An Open Label, Multi-center, Phase I Clinical Study to Evaluate the Safety, Effectiveness and Pharmacokinetic Characteristics of SIM1803-1A in Patients With Locally Advanced/Metastatic Solid Tumors With NTRK, ROS1 or ALK Gene Fusion Mutations.

Study Overview
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Brief Summary
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This research study is done to test the safety, effectiveness and pharmacokinetic characteristics of SIM1803-1A in patients with locally advanced/metastatic solid tumors with NTRK, ROS1 or ALK gene fusion mutations. The cancer must have a change in a particular gene (NTRK1, NTRK2, NTRK3, ROS1 or ALK). SIM1803-1A is a drug that blocks the actions of these NTRK/ ROS1 /ALK genes in cancer cells and can therefore be used to treat cancer.

Official Title
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An Open Label, Multi-center, Phase I Clinical Study to Evaluate the Safety, Effectiveness and Pharmacokinetic Characteristics of SIM1803-1A in Patients With Locally Advanced/Metastatic Solid Tumors With NTRK, ROS1 or ALK Gene Fusion Mutations.

Conditions
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Advanced or Metastatic Solid Tumors With NTRK, ROS1 or ALK Gene Fusion

Intervention / Treatment
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* Drug: SIM1803-1A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with a locally advanced or metastatic solid tumor that has progressed or was nonresponsive to available therapies, are unfit for standard chemotherapy or for which no standard or available curative therapy exists；Proof of a malignancy harboring a NTRK、ROS1 or ALK fusion；Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and a life expectancy of at least 3 month；Adequate hematologic, hepatic, and renal function；Signed informed consent form； Exclusion Criteria: Any contraindications as listed in the local approved product information；Patients with unstable primary central-nervous-system tumors or metastasis, exceptions possible；Pregnancy or lactation；Clinically significant active cardiovascular disease or history of myocardial infarction；Participation in an investigational program with interventions outside of routine clinical practice；Prior treatment with other kinase inhibitor with tropomyosin receptor kinase inhibition；Active uncontrolled systemic bacterial, viral, or fungal infection；Current treatment with a strong CYP3A4 inhibitor or inducer；

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: adult patients_Dose 1<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 2<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 3<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 4<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 5<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 6<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 7<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|
| Experimental: adult patients_Dose 8<br> | Drug: SIM1803-1A<br>* SIM1803-1A will be administered orally as tablets at a given dose once daily in continuing 21-days cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | Number of participants with adverse events | 5 years | 
| Severity of adverse events | Severity of adverse events | 5 years | 
| Maximum tolerated dose | Maximum tolerated dose | 5 years | 
| Recommended dose for dose expansion | Recommended dose for dose expansion | 5 years | 
| Maximum concentration of SIM1803-1A in plasma (Cmax) | Maximum concentration of SIM1803-1A in plasma (Cmax) | Predose and 0.25, 0.5, 1, 2, 4, 8，12，24and 48 hours after drug administration on Days 1 and 8 of Cycle 1（each cycle is 21 days） | 
| Area under the concentration-time curve of SIM1803-1A in plasma from time 0 to 24 hours in fasted state (AUC(0-24)_fasted) | Area under the concentration-time curve of SIM1803-1A in plasma from time 0 to 24 hours in fasted state (AUC(0-24)_fasted) | Up to 1 day | 
| Area under the concentration-time curve of SIM1803-1A in plasma from time 0 to infinity in fasted state (AUC_fasted) | Area under the concentration-time curve of SIM1803-1A in plasma from time 0 to infinity in fasted state (AUC_fasted) | Up to 3 days | 
| Number of participants with treatment-emergent adverse events (TEAEs) | Number of participants with treatment-emergent adverse events (TEAEs) | Up to 24 weeks | 
| Time to maximum concentration of SIM1803-1A in plasma (Tmax) | Time to maximum concentration of SIM1803-1A in plasma (Tmax) | Predose and 0.25, 0.5, 1, 2, 4, 8，12，24and 48 hours after drug administration on Days 1 and 8 of Cycle 1（each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall Response Rate (ORR) | Up to 60 months | 
| Duration of Response (DOR) | Duration of Response (DOR) | Up to 60 months | 
| progression-free survival（PFS） | progression-free survival（PFS） | Up to 60 months |