A Phase 1B Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Combination of Encorafenib, Binimetinib and Palbociclib in Patients With BRAF-mutant Metastatic Melanoma (The CELEBRATE Study)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 78
- 试验地点
- 4
- 主要终点
- Dose-limiting toxicity (DLTs)
研究概览
简要总结
This is an open-label, phase IB, non-randomised study consisting of a dose escalation phase and expansion phase, evaluating the safety, tolerability and preliminary efficacy of the combination of encorafenib, binimetinib and palbociclib in patients with BRAF-mutant metastatic melanoma.
Dose escalation phase: Previously treated or treatment-naïve patients will be evaluated after the first cycle for dose-limiting toxicities to ascertain the recommended phase 2 dose (RP2D) of encorafenib, binimetinib and palbociclib.
Expansion phase: Two cohorts of patients will be further evaluated for the efficacy and safety of the RP2D of palbociclib with encorafenib and binimetinib. Cohort 1 will include patients naïve to both BRAF and MEK inhibitors. Cohort 2 will include patients with either primary or acquired resistance to both BRAF and MEK inhibitors.
详细描述
This is an open-label, multicentre, Phase IB, dose escalation study with dose expansion designed to assess the safety, tolerability, and pharmacokinetics of the encorafenib, binimetinib and palbociclib combination. Patients with untreated or previously treated BRAFV600 mutation-positive, locally advanced/unresectable or metastatic melanoma are eligible. There will be 3 dose levels:
Table 1: Dose Level Description Dose Level Encorafenib Binimetinib Palbociclib D1 450mg daily 45mg BID 75mg daily 21/7* D2 450mg daily 45mg BID 100mg daily 21/7* D3 450mg daily 45mg BID 125mg daily 21/7*
* 21 consecutive days on treatment, followed by 7 consecutive days off treatment in a 28 day cycle.
Alternate dosing regimens and schedules may be interrogated depending on the nature and timing of the toxicities encountered.
The first dose to be evaluated will be dose level D1 and dose escalation will follow using a standard 3 + 3 design (refer to Figure 6). Dose escalation/de-escalation decisions will be made by the Trial Management Committee.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Dose Escalation Phase only: (Australia only)
- •Patients who are naïve to, or have received prior BRAF and MEK inhibitor combination therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.
- •Dose Expansion Phase only: (All sites)
- •Cohort 1: Patients who are naïve to BRAF and MEK inhibitor therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.
- •Cohort 2: Patients who have progressed on prior BRAF and MEK inhibitor combination therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.
- •For both phases (All sites):
- •Patients (male and female) age ≥ 18 years
- •Has provided written informed consent prior to any screening procedure
- •Histologically confirmed diagnosis of unresectable stage III or IV melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC] 8th edition).
- •Documented evidence of BRAF V600 mutation.
- •Patients must provide either archival or newly obtained tumour sample at baseline. In addition, patients must agree to a mandatory biopsy during treatment and at the time of progression, if not medically contraindicated.
- •Evidence of measurable disease, as determined by RECIST v1.
- •Note: Lesions in areas of prior radiotherapy or other locoregional therapies (e.g., percutaneous ablation) should not be considered measurable, unless lesion progression has been documented since the therapy.
- •Patients must have adequate haematological, coagulation, renal and hepatic functions as defined by:
- •Absolute neutrophil count ≥ 1.5 x 109/L Haemoglobin ≥ 10 g/L without transfusions Platelet count ≥ 100 x 109/L without transfusions Total serum creatinine ≤ 1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower limit of normal) Serum total bilirubin ≤ 1.5 x ULN ( 3 x ULN in cases of known Gilbert's syndrome) AST/SGOT or ALT/SGPT ˂ 3 x ULN, or ˂ 5 x ULN if liver metastases are present PT/INR or aPTT < 1.5xULN
- •ECOG Performance Status ≤ 2
- •Able to take oral medications
- •Be willing and able to comply with all study requirements, including treatment, attending assessments and follow-up.
- •Female patients of childbearing potential must have a negative serum pregnancy test at screening: and be willing to use two methods of birth control or be surgically sterile: or abstain from heterosexual activity for the course of the study through to 3 months after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilised or have not been free from menses for > 1 year.
- •Sexually active males must use a condom during intercourse while taking the study drugs and for 3 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid.
排除标准
- •Patients with uveal melanoma.
- •Patients with symptomatic or untreated brain metastases or leptomeningeal disease. Patients with previously treated or untreated for brain metastasis that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for 4 weeks prior to registration are allowed to enroll. Brain metastases must be stable at least 4 weeks prior to registration with verification by imaging (e.g. brain MRI completed at screening demonstrating no current evidence of progressive brain metastases).
- •Patients receiving enzyme inducing anti-epileptic drugs (as listed in Appendix 5).
- •History of acute or chronic pancreatitis.
- •History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
- •Impaired cardiovascular function or clinically significant cardiac disease including any of the following:
- •CHF requiring treatment (NYHA grade ≥ 2)
- •LVEF < 50% as determined by MUGA scan or ECHO
- •History or presence of clinically significant ventricular arrhythmias or uncontrolled atrial fibrillation
- •Clinically significant resting bradycardia
- •Unstable angina pectoris ≤ 3 months prior to registration
- •Acute Myocardial Infarction (AMI) ≤ 3 months prior to registration
- •QTcF > 480 ms
- •Any heart disease that requires the use of a cardiac pacemaker or implantable cardioverter defibrillator ≤ 3 months prior to registration
- •History of QT syndrome, Brugada syndrome or known
研究组 & 干预措施
Dose escalation phase
Encorafenib (tablet) 450mg PO daily
Binimetinib (tablet) 45mg PO BD
Palbociclib (tablet) variable dose PO daily for 21 consecutive days on treatment, followed by 7 consecutive days off treatment in a 28 day cycle
干预措施: Binimetinib (Drug)
Dose escalation phase
Encorafenib (tablet) 450mg PO daily
Binimetinib (tablet) 45mg PO BD
Palbociclib (tablet) variable dose PO daily for 21 consecutive days on treatment, followed by 7 consecutive days off treatment in a 28 day cycle
干预措施: Encorafenib (Drug)
Dose escalation phase
Encorafenib (tablet) 450mg PO daily
Binimetinib (tablet) 45mg PO BD
Palbociclib (tablet) variable dose PO daily for 21 consecutive days on treatment, followed by 7 consecutive days off treatment in a 28 day cycle
干预措施: Palbociclib (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLTs)
时间窗: The assessment period of DLT for each patient is the first cycle (28 days) of treatment
Dose-Limiting Toxicity is defined as a toxicity that prevents further administration of the trial treatment at that dose level
次要结局
- Clinical effficacy defined by response(8 weeks after commencement of treatment)
- Tolerability as defined 80% compliance with each of Encorafenib, Binimetinib and Palbociclib individually.(28 days for encorafenib and binimetinib, 21 days for palbociclib)
- Adverse events (AEs) of Encorafenib, Binimetinib and Palbociclib(Trough study completion, up until 12 months after last patient commences treatment)
- Clinical efficacy as defined by progression free survival(From the date of registration until the date of first documented disease progression or date of death due to any cause, whichever occurs first (up to approximately 18 months))
- Clinical efficacy as defined by time to progression(From the date of registration until the date of disease progression)
- Clinical efficacy as defined by overall survival(From start of treatment until the date of death from any cause, up to approximately 18months))