A Phase I Study to Evaluate the Pharmacokinetics and Safety of Single and Repeat Oral Doses of Trametinib in Chinese Subjects With Solid Tumours
Overview
- Phase
- Phase 1
- Intervention
- Trametinib
- Conditions
- Cancer
- Sponsor
- GlaxoSmithKline
- Primary Endpoint
- PK parameters of trametinib following single and repeat dose(2mg QD): AUC (0-24h)
- Status
- Withdrawn
- Last Updated
- 7 years ago
Overview
Brief Summary
Present clinical study will be conducted in China to evaluate the pharmacokinetics of single and repeat oral doses of trametinib, the safety profile and the clinical activity in Chinese subjects with solid tumor. Approximately 10 evaluable subjects will be enrolled in the study, Subjects will receive trametinib 2 mg once daily (QD). Study treatment will continue until disease progression, death or unacceptable toxicity. The study will be completed after all subjects have discontinued from study treatment or last enrolled subject has had at least 16 weeks of follow-up, whichever occurs first.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provided signed written informed consent
- •Males and females ≥18 years of age (at the time consent is obtained).
- •Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumours, melanoma subjects will be eligible if BRAF V600 mutation was confirmed in the tumour tissue by qualified clinical laboratories. The disease is not responsive to standard therapies, or for which there is no approved or curative therapy.
- •Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
- •Adequate baseline organ function defined by: Absolute neutrophil count (ANC): \>=1,200 /microliter (uL); Hemoglobin: \>=9 grams (g)/deciliter (dL); Platelets: \>=75,000 /uL; Prothrombin time/ International normalization ratio and activated partial thromboplastin time: \<=1.5 x Upper Limit of Normal (ULN); Total bilirubin: \<=1.5 x ULN; Aspartate aminotransferase and Alanine aminotransferase: \<=2.5 x ULN; Calculated creatinine clearance (Calculate creatinine clearance using standard Cockcroft-Gault formula): \>=50 milliliter (mL)/ minute (min) or 24-hour urine creatinine clearance\>=50 mL/min; Left ventricular Ejection fraction (LVEF): \>/= 50% LVEF in case there is no established Lower limit of normal (LLN) for a given institution.
- •Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. Subjects with prior Whipple procedure (pancreaticoduodenectomy) are eligible (if meeting above criteria).
- •Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from the time of the first dose of trametinib until 16 weeks after the last dose of trametinib.
- •Women of child-bearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception from 14 days prior to enrolment, throughout the treatment period and for 4 months after the last dose of study treatment.
Exclusion Criteria
- •Pregnant or Lactating female.
- •History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
- •Use of an investigational drug within 28 days or five half-lives, whichever is longer preceding the first dose of trametinib.
- •Previous treatment with a MEK inhibitor.
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or sub-investigator, contraindicates their participation.
- •History of interstitial lung disease or pneumonitis.
- •Current use of a prohibited medication as described in Section 10.
- •Colony-stimulating factors like filgrastim are prohibited during treatment as a prophylactic management.
- •Any major surgery, radiotherapy, or immunotherapy within 21 days before initiation of trametinib. Chemotherapy regimens with delayed toxicity within 21 days before initiation of trametinib (42 days for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the two weeks before initiation of trametinib.
- •Note: Use of bisphosphonates is considered supportive care and their use is permitted.
Arms & Interventions
Trametinib
Subjects will be administrated with trametinib 2 mg once daily until disease progression.
Intervention: Trametinib
Outcomes
Primary Outcomes
PK parameters of trametinib following single and repeat dose(2mg QD): AUC (0-24h)
Time Frame: At Day 1:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
PK parameters of trametinib following single and repeat dose(2mg QD): Cmin.ss
Time Frame: At Day 22:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
PK parameters of trametinib following single and repeat dose(2mg QD): Cavg.ss
Time Frame: At Day 22:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
PK parameters of trametinib following single and repeat dose(2mg QD): AUC(0-24h)
Time Frame: At Day 22:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
PK parameters of trametinib following single and repeat dose(2mg QD): Cmax
Time Frame: At Day 1:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
PK parameters of trametinib following single and repeat dose(2mg QD): Tmax
Time Frame: At Day 1:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
Accumulation ratio of trametinib following single and repeat dose(2mg QD)
Time Frame: At Day 22
PK parameters of trametinib following single and repeat dose(2mg QD): Cmax.ss
Time Frame: At Day 22:Pre-dose, 0.5hr,1hr, 2hr,3hr,4hr, 6hr,10hr,24hr
Effective half-life of trametinib following single and repeat dose(2mg QD)
Time Frame: At Day 22
Secondary Outcomes
- Number of subjects with Serious Adverse events (SAEs)(Up to 30 days of the subject's last dose.)
- Composite of Safety and tolerability as assessed by vital signs assessment: blood pressure, temperature and pulse rate(Up to 30 days of the subject's last dose.)
- Composite of Physical examination assessment(Up to 30 days of the subject's last dose)
- Number of subjects with Adverse events (AEs)(Up to 30 days of the subject's last dose.)
- Electrocardiogram (ECG) assessment(Every week in the 1st month, week 8, and then every 8 weeks until treatment discontinuation up to 30 days of the subject's last dose (assessed up to 5 years))
- Objective response rate (ORR)(Every 2 months until disease progression up to 5 years)
- Echocardiogram (ECHO) assessment(At week 4, week 8, and then every 8 weeks until treatment discontinuation up to 5 years)
- Eye exams assessment(At screening, and when clinical indicated until treatment discontinuation up to 5 years)
- Chemistry laboratory values assessment(Up to 30 days of the subject's last dose.)
- Urinalysis laboratory values assessment(Up to 30 days of the subject's last dose)
- Progression free survival(PFS)(Every 2 months until disease progression up to 5 years)
- Hematology laboratory values assessment(Up to 30 days of the subject's last dose)