is planned to share global data analysis

Occurrence of complete and almost complete responses assessed by MRI and confirmed by endoscopy after neoadjuvant treatment

Treatment administered in case of relapse

Patients with a complete or almost complete response after a neoadjuvant treatment will be offered an organ preservation strategy

Occurrence of local relapse in patients with an organ preservation strategy

Occurrence of distant relapse in patients with an organ preservation strategy

Assess QLQ-C30 in patients with an organ preservation strategy

Assess QLQ-CR38 in patients with an organ preservation strategy

Hospital General Universitario Elche

Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana

1) RT (54Gy) plus daily concomitant capecitabine 825mg/m2 bid, followed by mFOLFOX6 or XELOX for 4 cycles (12 weeks), starting 1 week after radiotherapy ended;

2) RT (54Gy) plus daily concomitant capecitabine 825mg/m2 bid, followed by capecitabine 2000mg/m2/day for 14 days in a 21 days cycle for 4 cycles (12 weeks), starting 1 week after radiotherapy ended;

Patients will receive 5FU + Oxaliplatin during the consolidation chemotherapy after long course chemoradiation

Patients will receive 5FU during the consolidation chemotherapy after long course chemoradiation

Rodrigo O Perez, Dr

Gustavo Rossi

Adrian Mattacheo

Soledad Iseas

Maria Dolores Daneri

Julio Lococo

Fabio Lopez Queiroz

Marcela Maria Silvino Craveiro

Fabio Henrique de Oliveira

Miguel Dutra Schmitz

Daniel de Barcellos Azambuja

Daniel de Carvalho Damin

Gabriel Prolla

Fabricio Marcondes

Rafael Dutra Vila

Marcus Vinicius Motta Valadão da Silva

Anelisa Kruschewsky Coutinho Araujo

Anelisa Kruchewsky Coutinho Araujo

Maurício Fraga da Silva

Mauricio Fraga da Silva

Fabio Roberto Kater

Pedro Luiz Serrano Uson Junior

Renata D'Alpino Peixoto

Michel Fabiano Silva Alves

Marcia Rachel da Fonseca

Marcelo Viola

Background: Neoadjuvant chemoradiation (nCRT) has been considered the preferred initial treatment strategy for distal rectal cancer. Advantages of this approach include improved local control after radical surgery but also the opportunity for organ preserving strategies (Watch and Wait - WW). Consolidation chemotherapy (cCT) regimens using fluoropyrimidine-based with or without oxaliplatin following nCRT have demonstrated to increase complete response and organ preservation rates among these patients. However, the benefit of adding oxaliplatin to cCt compared to fluoropyrimidine alone regimens in terms of primary tumor response remains unclear. Since oxaliplatin-treatment may be associated with considerable toxicity, it becomes imperative to understand the benefit of its incorporation into standard cCT regimens in terms of primary tumor response. The aim of the present trial is to compare the outcomes of 2 different cCT regimens following nCRT (fluoropyrimidine-alone versus fluoropyrimidine+oxaliplatin) for patients with distal rectal cancer.

Methods: In this multi-centre study, patients with magnetic resonance-defined distal rectal tumors will be randomized on a 1:1 ratio to receive long-course chemoradiation (54Gy) followed by cCT with fluoropyrimidine alone versus fluoropyrimidine+oxaliplatin. Magnetic resonance (MR) will be analyzed centrally prior to patient inclusion and randomization. mrT2-3N0-1 tumor located no more than 1cm above the anorectal ring determined by sagittal views on MR will be eligible for the study. Tumor response will be assessed after 12 weeks from radiotherapy (RT) completion. Patients with clinical complete response (clinical, endoscopic and radiological) will be enrolled in an organ-preservation program (WW). The primary endpoint of this trial is decision to organ-preservation surveillance (WW) at 18 weeks from RT completion.

Discussion: Long-course nCRT with cCT is associated with improved complete response rates and may be a very attractive alternative to increase the chances for organ-preservation strategies. Fluoropyrimidine-based cCT with or without oxaliplatin has never been investigated in the setting of a randomized trial to compare clinical response rates and the possibility of organ-preservation. The outcomes of this study may significantly impact clinical practice of patients with distal rectal cancer interested in organ-preservation.

Patients and Methods

Patients with distal rectal cancer will be eligible for the study after initial clinical, endoscopic and radiological assessment. At this point, patients will be offered to participate in the study and after informed consent, randomized to control or experimental arms as follows.

Endpoints

Primary endpoint: Decision to Watch and Wait due to clinical complete response achieved at 18 weeks from last date of radiation using clinical (DRE), endoscopic and radiological criteria (mrTRG grade) or near-complete clinical response (no progressive disease clinically, endoscopically or radiologically)

Definition of clinical complete response (cCR) available below and at the discretion of the attending surgeon.

Definition of radiological complete response as described below (centralized).

Patients will be counted as event if at 18 weeks the decision is to interrupt Watch and Wait and proceed to surgery (any kind) because of overt incomplete clinical response. In order to standardize assessment of response and reduce inter-observer variability, the decision to continue on Watch and Wait (or not) will be at the discretion of the central committee during central revision of studies.

Secondary endpoints:

* Surgery-free survival at 3 years
* TME-free survival at 3 years
* Distant metastases free survival at 3 years
* Local regrowth-free survival at 3 years
* Colostomy-free survival at 3 years

Definitions

Definition of cCR:

* Endoscopic: white scar, teleangiectasia, absence of ulceration and/or mass 6
* Clinical: no irregularity, firm area with minor induration6
* Radiological: mrTRG1: fibrosis with low signal intensity seen on T2 weighted images replacing the primary tumor; no restricted diffusion on diffusion weighted images; no nodes with border irregularity or mixed signal intensity; no extramural vascular invasion23-26

Definition of near-complete response:

* Endoscopic: residual tumor size ≤2cm (or reduction of ≥70% original tumor volume/size) 4,27,28
* Clinical: only superficial ulceration or minor (questionable) irregularities of the mucosal/rectal wall
* Radiological: mrTRG2 predominant fibrosis with low signal with foci of intermediate tumor signal intensity seen on T2 weighted images with or without restricted diffusion; mrTRG1: fibrosis with low signal intensity seen on T2 weighted images replacing the primary tumor with restricted diffusion; no nodes with border irregularity or mixed signal intensity; no extramural vascular invasion 27

Central Committee

The central committee is multidisciplinary group of surgeons, medical oncologists and radiologists previously appointed at the beginning of the recruitment of patients and with previous experience with organ preservation.2, 21 This group of specialist will be responsible to assess the baseline staging and define if the patients fulfill all the inclusion/exclusion criteria prior to randomization. The committee will also be responsible to evaluate the endoscopic and radiological tumor re-assessment studies at 12 and 18 weeks from radiation completion. The definition to continue on the Watch and Wait pathway or not will be at the discretion of this committee.

Technical aspects of assessment tests:

Suggested MR protocol:

1.5T - FRFSE; TR/TE: 3300/120 (ms); slice thickness/gap: 3.0/0; Matrix: 256 x 256; NSA 8) 3.0T - FRFSE; TR/TE: 8000/150 (ms); slice thickness/gap: 3.0/0; Matrix: 288 x 288; NSA 5) DWI - inclusion of a high b-value of at least 800

Suggested Endoscopic assessment:

Endoscopic assessment using a flexible scope (gastroscope preferred for retroflexion); direct endoscopic and retroflexion view of the primary tumor/scar; endoscopic biopsies at discretion of participating center.

Radiotherapy

Preoperative radiotherapy will be delivered on a linear accelerator in prone or supine position, preferably with full bladder. The use of a belly board is allowed. Isocentric 3 or 4 fields, as well as an IMRT technique is allowed, as long as all beams are treated on a daily basis. The dose distribution and calculation should be performed on CT or MRI and specified according to the ICRU 50 guidelines.

Dose specification: All patients will receive 25 daily fractions of 1.8 Gy up to a total dose of 45 Gy to the pelvic field including the tumor bed with a margin and the regional lymph nodes. A field reduction after 45 Gy is recommended up to 54 Gy. The last 5 fractions will then be given to the tumor bed with a margin.

