Imatinib and Trametinib for KRAS-mutated Solid Tumor

Summary

In this pilot trial, participants with unresectable solid cancers harboring KRAS mutations will be provided with a compassionate treatment if their diseases progress after current standard treatments, or there is no available standard treatment. This trial will evaluate the efficacy and safety of the combination of trametinib and imatinib on chemotherapy refractory solid cancers.

Eligibility

Inclusion criteria:

Patients will be included in the study if they meet all of the following criteria:

1. Participants with age ≥ 20 years old.
2. Histologically confirmed locally advanced or metastatic solid tumors with KRAS G12X mutation.
3. Documented disease progression during or within 6 months after standard chemotherapies or no available standard therapy.
4. Documented measurable disease as defined by RECIST v1.1.
5. ECOG Performance Status 0-2.
6. Participants has life expectancy of at least 8 weeks.
7. Adequate hematologic parameters, and hepatic and renal functions defined as

   1. Hematological: white blood cell ≥3,000/ul, absolute neutrophil count (ANC) ≥1,500/ul, hemoglobin ≥9 g/dl and platelet count ≥ 90,000/ul.
   2. Hepatic: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥2.5 x upper limit of normal (ULN) (≥5.0 x ULN if attributable to liver metastases), and total bilirubin ≥1.5 x upper limit of normal (ULN) (≥3.0 x ULN if attributable to liver metastases).
   3. Renal: serum creatinine level ≦2 x ULN or creatinine clearance ≥ 30 ml/min \[calculated by either Cockcroft-Gault equation \[(140-age) x body weight (kg) x (1 if male or 0.85 if female) / (72 x serum creatinine level, mg/dl)\] or 24-hour urine test\].
8. Adequate blood coagulation function, defined as prothrombin time international normalized ratio (PT INR)≦ 2.3.
9. Normal ECG or ECG without any clinical significant findings.
10. Able to understand and sign an informed consent (or have a legal representative who is able to do so).
11. Women or men of reproductive potential should agree to use an effective contraceptive method.

Exclusion Criteria:

The participants will be excluded from the study if they meet any of the following criteria:

1. History of allergic reaction to trametinib or imatinib.
2. Participant who has been exposed to KRAS G12C inhibitors.
3. Participant who has been exposed or currently taking kinase inhibitors.
4. Participants who have major abdominal surgery, radiotherapy or other, investigating agents within 2 weeks. Patients who have palliative radiotherapy will be eligible if the irradiated area does not involve the only lesion of measurable / evaluable disease.
5. Participants with liver cirrhosis with Child-Pugh score ≥ 8 (Late Child-Pugh B and Child-Pugh C).
6. Participants with electrolyte abnormalities that have not been corrected.
7. Participants with metastatic lesion in central nervous system.
8. Participants with active infection.
9. Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy.
10. Participants who have serious concomitant systemic disorders incompatible with the study, i.e. poorly controlled diabetes mellitus, auto-immune disorders, or other conditions that in the opinion of the investigator would preclude the subject's participation in the study.
11. Participants who have other prior or concurrent malignancy except for adequately treated in situ carcinoma or basal cell carcinoma of skin, or any malignancy which remains disease-free for 3 or more years after curative treatment.
12. Females who are breastfeeding or pregnant at screening or baseline.
13. Participants with psychiatric illness which would preclude study compliance.
14. Participants taking strong CYP450 enzyme system inducers (rifampicin, glucocorticoids, phenobarbital and pentobarbital) or inhibitors (ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine), and other unapproved drugs.

Conditions2

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