Inclusion Criteria:
1. Age of both sexes ranged from 18 to 75 years (inclusive of 18 and 75 years old).
2. For dose escalation phase only:
Patients with locally advanced or metastatic solid tumors with histologically or
cytologically confirmed MAPK signaling pathway mutations who are unresponsive to
standard treatment regimens or for whom no standard treatment regimens are available;
3. Only in the extension stage (all the following conditions must be met):
Patients who have histologically or cytologically confirmed, locally advanced or
metastatic solid tumors with the following MAPK signaling pathway mutations that do
not respond to or have no standard treatment options:
Locally advanced or metastatic head and neck cancer, melanoma, small bowel cancer,
bile duct cancer, and gallbladder cancer with BRAF non-V600 (G469, L597, L485, etc.)
mutation (approximately 10-30 cases, subject number adjusted according to efficacy);
Locally advanced or metastatic colorectal cancer, cholangiocarcinoma, gallbladder
cancer, small bowel cancer or other solid tumors with BRAF V600 E mutation
(approximately 10-20 cases, of which colorectal cancer is expected to be 3-6 cases,
the number of subjects will be adjusted according to efficacy); KRAS G12V-mutated,
locally advanced or metastatic non-small- cell lung cancer (approximately 10 patients,
adjusted for the number of participants according to efficacy).
4. ECOG performance status (Appendix 2) is 0-2.
5. Life expectancy of ≥12 weeks.
6. patients should have adequate end-organ function, with laboratory results 7 days
before the first dose meeting the following requirements: Bone marrow reserve:
absolute neutrophil count (ANC) ≥1.5×109/L, platelet ≥100×109/L, and hemoglobin ≥90
g/L;(no use of hematopoietic stimulating factors such as EPO, G-CSF or GM-CSF in the
14 days before the test, and no blood transfusion in the 14 days before the test)
Liver function: serum albumin ≥3.0 g/dL; Total bilirubin ≤1.5× upper limit of normal
value (ULN), ALT and AST≤ 2×ULN, if liver metastasis or liver cancer patients, ALT or
AST≤3×ULN; Renal function: creatinine ≤1.5×ULN or creatinine clearance ≥60 mL per
minute (according to the Cockcroft-Gault formula; see Appendix 3); Coagulation
function: INR≤1.5×ULN, APTT ≤1.5×ULN.
7. Cardiac function: left ventricular ejection fraction (LVEF)≥50%.
8. Female or male participants of childbearing age and their partners are required to use
a medically approved contraceptive method (Annex 4) during the study treatment period
and for 3 months after the end of the study treatment period if the women of
childbearing age (defined as those younger than 50 years old or older than 50 years of
age who are amenorrheic for less than 12 months before screening) tested negative for
serum β-HCG.
9. Participants are required to provide informed consent for the study and to sign an
informed consent form before the trial.
10. At least one measurable lesion was present according to RECIST 1.1 criteria.
Exclusion Criteria:
1. Patients with a history of allergy to any component of JSI-1187 or its pharmaceutical
excipients.
2. Patients with prolonged QTcF (QTcF: male >450 ms, female >470ms, QTcF formula is
shown in Appendix 5).
3. Patients who has previously received other ERK inhibitors.
4. Active central nervous system tumors or central nervous system metastases, as
indicated by clinical symptoms, cerebral edema, need for systemic hormone use, and
disease progression. Patients with treated tumors or metastases of the central nervous
system are eligible if they have been clinically stable (as determined by imaging or
other clinical testing) for at least 8 weeks and if they had stopped immune
suppressive systemic hormones (> 10 mg per day of prednisone or equivalent) for at
least 4 weeks before the first dose of study drug.
5. Patients with basal-cell, squamous-cell, or carcinoma in situ are excluded if they had
a history of other malignancies within 2 years before enrollment, have undergone
potentially curative treatment, and have been free of disease recurrence for 5 years
after the initiation of treatment.
6. History of or current evidence/risk of retinal vein occlusion or central serous
retinopathy.
7. Have received antineoplastic therapy within 28 days before the first dose, including
but not limited to: chemotherapy, biotherapy, radiotherapy (except palliative
radiotherapy for patients with bone metastases), endocrine therapy, targeted
antineoplastic therapy (except nitrosourea and mitomycin C); Received nitrosourea or
mitomycin C within 6 weeks before the first dose. Had received treatment with a
traditional Chinese medicine with definite antitumor effects within 14 days before the
first dose. Except for alopecia and eligibility criteria, radiation-related toxicities
(including radiodermatitis dermatitis, post-radiation recall reactive dermatitis, soft
tissue fibrosis, etc.) did not recover to grade 1 or lower (according to CTCAE 5.0)
after palliative radiotherapy in patients with bone metastases.
8. Patients have received other drugs which are still in clinical trials within 28 days
before the first dose.
9. Patients who has undergone major surgical procedures or has active ulcers (which are
still present) or wounds that do not fully heal within 28 days before the first dose.
10. Chronic systemic comorbidities (e.g., severe chronic lung, liver, kidney, or heart
disease) that cannot be controlled (have received active treatment but is not
currently stable or may progress/relapse during the trial).
11. Patients with severe cardiac disease, such as uncontrolled arrhythmia, myocardial
infarction, unstable angina, or New York Heart Association (NYHA) class III-IV cardiac
dysfunction, within 6 months prior to the first dose (Annex 6).
12. Patients who have factors that increase the risk of QTc prolongation and the risk of
arrhythmias, such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome, sudden death of an immediate family member under 40 years
of age from an unknown cause, and taking any concomitant medications that cause
prolongation of the QT interval (Appendix 7).
13. Patients with uncontrolled (actively treated but not currently stable or with
potential disease progression/recurrence during the trial) body fluid (pleural
effusion, pericardial effusion, or ascites).
14. Patients who are in the acute phase of infection and require medical therapy.
15. Unable to swallow capsules or suffering from a condition that significantly affects
gastrointestinal function, such as malabsorption syndrome, gastric or small bowel
resection, symptomatic inflammatory bowel disease, partial or complete bowel
obstruction.
16. Patients who are taking (or could not be discontinued 2 weeks before the first dose)
any known strong inhibitor or strong inducer of CYP3A4, BCRP substrate, or who needed
to continue receiving these drugs during the study (Appendix 8).
17. Positive human immunodeficiency virus antibody (HIV-Ab) within 1 week before the first
dose; Or HCV antibody (HCV-Ab) positive and HCV RNA quantification > the upper
limit of normal value of the detection unit;Or patients with positive hepatitis B
surface antigen (HBsAg) and HBV DNA > the upper limit of normal value.
18. The presence of serious psychological or psychiatric abnormalities that affect the
patient's compliance to participate in this clinical study.
19. Patients with a history of psychotropic substance abuse or drug use.
20. Patients with adverse event worse than CTCAE1 that is not resolved due to previous
antineoplastic therapy before the first dose (except alopecia, sensory neuropathy, and
eligibility criteria otherwise required).
21. Women who are lactating.
22. Any other condition judged by the investigator to be inappropriate for study
participation.
