A Phase 1, Study of YL-15293 in Subjects With Advanced Solid Tumors With a KRAS G12C Mutation
Study Details
Study Description
Brief Summary
This is a phase 1 / 2 open label multicenter study to evaluate the maximum tolerance, safety, tolerance and PK of oral yy-15293 in patients with advanced solid tumors with KRAS G12C mutation, so as to confirm the recommended phase 2 dose of yy-15293 and obtain the preliminary efficacy information of patients with advanced solid tumors with KRAS G12C mutation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
Dose escalation stage:
It is planned to enroll 15-30 subjects into 5 dose groups of 100 mg/d, 200 mg/d, 400 mg/d, 600 mg/d, and 800 mg/d respectively. Three to six cases were enrolled in each dose group. In the single-dose period, only one dose is taken, half of the total daily dose is taken, and the daily dose in the multiple-dose period is taken orally in 2 doses. DLT evaluation is carried out in the first cycle (21 days).
Single-dose PK study: The drug was given once on an empty stomach in the morning on the first day, and the dose was half of the total dose of the day. Before administration (within 30 minutes before administration), pharmacokinetic samples were collected at 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours after administration. A total of 10 blood sampling points were collected, with 4ml blood taken each time .
Multi-dose PK study: 7 days after a single dose, 21 days of continuous administration is a treatment cycle, 2 times a day. On the first day, the 7th day and the 21st day, within 30 minutes before the administration, and 0.5, 1, 2, 3, 4, 6, 8, 10, 24h after the administration on the 21st day, collect the pharmacokinetics Samples, a total of 12 blood collection points, 4ml blood each time.
In addition, in the presence of DLT and SAE, a blood sample must be collected immediately for pharmacokinetic analysis.
Clinical expansion stage:
After the dose escalation test, it is planned to conduct a dose extension test in the recommended dose group for phase 2 clinical trials, and the indication is advanced or metastatic non-small cell lung cancer with KRAS G12C mutation. Approximately 60 subjects were enrolled in the clinical expansion plan. The first 12 subjects of the dose extension were subjected to pharmacokinetic studies. The dose used for the extended test may be an intermediate dose between the two climbing doses.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: yl-15293 Single arm, open, single and multiple doses; Dosage form: YL-15293 tablets Specification: 50mg, 200mg Storage conditions: refrigerated and sealed at 2-8℃ Way of administration: Single-dose study: Oral administration, once a day, with warm water, fasting administration, fasting 1 hour before and 2 hours after administration. Multiple administration studies: oral administration, warm water delivery, fasting administration, fasting 1 hour before administration and 2 hours after administration, continuous administration for 21 days as a treatment cycle. The way of taking the medicine is twice a day. |
Drug: YL-15293
After enrollment, patients will receive oral yl-15293 twice a day until disease progression, unacceptable adverse events, concurrent diseases prevent further study treatment, the investigator decides to withdraw the patient, the patient withdraws consent, the patient is pregnant, or for administrative reasons. After treatment, the patients will continue to be followed up for 30 days. Patients who permanently stop the study treatment for reasons other than disease progression will be followed up for disease evaluation after treatment until the start of new anti-cancer treatment, withdrawal of consent, loss of follow-up, death or until the sponsor stops the study, whichever comes first.
|
Outcome Measures
Primary Outcome Measures
- The overall response rate (ORR) [Throughout the study for approximately 2 years]
The overall response rate (ORR) will be estimated based on the proportion of evaluable patients whose overall response (ORR) during study treatment is CR or PR. Disease response will be assessed by the investigator using RECIST v1.1.
- Progression free survival, PFS [Throughout the study for approximately 2 years]
PFS, defined as the time from the first dose of study treatment to first
- Overall survival, OS [Throughout the study for approximately 2 years]
The time from randomization to death for any reason
- Disease control rate, DCR [Throughout the study for approximately 2 years]
The percentage of cases with remission (PR+CR) and stable lesions (SD) after treatment
Eligibility Criteria
Criteria
Patients must meet all of the following inclusion criteria before they can be enrolled in this trial:
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Age ≥ 18 years
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Histologically and genomically confirmed locally advanced or metastatic malignant solid tumors with KRAS p.g12c mutation.
- For patients with NSCLC, previous first-line treatment based on platinum failed; B. For patients with colorectal cancer, at least two-line systemic treatment regimens have been experienced previously（Patients with colorectal cancer and high microsatellite instability must receive at least nivolumab or pembrolizumab if clinically applicable） C. Patients with solid tumors other than NSCLC or colorectal cancer should have received systematic treatment at least once.
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It can provide core or excised biopsy tissue from archival tissue samples or newly obtained tumor lesions（Expansion phase only）
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According to recist1.1 standard, there are measurable or evaluable tumor lesions
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performance status，PS≤1
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Estimated survival time > 3 months
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QTcF ≤ 470 msec
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It has a good level of organ function A. Bone marrow function needs to meet：ANC≥1.5×109/L；PLT≥100×109/L；Hb≥9g/dL B. renal function：Cr≤1.5 times the upper limit of normal value；or Creatinine clearance≥50ml/min C. liver function：total bilirubin<1.5 x ULN（For subjects with documented Gilbert syndrome,< 2.0 x ULN or subjects with indirect bilirubin levels suggesting a source of extrahepatic elevation<3.0 x ULN）；ALT and AST≤ 2.5 x ULN（If liver metastasis occurs≤ 5 x ULN）；Alkaline phosphatase < 2.0 x ULN (if there is liver or bone metastasis, < 3.0 x ULN) D. Coagulation function：Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper normal limit (ULN), or international normalized ratio (INR) < 1.5 or within the target range (if preventive anticoagulant therapy is performed）
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The elution period of macromolecular drugs is ≥ 4 weeks, and that of oral fluorouracil and small molecule targeted drugs is ≥ 2 weeks
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Fertile women must have a negative blood pregnancy test within 72 hours before receiving the first study drug;
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For fertile men and women, they must be willing to use appropriate contraceptive methods 30 days before the first study drug administration and 120 days after the last study drug administration;
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Did not participate in the clinical trial as a subject within 1 month before participating in the trial;
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According to the judgment of the researcher, the compliance is high, willing to complete the test and can abide by the test scheme;
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Voluntarily participate in this clinical trial, understand the research procedures and be able to sign the informed consent in writing.
Patients with any of the following items cannot be enrolled in this study:
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Untreated patients with active brain metastases (except those with treated or asymptomatic brain metastases);
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Other malignant tumors in recent five years. Basal cell carcinoma of the skin, except squamous cell carcinoma of the skin or cervical carcinoma in situ after potential treatment;
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Myocardial infarction, symptomatic congestive heart failure (New York Heart Association > grade II), unstable angina pectoris or arrhythmia requiring drug treatment occurred within 6 months before enrollment
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Have a history of gastrointestinal diseases or gastric surgery or inability to swallow oral drugs
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Active infection requiring treatment
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Patients with active hepatitis B (hepatitis B surface antigen and / or hepatitis B core antibody positive and HBV-DNA > 103 copies /mL or 200IU/mL) or hepatitis C patients (hepatitis C virus positive and / or HCV-RNA positive) or HIV positive patients are required to receive treatment.
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Major organ surgery (excluding puncture biopsy) or significant trauma within 4 weeks before the first use of the study drug, or elective surgery during the trial, or therapeutic or palliative radiotherapy within 2 weeks before the first use of the study drug
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Allergic constitution, or known history of allergy to this drug component
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According to the researchers' judgement, there are serious diseases that may endanger the safety of patients or affect the completion of research, such as uncontrollable hypertension, uncontrollable diabetes and thyroid diseases.
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CYP3A4 or P-gp strong inhibitors were used within 14 days before study enrollment
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There is third space effusion that cannot be controlled by drainage or other methods (such as massive pleural effusion and ascites)
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Have a clear history of neurological or mental disorders
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The researchers believe that the subjects are not suitable to participate in this study for other reasons
In case of one or more of the following circumstances, the subject shall suspend the test:
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Subjects asked to withdraw from the study;
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Imaging evidence shows that the disease is progressing
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Pregnancy events occurred during the study
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After dose adjustment, the subject still could not tolerate the toxicity
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The researcher considers it necessary to withdraw from the study
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Shanghai YingLi Pharmaceutical Co. Ltd.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- YL-15293-002