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

Официальное название

A Multicenter, Prospective, Phase II Clinical Trial of Short-Course Radiotherapy Followed by QL1706 Plus mFOLFOX6 as Total Neoadjuvant Therapy for Patients With pMMR/MSS Locally Advanced Rectal Cancer

Обзор

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.

Вмешательства

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

Первичные конечные точки

• Pathologic Complete Response (pCR) Rate [Срок оценки: At the time of surgery following completion of total neoadjuvant therapy (approximately 16-24 weeks after enrollment).]

Вторичные конечные точки (5)

• Clinical Complete Response (cCR) Rate [Срок оценки: At response evaluation after neoadjuvant therapy and before surgery (approximately 12-20 weeks after enrollment).]
• Major Pathologic Response (MPR) Rate [Срок оценки: At the time of surgery following neoadjuvant therapy.]
• R0 Resection Rate [Срок оценки: At the time of surgery]
• Overall Survival (OS) [Срок оценки: Up to 3 years after treatment.]
• Disease-Free Survival (DFS) [Срок оценки: Up to 3 years after treatment.]

Критерии участия

Критерии включения

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

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

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• 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):882-89 PMID 38964714
• 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
• 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
• 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 A PMID 35660797
• 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 PMID 32251400
• 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
• 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

Идентификаторы

NCT: NCT07175636 · B2025-431

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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