Trial Title:
Cadonilimab/Anlotinib in Locally Advanced or Relapsed/Metastatic ESCC Patients After Failure of PD-1 Combined With Platinum-containing Chemotherapy
NCT ID:
NCT05990231
Condition:
Esophageal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Conditions: Keywords:
Esophageal Squamous Cell Carcinoma
Cadonilimab
Anlotinib
CTLA-4
PD-1
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 combined Anlotinib
Description:
Cadonilimab: intravenous administration at a dose of 10mg/kg on day 1 of each cycle,
every 3 weeks (Q3W) Anlotinib: 12mg, orally once a day (orally before breakfast, the
daily medication time should be as the same as possible), continuous taking for 2 weeks,
stopping for 1 week, 3 weeks (21 days) as a treatment cycle
Arm group label:
Cadonilimab combined with anlotinib
Summary:
Advanced esophageal squamous cell carcinoma patients who have failed first-line PD-1
inhibitor combined with chemotherapy lack a standard treatment option. Second-line
treatments have limited efficacy, indicating a significant unmet clinical need. Anlotinib
is a novel multi-target tyrosine kinase inhibitor (TKI) has anti-tumor angiogenesis and
tumor growth inhibition effects. Cadonilimab is a human immunoglobulin (Ig) G1 monoclonal
antibody (mAb), which is a bispecific antibody that blocks both PD-1 and CTLA-4. Both of
them have shown certain efficacy and good safety in more than second-line therapy for
patients with advanced esophageal squamous cell carcinoma as monotherapy. This study aims
to evaluate the efficacy and safety of cadonilimab combined with anlotinib in patients
with locally advanced or recurrent/metastatic esophageal squamous cell carcinoma who have
progressed on PD-1 inhibitor combined with platinum-containing chemotherapy.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Voluntarily sign a written informed consent form.
2. Age ≥18 and ≤80 years, both males and females are eligible.
3. ECOG performance status score of 0 or 1.
4. Expected survival≥3 months.
5. Patients with locally advanced or recurrent/metastatic esophageal squamous cell
carcinoma confirmed by histology and/or cytology that is incurable (including
curative surgery and curative radio/chemotherapy). Patients with locally advanced or
recurrent/metastatic esophageal squamous cell carcinoma who have failed of PD-1
inhibitor combined with platinum-based chemotherapy , and are not allowed to receive
other systemic anti-tumor treatments. Note: For patients who have received
adjuvant/neoadjuvant PD-1 inhibitor combined with platinum-based chemotherapy for
non-metastatic disease with curative intent, or curative platinum-based
radio/chemotherapy combined with PD-1 inhibitor for locally advanced or
recurrent/metastatic disease, if disease progression occurs within <6 months after
the end of the last treatment, and the patients has not received other systemic
anti-tumor treatments after disease progression, they are allowed to be enrolled.
6. According to RECIST v1.1, patients must have at least one measurable lesion. For
patients who have received radiotherapy previously and have no other target lesions
available, when there is objective evidence of significant progression after
radiotherapy, the lesion treated with radiotherapy can be considered as a target
lesion.
7. The function of important organs meets the following requirements (excluding any
blood components and growth factors used within 14 days):
1. Normal bone marrow function, neutrophils ≥1,500/mm3, platelet count
≥100,000/mm3, hemoglobin ≥5.6 mmol/L (9g/dL);
2. Normal renal function or serum creatinine ≤1.5 mg/dL and/or creatinine
clearance rate ≥60 ml/min;
3. Normal liver function or bilirubin ≤1.5 times ULN, ASAT & ALST ≤1.5 times ULN.
8. Female patients of childbearing potential must undergo a urine or serum pregnancy
test within the first 3 days before the first dose (if the urine pregnancy test
result cannot be confirmed as negative, a serum pregnancy test must be performed,
and the serum pregnancy result will prevail), and the result must be negative. If a
female patient of childbearing potential has sexual intercourse with an
uncircumcised male partner, the subject must take effective contraceptive measures
from the beginning of screening and must agree to continue using contraceptive
methods for 120 days after the last dose of study drug; whether to stop
contraception after this time point should be discussed with the investigator.
9. If an uncircumcised male subject has sexual intercourse with a female partner of
childbearing potential, the subject must take effective contraceptive measures from
the beginning of screening until 120 days after the last dose; whether to stop
contraception after this time point should be discussed with the investigator.
