A Prospective, Open-Label, Single-Arm and Multicentre Phase II Study to Explore the Efficacy and Safety of Neoadjuvant Cadonilimab Plus Chemotherapy Following Short-Course Radiotherapy in Middle and Lower Locally Advanced Rectal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Cadonilimab Injection
- Conditions
- Locally Advanced Rectal Carcinoma
- Sponsor
- Shenzhen People's Hospital
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Pathological Complete Response Rate
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The goal of this clinical trial is to test the efficacy and safety in patients with locally advanced middle and lower rectal cancer. The main questions it aims to answer are:• Whether Cadonilimab combined with chemotherapy following short-course radiation can improve pathological complete response(pCR) rate? •Are the toxicities of the combination therapy manageable? Participants will be given radiation of 5 Gy for 5 days and then neoadjuvant Cadonilimab combined with modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) for 6 cycles. Without progressed disease, total mesorectal excision (TME) or transanal local excision will be performed. If clinical complete response was received, watch and wait strategy is one of choices. Adjuvant Cadonilimab plus mFOLFOX6 for another 6 cycles could be suggested for non-pCR participants,while surveillance is also suitable for pCR ones.
Detailed Description
Long-term synchronous chemoradiation (CRT) with sequential TME is the treatment recommended by current guidelines for locally advanced rectal cancer (LARC). The latest STELLAR study showed that preoperative short-course radiotherapy (SCRT) combined with preoperative chemotherapy is safe and effective and can be used as an alternative to conventional CRT in LARC \[1\]. In recent years, new therapies blocking immune checkpoints (cytotoxic T lymphocyte-associated molecular protein 4 (CTLA-4), programmed cell death 1 (PD1) and programmed cell death ligand 1 (PD-L1)) have achieved landmark achievements in the field of cancer therapy. Several clinical trials are evaluating the efficacy of a combination of RT and immune checkpoint inhibitors (ICIs) in rectal cancer (NCT02948348, NCT04124601, NCT04558684). The results of the study suggest that radioimmunotherapy is safe and effective in rectal cancer. A number of studies have shown that combined PD-1 and CTLA-4 blockade is associated with a higher response rate whereas more toxicities in multiple tumor types. Cadonilimab is a tetrameric PD-1/CTLA-4 bispecific antibody, based on the Akeso Tetrabody platform. It introduces novel T cell targeting mechanisms of action that may provide an improved therapeutic index and a favorable toxicity profile compared to PD-1 and CTLA-4 combination therapy. The study of SCRT combined with Cadonilimab and chemotherapy in middle and lower LARC has not been reported at home or abroad. Therefore, this study plans to recruit 27 patients with middle and lower LARC to explore the efficacy and safety of radiation of 5 Gy for 5 days followed by Cadonilimab 6mg/kg plus mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 h) every 2 weeks for total 6 cycles preoperatively. The primary endpoint is the pathological complete response (pCR) after surgery. The secondary endpoints consist of a clinical complete response (cCR), major pathological response (MPR), objective response rate (ORR), recurrence-free survival (RFS), overall survival (OS) and safety. Clinical response was evaluated by endoscopy, digital rectal examination and pelvic MRI. Safety was analyzed in all patients who receive at least one dose of treatment. The exploratory endpoint covers the quality of life. After surgery, non-pCR patients receive adjuvant Cadonilimab combined with mFOLFOX6 for 6 cycles while pCR ones have two options: adjuvant treatment which is the same as the neoadjuvant regimen or observation. As for cCR patients, TME or transanal local excision is one of options while the watch and wait (W\&W) strategy can also be considered especially for ultra-low rectal cancer.
Investigators
Wan He
Professor Wan He
Shenzhen People's Hospital
Eligibility Criteria
Inclusion Criteria
- •Age ≥18 yeas and ≤79 years. The gender is not limited.
- •Histopathology confirmed the diagnosis of rectal adenocarcinoma.
