Metastatic refractory pancreatic cancer. MedDRA version: 21.1 Level: LLT Classification code 10033605 Term: Pancreatic cancer metastatic System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Mekinist®
Product Name: Trametinib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Trametinib
Other descriptive name: TRAMETINIB DIMETHYL SULFOXIDE
Concentration unit: mg mill
Sponsors
Cancer Trials Ireland
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must have pathologically confirmed advanced metastatic pancreatic adenocarcinoma or poorly differentiated pancreatic adenocarcinoma that is amenable to tumour biopsy. 2. Patients have received at least one line of systemic therapy for metastatic disease and not be amenable to surgical resection. 3. Patients must have measurable disease by RECIST 1.1 criteria. 4. Age =18 years. 5. ECOG performance status = 1 6. Patients must have normal organ and marrow function as defined below: a. Serum creatinine = 1.5 x ULN. b. Adequate hepatic function defined by: o total bilirubin level = 1.5 × ULN, o an AST, level = 2.5 × ULN, and an ALT level = 2.5 × ULN (or, for subjects with documented metastatic disease to the liver, AST and ALT levels = 5 × ULN) c. Hematological eligibility parameters: o Absolute Neutrophil count = 1.5 x 10^9/L o Platelet count =100 x10^9/L o Hemoglobin = 9 g/dL 7. Ability of subject to understand and the willingness to sign a written informed consent document. 8. Women of child-bearing potential or sexually active males must agree to use highly effective contraceptive measures. This applies from starting treatment until at least 16 weeks after the last study drug administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: I. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). II. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable). III. Intrauterine device (IUD). IV. Intrauterine hormone-releasing system (IUS). V. Bilateral tubal occlusion. VI. Successfully vasectomised partner. VII. Sexual abstinence. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 11 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 11
Exclusion criteria
Exclusion criteria: 1. Persisting toxicity related to prior therapy (CTCAE Grade > 1); however alopecia, sensory neuropathy Grade = 2, or other Grade =2 AEs not constituting a safety risk based on investigator's judgment are acceptable. 2. Prior treatment with a MEK inhibitor. 3. Known history of testing positive for Human Immunodeficiency Virus (HIV) or known acquired immunodeficiency syndrome. 4. Any significant disease that, in the opinion of the investigator, may impair the patient’s tolerance of study treatment. 5. Patients who are receiving any other investigational agents within 28 days before start of study treatment. 6. Prior organ transplantation including allogenic stem-cell transplantation. 7. Patients with known central nervous system metastases. 8. Active uncontrolled infection, requiring systemic therapy. 9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke ( 500 msec. 15. Pregnant women and breastfeeding mothers are excluded due to unknown impact on embryos or infants. 16. Known prior severe hypersensitivity to investigational products or any component in its formulation. 17. Concurrent use of medicines known to induce retinal toxicity (e.g. tamoxifen) or QT interval prolonging agents. 18. Known congenital or documented acquired QT prolongation. 19. Uncorrected hypokalemia and/or hypomagnesemia.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the 12-week progression free survival (PFS) of trametinib and hydroxychloroquine in patients with metastatic refractory pancreatic cancer. ;Secondary Objective: SECONDARY OBJECTIVES: 1. To determine the response rate, duration of response& overall survival in patients with metastatic refractory pancreatic cancer treated with trametinib & hydroxychloroquine. 2. To assess the safety & tolerability of this regimen. EXPLORATORY/TRANSLATIONAL OBJECTIVES: 1. To establish patient-derived organoids from biopsies of patients with pancreatic cancer being treated with trametinib & hydroxychloroquine before treatment & on treatment. 2. To assess efficiency of treatment&potential emerging resistance mechanisms in patient derived organoid cultures from patients with pancreatic cancer treated with trametinib &hydroxychloroquine. 3. To deeply characterise resistance mechanisms&design &test potential rescue therapies in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib&hydroxychloroquine. 4. To further refine the computational resistance models using new methods of multi-omics data integration.;Primary end point(s): Anti-tumour efficacy of treatment will be primarily measured as 12-week progression free survival (PFS): that is, the percentage of patients free of progression at 12 weeks from starting treatment into the study as determined by radiographic disease assessments per RECIST version 1.1. Planned efficacy assessments will occur by Computed Tomography Thorax, Abdomen and Pelvis (CT TAP) at baseline, 6 weeks, 12 weeks post starting treatment and then q-8 weekly until disease progression or consent withdrawal.;Timepoint(s) of evaluation of this end point: An Interim Analysis will be performed after the first 10 patients have been enrolled and evaluated for radiological/clinical progression. A Final Analysis will be performed when the trial has been completed. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): SECONDARY ENDPOINTS: 1. Confirmed tumour response rate and duration of response as assessed by RECIST version 1.1. 2. Overall survival 3. To evaluate the safety and tolerability of this regimen as measured by incidence of adverse events reported and toxicity evaluation as per the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. EXPLORATORY ENDPOINTS 1. To establish patient-derived organoids from biopsies of patients with pancreatic cancer being treated with trametinib and hydroxychloroquine before treatment and on treatment. 2. To assess efficiency of treatment and potential emerging resistance mechanisms in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib and hydroxychloroquine. 3. To deeply characterise resistance mechanisms and design and test potential rescue therapies in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib and hydroxychloroquine. 4. To further refine the computational resistance models using new methods of multi-omics data integration.;Timepoint(s) of evaluation of this end point: A risk assessment will be performed at the beginning of the study and reviewed on an ongoing basis. The study will be reviewed on a regular basis by the Cancer Trials Ireland Safety Monitoring Committee while patients are on treatment or in the immediate follow-up period (30 days post last dose). The analysis of the secondary exploratory endpoints will be performed after the required number of tissue samples are available. An Interim Analysis will be performed after the first 10 patients have been enrolled and evaluated for radiological/clinical progression. A Final Analysis will be performed when the trial has been completed. | — |
Countries
Ireland
Contacts
Public ContactHead of Clinical Operations
Cancer Trials Ireland
Outcome results
None listed