Clinical trial NCT06962254: Imatinib and Trametinib for KRAS-mutated Solid Tumor
Official title: Treatment of Solid Tumors Harboring KRAS Mutation With Imatinib and Trametinib
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor Cancer
Keywords: KRAS G12D
KRAS G12V
KRAS G12R
MEK/ERK signaling pathway
MEK inhibitor
KRAS G12X
Imatinib
Trametinib
Lead sponsor: China Medical University Hospital
Sponsor class: OTHER
First posted: 2025-05-08
Enrollment: 10
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: KRAS gene mutations are commonly seen in cancers, practically pancreatic cancer, biliary tract cancer, and colorectal cancer. For example, KRAS gene mutations account for about 80% of pancreatic cancers. Clinical studies have found that tumors with KRAS gene mutations have a poor prognosis, inferior response to therapies, and are more likely to develop drug resistance. Therefore, new therapies are necessary for KRAS-mutant patients. Currently, only adagrasib (Krazati) and sotorasib (Lumakras) are approved for patients with KRAS G12C mutations in tumor. Unfortunately, they are ineffective for other KRAS mutations.

The mitogen-activated protein kinase (MEK/ERK) signaling pathway, downstream of KRAS, is hyperactivated in many cancers, making it a promising target for therapy. However, clinical trials targeting this pathway for patients with cancer have failed. Previous research found that a MEK inhibitor trametinib killed KRAS mutant cells but with feedback increased expression of PDGFR, a tyrosine kinase. Thus, the combination of MEK inhibitor with PDGFR inhibitor might be a promising therapeutic strategy.

Investigators have conducted in vivo experiments with two clinically used drugs, imatinib and trametinib, in tumor mouse experiments. The combination of trametinib and the tyrosine kinase inhibitor imatinib showed a good killing effect on pancreatic cancer cells with KRAS gene mutations. For cancers with KRAS non-G12C mutations, the effect of this combination is higher than sotorasib or adagrasib. For pancreatic cancer cells with KRAS G12C mutations, this combination therapy is equivalent to sotorasib or adagrasib alone. Therefore, the combination use of trametinib and imatinib is a potential drug combination that can target pan-KRAS mutant tumors.

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 of the combination of trametinib and imatinib on chemotherapy refractory solid cancers.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall response rate (ORR)
timeFrame: From the date of registration until the end of treatment, up to 2 years.
Secondary outcomes:
measure: Disease control rate
timeFrame: From the date of registration until disease progression or death, up to 3 years.
measure: Safety profile
timeFrame: From the date of registration until 1 month after disease progression or death, up to 3 years.
measure: Progression-free survival
timeFrame: From the date of registration until disease progression or death, up to 3 years.
measure: Overall survival
timeFrame: From the date of registration to the date of patients death, up to 3 years.
Other outcomes:
Locations:
city: Taichung
country: Taiwan
facility: China Medical University Hospital
Study officials:
References: