Study of Trametinib and Ruxolitinib in Colorectal Cancer and Pancreatic Adenocarcinoma

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Pancreatic Adenocarcinoma
• Intervention / Treatment: Drug: Trametinib; Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: David Tai, MD; Phone Number: +65 6436 8000; Email: david.tai.w.m@singhealth.com.sg

Study Locations

• Singapore
  • Singapore, Singapore, 169610
    • Recruiting
    • National Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose Escalation and Expansion; 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; Taken orally once daily; Other Names: Mekinist; Drug: Ruxolitinib; Taken orally twice daily; Other Names: Jakafi

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Centre, Singapore
• Investigators: Principal Investigator: David Tai, MD, National Cancer Centre, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2018
• Primary Completion (Actual): June 30, 2023
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: September 25, 2018
• First Submitted That Met QC Criteria: March 10, 2020
• First Posted (Actual): March 11, 2020

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: CTMT212XSG01T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No