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Rectal Artery Infusion Chemotherapy Combined With Anti-PD1 Antibody for MSS LARC (RAIC)

Primary Purpose

Rectal Neoplasms

Status

Recruiting

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Oxaliplatin

Rectectomy

Capecitabine

Anti-PD-1 monoclonal antibody

About this trial

This is an interventional treatment trial for Rectal Neoplasms

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Pathologically diagnosed rectal adenocarcinoma
Age ≥18 years old and ≤75 years old
MRI stage T3/4 and or N+, and no distant metastasis
Life expectancy of 1 year The above
Informed consent, no contraindications to chemotherapy exist
The distance from the lower edge of the tumor to the anus is less than or equal to 12cm by MRI

Exclusion Criteria:

Refused to participate in this study
Multifocal colorectal cancer
Past history of malignant tumors, except for basal cell carcinoma/papillary thyroid carcinoma/various types of carcinoma in situ
Unable to receive chemotherapy , such as but not limited to bone marrow suppression, etc
Major organ diseases (such as but not limited to COPD, coronary heart disease and renal insufficiency, etc.) acute attack and or severe acute infectious diseases (such as but not limited to hepatitis, pneumonia and myocarditis, etc.), ASA score> 3
Mental disorder or illiteracy or language and communication barriers cannot understand the research plan
There are contraindications to arterial puncture, such as but not limited to severe arteriosclerosis or even atresia, coagulation dysfunction, long-term use of anticoagulant drugs and cannot be stopped, etc
Rectal tumor has obstruction or high risk of obstruction and or there is bleeding and/or perforation
Peripheral sensory nerve disorder, unable to receive oxaliplatin chemotherapy
Lateral pelvic lymph node metastasis (mainly supplied by internal iliac artery)
Pregnancy or breastfeeding
Unable to accept MRI examination
Consecutive use of glucocorticoids for more than 3 days within 1 month before signing the consent form
Tumor directly invades or adheres to adjacent organs、structures(T4b) or tumor invaded MRF（Mesoretal Fascia）
Other scenarios deemed inappropriate by the investigators

Sites / Locations

Second Affiliated Hospital of Zhejiang University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rectal Artery Infusion Chemotherapy

Arm Description

Patients receive 2 cycles of Capecitabine and Oxaliplatin (CapeOx) chemotherapy and evaluated with rectum Magnetic Resonance Imaging (MRI). Patients with more than 20% regression of maximum diameter of rectal tumor in MRI image will entry into next step of rectal artery infusion of Oxaliplatin and oral Capecitabine（1000mg/㎡）with anti-PD1 antibody（200mg）every 3 weeks for 2 cycles.Then those patients will receive rectectomy including anterior resection or abdominoperineal resection by open or laparoscopy with TME.

Outcomes

Primary Outcome Measures

pCR rate

the pathological complete remission rate of the rectal carcinoma

Secondary Outcome Measures

DFS

3-year Disease-free survival

the rate of adverse event（AE）

Surgical Complication

the rate of surgical complication during or after operation

low anterior resection syndrome score

Low anterior resection syndrome (LARS) score of different time during treatment. The range (0-42) was divided into 0 to 20 (no LARS), 21 to 29 (minor LARS), and 30 to 42 (major LARS).

Concentration of FLT3LG

Fms Related Receptor Tyrosine Kinase 3 Ligand is a marker of immunogenic cell death

Concentration of cytokines

blood density measurement of immunoreaction associated cytokines

Concentration of DAMP

blood density measurement of damage-associated molecular pattern（DAMP）

Full Information

NCT ID

NCT05307198

First Posted

January 10, 2022

Last Updated

October 5, 2023

Sponsor

Second Affiliated Hospital, School of Medicine, Zhejiang University

1. Study Identification

Unique Protocol Identification Number

NCT05307198

Brief Title

Rectal Artery Infusion Chemotherapy Combined With Anti-PD1 Antibody for MSS LARC

Acronym

RAIC

Official Title

Rectal Artery Infusion Chemotherapy of Oxaliplatin Plus Capecitabine Combined With Anti-PD1 Antibody After Induction Chemotherapy for Microsatellite Stable Locally Advanced Rectal Cancer：a Prospective Single-arm Phase II Study

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 11, 2022 (Actual)

Primary Completion Date

April 25, 2024 (Anticipated)

Study Completion Date

April 25, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Second Affiliated Hospital, School of Medicine, Zhejiang University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to explore whether rectal artery infusion chemotherapy combined with anti-PD1 antibody is an effective neoadjuvant therapy for the microsatellite stable locally advanced rectal cancer.

