Rectal Cancer Patients
Conditions
Keywords
locally advanced rectal cancer, Retlirafusp alfa, neoadjuvant therapy
Brief summary
This study aims to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy in the treatment of locally advanced rectal cancer. This is a prospective, single-arm, phase II clinical trial planned to enroll 44 patients with locally advanced rectal cancer. The primary endpoint is the complete response rate, and secondary endpoints include objective response rate, pathological complete response rate, event-free survival, and overall survival, with the goal of providing evidence to optimize clinical treatment decisions.
Detailed description
The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy followed by total mesorectal excision. However, the pathological complete response rate of the traditional regimen is only 10%-15%, and the distant metastasis rate remains high, which falls short of clinical needs. In recent years, immune checkpoint inhibitors have demonstrated significant efficacy in various malignancies. However, microsatellite-stable (MSS) colorectal cancer responds poorly to immunotherapy monotherapy and is therefore considered a "cold tumor." Preclinical and clinical studies suggest that radiotherapy can enhance immune responses by remodeling the tumor microenvironment and promoting tumor antigen release, thereby exerting synergistic antitumor effects when combined with immunotherapy. In addition, the TGF-β signaling pathway plays an important role in immune evasion in colorectal cancer, and bifunctional fusion proteins that simultaneously target PD-L1 and TGF-β are expected to more effectively restore T-cell activity. Based on these findings, this study innovatively combines short-course radiotherapy, Retlirafusp alfa (an anti-PD-L1/TGF-βRII bifunctional fusion protein), and the CAPOX chemotherapy regimen as neoadjuvant therapy for locally advanced rectal cancer.This study plans to enroll 44 patients with previously untreated locally advanced rectal cancer (T3N+M0 or T4NanyM0, AJCC 8th edition). The treatment regimen consists of short-course radiotherapy (25 Gy/5 fractions, D2-D6) combined with Retlirafusp alfa and CAPOX chemotherapy in the first cycle, followed by Retlirafusp alfa plus CAPOX chemotherapy in cycles 2 through 4. Efficacy evaluations will be performed after cycles 2 and 4, respectively. Patients who achieve clinical complete response may opt for a watch-and-wait strategy, while those who do not are recommended to undergo total mesorectal excision. The primary endpoint is the complete response rate (cCR + pCR). Secondary endpoints include objective response rate, pathological complete response rate, major pathological response, tumor regression grade,event-free survival, overall survival, safety, and changes in patient quality of life and anal function. The conduct of this study will provide important evidence on the efficacy and safety of the "short-course radiotherapy + immunotherapy + chemotherapy" neoadjuvant treatment model for locally advanced rectal cancer, with the potential to offer patients greater opportunities for organ preservation and improved long term survival.
Interventions
DRUGShort-course radiotherapy combined with Retlirafusp alfa and CAPOX chemotherapy
Short-course radiotherapy + Retlirafusp alfa + CAPOX chemotherapy for 1 cycle, followed by Retlirafusp alfa + CAPOX chemotherapy for 3 cycles. Cycle 1: Retlirafusp alfa: 1800 mg or 30 mg/kg, IV infusion over 30-60 min, D1, q3w; administered at least 30 min before chemotherapy. Oxaliplatin: 130 mg/m², IV infusion over ≥2 h, D1, q3w. Capecitabine: 1000 mg/m², PO, twice daily (total 2000 mg/m²/day) for 14 days, q3w. Short-course radiotherapy: 25 Gy in 5 fractions, D2-D6. Cycles 2-4: Retlirafusp alfa: 1800 mg or 30 mg/kg, IV infusion over 30-60 min, D1, q3w. Oxaliplatin: 130 mg/m², IV infusion over ≥2 h, D1, q3w. Capecitabine: 1000 mg/m², PO, twice daily (total 2000 mg/m²/day) for 14 days, q3w. Efficacy evaluation is performed after cycles 2 and 4. Patients are reassessed 2-4 weeks after the last treatment. Those achieving clinical complete response (cCR) may opt for watch-and-wait (W\&W). Non-cCR patients (near-CR, PR, or SD) are recommended to undergo total mesorectal excision (
Sponsors
Harbin Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-70 years, male or female. 2. Histologically or cytologically confirmed rectal adenocarcinoma, stage T3N+M0 or T4NanyM0 (AJCC/UICC TNM 8th edition), with measurable lesion(s) per RECIST 1.1. 3. Tumor lower border 5-10 cm from the anal verge. 4. Expected to achieve R0 resection after neoadjuvant therapy, and planned for surgery thereafter. 5. ECOG PS 0-1. 6. No prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immune checkpoint inhibitors, or surgery. 7. Adequate organ function (without blood product or growth factor support during screening): ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L; hemoglobin ≥8.5 g/dL. TSH ≤1×ULN (if abnormal, T3/T4 must be within normal limits for enrollment). Bilirubin ≤1.5×ULN; ALT and AST ≤2.5×ULN. Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min (Cockcroft-Gault formula). INR ≤1.5×ULN; APTT ≤1.5×ULN. 8. Negative pregnancy test (β-hCG) for women of childbearing potential before treatment initiation.Women of childbearing potential and men (who are sexually active with women of childbearing potential) must agree to use effective contraception continuously during treatment and for 6 months after the last dose. 9. Voluntary participation with written informed consent.
Exclusion criteria
1. History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, cutaneous squamous cell carcinoma, or basal cell carcinoma. 2. Major surgery or severe trauma within 4 weeks prior to first study drug administration. 3. Systemic corticosteroids (equivalent to prednisone \>10 mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration. 4. Active, known, or suspected autoimmune disease. Patients with stable conditions not requiring systemic immunosuppression (e.g., type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders without systemic treatment) are eligible. 5. Immunodeficiency, including HIV positivity, other acquired/congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation. 6. Congestive heart failure, uncontrolled arrhythmia, myocardial infarction within 6 months, unstable angina, stroke, or other conditions precluding surgery. 7. Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function. 8. Uncontrolled symptomatic brain metastases, poorly controlled psychiatric disorders, or severe intellectual/cognitive impairment. 9. Known substance abuse or drug addiction. 10. Clinically significant bleeding symptoms or clear bleeding tendency within 3 months prior to enrollment. 11. Severe active infection requiring IV antibiotics during screening. 12. Known hypersensitivity to Retlirafusp alfa or any excipients (polysorbate 80 (II), sucrose, citric acid, sodium citrate, water for injection, etc.), or severe allergic reactions to other monoclonal antibodies. 13. Active hepatitis B (HBV DNA \>2000 IU/mL or 10⁴ copies/mL), or hepatitis C antibody-positive with HCV RNA above the lower limit of detection. 14. Receipt or planned receipt of live vaccine within 30 days prior to immunotherapy administration. 15. Intolerance to chemotherapy. 16. Inability to comply with the protocol or follow-up. 17. Other conditions deemed unsuitable for participation by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (cCR+pCR) | cCR assessed 2-4 weeks post-neoadjuvant therapy; pCR assessed within 2 weeks post-surgery; follow-up up to ~6 months. | Proportion of patients achieving clinical complete response (cCR, no tumor residue by imaging and endoscopy) after neoadjuvant therapy or pathological complete response (pCR, no residual viable tumor cells in tumor bed) post-surgery, reflecting overall tumor eradication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Imaging assessment after cycles 2 and 4, and post-surgery; follow-up up to ~6 months. | Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1 criteria on imaging. |
| Pathological Complete Response (pCR) | Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months. | Proportion of patients with no residual viable tumor cells in the tumor bed (ypT0N0) after neoadjuvant therapy and surgery. |
| Major Pathological Response (MPR) | Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months. | Proportion of patients with ≤10% residual viable tumor cells in the tumor bed post-surgery. |
| TRG Grade | Pathological assessment within 2 weeks post-surgery; follow-up up to ~6 months. | Assessment of pathological tumor regression grade (TRG 0-3) per AJCC 8th edition. |
| Event-Free Survival (EFS) | From treatment initiation to first event, follow-up every 3 months, up to 36 months. | Time from treatment initiation to first occurrence of: disease progression (local/distant) during neoadjuvant therapy, treatment discontinuation (toxicity/patient withdrawal), local/distant recurrence, new primary tumor, or death from any cause. |
| Overall Survival (OS) | From first dose to death or last follow-up, follow-up every 3 months, up to 36 months. | Time from first dose to death from any cause (censored at last follow-up for alive or lost patients). |
| Adverse Event Rate | Continuous monitoring from informed consent to 90 days post-last dose; follow-up up to ~36 months. | Incidence and severity of adverse events per NCI CTCAE 6.0; surgical complications graded per Clavien-Dindo classification. |
| Quality of Life (EORTC QLQ-CR29) | Assessed at baseline, pre-surgery post-neoadjuvant therapy, and 3, 6, 12 months post-surgery; follow-up up to 12 months. | Assessment of bowel symptoms, sexual function, and overall quality of life; higher scores indicate worse symptoms or better function. |
| Anal Function (LARS Score) | Assessed at baseline, pre-surgery post-neoadjuvant therapy, and 3, 6, 12 months post-surgery; follow-up up to 12 months. | Assessment of low anterior resection syndrome, total score 0-42 (0-20: no/mild LARS; 21-29: moderate; 30-42: severe). |
| Emotional Changes (GAD-7) | Generalized Anxiety Disorder Scale (GAD-7) assessed with a maximum follow-up of 12 months. | Assessment of anxiety status during treatment, total score 0-21; ≥10 indicates moderate-to-severe anxiety. |
| Biomarker Exploration | Tumor tissue and peripheral blood collected at baseline; peripheral blood collected periodically during treatment; follow-up up to ~6 months. | Collection of tumor tissue and peripheral blood samples for genomic, transcriptomic, proteomic, and immune microenvironment analyses to identify potential predictive and prognostic biomarkers associated with efficacy and safety. |
Countries
China
Outcome results
None listed