LIBRETTO-431: A Multicenter, Randomized, Open-Label, Phase 3 Trial Comparing Selpercatinib to Platinum-Based and Pemetrexed Therapy With or Without Pembrolizumab as Initial Treatment of Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 261
- 试验地点
- 194
- 主要终点
- Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) (With Pembrolizumab)
研究概览
简要总结
The reason for this study is to see if the study drug selpercatinib compared to a standard treatment is effective and safe in participants with rearranged during transfection (RET) fusion-positive non-squamous non-small cell lung cancer (NSCLC) that has spread to other parts of the body. Participants who are assigned to the standard treatment and discontinue due to progressive disease have the option to potentially crossover to selpercatinib.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed, Stage IIIB-IIIC or Stage IV non-squamous NSCLC that is not suitable for radical surgery or radiation therapy.
- •A RET gene fusion in tumor and/or blood from a qualified laboratory.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Adequate hematologic, hepatic and renal function.
- •Willingness of men and women of reproductive potential to observe conventional and highly effective birth control for the duration of treatment and for 6 months after.
- •Ability to swallow capsules.
排除标准
- •Additional validated oncogenic drivers in NSCLC if known.
- •Prior systemic therapy for metastatic disease. Treatment (chemotherapy, immunotherapy, or biological therapy) in the adjuvant/neoadjuvant setting is permitted if it was completed at least 6 months prior to randomization.
- •Major surgery within 3 weeks prior to planned start of selpercatinib.
- •Radiotherapy for palliation within 1 week of the first dose of study treatment or any radiotherapy within 6 months prior to the first dose of study treatment if more than 30 Gy to the lung.
- •Symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or untreated spinal cord compression.
- •Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of selpercatinib or prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 milliseconds.
- •Active uncontrolled systemic bacterial, viral, or fungal infection or serious ongoing intercurrent illness, such as hypertension or diabetes, despite optimal treatment.
- •Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
- •Pregnancy or lactation.
- •Other malignancy unless nonmelanoma skin cancer, carcinoma in situ of the cervix or other in situ cancers or a malignancy diagnosed ≥2 years previously and not currently active.
- •Uncontrolled, disease related pericardial effusion or pleural effusion.
- •Requiring chronic treatment with steroids.
- •Exclusion Criteria for Participants Receiving Pembrolizumab:
- •History of interstitial lung disease or interstitial pneumonitis.
- •Active autoimmune disease or any illness or treatment that could compromise the immune system.
研究组 & 干预措施
Selpercatinib - Treatment A (TRT A)
160 milligram (mg) Selpercatinib administered orally twice daily (BID) continuously in 21-day cycles.
干预措施: Selpercatinib (Drug)
Pemetrexed and Platinum with or without Pembrolizumab - (TRT B)
Pemetrexed 500 milligrams per meter squared (mg/m2) administered intravenously (IV) on Day 1, every 3 weeks (Q3W), plus investigator's choice of carboplatin area under the concentration versus time curve 5 (AUC 5 [maximum dose of 750 mg] IV), or cisplatin (75 mg/m2 cisplatin IV) on Day 1 Q3W for 4 cycles, plus investigator's choice with or without 200 mg pembrolizumab IV on Day 1 Q3W up to 35 cycles.
干预措施: Carboplatin (Drug)
Pemetrexed and Platinum with or without Pembrolizumab - (TRT B)
Pemetrexed 500 milligrams per meter squared (mg/m2) administered intravenously (IV) on Day 1, every 3 weeks (Q3W), plus investigator's choice of carboplatin area under the concentration versus time curve 5 (AUC 5 [maximum dose of 750 mg] IV), or cisplatin (75 mg/m2 cisplatin IV) on Day 1 Q3W for 4 cycles, plus investigator's choice with or without 200 mg pembrolizumab IV on Day 1 Q3W up to 35 cycles.
干预措施: Cisplatin (Drug)
Pemetrexed and Platinum with or without Pembrolizumab - (TRT B)
Pemetrexed 500 milligrams per meter squared (mg/m2) administered intravenously (IV) on Day 1, every 3 weeks (Q3W), plus investigator's choice of carboplatin area under the concentration versus time curve 5 (AUC 5 [maximum dose of 750 mg] IV), or cisplatin (75 mg/m2 cisplatin IV) on Day 1 Q3W for 4 cycles, plus investigator's choice with or without 200 mg pembrolizumab IV on Day 1 Q3W up to 35 cycles.