Detailed Description

Neoadjuvant chemoradiation is the standard treatment for locally advanced rectal cancer. Neoadjuvant chemoradiotherapy can achieve a pathological complete response rate (pCR) of about 20%. However, radiotherapy can cause tissue edema and fibrosis, increasing the risk of anastomotic leakage, resulting in rectal, urinary, and sexual dysfunction. Neoadjuvant chemotherapy or immunotherapy can avoid these adverse reactions, but the pCR rate of chemotherapy is significantly lower than that of neoadjuvant radiotherapy, and immunotherapy is less effective for MSS patients with weak immunogenicity. This study is a prospective, single-arm, single-center trial. The study will enhance the local killing effect of oxaliplatin through rectal artery infusion and induce immunogenic cell death (ICD) to enhance tumor antigen presentation, and then combine anti-PD1 antibody for neoadjuvant therapy. The study will address whether this treatment combination achieves pCR rates that are non-inferior to neoadjuvant RT for MSS-type locally advanced rectal cancer. It is known that the effective rate of oxaliplatin-containing intravenous chemotherapy for colorectal cancer is about 60%. In this study, 2 cycles of XELOX induction chemotherapy were firstly performed to screen out patients who were sensitive to chemotherapy. These patients were then infused with oxaliplatin via the superior rectal artery and oral capecitabine, combined with anti-PD1 antibody therapy for 2 cycles, and then underwent TME surgery. The primary endpoint of the study was the pCR rate.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Neoplasms

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

The pCR rate of neoadjuvant chemoradiotherapy is about 20% (null hypothesis). Assuming that the pCR of the RAIC scheme in this study would be in the range of 15%-35%. Using Simon's two-stage design, a total of 37 patients would provide 80% power at a one sided 5% alpha level. Considering the drop rate of 10%, 38 patients would be included (64 cases to be screened) in this study. 10 cases (17 cases were screened) and 28 cases (47 cases were screened) would be included in the first and second stages, respectively. If the number of patients with pCR in the first stage is less than 2, the study will be terminated. If the number of patients with pCR in the first stage is more than 2, a second-stage trial will be performed. If the total number of patients with pCR is more than 9, the effective remission rate of the RAIC regimen is considered to be acceptable.

Masking

None (Open Label)

Allocation

N/A

Enrollment

38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Rectal Artery Infusion Chemotherapy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Intervention Description

Drug: Oxaliplatin Oxaliplatin 130mg/m2 for inducing chemotherapy in Day 1 every 3 weeks and repeat for two cycles. The dose of oxaliplatin used for rectal artery infusion was uncertain because there were no previous study. We design this study with Oxaliplatin 85mg/㎡for rectal artery infusion chemotherapy in Day 1 every 3 weeks and repeat for 2 cycles, based on intravenous chemotherapy regimens recommended by NCCN（mFolfox6）.If there were severe side effects caused by oxaliplatin observed within first 5 patients, we would decreasing the dose of oxaliplatin depending on the multidisciplinary discussion of researchers. We acknowledged that our study did not determine the most appropriate dosage of oxaliplatin used for artery infusion, but rather performed a novel therapeutic method for microsatellite stable locally advanced rectal cancer.

Intervention Type

Procedure

Intervention Name(s)

Rectectomy

Intervention Description

Include anterior resection or abdominoperineal resection by open or laparoscopy with Total Mesorectal Excision (TME).

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

Oral Capecitabine 1000 mg/m2 twice daily combined with oxaliplatin chemotherapy in Day 1 to Day 14 every 3 weeks and repeat for 4 cycles.

Intervention Type

Drug

Intervention Name(s)

Anti-PD-1 monoclonal antibody

Other Intervention Name(s)

Sintilimab

Intervention Description

Anti-PD1 antibody 200mg/m2 in Day 2 after Rectal Artery Infusion Chemotherapy. Repeat every 3 weeks for 2 cycles.