Target volume:

Pelvic CTV

* The primary tumor
* Mesorectum: Distally, only lymph nodes or tumor deposits up to 4 cm are included. For tumors in lower rectum this means that the entire mesorectum down to the pelvic floor is included.
* Presacral nodes and nodes along the rectal superior artery: Since local recurrences are very unusual above S1 - S2, lymph nodes above this level should not be included unless there are signs of radiologically positive lymph nodes presacrally. If this is the case, the cranial limit of CTV should be at least 1 cm above the most cranial radiologically positive lymph node.
* Lateral lymph node stations: Until they reach the level of the obturator canal Internal iliac artery up to the bifurcation from the external iliac artery. The cranial border for the CTV is in most cases just below the bifurcation of the internal and external iliac arteries. In most patients this is at the level of S1 - S2.
* Ischio-rectal fossa and the anal canal: Included in pelvic CTV only if the tumor grows into the levators or down into the anal canal.
* Lymph nodes along the external iliac artery: Included if the tumor grows into anterior organs like the prostate, urinary bladder, cervix, vagina or uterus to such an extent that the external nodes are at risk for metastases.

Boost GTV:

GTV is the visible primary tumor and radiologically positive lymph nodes.

CTV boost:

GTV boost plus a margin of 2 cm within the same anatomical compartment as the tumour is in, for the dose of 45 Gy, also around radiologically engaged lymph nodes.

PTV:

The above description relates to the CTV. A PTV should normally be defined and includes CTV and internal target volume (ITV) and a margin necessary for the setup. These margins are depending upon several factors that are related to the equipment at each radiotherapy center.

Chemotherapy Protocols

Concomitant chemotherapy:

Concomitant capecitabine: 825mg/m2 bid on the radiotherapy days only

Consolidation chemotherapy:

1. Consolidation capecitabine (alone): 1000mg/m2 bid, for 14 days, in a 3 week cycle, for 4 cycles
2. Consolidation options with oxaliplatin:

2.1. mFOLFOX6: Oxaliplatin 85mg/m2 plus Leucovorin 400mg/m2 on a concomitant 2 hours infusion. 5FU 400mg/m2 on a bolus infusion, followed by 5FU 2400mg/m2 in 46 hours infusion, every 2 weeks, for 6 cycles 2.2. CAPOX: Oxaliplatin 130mg/m2 on a 2 hours infusion. Capecitabine 1000mg/m2 bid daily, for 14 days, starting on the evening of the oxaliplatin infusion. Repeat every 3 weeks, for 4 cycles

Assessment of Response

Assessment of response will be performed at 12 weeks (and 18 weeks from last date of radiation therapy if cCR or near-complete response is detected at 12 weeks). All patients will undergo endoscopic reassessment, DRE and high-resolution MR. Endoscopic biopsies will be at the discretion of the attending surgeon/endoscopist.

Patients with complete or near-complete clinical response at 12 weeks will be recommended reassessment at 18 weeks from RT. Patients with clinically overt incomplete clinical response at 12 or 18 weeks will be referred to immediate radical surgery.

Randomization

Individuals will be randomized and allocated at a 1:1 ratio to the two groups (control and experimental) using a permuted block design with a random block size of 4, 6, and 8. (1-3) A randomization list will be generated electronically using appropriate software immediately after being considered eligible.

Protocol Blinding

Patients and attending physicians will not be blinded to the treatment arm randomized for each patient. However, as a strategy to reduce investigator's expectations and reduce inherent bias, the central committee will be blinded to the treatment arm. It is expected that blinding the central committee, who will be responsible for assessing the primary endpoint, any bias related to the investigator's expectation about the treatment arm and the chances of Watch and Wait will be nulled.

Sample size calculation

The primary endpoint (decision to WW due to cCR/near CR) was observed in 55% and 85% at 12 weeks (in contrast to the 18 weeks used in the present trial) among patients with early cT3 and cT2 rectal cancer respectively.29 In this study, there was a distribution of 66% of cT3 and 33% cT2. Therefore, response rates appear to be highly dependent on exact T-stage distribution. Considering the expected inclusion of more advanced disease (late mrT3 or even mrT4 rectal cancers) the investigators expect 40% cCR/near-CR in the control arm. A similar difference 60% versus 40% was achieved in the preliminary report of the outcomes of the OPRA trial. This difference in TME-free survival at 3 years was statistically significant favoring patients undergoing nCRT with cCT in comparison to nCRT preceded by induction chemotherapy (both regimens incorporating oxaliplatin). In this setting, if experimental results in ≥60% cCR/near-CR, the study will be considered POSITIVE. The incorporation of oxaliplatin to a consolidation CRT regimen that results in ≥20% increase in cCR/near-CR exceeds the potential disadvantages of treatment-related toxicity.

