Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomized, prospective, multicentre, phase Ⅱ trial (TORCH-C)

doi:10.21203/rs.3.rs-2759620/v1

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Study protocol

Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomized, prospective, multicentre, phase Ⅱ trial (TORCH-C)

https://doi.org/10.21203/rs.3.rs-2759620/v1

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Background

The preliminary result of the TORCH trial has showed promising complete response (CR) for managing locally advanced rectal cancer (LARC) with neoadjuvant short-couse radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant short-couse radiotherapy combined with chemotherapy and PD-1 inhibitor in LACC.

Methods

TORCH-C is a randomized, prospective, multicentre, double-arm, open, phase Ⅱ trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite-stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisplinary team. 120 patients will be randomized 1:1 to the intervention or control arm. The patients in the control arm will receive 4 cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by 4 cycles of CAPOX and PD-1 inhibitor (Serplulimab). Both arms will receive curative surgery, followed by 4 cycles of CAPOX. The primary endpoint is pathologic complete regression (pCR).

Discussion

TORCH-C trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer (CRC).

Trial registration:

The trial has been registered in ClinicalTrials.gov on Feburary 16, 2023 (Registration No. NCT05732493).

locally advanced colon cancer

neoadjuvant

short-course radiotherapy

immunotherapy

microsatellite-stable

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the fifth in women [1]. Adjuvant chemotherapy is an established standard therapy for colon cancer (CC) patients with radically resected stage Ⅲ and 'high-risk' stage Ⅱ disease. For patients with stage Ⅲ colon cancer, and the 5-year disease-free survival (DFS) was 63.6%, the recurrence rate was more than 20% [2, 3]. And a higher T-stage and N-stage increase the risk of recurrence. For bulky nodal disease or clinical T4b disease, neoadjuvant treatment with FOLFOX or CAPOX may be considered before surgery. The recently published FOxTROT1 trial was a phase Ⅲ randomized-controled trial to illustrate the clinical benefit of neoadjuvant chemotherapy (NAC) in patients with LACC [4]. NAC was associated with a significant reduction in recurrence (16.8% vs. 21.2%, P = 0.042) and improvements in tumor downstaging, rate of complete (R0) resection, and CC-specific survival. However, the pCR rate was only 4%. Thus, developing novel and more effective treatment strategies for LACC is an area of clinical priority.

Radiotherapy (RT) is not widely used in colon cancer, because of the uncertern position and small bowel toxicity, but may be considered in certain clinical scenarios. Patients with stage T4 disease had a high likelihood of locoregional recurrence [5], and perhaps locoregional radiotherapy could reduce the recurrence. A small sampled study had showed that patients with pT4b disease receiving adjuvant chemoradiotherapy enhanced locoregional control and DFS [6]. A retrospective study analyzed the National Cancer Database (NCDB) for patients with pT4 and/or positive margins; and showed that adjuvant radiation was associated with improved overall survival (OS) in patients with both pT4 and positive margins [7]. A series of studies from Sun Yat-sen University Cancer Center, China have reported the effective and safety of neoadjuvant chemoradiotherapy (NACRT) with unresectable colon cancer [8–10]. Furthermore, pCR was 18–38% and a clinical-downstaging rate was 81–90% after received NACRT.

Recently, anti-PD-1/PD-L1 inhibitors have showed promising results for many kinds of malignant tumors. PD-1 antibody demonstrated excellent efficacy in advanced CRC patients with microsatellite instability-high (MSI-H) [11]. The anti-PD-1/PD-L1 alone did not show a good effect in patients with MSS. However, patients with MSI-H only account for about 5%, and the majority CRC population is MSS. Improving the immunotherapeutic sensitivity of patients with MSS remains a great challenge. Recent studies have showed promising synergistic effects of the combination of immunotherapy and radiotherapy, even in CRC patients with MSS. Preclinical studies have showed that radiation enhances the diversity of T-cell receptor (TCR) repertoire of intratumoral T cells, and anti-CTLA4 inhibits T-regulatory cells (Treg cells), while the addition of PD-L1 blockade reverses T-cell exhaustion; thus the combination of radiation and immune checkpoint inhibitors results in better anticancer effects because they promote response and immunity through distinct mechanisms [12, 13]. Therefore, the combination of radiotherapy and immunotherapy is promising. We have tried the combination of anti PD-1 antibody, chemotherapy and radiotherapy in LARC (TORCH trial, NCT04518280); the preliminary unpublished results showed a high CR rate and safety [14].

