Trial Title:
Study of Cadonilimab Combined With Bevacizumab and Chemotherapy for Advanced Nonsquamous Non-small Cell Lung Cancer Patients With Untreated Brain Metastases
NCT ID:
NCT05812534
Condition:
Non Small Cell Lung Cancer
Brain Metastases
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Brain Neoplasms
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet 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
Description:
Subjects who met the study population conditions were treated with Cadonilimab 10mg/kg +
bevacizumab 7.5 mg/kg + carboplatin (AUC 5) + pemetrexed 500mg/m2. Every 3 weeks is a
cycle, with a total of 4-6 cycles (the number of chemotherapy cycles is determined by the
researchers). Cadonilimab 10mg/kg, bevacizumab 7.5 mg/kg and pemetrexed 500mg/m2 were
then maintained until disease progression, intolerable toxicity or other causes specified
in the regimen occurred. When the subject first has imaging disease progression, if the
researcher judges that it is clinically beneficial and tolerant to the test drug, he will
be allowed to continue treatment.
Arm group label:
experimental group
Summary:
The purpose of this study was to investigate the efficacy and safety of Cadonilimab
combined with bevacizumab and chemotherapy for advanced non-squamous NSCLC with untreated
brain metastases. Cadonilimab is a bispecific antibody (BsAb), which can bind PD-1 and
CTLA-4 at the same time with high affinity. It is a new tumor immunotherapy drug with
tetravalent structure and short half-life. It has shown less toxicity than anti-PD-1 and
anti-CTLA-4 antibodies in monkey toxicity studies. These characteristics make the
application of Cadonilimab in tumor subjects may have better efficacy and safety.
AK104-207 is an open, multicenter, phase Ib/II clinical study, which aims to evaluate the
effectiveness and safety of Cadonilimab combined with chemotherapy as the first-line
treatment for locally advanced or metastatic non-small cell lung cancer that cannot be
operated and cannot receive radical concurrent/sequential radiotherapy and chemotherapy.
As of August 1, 2022, 19 subjects who can evaluate non-squamous NSCLC (cohort B), ORR is
63.2%, DCR is 100%, median PFS is 13.34 months (7.36, NE), median OS is not reached, and
12-month OS rate is 76.0% (95% CI 48.0-90.3). In PD-L1 positive patients (n=9), ORR was
55.6% and DCR was 100%. In PD-L1 negative patients (n=7), ORR was 85.7% and DCR was 100%.
In view of the early curative effect of Cadonilimab in NSCLC single drug or combination
therapy and the encouraging research results of PD-1 inhibitor combined with CTLA-4
double immune combination therapy, it is expected that Cadonilimab combined with
bevacizumab and chemotherapy will achieve good curative effect in NSCLC patients with
brain metastasis.
Detailed description:
Study Name:
Phase II study of Cadonilimab combined with bevacizumab and chemotherapy for advanced
nonsquamous non-small cell lung cancer patients with untreated brain metastases Purpose
of research MAIN OBJECTIVE: Total response rate (ORR) Secondary purposes:
progression-free survival (PFS), intracranial PFS (iPFS), overall survival (OS), Quality
of Life (QoL) and safety Exploratory Objective: To explore the potential evolutionary
mechanism of brain metastasis of lung cancer and the difference of immune
microenvironment between primary focus and metastatic focus.
Design type: Intervention research Subjects: Non-squamous NSCLC in advanced stage of
untreated brain metastasis Sample size: 36 cases Statistical analysis method: This cohort
was a one-arm test, using Simon-Minimax two-stage design, assuming that the ORR rate was
20% under the ineffective hypothesis and 40% under the hypothesis that the drug was
considered effective. The degree of assurance is 0.8, the test level α is set to 0.05,
and the sample size estimation result is a total sample of 33 cases. Eighteen subjects
who meet the admission criteria are planned to be enrolled first. If 4 patients have CR
or PR, they will continue to be enrolled until 33 patients are reached. Only when more
than 10 patients in the total sample reach CR or PR can the study reach the main
endpoint. Considering the shedding rate of 10%, the sample size of this study is
estimated to be 36 cases. Data were collected from the first day of treatment to the
death of the patient or the last follow-up. All rate estimates were evaluated by
Kaplan-Meier model (SPSS, version 25.0). Univariate analysis and multivariate analysis of
Cox regression model were used to analyze the related factors of prognosis. long-rank
test was used to compare the difference of observation endpoint. P < 0.05 was
statistically significant.