The investigators will assume that the primary outcome will occur in 40% of individuals in control group and 60% in the experimental group, which corresponds to an absolute difference in proportions of 20%. It is estimated that a sample of 194 (97 per group) provides 80% statistical power to detect this difference at a significance level of 5% using the Chi-square test and assuming a two-sided significance hypothesis and considering a 1:1 allocation. The estimated dropout rate is 10% in each group, so it is expected to include 216 individuals (108 per group). The sample size calculation was performed using SAS 9.4 (PROC POWER procedure).

Time-table

Patient accrual: 2 years and 6 months Patient/institution/year: 5-6 (20 institutions: 100-120/year - 2 years n=200-240)

Interim analysis:

If the arm of two drugs during consolidation shows ≥25% response rate after 72 patients, study will be interrupted (efficacy). If the arm of two drugs shows less than 5% response rate after 72 patients, the study will be interrupted.

Individuals will be randomized and allocated at a 1:1 ratio to the two groups using a permuted block design with a random block size of 4, 6, and 8. (1-3) A randomization list will be generated electronically using appropriate software immediately after being considered eligible.

Patients and attending phisicians will not be blinded to the treatment arm randomized for each patient. However, as a strategy to reduce investigator's expectations and reduce inherent bias, the central committee will be blinded to the treatment arm. It is expected that blinding the central committee, who will be responsible for assessing the primary endpoint, any bias related to the investigator's expectation about the treatment arm and the chances of Watch and Wait will be nulled.

Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait

Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait. A Multi-center Prospective Randomized Controlled Trial. (CCHOWW)

Decision to Watch and Wait due to clinical complete response achieved at 18 weeks from last date of radiation using clinical (DRE), endoscopic and radiological criteria (mrTRG grade) or near-complete clinical response (no progressive disease clinically, endoscopically or radiologically)

Investigate the risk of being surgery-free after 3 years from radiation completion according to the treatment arm

Investigate the risk of being total mesorectal excision-free after 3 years from radiation completion according to the treatment arm

Investigate the risk of being distant metastases-free after 3 years from radiation completion according to the treatment arm

Investigate the risk of being local regrowth-free after 3 years from radiation completion according to the treatment arm

Investigate the risk of being colostomy-free after 3 years from radiation completion according to the treatment arm

Hospital Alemão Oswaldo Cruz

Principal Investigator

Tislelizumab

Antineoplastic Agents, Immunological

CRT followed by 4 cycles of tislelizumab plus CAPOX and clinical response assessment:

participants with CR (cCR+ pCR confirmed by local resection of ncCR): another 4 cycles of tislelizumab plus CAPOX and 9 cycles of tislelizumab, then watch and wait.

participants with non-CR: underwent TME

45-50.4Gy in 25-28 fractions to the pelvis on Days 1-5 every week.

Radiotherapy

Capecitabine 1000 mg/m2 orally twice daily (bid) on Day 1 to 14 of each 21-day cycle in CAPOX regimen

130 mg/m2 IV on Day 1 of each 21-day cycle in CAPOX regimen

825 mg/m2 orally twice daily (bid) 5 days/week during radiotherapy.

Min Jian Xu, MD

Tao Wen Tang, MD

This is an open-label, multi-center, single-arm clinical study. All patients received concurrent chemoradiation therapy (CRT) followed by 4 cycles of tislelizumab combined with CAPOX, then underwent clinical response assessment. Patients who achieved CR (cCR+ pCR confirmed by local resection of ncCR) continue tislelizumab combined with CAPOX for another 4 cycles and tislelizumab for 9 cycles, then Watch and Wait. Patients who did not achieved CR underwent total mesorectal excision (TME).

Organ Preservation With Tislelizumab and Total Neoadjuvant Therapy in Patients With Low Rectal Cancer: RELIEVE -01 Study

A Single-arm, Multicenter, Phase II Clinical Study of Chemoradiotherapy Followed by Tislelizumab Combined With Chemotherapy for Organ Preservation in Resectable Low Rectal Cancer：the RELIEVE-01 Study

defined as the proportion of participants with clinical complete response(cCR) or near clinical complete response (ncCR) who achieved local resection confirmed pCR determined by the investigators after CRT and 4 cycles of CAPOX plus tislelizumab.

defined as the proportion of participants who survived and did not underwent TME in 1/2/3 year (in the CR set and full analysis set respectively)

defined as the proportion of participants who did not develop local recurrence, distant metastasis, new invasive primary lesions of colorectal cancer, or death in 1/2/3 year (in the CR set, non-CR set and full analysis set respectively)

defined as the proportion of participants who survived in 1/2/3 year (in the full analysis set)

Percentage of Participants With adverse events (AEs) , immune-related adverse events(irAE) and serious adverse events (SAEs) per the National Cancer Institute CommonTerminology Criteria for Adverse Events (NCI CTCAE) Version 5.0

Shanghai Zhongshan Hospital

Shanghai Changzheng Hospital

Huadong Hospital

RenJi Hospital

The Fourth Hospital of Hebei Medical University

First Hospital of China Medical University

Liaoning Cancer Hospital & Institute

Fudan University

Chief Physician

Colonic Diseases

After 4 cycles of neoadjuvant sintilimab treatment, the patients and doctors could choose one of the following treatments: (1) surgery, followed by 4 cycles of adjuvant sintilimab with or without Capeox chemotherapy; (2) another 4 cycles of sintilimab, followed by radical surgery or observation (only for patients with clinical complete response).

After four cycles of neoadjuvant Sintilimab, Capeox and radiotherapy, the patients and doctors could choose one of the following treatments: (1) curative surgery and four cycles of adjuvant Capeox chemotherapy;(2)four cycles of Capeox chemotherapy then observation (only for patients with clinical complete response after neoadjuvant therapy)

After four cycles of neoadjuvant Capeox chemotherapy and radiotherapy, the patients and doctors could choose one of the following treatments: (1) curative surgery and four cycles of adjuvant Capeox chemotherapy;(2)four cycles of Capeox chemotherapy then observation (only for patients with clinical complete response after neoadjuvant therapy)

130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion

1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration

neoadjuvant radiotherapy with 50Gy to GTV, 45Gy to CTV in 25 fractions.

radiotherapy

total mesorectal excision after neoadjuvant treatment

total mesorectal excision

Watch and wait for cCR patients after neoadjuvant treatment

Watch and wait

In this study, participants with locally advanced rectal cancer patients will be treated according to MMR/MSI status. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, dMMR or MSI-H patients will receive 4 cycles of neoadjuvant Pd1 antibody Sintilimab,followed by one of the following treatments: (1) surgery and adjuvant treatment, (2）another 4 cycles of sintilimab, followed by radical surgery or observation (only for cCR) . For Cohort B, pMMR/MSS/MSI-L patients will be randomized to receive neoadjuvant chemoradiotherapy ± four cycles of Pd1 antibody Sintilimab，followed by one of the following treatments: (1) curative surgery and four cycles of adjuvant chemotherapy;(2)four cycles of chemotherapy then observation (only cCR after neoadjuvant therapy)

Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer

the proportion of CR cases (pCR for those who underwent surgery and cCR for those who didn't receive surgery)

Tumor regresssion grade according to AJCC TRG grading system

tumor volume reduction rate (TVRR) reaching 20% or above

Sun Yat-sen University

Professor

Irinotecan

Folfirinox

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Arm 1 includes patients with MSS/pMMR. In this arm, patients receive consolidation chemotherapy after neoadjuvant chemoradiation (nCRT). The chemotherapy regimens either XELIRI or FOLFIRINOX, and the cycles of chemotherapy depend on patient tumor responses. For patients who reach cCR will enter the "W\&W" cohort and omit radical surgery, while those without cCR will receive radical surgery.

Arm 2 includes patients with MSI-H/dMMR status. In this arm, patients receive consolidation immunotherapy of 3 cycles of tislelizumab after nCRT. For patients who reach cCR will enter the "W\&W" cohort and omit radical surgery, while those without cCR will receive radical surgery.

CRT: 625mg/m2 bid Monday-Friday per week XELIRI: 1000mg/m2 bid d1-14

Capecitabine (Xeloda) Pharmacogenetic Test Reagents

CRT:80mg/m2 (UGT1A1\*28 6/6) or 65mg/m2 (UGT1A1\*28 6/7) XELIRI: 200mg/m2 bid d1 FOLFIRINOX: 150mg/m2 d1

irinotecan

IMRT

FOLFIRINOX: 400mg/m2 iv d1bolus, 2400mg/m2 ivgtt 46h

5Fluorouracil

Ji Zhu

The study is designed to test the hypothesis that the clinical complete response (CCR) rate of patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy will increase after an adaptive-design paradigm, as well as the rate of 2-year organ preservation, recurrence, quality of life, DFS and OS.

