QL1706 With Short-Course Radiotherapy and Chemotherapy for MSS Rectal Cancer

Sun Yat-sen University

Status and phase: Not yet enrolling; Phase 2

Conditions: Locally Advanced Rectal Cancer (LARC); Mismatch Repair-Proficient (pMMR) Rectal Cancer; Non-metastatic Rectal Cancer

Treatments: Drug: Drug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT)

Study type: Interventional

Funder types: Other

Identifiers

NCT07175636

B2025-431

Details and patient eligibility

About

This is a multicenter, prospective, phase II study evaluating total neoadjuvant therapy (TNT) consisting of short-course radiotherapy (SCRT; 5×5 Gy) followed by QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, code name only) plus mFOLFOX6 chemotherapy in patients with locally advanced rectal cancer (LARC) with proficient mismatch repair/microsatellite-stable (pMMR/MSS) biology. Patients with pMMR/MSS disease derive limited benefit from immune checkpoint inhibition alone. Preclinical and clinical evidence suggests that SCRT and oxaliplatin-based chemotherapy can enhance antitumor immunity (e.g., antigen release, T-cell infiltration), providing a biological rationale for combining QL1706 with SCRT-primed TNT.

Eligible adults with cT3-4 and/or N+ mid-to-low rectal adenocarcinoma (without distant metastasis), confirmed pMMR/MSS, and ECOG 0-1 will receive: SCRT (total 25 Gy over 5 fractions), then several cycles of QL1706 plus mFOLFOX6 as neoadjuvant systemic therapy. Definitive total mesorectal excision (TME) is planned per multidisciplinary assessment; a watch-and-wait approach may be considered for patients achieving a stringent clinical complete response per institutional criteria. Standard perioperative care and postoperative follow-up will be performed.

Primary endpoint is pathologic complete response (pCR, ypT0N0) rate at surgery. Key secondary endpoints include: clinical complete response (cCR) rate, major pathologic response rate, R0 resection rate, tumor downstaging, radiologic response, disease-free survival (DFS), overall survival (OS), organ preservation rate (for patients managed non-operatively), surgical morbidity, and safety/tolerability (CTCAE v5.0). Exploratory endpoints include correlations between efficacy and baseline clinicopathologic features; optional translational analyses may investigate immune-inflammation markers related to response and resistance.

This trial aims to determine whether SCRT-primed QL1706 plus mFOLFOX6 TNT can improve tumor eradication and organ preservation while maintaining acceptable safety in pMMR/MSS LARC-a population with unmet need for effective immunotherapy-based strategies.

Enrollment: 66 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Age 18-75 years, male or female.

Histologically confirmed rectal adenocarcinoma.

Locally advanced disease (cT3-4 and/or N+, M0) based on pelvic MRI and/or CT.

Tumor located within 12 cm from the anal verge.

Proven microsatellite stability (MSS) or proficient mismatch repair (pMMR) status.

ECOG performance status 0-1.

Adequate organ function:

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L

Platelet count ≥ 100 × 10⁹/L

Hemoglobin ≥ 90 g/L

ALT/AST ≤ 2.5 × ULN

Total bilirubin ≤ 1.5 × ULN

Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min

No prior pelvic radiotherapy, chemotherapy, immunotherapy, or targeted therapy for rectal cancer.

Signed written informed consent

Exclusion criteria

Evidence of distant metastasis.

Previous or concurrent malignant tumor (except cured basal cell carcinoma of skin or cervical carcinoma in situ).

Active autoimmune disease requiring systemic immunosuppressive therapy.

Active infection including hepatitis B, hepatitis C, HIV, or tuberculosis.

Known allergy or hypersensitivity to study drugs or excipients.

Uncontrolled cardiovascular disease (e.g., recent myocardial infarction, unstable angina, congestive heart failure, arrhythmia).

Pregnant or breastfeeding women.

Any condition judged by investigators to make the patient unsuitable for the study.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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66 participants in 1 patient group

Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6

Experimental group

Description:

Participants will receive short-course radiotherapy (SCRT, 25 Gy in 5 fractions over one week) followed by total neoadjuvant therapy (TNT) consisting of QL1706 (a bifunctional MabPair antibody targeting PD-1 and CTLA-4, investigational code name only) in combination with mFOLFOX6 chemotherapy for several cycles. After completion of neoadjuvant therapy, patients will undergo total mesorectal excision (TME) when operable, or may be managed with a watch-and-wait strategy if a strict clinical complete response (cCR) is achieved per institutional criteria. Standard perioperative care and follow-up will be provided.

Treatment:

Drug: Drug: QL1706 Drug: mFOLFOX6 Radiation: Short-Course Radiotherapy (SCRT)