Combining trametinib and ruxolitinib for treating colorectal and pancreatic cancer

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

This study is testing if combining two existing medications, trametinib and ruxolitinib, can help people with RAS mutant colorectal and pancreatic cancer who have already tried other treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 21 Years and up
• Sex: All
• Sponsor: National Cancer Centre, Singapore (Academic / other)
• Drugs / interventions: chemotherapy, radiation, trametinib, ruxolitinib
• Locations: 1 site (Singapore)
• Trial ID: NCT04303403 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the safety and tolerability of trametinib in combination with ruxolitinib in patients with RAS mutant colorectal cancer and pancreatic adenocarcinoma. Participants must have received at least one prior line of systemic therapy and have measurable lesions as defined by RECIST criteria. The study aims to evaluate the potential beneficial effects of this drug combination, which has not been previously studied together. Trametinib is already approved for melanoma treatment, while ruxolitinib is used for other blood disorders, making this a novel approach for these specific cancers.

Who should consider this trial

Good fit: Ideal candidates are adults aged 21 and older with RAS mutant advanced colorectal or pancreatic adenocarcinoma who have undergone at least one prior treatment.

Not a fit: Patients without RAS mutations or those who have not received prior systemic therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this combination therapy could provide a new treatment option for patients with advanced colorectal and pancreatic cancers.

How similar studies have performed: While trametinib and ruxolitinib have been studied individually, this combination approach is novel and has not been tested together in this context.

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.

Where this trial is running

Singapore

• National Cancer Centre — Singapore, Singapore (Recruiting)

Study contacts

• Principal investigator: David Tai, MD — National Cancer Centre, Singapore
• Study coordinator: David Tai, MD

Conditions Colorectal Cancer; Pancreatic Adenocarcinoma