From the dilemma of LACC and the inspiration of the studies of the combination of radiotherapy and immunotherapy in other cancers, especially the TORCH study, we attempted to perform TORCH-C trial to address the value of neoadjuvant radiotherapy and immunotherapy in LACC patients with MSS.

Hypothesis

We hypothesize that combining Serplulimab with SCRT and chemotherapy before surgery can increase the pCR rate compared with neoadjuvant chemotherapy in LACC patients with MSS.

Study Design

The study is a phase Ⅱ, multicenter, radonmized, prospective trial, comparing the adjuvant chemotherapy with short-course radiotherapy combined with chemotherapy and immunotherapy in clinically cT4 or bulky nodes patients confirmed colon adenocarcinoma. Patients will be assigned into two arms: intervention arm and control arm. Stratification factors are the location of tumor and N stage. Patients will be randomly assigned using a cental randomization system without masking. Patients in the control arm will receive 4 cycles of CAPOX chemotherapy and then receive surgery. Patients in the intervention arm will receive SCRT (25Gy/5Fx), followed by 4 cycles of CAPOX chemotherapy and anti-PD-1 antibody (Serplulimab, Shanghai Henlius Biopharmaceutical Co. LTD, China), and finally receive surgery. The trial has been registered in ClinicalTrials.gov on Feburary 16, 2023 (Registration No. NCT05732493). The outline of the study workflow and design is depicted in Fig. 1 and Fig. 2.

Trial Organization, Ethics Approval, Drug Supply And Insurance

The trial is principal-investigators initiated by the Department of Radiation Oncology and the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center. This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (Approval Number: 2211265-12). A total of Six other medical centers in China are involved in the study, including the first people's hospital of Changzhou, Yunnan Cancer Hospital, Anyang Cancer Hospital, Traditional Chisese Hospital of LuAn, the Second School of Medicine Wenzhou Medical University and the Second Affiliated Hospital of Soochow University. Serplulimab is free provided by Shanghai Henlius Biopharmaceutical Company, which has purchased liability insurance for clinical trial subjects. All participants will sign a written informed consent before randomization.

Study Population

Patients who present with LACC require a complete workup, including biopsy, pathologic tissue review, total colonoscopy, complete blood count (CBC), chemistry profile, tumor markers determination and baseline CT scans of the chest, abdomen, and pelvis. Testing for MMR/MSI should be done at diagnosis. CT should be with intravenous contrast. Participants are eligible to be included if they meet the inclusion criteria and exclusion criteria (Table 1).

Table 1

Inclusion and exclusion criteria
Inclusion criteria	Exclusion criteria
1. Pathological confirmed adenocarcinoma 2. Clinical stage T4 and/or bulky nodes 3. The distance from anal verge more than 15cm 4. Without distance metastases 5. Age ≥ 18 years old, female or male 6. KPS ≥ 70 7. Without previous anti-cancer therapy or immunotherapy 8. With good compliance 9. Signed the inform consent	1. Pregnancy or breast-feeding women 2. History of other malignancies within 5 years 3. Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc. 4. Immunodeficiency disease or long-term using of immunosuppressive agents 5. Baseline blood and biochemical indicators do not meet the following criteria: neutrophils ≥ 1.5 ×10 ⁹/L, Hb ≥ 90g/L, PLT ≥ 100 ×10 ⁹/L, ALT/AST ≤ 2.5 ULN, Serum Cr ≤ 1.5 ULN 6. Allergic to any component of the therapy 7.MSI-H
Notes: KPS: Karnofsky; Hb: Hemoglobin; PLT: platelet; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: upper limit of normal value; Cr: Creatine

The withdrawal criteria include: (1) Distant metastasis is confirmed by postoperative pathology. (2) Patients receive other treatment, which is not related to the present study. Patients receive subsequent therapy after relapse or metastasis is permitted. (3) Patients decide to withdraw from the study with any reasons. The trial was opened on March 1, 2023, and the first patient was recruited on March 24, 2023.

Statistical analysis

The primary endpoint of this study is pCR. In this study, the reference pCR rate of neoadjuvant chemotherapy was 5%. Our hypothesis is that the intervention increases a pCR rate to 30%. Patients will be randomly assigned to the two arms at a ratio of 1:1. If a probability value of at least 95% needs to be reached to select the superior group, the sample size shoule be 90 patients (45 patients/group). Taking into account the maximun fropout rate of 20%, the final total sample size in this study will be 120 cases (60 cases per group).

Study Interventions: The Clinical Trial Will Include The Following Theraputic Interventions

Neoadjuvant chemotherapy

Patients in the control arm will receive four cycles of CAPOX. The regimen of CAPOX includes oxaliplatin 130mg/m² intravenously (IV) d1 and capecitabine 1000mg/m² P.O d1-14 (3 weeks per cycle).

Neoadjuvant Radiotherapy

Patients in the intervention arm will first receive SCRT. The target volume is the colon primary lesion and enlarged lymph nodes, not including the lymphatic drainage area. The prescription dose is 25Gy in 5 fractions over 5 days. Intensity-modulated radiation therapy (IMRT) will be conducted. The titanium clip will be markered at the proximal and distant side of the tumor through coloscopy for image guiding during every fraction of radiation.

Neoadjuvant Immunotherapy

In the intervention arm, two weeks after the completion of radiotherapy, four cycles of CAPOX and anti-PD-1 antibody (Serplulimab) treatment will be performed. Serplulimab will be administrated IV at a fixed dose of 300mg on the first day and repeated every three weeks. The regimen of CAPOX is the same as in the control arm.

Surgery

All patients will undergo restaging 2 or 4 weeks after the completion of neoadjuvant treatment. Radical resection will be undertaken after evaluation. The specific surgical approach will be determined by the surgeons. The preferred surgical procedure is colectomy with en bloc removal of the regional lymph nodes. The extent of colectomy should be based on the tumor location.

Adjuvant Chemotherapy

All patients in both control and intervention arms will receive adjuvant chemotherapy of four cycles of CAPOX. The regimen of CAPOX is as the standard regimen.

Study Endpoints And Assessment

The primary endpoint of this study is the pCR. The second endpoint include tumor down-staging rate, the R0 resection, 3-year disease-free survival (DFS) rate, 3-year OS rate, 3-year local recurrence-free survival (LRFS), toxicity, post-operative complications and quality of life (QoL). The pCR status is defined as no viable tumor cells by a complete histological assessment. Pathological tumor regression grade (pTRG) and pCR will be evaluated by two independent pathologists.

Patients will receive evaluation at the following time points: baseline and before surgery and during regular follow-up. The examinations include imaging examinations (pelvic CT/MRI, abdominal CT/MRI, and chest CT), tumor markers (CAE, CA199, etc.), complete blood count (CBC), blood biochemical examination (AST, ALT, Cr, etc.), and toxicity associated examinations, including thyroid hormone, adrenal hormone and myocardial enzymogram, et al. The response evaluation criteria in solid tumors (RECIST v.1.1) and immune response evaluation criteria in solid tumor (iRECIST) will be used to assess the response.

