A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 590
- 试验地点
- 73
- 主要终点
- Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib
研究概览
简要总结
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), RET-altered NSCLC and other RET-altered solid tumors.
详细描述
The study consists of 2 parts, a dose-escalation part (Phase 1) and an expansion part (Phase 2). Both parts will enroll participants with advanced non-resectable NSCLC, advanced non-resectable thyroid cancer and other advanced solid tumors that have progressed following standard systemic therapy, have not adequately responded to standard systemic therapy, or the participants must be intolerant to or the Investigator has determined that treatment with standard therapy is not appropriate, or there must be no accepted standard therapy for their disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Diagnosis during dose escalation (Phase 1) - Pathologically documented, definitively diagnosed non-resectable advanced solid tumor.
- •All participants treated at doses > 120 mg per day must have MTC, or a RET-altered solid tumor per local assessment of tumor tissue and/or blood.
- •Diagnosis during dose expansion (Phase 2) - All participants (with the exception of participants with MTC enrolled in Groups 3, 4, and 9) must have an oncogenic RET-rearrangement/fusion or mutation (excluding synonymous, frameshift, and nonsense mutations) solid tumor, as determined by local or central testing of tumor or circulating tumor nucleic acid in blood; as detailed below.
- •Group 1 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion previously treated with a platinum-based chemotherapy.
- •Group 2 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion not previously treated with a platinum-based chemotherapy, including those who have not had any systemic therapy. Prior platinum chemotherapy in the neoadjuvant and adjuvant setting is permitted if the last dose of platinum was 4 months or more before the first dose of study drug.
- •Group 3 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was previously treated with cabozantinib and/or vandetanib.
- •Group 4 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit and was not previously treated with cabozantinib and/or vandetanib.
- •Group 5 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion, have previously received standard of care (SOC) appropriate for their tumor type (unless there is no accepted standard therapy for the tumor type or the Investigator has determined that treatment with standard therapy is not appropriate), and must not have been eligible for any of the other groups.
- •Group 6 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation that was previously treated with a selective tyrosine kinase inhibitor (TKI) that inhibits RET
- •Group 7 - participants must have a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET mutation previously treated with SOC appropriate for the tumor type and not eligible for any of the other groups
- •Group 8 - participants must have pathologically documented, definitively diagnosed locally advanced or metastatic NSCLC with a RET fusion that was previously treated with a platinum based chemotherapy (China only).
- •Group 9 - participants must have pathologically documented, definitively diagnosed advanced MTC that had progressed within 14 months prior to the Screening Visit, and was not previously treated with systemic therapy (except prior cytotoxic chemotherapy is allowed) for advanced or metastatic disease (China only).
- •Participants must have non-resectable disease.
- •Dose expansion (Phase 2): Participants in all groups (except Group 7) must have measurable disease per RECIST v1.1 (or RANO, criteria if appropriate for tumor type).
- •Participants agrees to provide tumor tissue (archived, if available or a fresh biopsy) for RET status confirmation and is willing to consider an on-treatment tumor biopsy, if considered safe and medically feasible by the treating Investigator. For Phase 2, Group 6, participants are required to undergo a pretreatment biopsy to define baseline RET status in tumor tissue.
- •Participants has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-
排除标准
- •Participant's cancer has a known primary driver alteration other than RET. For example, NSCLC with a targetable mutation in EGFR, ALK, ROS1 or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation.
- •Participants had any of the following within 14 days prior to the first dose of study drug:
- •Platelet count < 75 × 10^9/L.
- •Absolute neutrophil count < 1.0 × 10^9/L.
- •Hemoglobin < 9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug.
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present.
- •Total bilirubin > 1.5 × ULN; > 3 × ULN with direct bilirubin > 1.5 × ULN in presence of Gilbert's disease.
- •Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min.
- •Total serum phosphorus > 5.5 mg/dL
- •QT interval corrected using Fridericia's formula (QTcF) > 470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome.
- •Clinically significant, uncontrolled, cardiovascular disease.
- •Central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms.
- •Clinically symptomatic interstitial lung disease or interstitial pneumonitis including radiation pneumonitis
- •Participants in Groups 1-5 and 7 (Phase 2) previously treated with a selective RET inhibitor
- •Participant had a major surgical procedure within 14 days of the first dose of study drug
- •Participant had a history of another primary malignancy that had been diagnosed or required therapy within the a year prior to the study
- •Pregnant or breastfeeding female participants
研究组 & 干预措施
Phase 1 Dose Escalation
Multiple doses of pralsetinib (BLU-667) for oral administration.
干预措施: pralsetinib (BLU-667) (Drug)
Phase 2 Dose Expansion
Oral dose of pralsetinib (BLU-667) as determined during Dose Escalation.
干预措施: pralsetinib (BLU-667) (Drug)
结局指标
主要结局
Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib
时间窗: Up to approximately 30.8 months
MTD was defined as the highest tolerated dose of pralsetinib without causing dose limiting toxicities (DLTs). DLT was defined as any Grade ≥3 adverse event (AE) occurring during Cycle 1 during Phase 1 (dose escalation) that is not clearly caused by something other than pralsetinib. RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase.
Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)
时间窗: From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years)
An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. A SAE is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Phase 2: Overall Response Rate (ORR)
时间窗: Up to approximately 79.8 months
ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) for at least two assessments with at least 28 days apart and no disease progression (PD) in between. Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), were presented.
次要结局
- Phase 1: ORR(Up to approximately 28 months)
- Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 2: C24hr(24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Time to Maximum Plasma Concentration (Tmax)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation NSCLC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: DOR in RET-mutation MTC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status(Up to approximately 79.8 months)
- Phase 2: DOR(Up to approximately 79.8 months)
- Phase 2: CBR(Up to approximately 79.8 months)
- Phase 2: DCR(Up to approximately 79.8 months)
- Phase 2: Progression-free Survival (PFS)(Up to approximately 7 years)
- Phase 2: Overall Survival (OS)(Up to approximately 7 years)
- Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants(Up to approximately 79.8 months)
- Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants(Up to approximately 79.8 months)
- Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants(Up to approximately 79.8 months)
- Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants(Up to approximately 79.8 months)
- Phase 1: Maximum Plasma Concentration (Cmax)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)(24 hours postdose on Day 1 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)(24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Apparent Volume of Distribution (Vz/F)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Terminal Elimination Half-Life (t½)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Apparent Oral Clearance (CL/F)(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Accumulation Ratio for Cmax (RCmax)(24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Accumulation Ratio for AUC (RAUC)(24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: Cmax(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: Tmax(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: Tlast(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: AUC0-24(24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: t½(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 2: CL/F(Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days))
- Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6)(Baseline, Week 4)
- Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4)(Baseline, Week 4)