Trial Title:
Neoadjuvant Cadonilimab Plus Chemotherapy Following Short-Course Radiotherapy in Locally Advanced Rectal Cancer
NCT ID:
NCT05792735
Condition:
Locally Advanced Rectal Carcinoma
Conditions: Official terms:
Rectal Neoplasms
Conditions: Keywords:
Anti-CTLA-4/PD-1 bispecific antibody
Neoadjuvant chemotherapy
Rectal cancer
Short-course radiotherapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cadonilimab Injection
Description:
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.
Arm group label:
Cadonilimab group
Other name:
AK104
Intervention type:
Radiation
Intervention name:
Short-course radiotherapy
Description:
Preoperative short-course radiotherapy (5x5 Gy)
Arm group label:
Cadonilimab group
Other name:
SCRT
Intervention type:
Drug
Intervention name:
Consolidation chemotherapy
Description:
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.
Arm group label:
Cadonilimab group
Other name:
mFOLFOX6
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age ≥18 yeas and ≤79 years. The gender is not limited.
2. Histopathology confirmed the diagnosis of rectal adenocarcinoma.
3. 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.
4. 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.
5. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0- 1.
6. Adequate bone marrow and organ function meets the following criteria:
1. Neutrophil count (ANC)≥1.5×l09/L
2. Platelet (PLT) ≥80×109/L
3. Hemoglobin (Hb) level ≥90 g/L
4. Total bilirubin level≤1.5×ULN
5. Alanine aminotransferase (ALT) level≤3×ULN
6. Aspartate aminotransferase (AST) level ≤3×ULN
7. International normalized value (INR) or prothrombin time (PT) or activated
partial thromboplastin time (aPTT) ≤1.5×ULN
8. Serum creatinine (Cr) level ≤1.5×ULN
9. Creatinine clearance #50 ml/min (Calculated according to the Cockcroft-Gault
formula)
Exclusion Criteria:
1. Previous history of severe hypersensitivity to other monoclonal antibodies or any
component of Cadonilimab.
2. Preoperative pathology was diagnosed as squamous cell carcinoma or neuroendocrine
tumor
3. 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).
4. Previous treatment against the PD-1 receptor or its ligand PD-L1 or the cytotoxic T
lymphocyte-associated protein-4 (CTLA-4) receptor.
5. 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;
6. 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);
7. 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;
8. Patients requiring baseline and subsequent MRI tumor evaluation with previous
allergic reactions to intravenous contrast agents may use preventive steroids;
9. 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.
10. Patients with previous allogeneic bone marrow transplantation or previous solid
organ transplantation.
11. 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.
12. 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).
13. 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);
14. Patients with positive hepatitis C (HCV) antibody are not eligible for the study
only if polymerase chain reaction shows negative HCVRNA;
15. 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).
16. Presence of severe neurological or psychiatric disorders, including dementia and
epileptic seizures.
17. The NCI-CTCAE grade 2 peripheral neuropathy.
18. Female patients during pregnancy or lactation.
19. Chronic bowel disease or short bowel syndrome.
20. Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
21. Major cardiovascular diseases, such as New York Heart Association heart disease
(grade II or higher), myocardial infarction within 3 months before randomization,
unstable arrhythmia, or unstable angina pectoris.
22. Patients with known coronary artery disease, congestive heart failure not meeting
the above criteria, or left ventricular ejection fraction <50% must have an
optimized stable medical regimen as determined by the treating physician, consulting
a cardiologist if required.
Gender:
All
Minimum age:
18 Years
Maximum age:
79 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Shenzhen People's Hospital
Address:
City:
Shenzhen
Zip:
518020
Country:
China
Status:
Recruiting
Contact:
Last name:
Wan He, PhD,MD
Phone:
+8675522948111
Phone ext:
5075
Email:
hewanshenzhen@hotmail.com
Contact backup:
Last name:
Guixiang Liao, PhD,MD
Phone:
+8675522948111
Phone ext:
5168
Email:
liaoguixiang@163.com
Start date:
April 11, 2023
Completion date:
December 31, 2026
Lead sponsor:
Agency:
Shenzhen People's Hospital
Agency class:
Other
Collaborator:
Agency:
Sixth Affiliated Hospital, Sun Yat-sen University
Agency class:
Other
Collaborator:
Agency:
The University of Hong Kong-Shenzhen Hospital
Agency class:
Other
Source:
Shenzhen People's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05792735
