A Phase 1/2 Study of the Oral RET Inhibitor LOXO 292 in Pediatric Patients With Advanced RET-Altered Solid or Primary Central Nervous System Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 36
- 试验地点
- 51
- 主要终点
- Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric participants with an activating rearranged during transfection (RET) alteration and an advanced solid or primary CNS tumor.
详细描述
This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, participants will be enrolled using a rolling 6 dose escalation scheme. The starting dose of LOXO-292 is equivalent to the adult recommended phase 2 dose of 160 milligrams (mg) twice a day (BID). Once the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is identified, participants will be enrolled to one of four phase 2 dose expansion cohorts depending on tumor histology and tumor genotype. Cycle length will be 28 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Advanced or metastatic solid or primary CNS tumor which has failed standard of care therapies
- •Evidence of an activating RET gene alteration in the tumor and/or blood
- •Measurable or non-measurable disease
- •Karnofsky (participants 16 years and older) or Lansky (participants younger than 16) performance score of at least 50
- •Participant with primary CNS tumors or cerebral metastases must be neurologically stable for 7 days prior and must not have required increasing doses of steroids within the last 7 days
- •Adequate hematologic, hepatic and renal function.
- •Ability to receive study drug therapy orally or via gastric access
- •Willingness of men and women of reproductive potential to observe conventional and effective birth control
排除标准
- •Major surgery within two weeks prior to planned start of LOXO-292
- •Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292
- •Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
- •Clinically significant active malabsorption syndrome
- •Pregnancy or lactation
- •Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant required a modification to current thyroid medication in the 7 days before start of LOXO-292)
- •Uncontrolled symptomatic hypercalcemia or hypocalcemia
- •Known hypersensitivity to any of the components of the investigational agent, LOXO-292 or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
- •Prior treatment with a selective RET inhibitor(s) (including investigational selective RET inhibitor[s])
研究组 & 干预措施
Cohort 1: Medullary Thyroid Cancer (MTC) Group
Participants in this cohort had MTC and received 160 mg of selpercatinib BID orally on Days 1 through 28 of a 28-day cycle.
The treatment was continued until participants experienced a progressive disease, unacceptable toxicity, or other protocol-defined reason for discontinuation.
干预措施: Selpercatinib (Drug)
Cohort 2: Papillary Thyroid Cancer (PTC) Group
Participants in this cohort had PTC and received 160 mg of selpercatinib BID orally on Days 1 through 28 of a 28-day cycle.
The treatment was continued until participants experienced a progressive disease, unacceptable toxicity, or other protocol-defined reason for discontinuation.
干预措施: Selpercatinib (Drug)
Cohort 3: Other Cancer Group
Participants in this cohort had other (REarranged during Transfection (RET)-altered non-thyroid) cancer and received 160 mg of selpercatinib BID orally on Days 1 through 28 of a 28-day cycle.
The treatment was continued until participants experienced a progressive disease, unacceptable toxicity, or other protocol-defined reason for discontinuation.
干预措施: Selpercatinib (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Cycle 1 (28 Day Cycle)
A DLT was any of the adverse events that starts on or after the first administration of study drug listed below, as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. * Any Grade(G) ≥3 nonhematologic toxicity except G3 fatigue, nausea, tendon reflex decrease, weight gain attributable to normal growth and development. * G3 vomiting/diarrhea was DLT only if it persists \>48 h despite standard of care treatment. * G4 vomiting/diarrhea was DLT regardless of duration. * Any toxicity, regardless of the NCI CTCAE v5.0 grade, resulting in discontinuation or dose reduction of treatment (except symptoms related to progressive disease (PD)). * G4/G3 thrombocytopenia with G1 or higher bleeding. * G4 anemia lasting \>8 days, despite supportive therapy. * G4 neutropenia, lasting \>8 days, despite supportive therapy
Phase 2: Percentage of Participants With Overall Response Rate (ORR) in Study
时间窗: Date of first dose to disease progression or death (Up to 62.4 Months)
ORR: Percentage of participants who achieve best overall response Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST). * CR is defined as disappearance of all target lesions. * PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
次要结局
- Plasma Concentrations of LOXO-292(Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days))
- Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of LOXO-292(Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days))
- Maximum Concentration (Cmax) of LOXO-292(Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days))
- Time to Maximum Concentration (Tmax) of LOXO-292(Days 1 and 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-participant Dose Escalation (each cycle is 28 days))
- Recommended LOXO-292 Dose for Phase 2 (MTD)(Cycle 1 (28 days))
- To Assess the Preliminary Anti-Tumor Activity of LOXO-292 in Pediatric Participants With Tumors Harboring an Activating RET Alteration as Determined by ORR Based on RECIST v1.1(Baseline to Progressive Disease or Death due to any cause (Estimated up to 12 months))
- Changes From Baseline in Pain Measures as Measured by Wong Baker Faces Scales. Wong-Baker Faces Pain Scale Includes Pictures of Facial Expressions With Correlating Scores of 0 Being 'no Hurt' and 10 Being 'Hurts Worst'.(Up to 24 months)
- Changes From Baseline in Health Related Quality of Life Measures as Measured by Pediatric Quality of Life (PedsQoL) Inventory Core. PedsQoL Includes a List of Problems With Scores of 0 Being 'Never a Problem' and 4 Being 'Almost Always a Problem'.(Up to 24 months)
- Objective Response Rate as Assessed by RECIST v1.1, as Assessed by Investigator(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Objective Response Rate as Assessed by RANO, as Assessed by Investigator(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Duration of Response (DOR) as Assessed by Investigator(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Duration of Response (DOR) as Assessed by the IRC(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Progression Free Survival (PFS) as Assessed by Investigator(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- PFS as Assessed by IRC(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Overall Survival (OS)(Approximately every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Clinical Benefit Rate (by Investigator)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Clinical Benefit Rate (by IRC)(Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in participants who have not progressed.)
- Frequency of Adverse Events (AEs)(From the time of informed consent, for approximately 24 months (or earlier if the participants discontinues from the study), and through Safety Follow-up (28 days after the last dose))
- To Evaluate the Concordance of Prior Molecular That Detected a RET Alteration Within the Participant's Tumor With Diagnostic Tests Being Evaluated by Sponsor(6 months)
- Phase 2: Post-Operative Stage on Participants Treated With LOXO-292(Up to 3 years)
- Phase 2: Surgical Margin Status in Participants Treated With LOXO-292(Up to 3 years)
- Descriptive Analysis of Pretreatment Surgical Plan(Up to 3 years)
- Descriptive Analysis of Post-Treatment Plans(Up to 3 years)