| Eligibility |
Inclusion Criteria:
- The patient or his legal representative is able to understand and voluntarily sign a
written informed consent (before commencing this study and any research procedure);
- Age =18 years old, male or female;
- Dose escalation stage (Stage Ib) : advanced solid tumors with KRAS G12C mutation in
patients who have previously failed standard therapy or have no standard therapy or
are intolerant to standard therapy.
- Dose Expansion Phase (Phase II) :
Cohort 1: advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation; .
Cohort 2: G12Ci naïve advanced solid tumors with KRAS G12C mutation. Cohort 3: G12Ci
treated advanced solid tumors with KRAS G12C.
- The patient must have at least one measurable lesion that meets the RECIST v1.1
definition (tumor lesion located in the area of prior radiotherapy or other local
regional treatment site is generally not considered as a measurable lesion unless
there is definite progression of the lesion);
- Expected survival =3 months;
- ECOG Physical strength score: 0-1;
- The patient must have adequate organ function, defined as follows:
blood Absolute neutrophil count (ANC) =1.5×109/L within 14 days without the support of
granulocyte colony-stimulating factor; No blood transfusion within 14 days, platelets
=100×109/L without the use of thrombopoietin (TPO) and interleukin-11 (IL-11); Hemoglobin
=90 g/L without blood transfusion within 14 days, without erythropoietin (EPO); kidney
Serum creatinine =1.5 times the upper limit of normal (ULN) or creatinine clearance =
60ml/min calculated using the modified Cockcroft-Gault equation or eGFR= 60ml/min estimated
by the MDRD equation; liver albumin =3.0 g/dL; Total bilirubin =1.5×ULN; In patients with
liver metastasis, total bilirubin =2.5×ULN; AST/ALT=2.5 x ULN; In patients with liver
metastasis, AST/ALT=5×ULN; Coagulation function International Normalized ratio (INR) and
prothrombin time (PT) =1.5×ULN, unless the patient is being treated with anticoagulants
(INR<2.5×ULN) and PT or PTT is within the therapeutic range for which the anticoagulant is
intended to be used; Activated partial thromboplastin time (APTT) =1.5×ULN, unless the
patient is being treated with an anticoagulant (APTT<2.5×ULN) and PT or PTT is within the
therapeutic range for which the anticoagulant is intended to be used.
- Fertile men and women of childbearing age must agree to use reliable contraception
(hormonal or barrier or abstinence) from the time they sign an informed consent until
6 months after the final administration of the investigational drug. Pregnancy test
results for women of reproductive age must be negative within =7 days before the first
study drug administration.
Exclusion Criteria:
- Received biological agents of chemotherapy and anti-tumor therapy within 3 weeks
before the first administration, and received anti-tumor drugs such as radiotherapy
and endocrine therapy within 4 weeks before the first administration, except for the
following:
nitrosourea or mitomycin C within 6 weeks prior to first use of the study drug; Oral
fluorouracil, small molecule targeted drugs, and Chinese herbal medicines or proprietary
Chinese medicines with anti-tumor indications within 5 half-lives or 2 weeks prior to the
first use of the study drug (whichever is shorter); local palliative radiotherapy within 2
weeks prior to the first use of the study drug;
- Received other investigational drugs or treatments that are not on the market within 5
half-lives or 4 weeks (whichever is shorter) prior to initial administration;
- Had major organ surgery (excluding needle biopsy) or significant trauma within 4 weeks
prior to the first dose, or required elective surgery during the trial;
- Use of CYP3A4 or P-gp suppressor or strong inducer within 2 weeks or 5 half-lives
prior to initial administration;
- There is evidence of the following heart diseases:
acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting,
cerebrovascular accident, or transient ischemic attack within 6 months before first
administration; Grade III-IV heart failure based on the New York Heart Association Cardiac
Function Scale at screening; During screening, echocardiography (ECHO) showed left
ventricular ejection fraction (LVEF) =50%.
Fridericia adjusted QT interval (QTcF) =450ms (male), =470ms (female) at screening; The
presence of poorly controlled hypertension (systolic blood pressure =160mmHg and/or
diastolic blood pressure =100mmHg) after medication at screening;
- Has difficulty swallowing or has a gastrointestinal disease or other malabsorption
condition that affects drug absorption, such as intestinal obstruction, Crohn's
disease, ulcerative colitis, short bowel syndrome, gastric emptying disorder, or has
severe gastrointestinal related toxicity before first administration and does not
recover below grade 2; Or confirmed clinically significant or acute gastrointestinal
disease;
- Uncontrolled pleural effusion, pericardial effusion, or pleural effusion requiring
repeated drainage (once a month or more frequently);
- Patients with active brain metastases or with symptoms of active central nervous
system metastases, including headache, vomiting, and vertigo, are eligible only if
they meet all of the following criteria and are asymptomatic and have treated or
untreated CNS lesions:
The presence of measurable lesions outside the CNS as determined by RECIST v1.1; Stable
brain metastases after treatment, defined as no evidence of disease progression or bleeding
during the 28 days prior to initiation of treatment and discontinuation of steroid hormones
and other therapeutic agents for at least 14 days prior to enrollment;
- Patients with interstitial pneumonia, or any evidence of clinically active
interstitial lung disease, within 6 months prior to first dosing;
- Arteriovenous thrombosis events, such as cerebrovascular accidents (including
transient ischemic attacks), deep vein thrombosis, and pulmonary embolism, occurred
within 6 months prior to initial administration;
- Have a history of other malignancies (except skin squamous cell carcinoma in situ that
has been cured and has not recurred for 5 years, basal cell carcinoma and cervical
carcinoma in situ, etc., which are considered by researchers to be eligible for
inclusion; Dose escalation phase, except for those deemed acceptable by the
investigator);
- Patients who have a history of severe allergy, or have a history of allergy to the
experimental drug/any excipient/combination drug, or have a history of allergy to
multiple drugs;
- Hepatitis B virus infection (HBsAg positive and DNA copy number >1000 IU/ml); Or
infected with hepatitis C virus (HCV antibody positive and HCV RNA > the upper limit
of normal); Or infected with human immunodeficiency virus (HIV antibody positive); Or
infected with treponema pallidum (defined as TP-Ab positive);
- There is an active infection (= grade 2) requiring anti-infective treatment or an
unexplained fever exceeding 38 ° C within 28 days before the first dose;
- Active stage of autoimmune disease as determined by the investigator within 28 days
before the first dose;
- Any toxicity from previous antitumor therapy prior to initial administration has not
returned to CTCAE 5.0 rating = Class 1 (unless hair loss, grade 2 peripheral
neuropathy, and/or other grade =2 adverse events that do not pose a safety risk);
- Pregnant and lactating women;
- The investigator considers that there are any clinical or laboratory abnormalities or
other reasons to be unsuitable for participating in this clinical study.
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