Clinical trial NCT05969847: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Rectal Cancer
Keywords: Locally advanced very low rectal cancer
Total neoadjuvant therapy
Hypofraction radiotherapy
CAPOX
Envafolimab
Local excision
Lead sponsor: Fujian Medical University Union Hospital
Sponsor class: OTHER
First posted: 2023-08-01
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Organ preservation
timeFrame: 36 months
Secondary outcomes:
measure: ypT0-1 rate
timeFrame: 36 months
measure: Pathological complete response (pCR) rate
timeFrame: 36 months
measure: Acute and late toxicity
timeFrame: 36 months
measure: Local recurrence rate
timeFrame: 36months
measure: Local regional recurrence rate
timeFrame: 36 months
measure: Disease-free survival
timeFrame: 36 months
measure: Quality of life-based on EORTC QLQ-C30 and EORTC QLQ-CR29
timeFrame: baseline, 3 months, 12 months, 24 months, and 36 months after LE or TME
measure: Anorectal function
timeFrame: baseline, 3 months, 12 months, 24 months, and 36 months after LE or TME
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: Pan Chi
state: Fujian
Study officials:
affiliation: Fujian Medical University Union Hospital
name: Pan Chi, MD
role: PRINCIPAL_INVESTIGATOR
References: