Clinical trial NCT04303403: Study of Trametinib and Ruxolitinib in Colorectal Cancer and Pancreatic Adenocarcinoma
Official title: Phase Ib Study Evaluating Safety and Tolerability of Combination Trametinib and Ruxolitinib in Patients With Advanced RAS Mutant Colorectal Cancer and Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Colorectal Cancer
Pancreatic Adenocarcinoma
Lead sponsor: National Cancer Centre, Singapore
Sponsor class: OTHER
First posted: 2020-03-11
Enrollment: 48
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: The first part of this study will be a standard 3+3 dose-escalating
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: 28 days (1 cycle)
Secondary outcomes:
measure: Frequency and severity of treatment-emergent Adverse Events and Serious Adverse Events
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline hematology laboratory parameters during treatment - Haemoglobin
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline hematology laboratory parameters during treatment - White blood count, Platelets, Absolute neutrophil count
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline hematology laboratory parameters during treatment - Neutrophils
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: 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
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Uric acid, Creatinine, Total bilirubin
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Total protein, Albumin
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Alkaline phosphatase, Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase, Beta-human chorionic gonadotrophin
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Frequency of dose interruptions
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Frequency of dose reductions
timeFrame: From time of first study drug administration until 30 days after last dose of study drug
measure: Pharmacokinetics (PK): Trough concentrations of trametinb
timeFrame: From cycle 1-6 of study (each cycle is 28 days)
measure: Tumour Markers: CEA and CA 19-9 in blood samples
timeFrame: From cycle 1 up to last cycle of treatment (each cycle is 28 days)
measure: Overall Response Rate
timeFrame: From time of first study drug administration until first occurrence of disease progression, up to 2 years
measure: Disease Control Rate
timeFrame: From time of first study drug administration until best overall response, first occurence of disease progression, up to 2 years
measure: Progression Free Survival
timeFrame: From time of first study drug administration until first occurence of disease progression, or death from any cause, up to 2 years
measure: Overall Survival
timeFrame: From time of first study drug administration to death from any cause, up to 2 years
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National Cancer Centre
Study officials:
affiliation: National Cancer Centre, Singapore
name: David Tai, MD
role: PRINCIPAL_INVESTIGATOR
References: