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

NCT07175636 | Not Yet Recruiting Phase 2

• 1 other identifier: B2025-431
• Study Type: interventional
• Target: 66
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Pathologic Complete Response (pCR) Rate

  The proportion of patients who achieve pathologic complete response, defined as the absence of viable tumor cells in both the resected primary rectal specimen and the resected lymph nodes (ypT0N0), as assessed by central pathology review.

  At the time of surgery following completion of total neoadjuvant therapy (approximately 16-24 weeks after enrollment).

Secondary Outcomes (5)

• Clinical Complete Response (cCR) Rate

  At response evaluation after neoadjuvant therapy and before surgery (approximately 12-20 weeks after enrollment).

• Major Pathologic Response (MPR) Rate

  At the time of surgery following neoadjuvant therapy.

• R0 Resection Rate

  At the time of surgery

• Overall Survival (OS)

  Up to 3 years after treatment.

• Disease-Free Survival (DFS)

  Up to 3 years after treatment.

Study Arms (1)

Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6

EXPERIMENTAL

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.

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

Interventions

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

QL1706 is an investigational bifunctional MabPair antibody that simultaneously targets PD-1 (IgG4) and CTLA-4 (IgG1). It is administered intravenously according to the study protocol during the neoadjuvant chemotherapy cycles. The use of QL1706 aims to enhance antitumor immunity in the pMMR/MSS rectal cancer setting, a population typically unresponsive to immune checkpoint blockade alone. mFOLFOX6 is a standard oxaliplatin-based chemotherapy regimen composed of oxaliplatin, leucovorin, and 5-fluorouracil. It is administered in combination with QL1706 during the neoadjuvant phase as part of total neoadjuvant therapy (TNT). The regimen is modified to optimize tolerability while maintaining efficacy in locally advanced rectal cancer. Short-course radiotherapy consists of a total dose of 25 Gy delivered in 5 fractions over one week to the pelvis. This approach is designed to rapidly downstage tumors, release tumor antigens, and prime the immune microenvironment for subsequent immunotherapy

Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sun Yat-sen University: lead

Related Publications (16)

• Xiao WW, Chen G, Gao YH, Lin JZ, Wu XJ, Luo HL, Lu ZH, Wang QX, Sun R, Cai PQ, Zhu CM, Liu M, Li JB, Wang YR, Jin Y, Wang F, Luo HT, Li CL, Pan ZZ, Xu RH. Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial. Cancer Cell. 2024 Sep 9;42(9):1570-1581.e4. doi: 10.1016/j.ccell.2024.07.004. Epub 2024 Aug 1.

  PMID: 39094560 BACKGROUND

• Lin ZY, Zhang P, Chi P, Xiao Y, Xu XM, Zhang AM, Qiu XF, Wu JX, Yuan Y, Wang ZN, Qu XJ, Li X, Nie X, Yang M, Cai KL, Zhang WK, Huang Y, Sun Z, Hou ZG, Ma C, Cheng FZ, Tao KX, Zhang T. Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial. Ann Oncol. 2024 Oct;35(10):882-891. doi: 10.1016/j.annonc.2024.06.015. Epub 2024 Jul 2.

  PMID: 38964714 BACKGROUND

• Fakih M, Sandhu J, Lim D, Li X, Li S, Wang C. Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol. 2023 May 1;9(5):627-634. doi: 10.1001/jamaoncol.2022.7845.

  PMID: 36892833 BACKGROUND

• Versluis JM, Long GV, Blank CU. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat Med. 2020 Apr;26(4):475-484. doi: 10.1038/s41591-020-0829-0. Epub 2020 Apr 9.

  PMID: 32273608 BACKGROUND

• Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, Stadler Z, Yaeger R, Smith JJ, Rousseau B, Argiles G, Patel M, Desai A, Saltz LB, Widmar M, Iyer K, Zhang J, Gianino N, Crane C, Romesser PB, Pappou EP, Paty P, Garcia-Aguilar J, Gonen M, Gollub M, Weiser MR, Schalper KA, Diaz LA Jr. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun 23;386(25):2363-2376. doi: 10.1056/NEJMoa2201445. Epub 2022 Jun 5.

  PMID: 35660797 BACKGROUND

• Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, Lopez-Yurda M, Grootscholten C, Beets GL, Snaebjornsson P, Maas M, Mertz M, Veninga V, Bounova G, Broeks A, Beets-Tan RG, de Wijkerslooth TR, van Lent AU, Marsman HA, Nuijten E, Kok NF, Kuiper M, Verbeek WH, Kok M, Van Leerdam ME, Schumacher TN, Voest EE, Haanen JB. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020 Apr;26(4):566-576. doi: 10.1038/s41591-020-0805-8. Epub 2020 Apr 6.

  PMID: 32251400 BACKGROUND

• Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM; Timing of Rectal Cancer Response to Chemoradiation Consortium. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg. 2011 Jul;254(1):97-102. doi: 10.1097/SLA.0b013e3182196e1f.

  PMID: 21494121 BACKGROUND

• Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, Reidy-Lagunes DL, Gollub MJ, Shia J, Guillem JG, Temple LK, Paty PB, Saltz LB. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014 Feb 20;32(6):513-8. doi: 10.1200/JCO.2013.51.7904. Epub 2014 Jan 13.

  PMID: 24419115 BACKGROUND

• Fernandez-Martos C, Pericay C, Aparicio J, Salud A, Safont M, Massuti B, Vera R, Escudero P, Maurel J, Marcuello E, Mengual JL, Saigi E, Estevan R, Mira M, Polo S, Hernandez A, Gallen M, Arias F, Serra J, Alonso V. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study. J Clin Oncol. 2010 Feb 10;28(5):859-65. doi: 10.1200/JCO.2009.25.8541. Epub 2010 Jan 11.

  PMID: 20065174 BACKGROUND

• Cercek A, Goodman KA, Hajj C, Weisberger E, Segal NH, Reidy-Lagunes DL, Stadler ZK, Wu AJ, Weiser MR, Paty PB, Guillem JG, Nash GM, Temple LK, Garcia-Aguilar J, Saltz LB. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Canc Netw. 2014 Apr;12(4):513-9. doi: 10.6004/jnccn.2014.0056.

  PMID: 24717570 BACKGROUND

• Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, Marchal D, Van Laethem JL, Klein V, Giralt J, Clavere P, Glanzmann C, Cellier P, Collette L; EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014 Feb;15(2):184-90. doi: 10.1016/S1470-2045(13)70599-0. Epub 2014 Jan 17.

  PMID: 24440473 BACKGROUND

• Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829.

  PMID: 16971718 BACKGROUND

• Pucciarelli S, Del Bianco P, Efficace F, Serpentini S, Capirci C, De Paoli A, Amato A, Cuicchi D, Nitti D. Patient-reported outcomes after neoadjuvant chemoradiotherapy for rectal cancer: a multicenter prospective observational study. Ann Surg. 2011 Jan;253(1):71-7. doi: 10.1097/SLA.0b013e3181fcb856.

  PMID: 21135694 BACKGROUND

• Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N. Colorectal cancer. Lancet. 2010 Mar 20;375(9719):1030-47. doi: 10.1016/S0140-6736(10)60353-4.

  PMID: 20304247 BACKGROUND

• Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694.

  PMID: 15496622 BACKGROUND

• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12.

  PMID: 33433946 BACKGROUND

MeSH Terms

Conditions

Rectal Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Central Study Contacts

Zhenhai Lu, MD

CONTACT

+862087343124; luzhh@sysucc.org.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof

Study Record Dates

• First Submitted: September 9, 2025
• First Posted: September 16, 2025
• Study Start: September 20, 2025
• Primary Completion (Estimated): September 20, 2026
• Study Completion (Estimated): September 20, 2029
• Last Updated: September 16, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share