Acute adverse effects will be documented at every cycle of treatment and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0. The quality of life will be evaluated at the end of neoadjuvant therapy and at every 6 month during the follow-up using the EORTC QLQ-C30.

Protocol Version

Version 1.0.

LACC has traditionally been managed with surgical resection followed by adjuvant chemotherapy. To achieve R0 resection, about 30% T4 stage colon cancer patients must receive multivisceral resection [15]. However, locoregional recurrence and distant metastase rate were still high. Lymph node metastasis is a major predictor of survival outcome; furthermore, it is difficult to acquire R0 resection for bulky nodes. Hence, local and systemic therapy should be strengthened for patients with T4 and bulky node disease.

Presently, some prospective neoadjuvant chemotherapy clinical studies on locally advanced colon cancer have been carried out. The FOxTROT trial was the first prosepctive randomized controlled clinical study showed that neoadjuvant chemotherapy combining two chemotherapeutic agents (oxaliplatin and 5-fluorouracil) had a significant effect on tumor down-staging, but only 2% pCR rate [16]. A pilot phase Ⅱ study has showed that patients received neoadjuvant triple chemotherapy (oxaliplatin and irinotecan combined with folinic acid and 5-fluorouracil), 91.5% had reduction in tumor volume, and 56.5% had grade 3–4 toxicity, only 4% (1/23) had gained pathological pCR rate [17].

Adjuvant RT presented better OS and cancer-specific survival (CSS) than patients did not receive RT for pT4N2M0 colon cancer patients from the data of the SEER database [18]. From several small sampled studies, neoadjuvant RT improved the R0 resection rate and decreased local recurrence in LACC. A retrospective study with NCDB have showed that the use of neoadjuvant RT for T4 disease had higher R0 resection rates and increased 5-year OS rates [19]. Cukier et al. performed a retrospective study found that neoadjuvant CRT in LACC patients with T4b disease could lead to high R0 resection and excellent local control [20]. These studies showed that T4 colon cancer patients benefitted from neoadjuvant RT. A phase Ⅲ study intergroup 0130 compared adjuvant chemoradiotherapy with adjuvant chemotherapy alone in patients with colon cancer [21], no significant difference in severe nonhematologic toxicity was observed. Long-course radiotherapy was used in all of the published studies in colon cancer. The radiation dose was 1.8-2.0 Gy per fraction and was given five times per week. The total irradiation dose was 45-50.4Gy.

The Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in cancer treatment among different tumor types, including CRC.The effect of ICBs has so far been demonstrated in small phase Ⅰ/Ⅱ studies and predominantly in treatment-refractory stage Ⅳ disease and disease with dMMR. The Keynote-177 trial has showed that single-agent immunotherapy Pembrolizumab improved PFS versus chemotherapy (16.5m vs. 8.2m) in patients with newly diagnosed MSI-H or dMMR metastatic colorectal cancer (mCRC) [11]. Immunotherapy has recently emerged as a neoadjuvant therapy that could change the treatment strategy in CRC. In the NICHE trial [22], the effect of neoadjuvant immunotherapy by doublet ICB nivolumab and ipilimumab were investigated both in MSI-H/dMMR and MSS/pMMR patients, among the pMMR tumors, 4 (3 major and 1 partial response) of 15 had pathological responses.

Preoperative radiotherapy combined with chemotherapy and immunotherapy showed a satisfied effect in LARC. A phase Ⅱ Chinese study used 5×5 Gy SCRT followed by 2 cycles of CAPOX and camrelizumab before surgery in LARC. Among the 26 patients with MSS disease, the pCR rate was as high as 48.1% [23], and no grade 3–4 immune-related adverse effects were observed. The Averectal trial performed SCRT followed by 6 cycles of FOLFOX and avelumab in LARC, and found that 37.5% of the patients achieved pCR [24]. No grade 3–4 immune-related adverse effects were found. Furthermore, there are many ongoing studies on neoadjuvant immunotherapy combined with chemoradiotherapy in rectal cancer. However, very few similar studies on colon cancer. We have tried the combination of anti PD-1 antibody, CAPOX, and SCRT in LARC in the TORCH trial at our center; the preliminary unpublished results showed a high CR rate and safety in patients with MSS [14]. Colon cancer and rectal cancer have similar biological behavior, we believe that the TORCH mode will also play good in LACC.

