An Open Label, Single Centre, Phase II Pilot Study of Neoadjuvant Dabrafenib + Trametinib in Patients With Resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 Mutation Positive Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- The proportion of viable melanoma tissue, compared to baseline, in dissected lymph node and / or in-transit tumour tissue after 12 weeks of neoadjuvant treatment.
研究概览
简要总结
This is an open label, single centre, phase II study of neoadjuvant drug treatment with dabrafenib + trametinib in patients with resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 mutation positive melanoma.
The main aim of this study is to find out if giving of a new combined drug treatment to patients with melanoma that has spread to the lymph nodes BEFORE they have surgery, will result in improved clinical and pathological response of the melanoma tissue after 12 weeks treatment.
详细描述
Neoadjuvant therapy has been demonstrated to improve outcome in the management of patients of multiple different solid tumours. The advantage of a neoadjuvant therapy in melanoma is that it provides in vivo assessment of tumour responsiveness to systemic therapy, potentially eradicates micrometastatic disease, and may improve the surgical result. It also provides an opportunity to obtain tumour samples before and after treatment to study variation of response and effects of treatment on tumour characteristics.
This pilot study explores pathological response rates, Response Evaluation Criteria in Solid Tumors (RECIST) response rates and biomarkers for a 12-week duration of neoadjuvant therapy with combined MAP kinase inhibition (MAPKi) with dabrafenib and trametinib and to establish guidelines for an expanded Phase II or III study.
The biomarker component of this study will compare pre-treatment (PRE) with day 4-7, 'early during treatment' biopsies (EDT) and 12 week lymphadenectomy samples (POST). The tissue will be interrogated for immunologic, proteomic and genetic (RNA and DNA) features and changes in tissue and blood. The baseline PRE specimen will consist of at least two core, excisional or incisional biopsies taken prior to commencing combined dabrafenib and trametinib. The EDT specimen will consist of at least two core, excisional or incisional biopsies taken at days 4-7, very early after commencing combined dabrafenib and trametinib. The POST specimen will be the complete lymph node dissection specimen performed after 12 weeks of treatment with combined dabrafenib and trametinib.
The EDT specimen provides a unique opportunity to investigate the early changes that occur in a melanoma tumour with MAPK inhibitors that may set up for later resistance or complete response, and that may be amenable to therapeutic manipulation. For example, EDT samples collected on patients treated with single agent BRAF inhibitors showed increased T cell infiltrate that was associated with a better response in the lesion. The T cell infiltrate has also been associated with increased expression of melanoma antigens, a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Additional studies have shown the expected suppression in pERK, and in paired PRE-EDT samples, the decreased ERK suppression is associated with a better RECIST response. There have been no reports of the effects of BRAF and MEK inhibitors as single agent or in combination on responding melanoma tissue taken more than 15 days after commencement of treatment. As the median PFS for the combination of dabrafenib and trametinib is 9.4 months, >95% of the POST samples will be responding, and provide an opportunity to 1) compare the responding POST with the EDT sample (and the baseline PRE samples prior to treatment) to investigate how signalling pathways (as determined by RNA gene expression and protein expression) alter with time, and 2) how the changes in signalling pathways correlate with clinical and pathological response.
Study treatment will be continued as adjuvant therapy. The goal is to improve the cure rate after surgery through eradication of occult micrometastatic disease. Notable successes have been achieved in oncology when highly effective therapies were available for advanced stage disease (e.g., breast cancer, Hodgkin's and non-Hodgkin's lymphoma, embryonal tumours, osteosarcoma). High-risk, resected BRAF V600 mutation positive melanoma represents another attractive setting for testing this paradigm since: 1) the population is at high risk for relapse and death without further therapy and 2) the BRAF/MAP-ERK kinase combination is highly effective in the metastatic setting and can be targeted to the population most likely to benefit. The study design will test the efficacy of study treatment in both the neoadjuvant and adjuvant settings for the first time in this patient population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 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
- •Age ≥18 years
- •Histologically confirmed AJCC Stage IIIB or IIIC (Tx, T1-4, N1b, N2b, N2c, N3, Mo) cutaneous melanoma or unknown primary determined to be BRAF V600 mutation positive, with sufficient nodal or in-transit disease to enable biopsies prior to surgery.Patients must have disease that is measurable per RECIST version 1.1
- •Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
- •Adequate baseline organ function
- •Women of childbearing 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 commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment
- •Men with any female partner of childbearing potential must agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment
排除标准
- •Known mucosal or ocular melanoma or any unresectable in-transit metastases
- •Evidence of distant metastatic disease on screening evaluation
- •Prior anti-cancer treatment for melanoma (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, investigational treatment or radiotherapy). Prior surgery for melanoma is allowed.
- •Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to commencing study treatment.
- •Current or expected use of a prohibited medication(s)
- •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
- •Known HIV
- •A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
- •History of another malignancy or a concurrent malignancy except:
- •Patients who have been disease-free for 3 years and have a life expectancy of > 5 years;
- •Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas.
- •A history or evidence of cardiovascular risk including any of the following: a. QT interval corrected for heart rate using the Bazett's formula ≥480 msec or ≥ 450 msec for patients with bundle branch block; b. History or evidence of current clinically significant uncontrolled arrhythmias; c. History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to commencement of study treatment; d. History or evidence of current ≥ Class II congestive heart failure; e. Abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.
- •f. Treatment refractory hypertension defined as a blood pressure of systolic > 140 mm Hg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy.
- •A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
- •Any serious or unstable pre-existing medical conditions (aside from the malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the treating clinician, could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures.
- •Breastfeeding females
研究组 & 干预措施
Dabrafenib and Trametinib
Dabrafenib 150mg bid orally and Trametinib 2mg od orally for 52 weeks
干预措施: Dabrafenib (Drug)
Dabrafenib and Trametinib
Dabrafenib 150mg bid orally and Trametinib 2mg od orally for 52 weeks
干预措施: Trametinib (Drug)
结局指标
主要结局
The proportion of viable melanoma tissue, compared to baseline, in dissected lymph node and / or in-transit tumour tissue after 12 weeks of neoadjuvant treatment.
时间窗: 12 weeks
The proportion of viable melanoma tissue, compared to baseline, in dissected lymph node and / or in-transit tumour tissue after 12 weeks of neoadjuvant treatment.
次要结局
- Overall survival(52 weeks plus until the time that 70% of patients have died)
- Effects of neoadjuvant study treatment on surgical outcomes after complete lymph node and / or in-transit disease dissection.(12 weeks)
- Effects of study treatment on host immune response in tumour tissue and peripheral blood.(12 weeks)
- Description of specific blood and serum changes that occur with pyrexia.(52 weeks)
- Correlation of pyrexia episodes and signs with baseline melanoma disease burden (number and size of lymph nodes), RECIST response, pathological response, immune related changes in tumour tissue and peripheral blood.(52 weeks)
- The clinical response to 12 weeks neoadjuvant treatment(12 weeks)
- Relapse free survival(52 weeks plus the time when 70% of patients have died)
- Description of adverse events and how these correlate with clinical outcomes(52 weeks)
- Correlation of a range of tumour biomarkers at baseline, early treatment and 12 week intervals with pathological and clinical response.(12 weeks)