A Phase 1 Study of LY3039478 in Patients With Advanced or Metastatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 247
- 试验地点
- 6
- 主要终点
- Part A and F: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The purpose of this study is to find a recommended dose level of LY3039478 that can safely be taken by participants with advanced cancer or cancer that has spread to other parts of the body, including but not limited to lymphoma. The study will also explore changes to various markers in blood cells and tissue. Finally, the study will help to document any tumor activity this drug may have.
详细描述
In Part A of this study, participants with advanced/metastatic cancer (including lymphoma) will receive increasing doses of LY3039478 to define the dose level for Part B, C, D and E. In Part B, C, D and E LY3039478 will be explored at a predefined fixed dose level. Participants in Part B and D must have a defined alteration in a certain molecular pathway. Enrollment of participants in Part B, C, D and E will start once Part A is completed. In Part F participants will receive increasing doses of LY3039478 in combination with prednisone to define the maximum tolerated dose level.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •For all parts: The participant must be, in the judgment of the investigator, an appropriate candidate for experimental therapy after available standard therapies have failed to provide clinical benefit for their advanced or metastatic cancer.
- •For Dose Escalation (Part A): The participant must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced or metastatic.
- •For Part B: All participants must have a histological evidence of their advanced or metastatic cancer and prescreened alterations in a defined pathway.
- •For Part C: All participants must have histological evidence of advanced or metastatic specific subtypes of soft tissue sarcoma.
- •For Part D: All participants must have histological evidence of advanced or metastatic cancer and prescreened alterations in a defined pathway.
- •Cohort 1: Participants must have triple negative breast cancer.
- •Cohort 2: Participants must have hepatocellular carcinoma (HCC). These participants should have Child-Pugh stage A.
- •Cohort 3: Participants must have cholangiocarcinoma.
- •Cohort 4: Participants must have chronic lymphocytic leukemia.
- •Cohort 5: Participants must have a mature T cell, B cell, or natural killer (NK) cell neoplasm.
- •For Part E: Participants must have adenoid cystic carcinoma (ACC).
- •For Part F dose confirmation: Participants must have leiomyosarcoma and prescreened alterations in a defined pathway.
- •As defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the Revised Response Criteria for Malignant Lymphoma or the Response Assessment in Neuro Oncology (RANO) criteria for glioblastoma:
- •For Dose Escalation (Part A): Have measurable or nonmeasurable disease.
- •For Parts B, C, D, E and F: Have measurable disease or reliable biomarker measure.
- •For Parts B, C, D, E and F: Have available tumor tissue.
- •Have adequate organ function.
- •Have a performance status of less than or equal to 1 on the Eastern Cooperative Oncology Group (ECOG) scale and life expectancy of more than 12 weeks.
排除标准
- •Have symptomatic or non stable central nervous system (CNS) malignancy.
- •Females who are pregnant or lactating.
- •Have active bacterial, fungal, and/or known viral infection.
- •Have malabsorptive syndromes, enteropathies, gastroenteritis (acute or chronic), or diarrhea (acute or chronic).
- •Participants with HCC that:
- •Have known HCC with fibro-lamellar or mixed histology.
- •Have presence of clinically relevant ascites.
- •Have had a liver transplant.
- •Have active or uncontrolled clinically serious hepatitis B virus or hepatitis C virus infection.
研究组 & 干预措施
LY3039478 - Dose Escalation
Part A: LY3039478 administered orally three times per week (TIW) at escalating doses (2.5 milligrams [mg], 5 mg, 10 mg, 20 mg, 30 mg, 45 mg, 60 mg, 75 mg and 100 mg) for two 28 day cycles. Participants receiving benefit may continue until disease progression
干预措施: LY3039478 (Drug)
LY3039478 - Cohort Expansion
Part B,C,D & E:LY3039478 administered orally three times per week(TIW) at a fixed dose determined in Part A for two 28 day cycles.Participants receiving benefit may continue until disease progression.The doses administered were as follows:Part B:50 mg or 75 mg for participants(pts) who had tumors with molecular alterations related to the Notch pathway;Part C:50 mg or 75 mg for pts who had Leiomyosarcoma(LMS),50 mg or 75 mg for pts who had other Sarcoma, 50 mg for pts who had gastrointestinal stromal tumors(GIST);Part D: 75 mg for pts in the Triple Negative Breast Cancer cohort,75 mg for pts in Cholangiocarcinoma cohort,50 mg for pts in Triple Negative Breast Cancer cohort,50 mg for pts in the Hepatocellular Carcinoma cohort,50 mg for pts in the Cholangiocarcinoma cohort, 50 mg for pts in the Chronic lymphocytic leukemia(CLL) cohort, 50 mg for pts in the Mature T cell, B cell or Natural Killer(NK) cell neoplasms cohort; Part E: 50 mg for pts in the Triple Negative Breast Cancer cohort.
干预措施: LY3039478 (Drug)
Dose 1 LY3039478 + Prednisone
Part F1: Participants received a loading dose of 75 mg or 100 mg administered 3 times per week for 2 weeks during Cycle 1.
50 mg LY3039478 administered orally TIW (twice a week in cycle 1) for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles). Participants receiving benefit may continue until disease progression.
干预措施: LY3039478 (Drug)
Dose 1 LY3039478 + Prednisone
Part F1: Participants received a loading dose of 75 mg or 100 mg administered 3 times per week for 2 weeks during Cycle 1.
50 mg LY3039478 administered orally TIW (twice a week in cycle 1) for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles). Participants receiving benefit may continue until disease progression.
干预措施: Prednisone (Drug)
Dose 2 LY3039478 + Prednisone
Part F2: Participants received a loading dose of 75 mg, 100 mg or 125 mg 2 times per week for 2 weeks during Cycle 1.
50 mg LY3039478 administered orally TIW for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles).
Participants receiving benefit may continue until disease progression.
干预措施: LY3039478 (Drug)
Dose 2 LY3039478 + Prednisone
Part F2: Participants received a loading dose of 75 mg, 100 mg or 125 mg 2 times per week for 2 weeks during Cycle 1.
50 mg LY3039478 administered orally TIW for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles).
Participants receiving benefit may continue until disease progression.
干预措施: Prednisone (Drug)
结局指标
主要结局
Part A and F: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Baseline through the end of Cycle 1, Up to 28 Days
DLT was defined as an adverse event (AE) during Cycle 1 (Up to 28 Days) that was related to LY3039478 and fulfilled any 1 of the following criterion using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v 4.0): CTCAE Grade 3 non-hematological toxicity with a few exceptions, CTCAE Grade 4 hematological toxicity of greater than 5 days duration, any febrile neutropenia,Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting (for example, any toxicity that is possibly related to the study medication that requires the withdrawal of the participant from the study during Cycle 1).
Part A: Recommended Phase 2 Dose of LY3039478 : Maximum Tolerated Dose (MTD)
时间窗: Baseline though the end of cycle 1 (28 days cycle)
MTD is defined as the highest tested dose that has less than 33% probability of causing a DLT during Cycle 1.
Part B, C, D and E: Recommended Phase 2 Dose of LY3039478 : Maximum Tolerated Dose (MTD)
时间窗: Baseline through the end of cycle 1 (28 days Cycle)
MTD is defined as the highest tested dose that has less than 33% probability of causing a DLT during Cycle 1.
Part F1 and F2: Recommended Phase 2 Dose of LY3039478
时间窗: Baseline Up to 2 Months
Parts F1 and F2 compared loading dose three time per week with prednisone versus two times per week with prednisone. Even though the trial may have found an MTD, it did not identify an Recommended Phase 2 dose (RP2D).
Part B, C, D, E and F: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])
时间窗: Baseline to Disease Progression or Participant Discontinuation (Up To 20 Months)
Objective response is complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.1 ) guidelines. CR is disappearance of all target and non-target lesions; PR is greater than or equal to (\>=) 30% decrease in sum of longest diameter of target lesions. Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants treated multiplied by 100. Analysis Population Description: Part D: 50 mg LY3039478 (Cohort 5) was assessed using Cheson criteria. Zero participants were analyzed for Part D: 50 mg LY3039478 (Cohort 4) because data were not collected. Data was not reported because both enrolled participants discontinued treatment early-one on Day 1 due to investigator decision and the other on Day 26 due to myocardial infarction, with no efficacy assessments performed.
次要结局
- Parts A, B, C, D and E: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose, 0.5,1,2,4,6-8,8-10,24-30 hours)
- Part F1 Cohort1 and Part F2 Cohort 1: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose, 0.5,1,2,4,6-8,8-10,24-30 hours)
- Parts A and B: PK: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Part F1 Cohort1 and Part F2 Cohort 1: PK: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Parts A and B: PK: Area Under the Concentration-Time Curve From Time 0 to Tau (AUC[0-Tau]) of LY3039478(Day 22: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Part F1 Cohort1 and Part F2 Cohort 1: PK: Area Under the Concentration-Time Curve From Time 0 to Tau (AUC[0-Tau]) of LY3039478(Day 22: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Parts A, B, C, D and E: PK: Time to Maximum Concentration (Tmax) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Part F1 Cohort1 and Part F2 Cohort 1: PK: Time to Maximum Concentration (Tmax) of LY3039478(Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose,0.5,1,2,4,6-8,8-10,24-30 hours)
- Part A: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])(Baseline to Disease Progression or Participant Discontinuation (Up To 17 Months))
- Part B, C, D, E and F: Duration of Response (DoR)(Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death Due to Any Cause (Up To 20 Months))
- Part B, C, D, E and F: Progression Free Survival (PFS)(Baseline to Objective Progression or Death from Any Cause (Up To 17 Months))
- Part B, C, D, E and F: Overall Survival (OS)(Baseline to Date of Death from Any Cause (Up To 49 Months))