Phase Ib Study Evaluating Safety and Tolerability of Combination Trametinib and Ruxolitinib in Patients With Advanced RAS Mutant Colorectal Cancer and Pancreatic Adenocarcinoma
Overview
- Phase
- Phase 1
- Intervention
- Trametinib
- Conditions
- Colorectal Cancer
- Sponsor
- National Cancer Centre, Singapore
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this research study to find out if the drug trametinib in combination with ruxolitinib is safe, tolerable and has beneficial effects in people who has certain type of cancers including the type that you have. Patients with RAS mutant colorectal cancer and pancreatic adenocarcinoma are invited to participate in this study. This is the first time that both trametinib and ruxolitinib are studied in combination. Trametinib is marketed in several countries with the brand name Mekinist® for the treatment of melanoma (a type of skin cancer). Trametinib has been studied extensively in cancer and has been tested in many patients. Ruxolitinib is an oral inhibitor of JAK1 and JAK2 tyrosine kinases and is approved for treatment of adult polycythemia vera and myelofibrosis. Ruxolitinib has been studied extensively in many patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients (male or female) ≥
- •Patients with histological diagnosis of RAS mutant advanced colorectal and pancreatic adenocarcinoma having received at least 1 prior line of systemic therapy. Pancreatic cancer patients with KRAS mutation detected on plasma profiling having received at least 1 prior line of systemic therapy.
- •Patients must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.
- •Life expectancy of at least 3 months.
- •Written informed consent that is consistent with ICH-GCP guidelines.
- •Eastern Cooperative Oncology Group (ECOG) performance score ≤
- •Have adequate organ and hematologic function, as determined by:
- •Absolute neutrophil count (ANC) ≥ 1,500/μl.
- •Platelets ≥ 100,000/μl.
- •Haemoglobin ≥ 9g/dL.
Exclusion Criteria
- •Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days of study drug commencement, or 5 half-lives, whichever is shorter, and with recovery of clinically significant toxicities from that therapy.
- •Received monoclonal antibodies or had surgery within 30 days of the first dose of study drug.
- •Have been diagnosed with another primary malignancy within the past 3 years of study drug commencement (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer).
- •Have CNS metastases that are symptomatic, neurologically unstable, or requiring an increasing dose of corticosteroids.
- •Have meningeal involvement or spinal cord compression.
- •Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
- •Myocardial infarction (MI) within 6 months prior to the first dose.
- •Unstable angina within 6 months prior to first dose.
- •History of congestive heart failure (CHF).
- •History of clinically significant atrial arrhythmia.
Arms & Interventions
Dose Escalation and Expansion
Dose Escalation: Trametinib 2mg daily monotherapy for 14 days. Followed by combination oral trametinb (2mg starting dose) daily and oral ruxolitinib (5mg starting dose) twice daily at assigned doses. Dose Expansion: Combination oral trametinb daily and oral ruxolitinib twice daily at the maximum tolerated dose (MTD) established at the Dose Escalation phase. A cycle of therapy will comprise of 28 days of combination trametinib and ruxolitinib treatment.
Intervention: Trametinib
Dose Escalation and Expansion
Dose Escalation: Trametinib 2mg daily monotherapy for 14 days. Followed by combination oral trametinb (2mg starting dose) daily and oral ruxolitinib (5mg starting dose) twice daily at assigned doses. Dose Expansion: Combination oral trametinb daily and oral ruxolitinib twice daily at the maximum tolerated dose (MTD) established at the Dose Escalation phase. A cycle of therapy will comprise of 28 days of combination trametinib and ruxolitinib treatment.
Intervention: Ruxolitinib
Outcomes
Primary Outcomes
Maximum Tolerated Dose
Time Frame: 28 days (1 cycle)
Highest dose level at which less than one-third of the patients in the dose level experienced dose limiting toxicities (DLTs) during the first cycle of treatment
Secondary Outcomes
- Frequency and severity of treatment-emergent Adverse Events and Serious Adverse Events(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - Haemoglobin(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - White blood count, Platelets, Absolute neutrophil count(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Urea, Sodium, Potassium, Chloride, Bicarbonate, Glucose, Magnesium, Calcium, Phosphate, Total cholesterol, High and low density lipoprotein, Triglycerides(From time of first study drug administration until 30 days after last dose of study drug)
- Tumour Markers: CEA and CA 19-9 in blood samples(From cycle 1 up to last cycle of treatment (each cycle is 28 days))
- Overall Response Rate(From time of first study drug administration until first occurrence of disease progression, up to 2 years)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Uric acid, Creatinine, Total bilirubin(From time of first study drug administration until 30 days after last dose of study drug)
- Overall Survival(From time of first study drug administration to death from any cause, up to 2 years)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - Neutrophils(From time of first study drug administration until 30 days after last dose of study drug)
- Disease Control Rate(From time of first study drug administration until best overall response, first occurence of disease progression, up to 2 years)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Total protein, Albumin(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Alkaline phosphatase, Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase, Beta-human chorionic gonadotrophin(From time of first study drug administration until 30 days after last dose of study drug)
- Frequency of dose interruptions(From time of first study drug administration until 30 days after last dose of study drug)
- Frequency of dose reductions(From time of first study drug administration until 30 days after last dose of study drug)
- Pharmacokinetics (PK): Trough concentrations of trametinb(From cycle 1-6 of study (each cycle is 28 days))
- Progression Free Survival(From time of first study drug administration until first occurence of disease progression, or death from any cause, up to 2 years)