Phase II Biomarker Study Evaluating The Upfront Combination Of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus The Combination After Eight Weeks Of Monotherapy With Dabrafenib Or Trametinib In Patients With Metastatic And Unresectable Stage III Or IV Melanoma Harbouring An Activating BRAF Mutation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2
研究概览
简要总结
This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant with signed written informed consent;
- •Participants of age >=18 years;
- •Participants with histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) (according to American Joint Committee on Cancer [AJCC] staging 7th edition).
- •BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory.
- •Accessible melanoma tumours for biopsies (locally advanced primary melanoma or metastases)
- •Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1) on not biopsied lesions.
- •All prior anti-cancer treatment-related toxicities (except alopecia) must be <= Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomisation.
- •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.
- •Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomisation and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or
- •Adequate baseline organ function as defined : absolute neutrophil count >= 1.2 × 109/Liters (L); Haemoglobin >= 9 grams(g)/Deciliter (dL); Platelet count >= 75 x 109/L; prothrombin time(PT)/ international normalized ratio (INR) and partial thromboplastin time (PTT) <= 1.5 x Upper limit of normal (ULN); Albumin >= 2.5 g/dL; Total bilirubin- <= 1.5 x ULN; aspartate aminotransferase(AST) and alanine transaminase (ALT) <= 2.5 x ULN; Calculated creatinine clearance >=50 mL/min; Left Ventricular Ejection fraction (LVEF) >= Lower limit of normal (LLN) by Echocardiogram (ECHO)
排除标准
- •Prior treatment with a BRAF or MEK inhibitor
- •Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomisation and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomisation.
- •Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomisation
- •Current use of a prohibited medication.
- •Refusal of tumour and skin biopsies.
- •History of another malignancy.
- •Any serious and/or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the participant's safety, obtaining informed consent, or compliance with study procedures.
- •Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed).
- •A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- •Brain metastases are excluded unless: All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery), OR Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for >= 12 weeks prior to randomisation (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, AND No enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation.
- •A history or evidence of cardiovascular risk including any of the following: LVEF < LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480 milliseconds (msec); A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Participants with atrial fibrillation controlled for > 30 days prior to randomisation are eligible; A history (within 6 months prior to randomisation) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty; A history or evidence of current >= Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic > 140 millimetres of mercury (mmHg) and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy; Participants with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases; Abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (Participants with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Participants with moderate valvular thickening should not be entered on study.
- •A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: Evidence of new optic disc cupping; Evidence of new visual field defects on automated perimetry; Intraocular pressure >21 mmHg as measured by tonography.
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
- •Pregnant or lactating females
- •Interstitial lung disease or pneumonitis
研究组 & 干预措施
Combination therapy
Eligible subjects will receive trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
干预措施: Dabrafenib (Drug)
Dabrafenib followed by combination therapy
Eligible subjects will receive dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
干预措施: Dabrafenib (Drug)
Dabrafenib followed by combination therapy
Eligible subjects will receive dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
干预措施: Trametinib (Drug)
Trametinib followed by combination therapy
Eligible subjects will receive trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
干预措施: Dabrafenib (Drug)
Trametinib followed by combination therapy
Eligible subjects will receive trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity.
干预措施: Trametinib (Drug)
Combination therapy
Eligible subjects will receive trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.
干预措施: Trametinib (Drug)
结局指标
主要结局
Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2
时间窗: Baseline (Week 0) and up to 2 weeks
Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.
Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10
时间窗: Week 8 and up to 10 weeks
Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 \[no staining\], 1+ \[weak staining\], 2+ \[medium staining\] and 3+ \[strongest staining\]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.
次要结局
- Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline(Baseline and up to 3.2 years)
- Number of Participants With Change in Hematology Parameters From Baseline(Baseline and up to 3.2 years)
- Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs(Up to 3.2 years)
- Number of Participants With Overall Response Rate (ORR)(Up to 3.2 years)
- Number of Participants With Abnormal Electrocardiograms (ECG) Findings(Up to 3.2 years)
- Number of Participants With Change in Clinical Chemistry Parameters From Baseline(Baseline and up to 3.2 years)
- Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations(Up to 3.2 years)
- Number of Participants With Change in Vital Signs From Baseline(Baseline and up to 3.2 years)
- Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline(Baseline and up to 3.2 years)
- Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma(Up to 3.2 years)
- Plasma Pharmacokinetic Concentration of Trametinib(4 to 8 hours post-dose at Weeks 2, 8 and 10)
- Plasma Pharmacokinetic Concentration of Dabrafenib(4 to 8 hours post-dose at Weeks 2, 8 and 10)