Study of Trametinib and Ruxolitinib in Colorectal Cancer and Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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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.

Official Title
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Phase Ib Study Evaluating Safety and Tolerability of Combination Trametinib and Ruxolitinib in Patients With Advanced RAS Mutant Colorectal Cancer and Pancreatic Adenocarcinoma

Conditions
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Colorectal Cancer, Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Trametinib
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: The first part of this study will be a standard 3+3 dose-escalating
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation and Expansion<br>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. | Drug: Trametinib<br>* Taken orally once daily<br>* Other names: Mekinist;Drug: Ruxolitinib<br>* Taken orally twice daily<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | 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 | 28 days (1 cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of treatment-emergent Adverse Events and Serious Adverse Events | 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. | 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 | Unit of measure: g/dL. To assess the safety of the drug combination | 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 | Unit of measure: x 10^9/L. To assess the safety of the drug combination. | 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 - Neutrophils | Unit of measure: Percentage component of white blood cells. To assess the safety of the drug combination. | 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 | Unit of measure: mmol/L. To assess the safety of the drug combination | 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 - Uric acid, Creatinine, Total bilirubin | Unit of measure: umol/L. To assess the safety of the drug combination | 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 - Total protein, Albumin | Unit of measure: g/L. To assess the safety of the drug combination | 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 | Unit of measure: U/L. To assess the safety of the drug combination | From time of first study drug administration until 30 days after last dose of study drug | 
| Frequency of dose interruptions | To assess the tolerability of the drug combination. | From time of first study drug administration until 30 days after last dose of study drug | 
| Frequency of dose reductions | To assess the tolerability of the drug combination | From time of first study drug administration until 30 days after last dose of study drug | 
| Pharmacokinetics (PK): Trough concentrations of trametinb | Trough concentrations of trametinb at different cycles of combination treatment with ruxolitinib | From cycle 1-6 of study (each cycle is 28 days) | 
| Tumour Markers: CEA and CA 19-9 in blood samples | Changes from baseline 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 | 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). | From time of first study drug administration until first occurrence of disease progression, up to 2 years | 
| Disease Control Rate | Percentage of patients who have achieved complete response, partial response and stable disease in accordance to RECIST 1.1. | From time of first study drug administration until best overall response, first occurence of disease progression, up to 2 years | 
| Progression Free Survival | Time elapsed between treatment initiation and tumour progression or death from any cause, with censoring of patients who are lost to follow-up. | From time of first study drug administration until first occurence of disease progression, or death from any cause, up to 2 years | 
| Overall Survival | Time elapsed between treatment initiation and death from any cause, with censoring of patients who are lost to follow-up. | From time of first study drug administration to death from any cause, up to 2 years |