Treatment of Solid Tumors Harboring KRAS Mutation With Imatinib and Trametinib
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 10
- Locations
- 1
- Primary Endpoint
- Overall response rate (ORR)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 20 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- •The participants will be excluded from the study if they meet any of the following criteria:
- •History of allergic reaction to trametinib or imatinib.
- •Participant who has been exposed to KRAS G12C inhibitors.
- •Participant who has been exposed or currently taking kinase inhibitors.
- •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.
- •Participants with liver cirrhosis with Child-Pugh score ≥ 8 (Late Child-Pugh B and Child-Pugh C).
- •Participants with electrolyte abnormalities that have not been corrected.
- •Participants with metastatic lesion in central nervous system.
- •Participants with active infection.
- •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.
- •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.
- •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.
- •Females who are breastfeeding or pregnant at screening or baseline.
- •Participants with psychiatric illness which would preclude study compliance.
- •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.
Arms & Interventions
Imatinib + Trametinib
- Participants will receive oral imatinib 100 mg/day and trametinib 2 mg/day.
- If there is no severe adverse event, the dose of imatinib could be increased to 200mg/day and the dose of trametinib reduced to 1 mg/day since cycle 2 per treating physician's judgement.
- Four weeks of treatment is regarded as one cycle.
Intervention: Imatinib (Drug)
Imatinib + Trametinib
- Participants will receive oral imatinib 100 mg/day and trametinib 2 mg/day.
- If there is no severe adverse event, the dose of imatinib could be increased to 200mg/day and the dose of trametinib reduced to 1 mg/day since cycle 2 per treating physician's judgement.
- Four weeks of treatment is regarded as one cycle.
Intervention: Trametinib (Drug)
Outcomes
Primary Outcomes
Overall response rate (ORR)
Time Frame: From the date of registration until the end of treatment, up to 2 years.
Overall response is evaluated using Response Evaluation Criteria in Solid Tumors criteria (RECIST 1.1). A participant is considered to have responded if either of the following outcomes is achieved: 1. Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm 2. Partial Response: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Secondary Outcomes
- Overall survival(From the date of registration to the date of patients death, up to 3 years.)
- Disease control rate(From the date of registration until disease progression or death, up to 3 years.)
- Safety profile(From the date of registration until 1 month after disease progression or death, up to 3 years.)
- Progression-free survival(From the date of registration until disease progression or death, up to 3 years.)
Investigators
Li-Yuan Bai
Director, Division of Hematology and Oncology
China Medical University Hospital