Screening period: Subjects will complete screening evaluation within 28 days before the
first medication to determine whether they meet the research conditions. During the
screening period, the peripheral blood of the subjects should be collected.
Treatment period: The subjects who met the conditions of the study population were
treated with Cadonilimab 10mg/kg + bevacizumab 7.5 mg/kg + carboplatin (AUC 5) +
pemetrexed 500mg/m2. Every 3 weeks is a cycle, with a total of 4-6 cycles (the number of
chemotherapy cycles is determined by the researchers). Cadonilimab 10mg/kg, bevacizumab
7.5 mg/kg and pemetrexed 500mg/m2 were then maintained until disease progression,
intolerable toxicity or other causes specified in the regimen occurred. When the subject
first has imaging disease progression, if the researcher judges that it is clinically
beneficial and tolerant to the test drug, he will be allowed to continue treatment.
During the treatment, the researchers evaluated the curative effect according to RECIST
1.1 standard. ORR evaluated by researchers was used as the main curative effect index.
Subjects were evaluated for tumor every 6 weeks (7 days) within 54 weeks after
enrollment, and every 12 weeks (7 days) after enrollment. Subjects who stop taking drugs
for non-disease progression reasons will continue to follow up their disease status until
the subjects start other anti-tumor treatment, disease progression, withdrawal of
consent, death or end of study, whichever occurs first.
During the treatment, researchers will collect a series of blood samples for
pharmacokinetics, immunogenicity and exploratory research and analysis.
Adverse events (AE) of each subject will be collected until 30 days after the last
administration or new anti-tumor treatment will be started, whichever occurs first.
Serious adverse events (SAE) will be collected until 90 days after the last
administration or new anti-tumor treatment will be started, whichever occurs first.
Immune-related AE (irAE) will be collected until 90 days after the last administration or
new anti-tumor therapy will be started, whichever occurs first. Survival assessment was
performed every 3 months after the last dose to obtain survival information and collect
information on subsequent anti-tumor treatment after termination of study treatment.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- The patient was over 18 years old.
- The Eastern Cooperative Oncology Group Performance Status score ranged from 0 to 1.
- Patients with asymptomatic brain metastases confirmed by histology or cytology as
EGFR and ALK negative stage IV non-squamous NSCLC who have not received any
chemotherapy or brain radiotherapy before.
- Patients with non-metastatic diseases who have received neoadjuvant chemotherapy,
adjuvant chemotherapy or radiotherapy must experience a no-treatment interval of at
least 6 months since the last chemotherapy and/or radiotherapy.
- Steroid therapy (dexamethasone) is allowed. When dexamethasone ≤ 4mg once a day,
patients who are still asymptomatic or less symptomatic after 2 weeks of steroid use
will be eligible.
- Extracranial measurable lesions assessed by CT (RECIST 1.1 standard), Intracranial
measurable lesions (RANO-BM standard or brain MRI).
- Formalin-fixed paraffin embedded blocks (cell wax blocks are acceptable if no tumor
biopsy is available) containing tumor tissue or 10 unstained slides can be obtained.
- Adequate hematopoiesis and liver and kidney function: ANC ≥ 1,500 cells/μ L,
lymphocyte count ≥ 500 cells/μ L, platelet count ≥ 100,000 cells μ L, hemoglobin ≥
9.0 g/dL (blood transfusion allowed); INR or aPTT ≤ 1.5 x upper normal limit (ULN);
Patients receiving therapeutic anticoagulant therapy should use stable doses of ALT,
AST and/or ALP ≤ 2.5 x ULN, except for the following (ALT and/or AST ≤ 5 x ULN in
patients with known liver metastasis; ALP ≤ 5 x ULN in patients with known bone
metastasis; Serum bilirubin ≤ 1.5 x ULN; Serum bilirubin ≤ 3 x ULN in patients with
known Gilbert disease). Creatinine clearance rate (CRCL) ≥ 45 mL/min (based on
standard Cockcroft and Gault formulas).
- For fertile women: agree to abstinence or use non-hormonal contraceptive methods
during treatment and for 3 months after treatment in the last study. A woman is
considered to have fertility potential if she is in the post-menarche state, has not
reached the post-menopausal state (amenorrhea for 12 consecutive months, with no
definite cause other than menopause) and has not undergone surgical sterilization
(ovariectomy and/or uterus removal).
- For men: agree to keep abstinence or use condoms, and agree not to donate sperm. For
fertile female partners or pregnant female partners, men must keep abstinence or use
condoms during treatment and for three months after the last study treatment to
avoid exposing embryos. In the meantime, men must avoid donating sperm.
- Sign the informed consent form.
Exclusion Criteria:
- History of other malignant tumors within 3 years before screening, except properly
treated cervical carcinoma in situ, non-melanoma skin cancer or stage I uterine
cancer.
- Patients with EGFR mutations or ALK fusion will be excluded.
- Metastasis of pia mater, brain stem, midbrain, pons and medulla or metastasis
leading to obstructive hydrocephalus.
- Patients with neurological symptoms, including those receiving > 4mg dexamethasone,
will not be eligible for inclusion in this study.
- Spinal or hemorrhagic metastases will be excluded.
- Surgical treatment of brain or spinal lesions within 14 days before.
- The previous systemic treatment or neoadjuvant or adjuvant chemotherapy before
admission was less than 6 months.
- With clinically significant complications affecting platinum chemotherapy
administration.
- Autoimmune history, including but not limited to myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener granuloma, Sjogren's syndrome, Guillain-Barre syndrome, multiple
sclerosis, vasculitis or glomerulonephritis. Exceptions to the following：①Patients
with a history of autoimmune-associated hypothyroidism and taking a stable dose of
thyroid replacement hormone are eligible for this study.
②Patients with controlled type 1 diabetes who received a steady dose of insulin were
eligible for this study.
③Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only
dermatological manifestations (e.g. psoriatic arthritis patients will be excluded)
provided they meet the following conditions: the rash covers less than 10% of the
body surface area, the disease is well controlled at baseline, only inefficient
topical steroids are required, and there is no acute attack in the past 12 months.
- History of idiopathic pulmonary fibrosis, drug-induced pneumonia or active radiation
pneumonia in radiation field.
- Previous treatment was with immune checkpoint inhibitors or CD137 and OX-40
agonists.
- Receive research treatment within 28 days before starting the study drug, and screen
for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg).
Patients with previous or cured hepatitis B virus (HBV) infection (HBcAb positive
but no HBsAg) are eligible regardless of their HBV DNA negative. Patients with
positive HCV antibody are eligible regardless of whether HCV RNA is negative or not.
- Active tuberculosis or HIV infection.
- Abuse of drugs or alcohol within 12 months before screening.
- Any serious medical condition or abnormality in clinical laboratory examination
prevents patients from safely participating in and completing the study according to
the judgment of the researcher.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
December 2023
Completion date:
June 2025
Lead sponsor:
Agency:
Second Affiliated Hospital of Nanchang University
Agency class:
Other
Collaborator:
Agency:
Hunan Cancer Hospital
Agency class:
Other
Collaborator:
Agency:
Fujian Cancer Hospital
Agency class:
Other
Source:
Second Affiliated Hospital of Nanchang University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05812534
