Colorectal Cancer, Pancreatic Adenocarcinoma
Conditions
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.
Interventions
DRUGTrametinib
Taken orally once daily
DRUGRuxolitinib
Taken orally twice daily
Sponsors
National Cancer Centre, Singapore
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The first part of this study will be a standard 3+3 dose-escalating
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients (male or female) ≥ 21. * 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 1.1. * Life expectancy of at least 3 months. * Written informed consent that is consistent with ICH-GCP guidelines. * Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2. * Have adequate organ and hematologic function, as determined by: * Absolute neutrophil count (ANC) ≥ 1,500/μl. * Platelets ≥ 100,000/μl. * Haemoglobin ≥ 9g/dL. * Aspartate Amino Transferase (AST)/ Alanine Amino Transferase (ALT) ≤ 2.5 x upper limit of normal (ULN ≤ 5 x ULN is acceptable if liver metastases are present). * Total bilirubin ≤1.5 x ULN (\< 3 ULN for patients with Gilbert syndrome). * Creatinine clearance ≥ 60ml/min. * Prothrombin time and activated partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN) per institutional laboratory normal range. * Ejection fraction ≥ 50% with no symptoms attributable to heart failure. * Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females. * For female patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment. * Female and male patients who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation. * Have the willingness and ability to comply with scheduled visits and study procedures.
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. * Any history of ventricular arrhythmia. * Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose. * Have history or the presence of pulmonary interstitial disease or drug related pneumonitis. * Have an ongoing or active infection. * Patients with active HBV and HCV are excluded unless they are undergoing treatment for HBV and HCV. * Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose. * Patients who are on immunosuppressive therapy. * Patients who have retinal vein occlusion and retinal pigment epithelial detachment. * On medications which are potent and moderate inhibitor and inducers of CYP3A4. * Patients with moderate to severe hepatic impairment (Child Pugh B and C). * Patients with history of severe allergic skin reactions or current skin conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Unit of measure: g/dL. To assess the safety of the drug combination |
| 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 | Unit of measure: x 10\^9/L. To assess the safety of the drug combination. |
| 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 | Unit of measure: Percentage component of white blood cells. To assess the safety of the drug combination. |
| 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 | Unit of measure: mmol/L. To assess the safety of the drug combination |
| 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 | Unit of measure: umol/L. To assess the safety of the drug combination |
| 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 | Unit of measure: g/L. To assess the safety of the drug combination |
| 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 | Unit of measure: U/L. To assess the safety of the drug combination |
| 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 | To assess the safety of the drug combination. During the dose escalation phase, this includes the incidences of dose limiting toxicities during the first 2 cycles of treatment. |
| Frequency of dose reductions | From time of first study drug administration until 30 days after last dose of study drug | To assess the tolerability of the drug combination |
| Pharmacokinetics (PK): Trough concentrations of trametinb | From cycle 1-6 of study (each cycle is 28 days) | Trough concentrations of trametinb at different cycles of combination treatment with ruxolitinib |
| Tumour Markers: CEA and CA 19-9 in blood samples | From cycle 1 up to last cycle of treatment (each cycle is 28 days) | Changes from baseline tumour markers (CEA and CA 19-9) in blood samples |
| Overall Response Rate | From time of first study drug administration until first occurrence of disease progression, up to 2 years | The best overall response is the best response recorded from the start of the treatment until disease progression (PD)/ recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). |
| Disease Control Rate | From time of first study drug administration until best overall response, first occurence of disease progression, up to 2 years | Percentage of patients who have achieved complete response, partial response and stable disease in accordance to RECIST 1.1. |
| 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 | Time elapsed between treatment initiation and tumour progression or death from any cause, with censoring of patients who are lost to follow-up. |
| Overall Survival | From time of first study drug administration to death from any cause, up to 2 years | Time elapsed between treatment initiation and death from any cause, with censoring of patients who are lost to follow-up. |
| Frequency of dose interruptions | From time of first study drug administration until 30 days after last dose of study drug | To assess the tolerability of the drug combination. |
Countries
Singapore
Contacts
Primary ContactDavid Tai, MD
Outcome results
None listed