This study was a one-arm, single-center, phase II clinical study. Patients who meet the
enrollment criteria will receive CM082 tablets 150mg once daily (qd) orally (taken within
half an hour after daily breakfast) in combination with JS001 (3mg/kg, once every 2 weeks,
q2w), every 28 days a treatment cycle until the disease progresses, the toxicity is
intolerable, the investigator or subject decides to withdraw, loses to follow up, starts
using other anti-tumor treatments or dies.
The study is divided into the following five stages--screening period, treatment period, end
of treatment / withdrawal treatment, follow-up after treatment, survival follow-up.
Screening period Subjects should be informed and signed an informed consent form prior to
screening assessment. Screening should be performed within 28 days prior to dosing. After the
investigator confirms compliance with the inclusion criteria and does not meet the exclusion
criteria, the subject may be enrolled in the study drug.
Treatment period At this stage the subject will be treated with CM082 and JS001 until disease
progression, intolerable toxicity, the investigator or subject decides to quit, is lost to
follow-up, begins using other anti-tumor treatments or dies.
During the trial, subjects received a safety assessment every 4 weeks; tumor assessments were
performed 6 weeks after the first visit and every 8 weeks after the first tumor assessment.
Tumor progression will be evaluated simultaneously according to RECIST criteria and iRECIST
criteria. Subjects identified as confirmed progressive disease(iCPD) according to iRECIST
criteria should discontinue treatment.
End of treatment / withdrawal treatment End of treatment(EOT)visit evaluation should be
performed as soon as possible after the subject has discontinued the test drug. Anyone who
discontinues treatment or withdraws from treatment for reasons other than progression of the
disease should perform a safety assessment as soon as possible, while continuing to perform a
tumor assessment at the same frequency as the treatment period until disease progression or
initiation of other anti-tumor treatments. However, subjects who have terminated treatment
due to disease progression need only undergo a safety assessment and no longer have a tumor
assessment. If the subject terminates treatment due to toxicity or other reasons at the last
visit and does not continue taking the test drug afterwards, the visit is considered to be
the end of treatment/exit treatment visit.
Follow-up after treatment For subjects who completed the trial or withdrew their informed
consent, all adverse events (AEs) and concomitant medications must be recorded up to 30 days
after the last dose of the trial, and all new AEs were issued within 30 days of the last
trial dose. For subjects who started using other anti-tumor therapies, AEs that were not
severe and that the investigator considered unrelated to the test drug were no longer
recorded.
Survival follow-up Subjects with disease progression or other anti-tumor treatments will no
longer undergo safety and tumor assessment, but continue to collect data on overall survival
and follow-up treatment at telephone follow-up every 12 weeks until the patient dies or loses
visit.
Note: Patients who discontinue treatment due to disease progression (except for patients
withdrawing informed consent, loss of follow-up, death) should continue to follow the tumor
assessments according to the original frequency (no safety assessment). Once disease
progression has occurred or other anti-tumor drugs have been used, a telephone survival
follow-up is performed every 12 weeks thereafter.
Inclusion Criteria:
- Histologically or cytologically confirmed diagnosis of recurrence after surgery,
inoperable resection or metastasis advanced NSCLC (III/IV period), with no specific
driver gene mutations (EGFR or ALK).
- Has not received any systemic anti-tumor medication or adjust the chemotherapy regimen
because of intolerance( but the treatment should be completed for at least 4 weeks
prior to the first dose of study drug, and all related toxicity events have returned
to normal or no more than Grade I of CTCAE 4.03, except for hair loss).
- Eastern Cooperative Group (ECOG) Performance Status score of 0 or 1.
- Life expectancy of at least 12 weeks.
- All patients are suggested tumor tissue specimens (preferably fresh tissue specimens)
for PD-L1 expression analysis prior to enrollment. If the subject did not undergo a
pathological examination before participating in the trial, the collected tumor tissue
specimens will also be used for pathological examination to confirm the diagnosis of
NSCLC.
- There is at least one measurable lesion according to the RECIST 1.1 standard and the
lesion has not received radiotherapy.
- Patients may have a history of brain/meningeal metastases, but must undergo topical
treatment (surgery/radiotherapy) and be clinically stable for at least 3 months prior
to the start of the study .If corticosteroids have been used before, they should be
discontinued for at least 2 weeks before the first dose of study drug.