10. The patient is willing and able to comply with the scheduled visits, treatment plan,
laboratory tests, and other requirements of the study.
Exclusion Criteria:
Subjects who meet any of the following criteria will be ineligible to participate in this
study:
1. Subjects who have had other malignant tumors within 3 years prior to enrollment,
except those who have been cured by local treatment such as basal or squamous cell
skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ.
2. Subjects who are concurrently enrolled in another clinical study, unless it is an
observational, non-interventional clinical study or a follow-up period of an
interventional study.
3. Subjects who have received systemic anti-tumor therapy (chemotherapy, immunotherapy,
etc.) for non-target lesions within 3 weeks before the first dose of study drug;
palliative local therapy for non-target lesions within 2 weeks before the first dose
of study drug; non-specific immunomodulatory therapy (such as interleukin,
interferon, thymosin, tumor necrosis factor, etc., excluding IL-11 for
thrombocytopenia) within 2 weeks before the first dose of study drug; or Chinese
herbal medicine or traditional Chinese medicine with anti-tumor indications within 1
week before the first dose of study drug.
4. Subjects who have received any treatment targeting tumor immune mechanisms, such as
immunotherapy other than PD-1 inhibitors (including immune checkpoint inhibitors
such as anti-CTLA-4 antibodies, anti-CD47 antibodies, anti-SIRPα antibodies,
anti-LAG-3 antibodies, etc.), immune checkpoint agonists (such as ICOS, CD40, CD137,
GITR, OX40 antibodies, etc.), immune cell therapy, biologics, etc., other than PD-1
inhibitors.
5. Subjects who have experienced any of the following during previous PD-1 inhibitor
treatment:
1. Grade 3 or higher irAE caused by PD-1 inhibitor treatment (excluding endocrine
system-related irAEs), irAEs that led to permanent discontinuation of
treatment, grade 2 immune-related cardiac toxicity or any grade of neurologic
or ophthalmologic irAE.
2. All adverse events during previous PD-1 inhibitor treatment have not been
completely resolved or resolved to grade 1 before screening for this study. For
subjects with grade ≥2 endocrine adverse events, if the condition is stable
with appropriate alternative treatment and asymptomatic, enrollment is allowed.
3. Previous adverse events that required the use of immunosuppressive agents other
than glucocorticoids or recurrence of adverse events during previous
immunotherapy that required systemic use of glucocorticoids.
6. Screening imaging shows that the tumor surrounds or invades important blood vessels
or organs (such as the heart and pericardium, trachea, aorta, superior vena cava,
etc.), or there is obvious necrosis or cavity, and the investigator judges that
entering the study would increase the risk of bleeding; there are subjects at risk
of developing esophagotracheal fistula or esophageal pleural fistula.
7. Subjects who have had active autoimmune diseases requiring systemic treatment in the
past two years (such as use of disease-modifying drugs, corticosteroids,
immunosuppressive therapy), and replacement therapy (such as thyroid hormone,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered systemic treatment.
8. Subjects with non-infectious pneumonia/interstitial lung disease (including
radiation pneumonitis) requiring systemic glucocorticoid therapy that is currently
uncontrolled.
9. Presence of brainstem, meningeal metastasis, spinal cord metastasis or compression.
10. Presence of active central nervous system (CNS) metastatic lesions. Note: Subjects
with previously treated brain metastases (such as surgery or radiotherapy) are
allowed to enroll if they are clinically stable for at least 2 weeks (from the time
of first administration of study drug) and have discontinued corticosteroid hormones
for 7 days before administration of study drug; untreated asymptomatic brain
metastases (i.e., no neurological symptoms, no need for corticosteroid hormones, no
brain metastases with a long axis >1.5 cm and no obvious peritumoral edema) are
eligible to enroll.
11. Presence of pleural effusion, pericardial effusion or ascites with clinical symptoms
or requiring repeated drainage.
12. Presence of uncontrolled comorbidities currently including but not limited to
decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders,
or psychiatric/social conditions that would limit compliance with study requirements
or affect the subject's ability to provide written informed consent.
13. History of myocarditis, cardiomyopathy or malignant arrhythmia. Unstable angina
pectoris requiring hospitalization within 12 months before the first dose of study
drug, myocardial infarction, congestive heart failure (New York Heart Association
functional class II or higher), vascular disease (such as aortic aneurysm at risk of
rupture), or other cardiac damage that may affect the safety evaluation of the study
drug (such as poorly controlled arrhythmia or myocardial ischemia) within 12 months
before the first dose of study drug.