- •Patients with rectal cancer based on endoscopic ultrasound and / or pelvic MRI contrast + contrast, chest CT, head MRI or CT + contrast, or positron emission tomography / computed tomography （PET / CT）, staging criteria per American Joint Committee on Cancer (AJCC) 8th edition cancer stage, cT 3-T4 / N + M
- •At least 20 unstained sections of formalin-fixed paraffin-embedded tumor tissue sections, or fresh tumor tissue, can be provided for genomic and proteomic testing.
- •The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-
- •Adequate bone marrow and organ function meets the following criteria:
- •Neutrophil count (ANC)≥1.5×l09/L
- •Platelet (PLT) ≥80×109/L
- •Hemoglobin (Hb) level ≥90 g/L
- •Total bilirubin level≤1.5×ULN
Exclusion Criteria
- •Previous history of severe hypersensitivity to other monoclonal antibodies or any component of Cadonilimab.
- •Preoperative pathology was diagnosed as squamous cell carcinoma or neuroendocrine tumor
- •Within 5 years before enrollment for malignancies other than colorectal cancer with negligible risk of metastasis or death (e. g., expected 5-year OS\> 90%) and expected radical results after treatment (e. g., adequately treated cervical carcinoma in situ, basal or squamous cell skin carcinoma, localized prostate carcinoma for curative intent, ductal carcinoma in situ surgically treated with curative intent).
- •Previous treatment against the PD-1 receptor or its ligand PD-L1 or the cytotoxic T lymphocyte-associated protein-4 (CTLA-4) receptor.
- •History of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, series, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis related to antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, vasculitis, or glomerulonephritis; patients with autoimmune-related hypothyroidism were eligible for stable-dose thyroid hormone replacement therapy; patients with type 1 diabetes under control after a stable insulin regimen were eligible to participate in this study;
- •Usage of systemic immune activation drugs (including but not limited to interferon or Interleukin-2) within 4 weeks prior to enrollment or within 5 half-lives of the drug (whichever is shorter);
- •Usage of systemic corticosteroids (\> 10 mg/d of prednisone equivalent) or other systemic immunosuppressive agents (including but not limited to prednisone, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents \[anti-TNF\]) within 2 weeks prior to enrollment. Local, ocular, intra-articular, nasal, and inhaled corticosteroids are permitted;
- •Patients requiring baseline and subsequent MRI tumor evaluation with previous allergic reactions to intravenous contrast agents may use preventive steroids;
- •Allowing the use of inhaled corticosteroids for chronic obstructive pulmonary disease, corticosteroid hydrochloride (e. g., fluorohydrocortisone) in patients with orthostatic hypotension, and low-dose corticosteroid maintenance for adrenal cortical insufficiency.
- •Patients with previous allogeneic bone marrow transplantation or previous solid organ transplantation.
Arms & Interventions
Cadonilimab group
Cadonilimab is administrated with 6mg/kg and repeated every 2 weeks.
Intervention: Cadonilimab Injection
Cadonilimab group
Cadonilimab is administrated with 6mg/kg and repeated every 2 weeks.
Intervention: Short-course radiotherapy
Cadonilimab group
Cadonilimab is administrated with 6mg/kg and repeated every 2 weeks.
Intervention: Consolidation chemotherapy
Outcomes
Primary Outcomes
Pathological Complete Response Rate
Time Frame: Up to 6 months
The proportion of patients with no tumor cells in the postoperative specimens
Secondary Outcomes
- Overall Survival(Up to 5 years)
- Clinical Complete Response(Up to 6 months)
- Disease Free Survival Time from the date of treatment administration until the date of the first documented event of: disease recurrence Disease Free Survival(Up to 5 years)
- Objective Response Rate(Up to 6 months)
- Major Pathological Response Rate (MPR)(Up to 6 months)
- Number of participants with treatment-related adverse events (TRAE) as assessed by CTCAE v5.0(Up to 6 months)