NCT07092410撤回4 期
Surgical or Radiotherapeutic Intervention Concerning Large Singular Stable to Progressive Metastases in Patients With BRAFV600-mutated Melanoma Receiving Treatment With Encorafenib + Binimetinib
干预措施
相关药物
试验速览
- 阶段
- 4 期
- 状态
- 撤回
- 入组人数
- 101
- 主要终点
- Progression Free Survival (PFS) after local treatment (radiotherapy / surgery / electrochemotherapy)
研究概览
简要总结
This is an open-label, prospective, single arm study conducted in Germany to investigate local treatment (i.e. surgery or radiotherapy or electrochemotherapy) of metastases showing no response to encorafenib (E) + binimetinib (B) combination therapy and continuation of EB therapy afterwards.
The purpose of this study is to determine PFS of individual patients treated with local intervention while continuing therapy with EB.
详细描述
The purpose of this prospective study is to evaluate progression free survival (PFS) of patients being treated for a minimum of 3 months with encorafenib and binimetinib and who have non-responding metastases that will be treated with local intervention while continuing combination therapy with encorafenib and binimetinib.
Patients fulfilling the screening-criteria will receive local treatment of 1-3 metastases according to the investigator's decision and according to standard of care. Local treatments are not considered as study related treatments and will be carried out prior to registration. After registration patients will continue approved EB therapy as study treatment.
The aim of the study is to evaluate the effects of local treatment of melanoma metastases that do not respond to EB combination therapy and subsequent continuation of EB therapy on progression-free survival. Local/surgical treatment according to standard of care (= surgery, radiotherapy, electrochemotherapy) will be at the discretion of the investigator. If there are more than one metastasis to be treated locally with different methods authorization of steering committee is required.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 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
- •Patients may be included in the study only if they meet all the following criteria:
- •Signed informed consent form
- •Female and male patients ≥ 18 years of age
- •Ability to comply with the study protocol, in the investigator's judgement
- •Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months
- •ECOG performance status 0-2
- •Life expectancy ≥ 12 weeks
- •Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging)
- •Presence of a BRAFV600-mutation according to a validated test
- •Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) [TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study] plus ≥ 1 additional target lesion [target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study] for continuous measurement Note: Localization of TLTs will be cohortly observed.
- •Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed).
- •Patient must fulfill one of the following conditions (= mixed tumor response) for TLT:
- •EB in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are progressing
- •EB in palliative 2nd line after progression upon checkpoint inhibition in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are progressing
- •Adjuvant BRAFi/MEKi pretreatment with > 6 months of treatment free interval between end of adjuvant and start of palliative 1st line treatment is allowed; any other prior adjuvant therapy is allowed.
- •Inclusion of patients switching from other BRAFi/MEKi to EB within the study treatment line is not allowed.
- •Only for b): BRAFi/MEKi pretreatment in palliative 1st line with direct switch to checkpoint inhibition within this line and without progression is allowed.
- •Mixed tumor response is defined as: some metastases decreasing in size (=responding), some metastases increasing in size (=growing) and/or new metastases appearing, some metastases are stable.
- •TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required.
- •Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis)
- •Patient with toxicities related to E and/or B [NCI CTCAE v5.0] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities
- •Adequate bone marrow, organ function and lab parameters:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Hemoglobin ≥ 9 g/dL without transfusion
- •Platelet count ≥ 100 x 109/L without transfusion
- •Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (Cockroft-Gault) ≥ 50 mL/min
- •Serum albumin ≥ 25 g/L
- •Serum bilirubin ≤ 2.0 x ULN, exception in case of known Gilbert's disease: ≤ 3.0 x ULN
- •AST/ALT ≤ 2.5 x ULN, exception in case of liver metastases: ≤ 5.0 x ULN
- •INR/PTT ≤ 1.5 x ULN
- •Adequate cardiac function:
- •Left ventricular ejection fraction (LVEF) ≥ 50 % as determined by echocardiogram
- •Triplicate average baseline QTcF interval ≤ 480 msec
- •Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including:
- •Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation >6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- •Male sterilization (>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient
- •Combination of two of the following:
- •Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1 %), for example hormone vaginal ring or transdermal hormone contraception
- •Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- •Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
- •A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
排除标准
- •Inclusion Criteria:
- •Patients may be included in the study only if they meet all the following criteria:
- •Signed informed consent form
- •Female and male patients ≥ 18 years of age
- •Ability to comply with the study protocol, in the investigator's judgement
- •Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months
- •ECOG performance status 0-2
- •Life expectancy ≥ 12 weeks
- •Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging)
- •Presence of a BRAFV600-mutation according to a validated test
- •Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) [TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study] plus ≥ 1 additional target lesion [target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study] for continuous measurement Note: Localization of TLTs will be cohortly observed.