Primary Outcome Measure Information:

Title

pCR rate

Description

the pathological complete remission rate of the rectal carcinoma

Time Frame

1 day of postoperative pathological examination.

Secondary Outcome Measure Information:

Title

DFS

Description

3-year Disease-free survival

Time Frame

From date of first chemotherapy until the date of first documented recurrence of tumor or date of death from any cause，whichever came first，assessed up to 36 months.

Title

Description

the rate of adverse event（AE）

Time Frame

From date of first chemotherapy until the date of patients were discharged from hospital after receiving TME operation, up to 20 weeks

Title

Surgical Complication

Description

the rate of surgical complication during or after operation

Time Frame

within 30 days since operation

Title

low anterior resection syndrome score

Description

Low anterior resection syndrome (LARS) score of different time during treatment. The range (0-42) was divided into 0 to 20 (no LARS), 21 to 29 (minor LARS), and 30 to 42 (major LARS).

Time Frame

3 months after operation; 6 months after operation;12 months after operation

Title

Concentration of FLT3LG

Description

Fms Related Receptor Tyrosine Kinase 3 Ligand is a marker of immunogenic cell death

Time Frame

blood test of FLT3LG at baseline , pre-intervention of neoadjuvant chemotherapy, pre-intervention of artery infusion chemotherapy and pre-surgery.

Title

Concentration of cytokines

Description

blood density measurement of immunoreaction associated cytokines

Time Frame

blood test of cytokines at baseline , pre-intervention of neoadjuvant chemotherapy, pre-intervention of artery infusion chemotherapy and pre-surgery.

Title

Concentration of DAMP

Description

blood density measurement of damage-associated molecular pattern（DAMP）

Time Frame

blood test of DAMP at baseline , pre-intervention of neoadjuvant chemotherapy, pre-intervention of artery infusion chemotherapy and pre-surgery.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Pathologically diagnosed rectal adenocarcinoma Age ≥18 years old and ≤75 years old MRI stage T3-4aNany and TanyN1-2, but not T4b and no distant metastasis Life expectancy of 1 year The above Informed consent, no contraindications to chemotherapy exist The distance from the lower edge of the tumor to the anus is between 5cm to 12cm by MRI Exclusion Criteria: Refused to participate in this study Multifocal colorectal cancer Past history of malignant tumors, except for basal cell carcinoma/papillary thyroid carcinoma/various types of carcinoma in situ Unable to receive chemotherapy , such as but not limited to bone marrow suppression, etc Major organ diseases (such as but not limited to COPD, coronary heart disease and renal insufficiency, etc.) acute attack and or severe acute infectious diseases (such as but not limited to hepatitis, pneumonia and myocarditis, etc.), ASA score> 3 Mental disorder or illiteracy or language and communication barriers cannot understand the research plan There are contraindications to arterial puncture, such as but not limited to severe arteriosclerosis or even atresia, coagulation dysfunction, long-term use of anticoagulant drugs and cannot be stopped, etc Rectal tumor has obstruction or high risk of obstruction and or there is bleeding and/or perforation Peripheral sensory nerve disorder, unable to receive oxaliplatin chemotherapy Lateral pelvic lymph node metastasis (mainly supplied by internal iliac artery) Pregnancy or breastfeeding Unable to accept MRI examination Consecutive use of glucocorticoids for more than 3 days within 1 month before signing the consent form Tumor directly invades or adheres to adjacent organs、structures(T4b) or tumor invaded MRF（Mesoretal Fascia） Other scenarios deemed inappropriate by the investigators

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Li Jun, MD

Phone

+86 13777878061

2307016@zju.edu.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Jiao Yurong

Phone

+86 13732206364

jiaoyurong@zju.edu.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jun Li, MD

Organizational Affiliation

Second Affiliated Hospital, School of Medicine, Zhejiang University

Official's Role

Study Director

Facility Information:

Facility Name

Second Affiliated Hospital of Zhejiang University School of Medicine

City

Hangzhou

State/Province

Zhejiang

ZIP/Postal Code

310000

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yurong Jiao

Phone

+8613732206364

jiaoyurong1990@163.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Rectal Artery Infusion Chemotherapy Combined With Anti-PD1 Antibody for MSS LARC

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