14. Occurrence of any arterial thrombotic events within 6 months before the first dose
of study drug; grade 3 or higher venous thromboembolic events according to NCI CTCAE
5.0; transient ischemic attacks; cerebrovascular accidents; hypertensive crises or
hypertensive encephalopathy; exacerbation of chronic obstructive pulmonary disease
within 1 month before the first dose of study drug; current hypertension with
systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite oral
antihypertensive therapy.
15. History of severe bleeding tendency or coagulation dysfunction; significant bleeding
symptoms within 1 month before the first dose of study drug, including but not
limited to gastrointestinal bleeding, bleeding peptic ulcer, hemoptysis (defined as
coughing up or spitting out ≥1 teaspoon fresh blood or small clots or coughing up
blood without sputum), which allows for inclusion if it is due to hemorrhoids and
does not require intervention.
16. Active or past history of confirmed inflammatory bowel disease (such as Crohn's
disease, ulcerative colitis, or chronic diarrhea).
17. Severe infection occurring within 4 weeks prior to the first dose of study drug,
including but not limited to complications requiring hospitalization, sepsis, or
severe pneumonia; active infection treated with systemic anti-infective therapy
within 2 weeks prior to the first dose of study drug (excluding antiviral therapy
for hepatitis B or C).
18. Known active tuberculosis (TB) or suspected active TB requiring clinical evaluation
to rule out; known active syphilis infection.
19. Participants with active hepatitis B (HBsAg-positive with HBV-DNA levels above 1000
copies/mL (200 IU/mL) or higher than the lower limit of detection, whichever is
higher) must receive antiviral therapy for hepatitis B during the study treatment
period; active hepatitis C infection (HCV antibody-positive with HCV-RNA levels
above the lower limit of detection).
20. History of immunodeficiency; positive HIV antibody test; current use of long-term
systemic corticosteroids or other immunosuppressive agents.
21. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem
cell transplantation.
22. Unresolved toxicities from prior anti-tumor therapy, defined as toxicities not yet
resolved to NCI CTCAE version 5.0 grade 0 or 1, or at a level dictated in the
inclusion/exclusion criteria, with the exception of alopecia. Participants with
irreversible toxicities that are not expected to be exacerbated by study drug may be
included in the study after consultation with the investigator (e.g., hearing loss).
Participants with radiation-induced long-term toxicities judged by the investigator
to be irreversible may be included in the study.
23. Major surgery or serious injury within 30 days prior to the first dose of study
drug, or planned major surgical procedure within 30 days after the first dose of
study drug (at the discretion of the investigator); minor surgical procedure within
3 days prior to the first dose of study drug (excluding peripheral venous
catheterization and placement of venous infusion port).
24. Known hypersensitivity to any component of the study drug; history of serious
hypersensitivity reaction to other monoclonal antibodies.
25. Receipt of live vaccine or attenuated live vaccine within 30 days prior to the first
dose of study drug, or planned receipt of live vaccine or attenuated live vaccine
during the study period; use of inactivated vaccine is allowed.
26. Known history of psychiatric illness, drug abuse, alcoholism, or drug addiction.
27. Pregnant or breastfeeding women.
28. Any past or current disease, treatment, or laboratory abnormality that may confound
the study results, interfere with subject participation for the full duration of the
study, or may not be in the best interest of the subject to participate in the
study.
29. Local or systemic diseases caused by non-malignant tumors; or diseases or symptoms
secondary to malignancy that may result in higher medical risk and/or uncertainty in
survival assessment, such as tumor leukemic reaction (white blood cell count
>20×109/L), cachexia (known weight loss exceeding 10% in the 3 months prior to
screening), etc.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
2nd Affiliated Hospital, School of Medicine, Zhejiang University, China
Address:
City:
Hangzhou
Zip:
310000
Country:
China
Status:
Recruiting
Contact:
Last name:
Hong Shen, MD
Phone:
+86 13857136137
Email:
shenhong0023@zju.edu.cn
Investigator:
Last name:
Hong Shen, MD
Email:
Principal Investigator
Investigator:
Last name:
Jing Zhao, MD
Email:
Sub-Investigator
Start date:
September 1, 2023
Completion date:
August 1, 2025
Lead sponsor:
Agency:
Second Affiliated Hospital, School of Medicine, Zhejiang University
Agency class:
Other
Source:
Second Affiliated Hospital, School of Medicine, Zhejiang University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05990231
