A Randomized, Open-label Phase III Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization lead-in [SEACRAFT-2]
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Erasca, Inc.
- 入组人数
- 470
- 试验地点
- 59
- 主要终点
- Stage 2: To compare PFS and OS for patients who are randomized to receive the combination of naporafenib + trametinib to that of patients who receive physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy)
研究概览
简要总结
Stage 1: To select the optimal dose of naporafenib + trametinib to be studied in Stage 2.
Stage 2: To compare progression free survival (PFS) and overall survival (OS) for patients with NRAS-mutant (NRASm) melanoma who are randomized to receive the combination of naporafenib + trametinib to that of patients who are randomized to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy).
详细描述
SEACRAFT-2 is a global, Phase III, open-label, randomized study to assess the efficacy and safety of naporafenib administered with trametinib compared to physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy) in patients with unresectable or metastatic NRAS mutant melanoma who have progressed on, or are intolerant to, an anti-programmed death-1 ligand 1 (PD 1/L1)-based regimen. The study will consist of 2 stages: dose optimization in Stage 1 and the Phase 3 portion in Stage 2.
A total of approximately 470 eligible patients will be randomized to receive study drug(s) in this study across 2 stages.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide written informed consent
- •Age ≥ 18 years
- •Histologically or cytologically confirmed unresectable or metastatic cutaneous (includes acral) melanoma.
- •Documentation of an NRAS mutation (tumor tissue or blood) prior to first dose of study drug(s) as determined locally with an analytically validated assay in a certified testing laboratory.
- •Archival tumor tissue collected within 5 years prior to enrollment must be confirmed to be available at the time of Screening, which may be submitted before or after enrollment for exploratory biomarker analysis.
- •Must have received an anti-PD-1/L1 based regimen (monotherapy or combination). Patient must have documented disease progression either while receiving therapy or within 12 weeks of last dose of the most recent anti-PD-1/L1 based regimen; the patient is eligible if they have received other therapies between the most recent anti-PD-1/L1 based regimen and enrollment.
- •ECOG performance status 0, 1 or 2
- •Presence of at least 1 measurable lesion according to RECIST v1.1
- •Able to swallow oral medication.
排除标准
- •Patients with uveal or mucosal melanoma
- •Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
- •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 syndrome)
- •Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
- •Patients receiving treatment with herbal medicine known to cause liver toxicity, which cannot be discontinued 7 days prior to first dose of study drug(s) and for the duration of the study.
- •Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial
研究组 & 干预措施
Stage 1 Dose selection Lead-in Arm 1
Naporafenib + Trametinib Naporafenib (ERAS-254) 100 mg administered orally twice daily (BID) Trametinib 1 mg once daily (QD)
干预措施: Naporafenib (Drug)
Stage 1 Dose selection Lead-in Arm 1
Naporafenib + Trametinib Naporafenib (ERAS-254) 100 mg administered orally twice daily (BID) Trametinib 1 mg once daily (QD)
干预措施: Trametinib (Drug)
Stage 1 Dose selection Lead-in Arm 2
Naporafenib + Trametinib Naporafenib (ERAS-254) 400 mg administered orally twice daily (BID) Trametinib 0.5 mg once daily (QD)
干预措施: Naporafenib (Drug)
Stage 1 Dose selection Lead-in Arm 2
Naporafenib + Trametinib Naporafenib (ERAS-254) 400 mg administered orally twice daily (BID) Trametinib 0.5 mg once daily (QD)
干预措施: Trametinib (Drug)
Stage 1 Dose selection Lead-in Arm 3 Trametinib monotherapy
Trametinib 2 mg once daily (QD)
干预措施: Trametinib (Drug)
Stage 2 Arm A
Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1
干预措施: Naporafenib (Drug)
Stage 2 Arm A
Naporafenib + Trametinib Naporafenib (ERAS-254) BID oral administration with Trametinib QD at the dose selected in Stage 1
干预措施: Trametinib (Drug)
Stage 2 Arm B - Physician's Choice
- Dacarbazine 1000 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle OR
- Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle OR
- Trametinib monotherapy, 2 mg PO QD
干预措施: Dacarbazine (Drug)
Stage 2 Arm B - Physician's Choice
- Dacarbazine 1000 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle OR
- Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle OR
- Trametinib monotherapy, 2 mg PO QD
干预措施: Temozolomide (Drug)
Stage 2 Arm B - Physician's Choice
- Dacarbazine 1000 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle OR
- Temozolomide 200 mg/m2/day PO on Day 1 to Day 5 of each 28-day cycle OR
- Trametinib monotherapy, 2 mg PO QD
干预措施: Trametinib (Drug)
结局指标
主要结局
Stage 2: To compare PFS and OS for patients who are randomized to receive the combination of naporafenib + trametinib to that of patients who receive physician's choice of therapy (dacarbazine, temozolomide, or trametinib monotherapy)
时间窗: Assessed up to 24 months from time of first dose
* Progression free survival (PFS) based on assessment of radiographic imaging per RECIST v1.1 * Survival status
Stage 1:To select the optimal dose of naporafenib + trametinib to be studied in Stage 2
时间窗: Study Day 1 up to Day 29
Area under the plasma concentration-time curve
次要结局
- Duration of Response (DOR)(Assessed up to 24 months from time of first dose])
- Time to Response (TTR)(Assessed up to 24 months from time of first dose])
- Adverse Events(Assessed up to 24 months from time of first dose)
- Disease Control Rate (DCR)(Assessed up to 24 months from time of first dose])
- Overall Response Rate (ORR)(Assessed up to 24 months from time of first dose)
- Plasma concentration (Cmax):Stage 1 only(Study Day 1 up to Day 29)
- Area under the curve (AUC):Stage 1 only(Study Day 1 up to Day 29)
- Quality of Life: To assess disease and treatment-related QOL in patients with NRASm melanoma.(Assessed up to 24 months from time of first dose)