Organ Preservation Following Enverolimab-based Total Neoadjuvant Therapy for Locally Advanced Very Low Rectal Cancer (TRACE-LE)

• ClinicalTrials.gov Identifier: NCT05969847
• Recruitment Status: Not yet recruiting
• First Posted: August 1, 2023
• Last Update Posted: August 1, 2023
• Sponsor: 池畔
• Information provided by (Responsible Party): 池畔, Fujian Medical University Union Hospital

Tracking Information

• First Submitted Date: July 23, 2023
• First Posted Date: August 1, 2023
• Last Update Posted Date: August 1, 2023
• Estimated Study Start Date: August 15, 2023
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 23, 2023)

Organ preservation [ Time Frame: 36 months ]

The rectum is intact, owing to no radical total mesorectal excision (TME), curative (R0) salvage surgery by local excision (LE), and no permanent stoma (including a never reversed protective stoma or a stoma owing to toxicities and/or poor functional outcomes).

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: July 23, 2023)

• ypT0-1 rate [ Time Frame: 36 months ]
  The proportion of subjects with primary rectal cancer assessed by hematoxylin and eosin staining including no evidence of primary tumor (T0) or carcinoma in situ: intramucosal carcinoma (invading lamina propria, not infiltrating muscularis mucosa) (Tis) or tumor invading submucosa (T1) (ypT0-1 based on the latest UICC/AJCC staging system)
• Pathological complete response (pCR) rate [ Time Frame: 36 months ]
  Proportion of subjects with primary rectal cancer and all sampled lymph nodes who did not find any invasive carcinoma and high-grade intraepithelial neoplasia/severe dysplasia after assessment by hematoxylin and eosin staining (Judged as ypT0N0 stage according to the latest UICC/AJCC staging system)
• Acute and late toxicity [ Time Frame: 36 months ]
  Acute and late toxicity, Incidence of Treatment-Emergent Adverse Events assessment according to NCICTCAE V.5.0
• Local recurrence rate [ Time Frame: 36months ]
  The proportion of patients in all subjects within 3 years from the start of the surgery to detection of a tumor involving the bowel wall only that occurs after LE or TME
• Local regional recurrence rate [ Time Frame: 36 months ]
  The proportion of patients in all subjects within 3 years from the start of the surgery to detection of a tumor involving either the bowel wall, mesorectum, and/or pelvic organs that occurs after LE or TME
• Disease-free survival [ Time Frame: 36 months ]
  The proportion of patients in all subjects within 3 years from the start of the surgery to recurrence, distant metastsis, or death from any cause (whichever occurs first)
• Quality of life-based on EORTC QLQ-C30 and EORTC QLQ-CR29 [ Time Frame: baseline, 3 months, 12 months, 24 months, and 36 months after LE or TME ]
  Quality of life measured using EORTC QLQ-C30 and EORTC QLQ-CR29
• Anorectal function [ Time Frame: baseline, 3 months, 12 months, 24 months, and 36 months after LE or TME ]
  Anorectal function based on LARS score

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Organ Preservation Following Enverolimab-based Total Neoadjuvant Therapy for Locally Advanced Very Low Rectal Cancer
• Official Title: Total Neoadjuvant Therapy With Split-course Hypofraction Radiotherapy Combined With CAPOX and Envafolimab Followed by Local Excision for Locally Advanced Very Low Rectal Cancer: an Open-label, Single-arm, Multi-center, Phase II Trial
• Brief Summary: Patients diagnosed with locally advanced very low rectal cancer were chosen to participate in a comprehensive neoadjuvant therapy (TNT) protocol. This treatment regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab. For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after undergoing TNT, an organ-preserving strategy involving local full-thickness resection was implemented.

Detailed Description

Locally advanced very low rectal cancer poses significant challenges in rectal cancer treatment. Presently, the prevailing approach in clinical practice involves neoadjuvant chemoradiotherapy in conjunction with total mesorectal excision (TME). Historically, abdominoperineal resection (APR) has been the conventional surgical procedure for managing locally advanced very low rectal cancer. However, the long-term presence of a colostomy following an abdominoperineal resection (APR) significantly impacts the quality of life for patients. Additionally, studies have revealed that 11.8-22% of rectal cancer patients who underwent APR after neoadjuvant chemoradiotherapy (nCRT) achieved a pathological complete response (pCR). Conversely, 11-52% of patients with pCR after nCRT for rectal cancer ultimately underwent APR surgery. Intersphincter resection (ISR) offers a highly beneficial surgical approach that preserves the anal sphincter, particularly for individuals with locally advanced very low rectal cancer. The patient's postoperative quality of life was significantly affected by severe low anterior resection syndrome (LARS), sexual dysfunction, and voiding dysfunction.

This study represents an exploratory phase II clinical trial in which patients diagnosed with locally advanced very low rectal cancer were chosen to undergo a total neoadjuvant therapy (TNT) regimen. This regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab.

For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after undergoing TNT, an organ-preserving strategy involving local full-thickness resection was implemented. Patients who achieve non-clinical complete response are subjected to traditional TME surgery.

This study aims to investigate the effectiveness and safety of organ preservation using the local resection approach in patients with locally advanced very low rectal cancer. By implementing this approach, the study aims to improve the quality of life for patients who achieve pathological complete response (pCR), thereby avoiding the need for conventional abdominoperineal resection (APR) and intersphincteric resection (ISR) procedures. Additionally, this study aims to address the issue of local regrowth associated with the "watch & wait" strategy and propose a novel treatment strategy for rectal-sparing surgery in patients with locally advanced very low rectal cancer.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Rectal Cancer

Intervention

• Radiation: split-course hypofraction radiotherapy
  After reaching a cumulative radiotherapy dose of 25Gy in the entire pelvic cavity (PTV1), the treatment field was subsequently narrowed to solely focus on the primary tumor (PTV2), with a total dose of 35Gy administered. All patients will undergo fractionated radiotherapy, following a regimen of 7Gy per fraction, delivered every 3 weeks for five cycles.
  Other Name: hypofraction radiotherapy
• Drug: CAPOX
  Drug: Oxaliplatin,130mg/m2，ivgtt，d1,for 6 cycles. Drug: Capecitabine,1000mg/m2，po，bid，d1-14, for 6 cycles.
  Other Name: Capecitabine+Oxaliplatin
• Drug: Envafolimab
  Envafolimab is administered by subcutaneous injection. The recommended dose is 300 mg per 3 weeks (Q3W) for 6 cycles.
  Other Name: KN035
• Procedure: Local excision
  Local full-thickness resection is employed for patients with clinical complete response (cCR) or near-clinical complete response (ncCR) following TNT.

Study Arms

Experimental: split-course hypofraction radiotherapy plus CAPOX and Envafolimab followed by local excision

Patients diagnosed with locally advanced very low rectal cancer were chosen to undergo a total neoadjuvant therapy (TNT) regimen. This regimen consisted of preoperative fractionated radiotherapy (5×7Gy) combined with 6 cycles of CAPOX chemotherapy and enverolimab.

For patients who achieved clinical complete response (cCR) or near-clinical complete response (ncCR) after TNT, an organ-preserving strategy involving local full-thickness resection was implemented. Patients who achieve non-clinical complete response are subjected to traditional TME surgery.

Interventions:

• Radiation: split-course hypofraction radiotherapy
• Drug: CAPOX
• Drug: Envafolimab
• Procedure: Local excision

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: July 23, 2023): 72
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2027
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Aged 18-75.
2. Histopathology confirmed the rectal adenocarcinoma,cT3-4N0 or cT1-4N1-2. The tumor's lower margin ≤ 2cm from the anorectal ring's upper edge (based on MRI measurement).
3. Eastern tumor cooperation group (ECOG) status:0-2.
4. American Association of Anesthesiologists (ASA) status: I-III.
5. No previous systemic therapy, including chemotherapy, immunotherapy, or radiotherapy for rectal cancer.
6. No previous history of pelvic radiotherapy.

7. Sufficient organ function based on the following parameters:

   An absolute neutrophil count≥ 1.5 × 109 / L, a thrombocyte count ≥ 100 × 109/ L, a glomerular filtration rate (calculated using the Cockcroft-Gault formula) with a creatinine level ≤ 1.5 × ULN or a creatinine clearance > 50ml/min, and AST and ALT levels ≤ 2.5 × ULN or a total bilirubin level ≤ 1.5 × ULN.

8. Effective contraception during the study.
9. Patients are willing and able to comply with the protocol during the study period.
10. Patients with written informed consent

Exclusion Criteria:

1. Poorly differentiated adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, and adenocarcinoma developed from inflammatory bowel disease.
2. Metastasis to para-aortic, lateral, or inguinal lymph nodes has been identified.
3. Suspected distant metastasis in organs other than para-aortic, lateral, or inguinal lymph nodes is being considered.
4. Known hypersensitivity to platinum drugs or capecitabine.
5. Patients receiving concomitant treatment with drugs that interact with capecitabine or oxaliplatin (such as flucytosine, phenytoin, and warfarin).
6. According to the New York Heart Association (NYHA) classification, III or IV heart failure, and angina pectoris have occurred in the past six months.
7. Uncontrolled active infection or severe concomitant systemic disease.
8. Patients who need immunosuppressive therapy for organ transplantation.
9. Uncontrolled epilepsy or mental illness.
10. Pregnant or lactating female patients.
11. Non-compliance or researchers believe that the patient will not be able to complete the entire trial

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pan Chi, MD; +8613675089677; cp3169@163.com

Contact: Jiabin Zheng; +8613365910080; xhyykjk@163.com

• Listed Location Countries: China

Administrative Information

• NCT Number: NCT05969847
• Other Study ID Numbers: 2023XHYG0026-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: 池畔, Fujian Medical University Union Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: 池畔
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Pan Chi, MD; Fujian Medical University Union Hospital

• PRS Account: Fujian Medical University Union Hospital
• Verification Date: July 2023