1. Primary objective:

   Evaluate the CCR rate of low rectal cancer using adaptive and optimized chemotherapy and radiotherapy strategies (all population and dMMR/MSI-H subgroup)
2. Secondary objectives:

   2.1 Evaluate the 2-year anal preservation rate, recurrence rate, quality of life, DFS and OS 2.2 Explore the subgroup of patients suitable for observation.
3. Outline:

Patients after long-course chemoradiation are grouped based on their MSI-H/dMMR status. For patients with MSI-H/dMMR, consolidation immunotherapy of Tislelizumab (BGB-A317) will be assigned. For patients with MSS/pMMR, consolidation chemotherapy will be given according to their tumor response. After completion of consolidation therapy, those who reach clinical complete response will receive organ preservation (watch and wait) strategy in place of radical surgery. During treatment, once local regrowth occurs or poor tumor response, total mesorectal excision (TME) surgery will be performed.

An Adaptive-design Prospective Cohort Study of Watch and Wait Strategy in Patients With Locally Advanced Rectal Cancer

Watch and Wait Strategy in Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy: A Multi-centre, Adaptive-design, Phase II Prospective Cohort Study

After nCRT, the lesions of rectal completely respond. Tumor residue cannot be found by digital rectal examination, endoscopic biopsy and radiology.

2-year anal preservation rate will be defined as the percentage of patients alive without receiving abdominoperineal resection at 2 years measured from the date of completion of CRT.

2-year local recurrence rate will be defined as the percentage of patients alive developing local recurrence at 2 years measured from the date of completion of CRT.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Multicenter Single-arm P2 to Evaluate Safety and Efficacy of the Total Neoadjuvant Therapy for cT2 Rectal Cancer	NCT05939661	Rectal Cancer	Radiation Chemotherapy Surgery	18 Years -	Osaka University
A Multicenter Single-arm P2 to Evaluate Safety and Efficacy of the Total Neoadjuvant Therapy for cT2 Rectal Cancer	NCT05939661	Rectal Cancer	Radiation Chemotherapy Surgery	18 Years -	Osaka University
Node-sparing Radiotherapy Combined With Total Neoadjuvant CAPOX and Sintilimab for MSS Middle and Low Rectal Cancer	NCT06204094	Locally Advance...	node-sparing sh... Sintilimab Capecitabine Oxaliplatin TME surgery watch and wait	18 Years - 75 Years	Jinhua Central Hospital
Organ Preservation in Locally Advanced Rectal Cancer	NCT03064646	LOCALLY ADVANCE...	Organ Preservat...	18 Years -	Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait	NCT05000697	Rectal Cancer Consolidation	Oxaliplatin 5FU	18 Years -	Hospital Alemão Oswaldo Cruz
Organ Preservation With Tislelizumab and Total Neoadjuvant Therapy in Patients With Low Rectal Cancer: RELIEVE -01 Study	NCT06390982	RECTAL NEOPLASM... Rectal Cancer	Radiotherapy Tislelizumab Capecitabine Oxaliplatin Capecitabine	18 Years - 75 Years	Fudan University
Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer	NCT04304209	Colorectal Canc... Colorectal Canc...	Oxaliplatin Capecitabine Sintilimab radiotherapy total mesorecta... Watch and wait	18 Years - 75 Years	Sun Yat-sen University
An Adaptive-design Prospective Cohort Study of Watch and Wait Strategy in Patients With Locally Advanced Rectal Cancer	NCT04443543	Rectal Cancer	Capecitabine (X... irinotecan IMRT Oxaliplatin 5Fluorouracil Tislelizumab	18 Years - 75 Years	Fudan University
Organ Preservation in Locally Advanced Rectal Cancer	NCT03064646	LOCALLY ADVANCE...	Organ Preservat...	18 Years -	Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
Chemoradiation and Consolidation Chemotherapy With or Without Oxaliplatin for Distal Rectal Cancer and Watch and Wait	NCT05000697	Rectal Cancer Consolidation	Oxaliplatin 5FU	18 Years -	Hospital Alemão Oswaldo Cruz

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