干预措施: Pemetrexed (Drug)
Pemetrexed and Platinum with or without Pembrolizumab - (TRT B)
Pemetrexed 500 milligrams per meter squared (mg/m2) administered intravenously (IV) on Day 1, every 3 weeks (Q3W), plus investigator's choice of carboplatin area under the concentration versus time curve 5 (AUC 5 [maximum dose of 750 mg] IV), or cisplatin (75 mg/m2 cisplatin IV) on Day 1 Q3W for 4 cycles, plus investigator's choice with or without 200 mg pembrolizumab IV on Day 1 Q3W up to 35 cycles.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) (With Pembrolizumab)
时间窗: Baseline to Progressive Disease or Death from Any Cause Up to 31 Months
PFS is defined as the time from randomization until the occurrence of documented disease progression by the BICR, per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, or death from any cause in the absence of BICR-documented progressive disease.
PFS by BICR (With or Without Pembrolizumab)
时间窗: Baseline to Progressive Disease or Death from Any Cause Up to 31 Months
PFS is defined as the time from randomization until the occurrence of documented disease progression by the BICR, per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, or death from any cause in the absence of BICR-documented progressive disease.
次要结局
- Percentage of Participant With Disease Control Rate (DCR) by BICR (With Pembrolizumab)(Baseline to Progressive Disease or Death from Any Cause Up to 31 Months)
- Overall Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) by BICR (With Pembrolizumab)(Baseline through Disease Progression or Death Up to 31 Months)
- Duration of Response (DoR) by BICR (With Pembrolizumab)(Date of CR or PR to Date of Disease Progression or Death Due to Any Cause Up to 31 Months)
- Percentage of Participant With DCR by BICR (With or Without Pembrolizumab)(Baseline to Progressive Disease or Death from Any Cause Up to 31 Months)
- DOR by BICR (With or Without Pembrolizumab)(Date of CR or PR to Date of Disease Progression or Death Due to Any Cause Up to 31 Months)
- OS (With or Without Pembrolizumab)(Baseline to Date of Death from Any Cause Up to 38 Months)
- PFS2 (With Pembrolizumab)(Baseline to Second Disease Progression or Death from Any Cause Up to 38 Months)
- Overall Survival (OS) (With Pembrolizumab)(Baseline to Date of Death from Any Cause Up to 38 Months)
- Median Intracranial DOR Per RECIST 1.1 by BICR (With or Without Pembrolizumab)(Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause Up to 31 Months)
- Time to Deterioration of Pulmonary Symptoms (With Pembrolizumab)(Baseline to Deterioration of Pulmonary Symptoms Up to 31 Months)
- Intracranial ORR: Percentage of Participants With Intracranial CR or PR Per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) by BICR (With Pembrolizumab)(Baseline through CNS Progression or Death Up to 31 Months)
- Median Intracranial DOR Per RECIST 1.1 by BICR (With Pembrolizumab)(Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause Up to 31 Months)
- Intracranial ORR: Percentage of Participants With Intracranial CR or PR Per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 by BICR (With Pembrolizumab)(Baseline through Central Nervous System (CNS) Progression or Death up to 31 Months)
- Intracranial ORR: Percentage of Participants With Intracranial CR or PR Per RECIST 1.1 by BICR (With or Without Pembrolizumab)(Baseline through CNS Progression or Death Up to 31 Months)
- The Concordance of the Local Lab and the Central Lab RET Results: Percentage of Participants With RET-Positive Specimens as Called by the Central Lab, Which is Also RET-Positive as Called by a Local Lab (Positive Percent Agreement)(Baseline)
- Median Time to CNS Progression Per RECIST 1.1 by BICR (With or Without Pembrolizumab)(Baseline through CNS Progression or Death Up to 31 Months)
- Intracranial DOR Per RANO-BM by BICR (With Pembrolizumab)(Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause Up to 31 Months)
- PFS2 (With or Without Pembrolizumab)(Baseline to Second Disease Progression or Death from Any Cause Up to 38 Months)
- ORR: Percentage of Participants With CR or PR by BICR (With or Without Pembrolizumab)(Baseline through Disease Progression or Death Up to 31 Months)
- Time to Deterioration of Pulmonary Symptoms (With or Without Pembrolizumab)(Baseline to Deterioration of Pulmonary Symptoms Up to 31 Months)
- Median Time to CNS Progression Per RECIST 1.1 by BICR (With Pembrolizumab)(Baseline through CNS Progression or Death Up to 31 Months)
- Intracranial DOR Per RANO-BM by BICR (With or Without Pembrolizumab)(Date of Intracranial CR or PR to Date of CNS Progression or Death Due to Any Cause Up to 31 Months)
- Intracranial ORR: Percentage of Participants With Intracranial CR or PR Per RANO-BM by BICR (With or Without Pembrolizumab)(Baseline through CNS Progression or Death Up to 31 Months)