Study of Trametinib and Ruxolitinib in Colorectal Cancer and Pancreatic Adenocarcinoma

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.