- The level of organ function must meet the following requirements (7 days before the
first dose of study drug):
- Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L, platelet (PLT) ≥
100 × 109 / L, hemoglobin (HB) ≥ 9g / dL (no blood transfusion or receiving blood
components within 14 days before detection);
- Liver: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal（ULN）,
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5*ULN (if
liver metastasis, AST, ALT allowed) ≤ 5 *ULN);
- Serum creatinine ≤ 1.5*ULN and endogenous creatinine clearance ≥ 50milliliter(ml)
/ min (Cockcroft-Gault formula);
- Well-controlled hypertensive patients can be enrolled;
- International normalized ratio (INR), activated partial thromboplastin time
(aPTT) ≤ 1.5 *ULN for patients who have not received anticoagulant therapy;
patients who receive anticoagulant therapy should be treated within the
requirements of label
- Urine protein ≤ 1+, if urine protein > 1+, 24 hours urine protein measurement is
required, the total amount of which needs ≤ 1 gram;
- Free Triiodothyronine(FT3), Free Thyroxine(FT4), Thyroid-Stimulating Hormone(TSH)
normal or abnormal has no clinical significance;
- The heart function is normal, that is, the electrocardiogram is normal or
abnormal has no clinical significance. The echocardiography shows that the left
ventricular ejection fraction (LVEF) is greater than 50%.
- Serum pregnancy test results must be negative within 7 days prior to the first dose of
the test drug for women of childbearing age; males with fertility or women who are at
risk of pregnancy must use highly effective methods of contraception throughout the
trial (eg oral contraceptives, intrauterine contraceptive device, controlled libido or
barrier contraceptive method combined with spermicide), and continued contraception
for 12 months after the end of treatment.
- Ability to understand the nature of this trial and give written informed consent.
Willingness and ability to comply with trial and follow-up procedures.
Exclusion Criteria:
- Patients who have previously received anti-PD-1, anti-PD-L1, anti-PD-L2 therapy, or
VEGFR Tyrosine Kinase Inhibitors(TKI) therapy.
- Patients currently receiving anti-tumor treatment.
- Patients who received large surgery within 4 weeks before the first dose of the test
drug or has not recovered from the side effects of this operation, received live
vaccination or immunotherapy within 4 weeks before the first dose of the test drug,
and radiotherapy was performed within 2 weeks.
- Subjects with a history of malignancy (unless NSCLC) were excluded unless complete
remission was achieved at least 2 years prior to enrollment and no further treatment
was required during the study period (the following conditions are not limited:
non-melanoma skin cancer) , bladder carcinoma in situ, gastric carcinoma in situ,
colonic carcinoma in situ, endometrial carcinoma in situ, cervical carcinoma in
situ/dysplasia, melanoma carcinoma in situ or breast carcinoma in situ)
- Hematopoietic stimulating factors were received within 1 week prior to the first dose
of the study drug, such as granulocyte colony-stimulating factor (G-CSF) and
erythropoietin.
- HIV antibody or Treponema pallidum antibody test results are positive.
- If HBsAg or HBcAb is positive, hepatitis B virus(HBV) DNA should be tested. Patients
should be excluded if the measurement is above the upper limit of the normal range. If
HCV antibody is positive, hepatitis C virus(HCV) DNA should be tested. Patients should
be excluded if the measurement is above the upper limit of the normal range.
- Those known to be allergic to recombinant humanized PD-1 monoclonal antibody drugs and
their components; those known to be allergic to CM082 and any of its excipients.
- A large amount of pleural or ascites with clinical symptoms and requiring symptomatic
treatment.
- Active lung disease (eg, interstitial pneumonia, pneumonia, obstructive pulmonary
disease, asthma) or a history of active tuberculosis.
- Have any clinical problems out of control, including but not limited to:
- Persistent or active (severe) infection;
- Hypertension that is not effectively controlled (blood pressure lasts greater
than 150/90mmHg);
- Diabetes that is not effectively controlled;
- Heart disease, defined as grade III/IV congestive heart failure or heart block
defined by the New York Heart Association
- Having a history of or suspected of having an autoimmune disease;Having a history
of any kind of disease requiring treatment with a steroid or immunosuppressive,
such as: pituitary inflammation, colitis, hepatitis, nephritis, hyperthyroidism,
Hypothyroidism, etc.;
- The following situation occurred within 6 months before the first dose:
- Deep vein thrombosis or pulmonary embolism;
- myocardial infarction;
- severe or unstable arrhythmia or angina;
- percutaneous coronary intervention, acute coronary syndrome, coronary artery
bypass grafting;
- Cerebrovascular accident, transient ischemic attack, and cerebral embolism.
- Have received a stem cell transplant or an organ transplant.
- Patients who need to use during the study or have used or the following drugs within
14 days prior to the first dose: CYP3A4 strong inhibitor or strong inducer; warfarin
or any other coumarin derivative anticoagulant.
- The investigator judges other severe, acute or chronic medical illness or laboratory
abnormalities that may increase the risk associated with the study or may interfere
with the interpretation of the findings.
- The investigator judged that the patient's compliance was poor or that there were
other conditions that were not suitable for the trial.
