Neoadjuvant Cadonilimab Plus Chemotherapy Following Short-Course Radiotherapy in Locally Advanced Rectal Cancer

NCT05792735 | Completed Phase 2

• 1 other identifier: Shenzhen CRC-004
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

Locally Advanced Rectal Carcinoma

Keywords

Anti-CTLA-4/PD-1 bispecific antibody; Neoadjuvant chemotherapy; Rectal cancer; Short-course radiotherapy

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response Rate

  The proportion of patients with no tumor cells in the postoperative specimens

  Up to 6 months

Secondary Outcomes (6)

• 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

• Overall Survival

  Up to 5 years

• Objective Response Rate

  Up to 6 months

• Clinical Complete Response

  Up to 6 months

• Major Pathological Response Rate (MPR)

  Up to 6 months

Other Outcomes (1)

• Quality of life (QoL)

  From date of randomization until the date of death from any cause, assessed up to 10 years

Study Arms (1)

Cadonilimab group

EXPERIMENTAL

Cadonilimab is administrated with 6mg/kg and repeated every 2 weeks.

Drug: Cadonilimab Injection; Radiation: Short-course radiotherapy; Drug: Consolidation chemotherapy

Interventions

Cadonilimab Injection DRUG

Cadonilimab, an anti-CTLA-4/PD-1 bispecific antibody, at a dose of 6mg/kg is given in combination with chemotherapy every 2 weeks preoperatively and postoperatively.

Also known as: AK104

Cadonilimab group

Short-course radiotherapy RADIATION

Preoperative short-course radiotherapy (5x5 Gy)

Also known as: SCRT

Cadonilimab group

Consolidation chemotherapy DRUG

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 and postoperatively.

Also known as: mFOLFOX6

Cadonilimab group

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 + M0.
• 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- 1.
• 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
• Alanine aminotransferase (ALT) level≤3×ULN
• Aspartate aminotransferase (AST) level ≤3×ULN
• International normalized value (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5×ULN
• Serum creatinine (Cr) level ≤1.5×ULN
• Creatinine clearance #50 ml/min (Calculated according to the Cockcroft-Gault formula)

You may not qualify if:

• 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.
• Idiopathic pulmonary fibrosis, drug-induced pneumonia, mechanical pneumonia (i. e. bronchiolitis obliterans), history of idiopathic pneumonia or chest CT scan at screening showed evidence of active pneumonia.
• Any live vaccine (e. g., vaccine against infectious diseases, such as influenza vaccine, varicella vaccine, etc.) within 4 weeks (28 days) before enrollment.13 Active infections, including tuberculosis (TB) (clinical diagnosis including clinical history, physical examination and imaging findings, and TB tests performed per local medical practice), hepatitis B {known HBV surface antigen (HBsAg) positive and HBVDNA 1000 cps / ml}, hepatitis C or human immunodeficiency virus (HIV antibody positive).
• Patients with prior or cured HBV infection (defined as hepatitis B core antibody positive and HBsAg negative) were to be eligible to participate in the study only if HBVDNA was negative (HBVDNA˂ 1000 cps / ml);
• Patients with positive hepatitis C (HCV) antibody are not eligible for the study only if polymerase chain reaction shows negative HCVRNA;
• Clinically meaningful basic medicine, disease (e. g., dyspnea, pneumonia, pancreatitis, poorly controlled, poorly controlled diabetes, infection active or poorly controlled, or drug or alcohol abuse).

Sponsors & Collaborators

• Shenzhen People's Hospital: lead
• Sixth Affiliated Hospital, Sun Yat-sen University: collaborator
• The University of Hong Kong-Shenzhen Hospital: collaborator

Study Sites (1)

Shenzhen People's Hospital

Shenzhen, Guangdong, 518020, China

Location

Related Publications (4)

• Jin J, Tang Y, Hu C, Jiang LM, Jiang J, Li N, Liu WY, Chen SL, Li S, Lu NN, Cai Y, Li YH, Zhu Y, Cheng GH, Zhang HY, Wang X, Zhu SY, Wang J, Li GF, Yang JL, Zhang K, Chi Y, Yang L, Zhou HT, Zhou AP, Zou SM, Fang H, Wang SL, Zhang HZ, Wang XS, Wei LC, Wang WL, Liu SX, Gao YH, Li YX. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol. 2022 May 20;40(15):1681-1692. doi: 10.1200/JCO.21.01667. Epub 2022 Mar 9.

  PMID: 35263150 BACKGROUND

• Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-1492. doi: 10.1016/S1470-2045(18)30700-9. Epub 2018 Oct 22.

  PMID: 30361170 BACKGROUND

• Sharma P, Siefker-Radtke A, de Braud F, Basso U, Calvo E, Bono P, Morse MA, Ascierto PA, Lopez-Martin J, Brossart P, Rohrberg K, Mellado B, Fischer BS, Meadows-Shropshire S, Abdel Saci, Callahan MK, Rosenberg J. Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results. J Clin Oncol. 2019 Jul 1;37(19):1608-1616. doi: 10.1200/JCO.19.00538. Epub 2019 May 17.

  PMID: 31100038 BACKGROUND

• Shamseddine A, Zeidan YH, El Husseini Z, Kreidieh M, Al Darazi M, Turfa R, Kattan J, Khalifeh I, Mukherji D, Temraz S, Alqasem K, Amarin R, Al Awabdeh T, Deeba S, Jamali F, Mohamad I, Elkhaldi M, Daoud F, Al Masri M, Dabous A, Hushki A, Jaber O, Charafeddine M, Geara F. Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma. Radiat Oncol. 2020 Oct 7;15(1):233. doi: 10.1186/s13014-020-01673-6.

  PMID: 33028346 BACKGROUND

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Consolidation Chemotherapy

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

Intervention Hierarchy (Ancestors)

Drug Therapy; Therapeutics

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Wan He

Study Record Dates

• First Submitted: February 9, 2023
• First Posted: March 31, 2023
• Study Start: April 11, 2023
• Primary Completion: October 31, 2024
• Study Completion: January 31, 2025
• Last Updated: February 5, 2025

Record last verified: 2025-02

Locations

CN (1)