- •Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed).
- •Patient must fulfill one of the following conditions (= mixed tumor response) for TLT:
- •EB in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with exception of 1 to 3 TLT that are progressing
- •EB in palliative 2nd line after progression upon checkpoint inhibition in palliative 1st line i. with current response of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are stable ii. with current response or stability of all metastases according to RECIST v1.1 with the exception of 1 to 3 TLT that are progressing
- •Adjuvant BRAFi/MEKi pretreatment with > 6 months of treatment free interval between end of adjuvant and start of palliative 1st line treatment is allowed; any other prior adjuvant therapy is allowed.
- •Inclusion of patients switching from other BRAFi/MEKi to EB within the study treatment line is not allowed.
- •Only for b): BRAFi/MEKi pretreatment in palliative 1st line with direct switch to checkpoint inhibition within this line and without progression is allowed.
- •Mixed tumor response is defined as: some metastases decreasing in size (=responding), some metastases increasing in size (=growing) and/or new metastases appearing, some metastases are stable.
- •TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required.
- •Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis)
- •Patient with toxicities related to E and/or B [NCI CTCAE v5.0] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities
- •Adequate bone marrow, organ function and lab parameters:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Hemoglobin ≥ 9 g/dL without transfusion
- •Platelet count ≥ 100 x 109/L without transfusion
- •Creatinine ≤ 1.5 mg/dL, or calculated creatinine clearance (Cockroft-Gault) ≥ 50 mL/min
- •Serum albumin ≥ 25 g/L
- •Serum bilirubin ≤ 2.0 x ULN, exception in case of known Gilbert's disease: ≤ 3.0 x ULN
- •AST/ALT ≤ 2.5 x ULN, exception in case of liver metastases: ≤ 5.0 x ULN
- •INR/PTT ≤ 1.5 x ULN
- •Adequate cardiac function:
- •Left ventricular ejection fraction (LVEF) ≥ 50 % as determined by echocardiogram
- •Triplicate average baseline QTcF interval ≤ 480 msec
- •Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including:
- •Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation >6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- •Male sterilization (>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient
- •Combination of two of the following:
- •Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1 %), for example hormone vaginal ring or transdermal hormone contraception
- •Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- •Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
- •A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
- •Exclusion Criteria:
- •Patients will be excluded from the study for any of the following reasons:
- •Uveal or mucosal melanoma
- •Presence of untreated brain metastases (exception if this is TLT) Note: Treated brain metastases (stereotactic or surgical intervention) are allowed, if these are stable for > 4 weeks and off corticosteroids for > 3 weeks.
- •Presence of any symptomatic brain and/or leptomeningeal metastases
- •Any previous radiation [including stereotactic radiosurgery (SRS)] therapy involving > 25 % of bone marrow and/or ongoing ≤ 28 days prior to registration (local/surgical intervention excluded)
- 另有 36 项未显示
研究组 & 干预措施
Single arm study. Surgery or radiotherapy or electrochemotherapy in melanoma patients receiving IMP
Other
Local intervention (surgery or radiotherapy or electrochemotherapy) concerning large singular stable to progressive metastases in patients with BRAFV600-mutated melanoma receiving treatment with Encorafenib + Binimetinib
干预措施: Encorafenib & Binimetinib Treatment (Drug)
结局指标
主要结局
Progression Free Survival (PFS) after local treatment (radiotherapy / surgery / electrochemotherapy)
时间窗: From enrollment up to end of treatment period after 52 weeks maximum.
The purpose of this study is to determine PFS of individual patients treated with local intervention while continuing therapy with EB.
次要结局
- progression-free survival rate (PFSR) at 1 year after local treatment (radiotherapy / surgery /electrochemotherapy)(From enrollment up to end of treatment period after 52 weeks maximum.)
- Overall Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), Duration of Disease Control (DoDC), Duration of Stable Disease (DoSD)(From enrollment up to end of treatment period after 52 weeks maximum.)
- time to treatment failure (TTF)(From enrollment up to end of treatment period after 52 weeks maximum.)
- overall survival (OS)(From enrollment up to end of treatment period after 52 weeks maximum.)
- Quality of Life (QoL)(From enrollment up to end of treatment period after 52 weeks maximum.)
- safety / toxicity according to CTCAE Version 5.0 criteria(From enrollment up to end of treatment period after 52 weeks maximum.)
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