In summary, TORCH-C is a randomized, prospective, multicenter, double-arm, phase Ⅱ trial of SCRT combined with CAPOX and Serplulimab in LACC patients to investigate whether neoadjuvant chemoradiotherapy combined with immunotherapy can bring good tumor response, good tolerance and better prognosis. We look forward to obtaining exciting results and bring a better treatment strategy for LACC.

CBC

complete blood count

colon cancer

complete response

CRC

colorectal cancer

CSS

cancer-specific survival

CTCAE

Common Terminology Criteria for Adverse Events

DFS

disease-free survival

ICB

immunocheckpoint blockade

IMRT

Intensity-modulated radiation therapy

iRECIST

immune response evaluation criteria in solid tumor

intravenously

LACC

locally advanced colon cancer

LARC

locally advanced rectal cancer

LRFS

local recurrence-free survival

mCRC

metastatic colorectal cancer

MSI-H

microsatellite instability-high

MSS

microsatellite-stable

NAC

neoadjuvant chemotherapy

NACRT

neoadjuvant chemoradiotherapy

NCDB

National Cancer Database

overall survival

pCR

pathologic complete regression

pTRG

pathological tumor regression grade

QoL

quality of life

RECIST

response evaluation criteria in solid tumors

SCRT

short-couse radiotherapy

radiotherapy

TCR

T-cell receptor

Ethics approval and consent to participate

This study was conducted in compliance with Declaration of Helsinsi principles. All procedures involving human subjects were approved by the Ethics Committee of Fudan University Shanghai Cancer Center. All patients signed informed consent forms before recruitment.

Consent for publication

Not Applicable.

Availability of data and meterials

The data and materials in the study are available from the corresponding authors on reasonable request.

Competing interests

The authors declare that they have no competition interests.

Funding

This work was supported by the Guangzhou Shared Future Charitable Foundation, "Dengfeng" research project of precision radiotherapy on cancer (ID: 2021-DF-015), and the National Natural Science Foundation of China (ID: 82272732).

Authors' contribution

Prof. Zhen Zhang, Fangqi Liu, and Sanjun Cai contributed to the conception and design of the trial. Hui Zhang, Fan Xia, and Yaqi Li were involved in drafting the manuscript or revising it critically for important intellectual content. Yiqun Sun assessed the images at the baseline and after the neoadjuvant treatment. Lijun Shen, Juefeng Wan, Yajie Chen, Yaqi Wang, Menglong Zhou, Ruiyan Wu, Shujuan Zhou ,and Yan Wang made substantial contributions to the organization of this trial.

All authors have given final approval of the version of the protocol, and it was also approved by local investigators at the participating centres.

Acknowledgements

We would like to thank Shanghai Henlius Biopharmaceutical Co. LTD for free providing Serplulimab and having pruchased liability insurance for clinical trial subjects. We thank all the subjects who participate in this study.

Authors' information

1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

3 Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China.

4 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

5 Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

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No competing interests reported.

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You are reading this latest preprint version

Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomized, prospective, multicentre, phase Ⅱ trial (TORCH-C)

Status:

Version 1

Abstract

Figures

Background

Methods/design

Hypothesis

Study Design

Trial Organization, Ethics Approval, Drug Supply And Insurance

Study Population

Statistical analysis

Study Interventions: The Clinical Trial Will Include The Following Theraputic Interventions

Neoadjuvant chemotherapy

Neoadjuvant Radiotherapy

Neoadjuvant Immunotherapy

Surgery

Adjuvant Chemotherapy

Study Endpoints And Assessment

Protocol Version

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1