A Phase 1b/2 Study of Abemaciclib in Combination With Irinotecan and Temozolomide (Part A) and Abemaciclib in Combination With Temozolomide (Part B) in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors and Abemaciclib in Combination With Dinutuximab, GM-CSF, Irinotecan, and Temozolomide in Pediatric and Young Adult Patients With Relapsed/Refractory Neuroblastoma (Part C)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 27
- 主要终点
- Recommended Phase 2 Dose (RP2D) of Abemaciclib in Combination With Irinotecan and Temozolomide (Part A)
研究概览
简要总结
The study's purpose is to see if the drug, abemaciclib, is safe and effective when given with other drugs to kill cancer cells. The study is open to children and young adults with solid tumors, including neuroblastoma, that did not respond or grew during other anti-cancer treatment. For each participant, the study is estimated to last up to 2 years.
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
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Parts A and B only:
- •Participants must be less than or equal to (≤)18 years of age.
- •Body weight greater than or equal to (≥)10 kilograms and body surface area (BSA) ≥0.5
- •Participants with any relapsed/refractory malignant solid tumor (excluding lymphoma), including central nervous system tumors, that have progressed on standard therapies.
- •For sites that are actively enrolling Parts B and C, participants with neuroblastoma who are eligible for Part C will be excluded from Part B unless approved by Lilly CRP/CRS.
- •Part C only:
- •Participants must be less than (<) 21 years of age.
- •Participants have a BSA ≥0.2 m².
- •Participants with first relapse/refractory neuroblastoma.
- •All Parts
- •Participants must have measurable or evaluable disease by RECIST v1.1 or RANO.
- •A Lansky score ≥50 for participants <16 years of age or Karnofsky score ≥50 for participants ≥16 years of age.
- •Participants must have discontinued all previous treatments for cancer or investigational agents and must have recovered from the acute effects to Grade ≤1 at the time of enrollment.
- •Able to swallow and/or have a gastric/nasogastric tube.
- •Adequate hematologic and organ function ≤2 weeks (14 days) prior to first dose of study drug.
- •Females of reproductive potential must have negative urine or serum pregnancy test at baseline (within 7 days prior to starting treatment).
- •Female participants of reproductive potential must agree to use highly effective contraceptive precautions during the trial. For abemaciclib, females should use contraception for at least 3 weeks following the last abemaciclib. For other study drugs, highly effective contraceptive precautions (and avoiding sperm donation) must be used according to their label.
- •Life expectancy of at least 8 weeks and able to complete at least 1 cycle of treatment.
- •Caregivers and participants willing to make themselves available for the duration of the trial.
排除标准
- •Received allogenic bone marrow or solid organ transplant.
- •Received live vaccination.
- •Intolerability or hypersensitivity to any of the study treatments or its components.
- •Diagnosed and/or treated additional malignancy within 3 years prior to enrollment that may affect the interpretation of results, with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected in situ cervical and/or breast cancers.
- •Pregnant or breastfeeding.
- •Active systemic infections.
- •Serious and/or uncontrolled preexisting medical condition(s) that would preclude participation in this study.
- •Parts A and C only: Have a bowel obstruction.
- •Prior treatment with drugs known to be strong inhibitors or inducers of isoenzyme cytochrome P450 3A (CYP3A) or strong inhibitors of uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) if the treatment cannot be discontinued or switched to a different medication at least 5 half-lives prior to starting study drug.
- •Received prior treatment with cyclin-dependent kinase (CDK) 4 & 6 inhibitor.
- •Part C only: Received prior systemic therapy for relapsed/refractory neuroblastoma.
- •Part C only, have received prior anti-GD2 therapy during induction phase.
- •Currently enrolled in any other clinical study involving an investigational product or non-approved use of a drug or device.
- •Has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer.
研究组 & 干预措施
Part A Cohort A1
Participants received:
- Abemaciclib: 70 mg/m², administered orally twice daily (BID).
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part A Cohort A1
Participants received:
- Abemaciclib: 70 mg/m², administered orally twice daily (BID).
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Irinotecan (Drug)
Part A Cohort A1
Participants received:
- Abemaciclib: 70 mg/m², administered orally twice daily (BID).
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part A Cohort A-1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part A Cohort A-1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Irinotecan (Drug)
Part A Cohort A-1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part B Cohort B1
Participants received:
- Abemaciclib: 70 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part B Cohort B1
Participants received:
- Abemaciclib: 70 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part B Cohort B2
Participants received:
- Abemaciclib: 90 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part B Cohort B2
Participants received:
- Abemaciclib: 90 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part B Cohort B3
Participants received:
- Abemaciclib: 115 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part B Cohort B3
Participants received:
- Abemaciclib: 115 mg/m², administered orally BID.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part B Cohort B5
Participants received:
- Abemaciclib: 115 mg/m², administered orally BID.
- Temozolomide: 150 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part B Cohort B5
Participants received:
- Abemaciclib: 115 mg/m², administered orally BID.
- Temozolomide: 150 mg/m²/day, administered orally on Days 1-5 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part C Cohort C1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
- Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Abemaciclib (Drug)
Part C Cohort C1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
- Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Irinotecan (Drug)
Part C Cohort C1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
- Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Temozolomide (Drug)
Part C Cohort C1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
- Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: Dinutuximab (Drug)
Part C Cohort C1
Participants received:
- Abemaciclib: 55 mg/m², administered orally BID.
- Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle.
- Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle.
- Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle.
Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days.
干预措施: GM-CSF (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D) of Abemaciclib in Combination With Irinotecan and Temozolomide (Part A)
时间窗: Cycles 1 and 2 (21 Day Cycles)
The RP2D of abemaciclib was determined based on the totality of safety, tolerability, and pharmacokinetic results. RP2D of abemaciclib in combination with 50 mg/m²/day irinotecan and 100 mg/m²/day temozolomide on days 1-5 of 21-day cycles was reported.
Number or Participants With Dose Limiting Toxicities (DLTs) in Part A
时间窗: Cycle 1 (21 Day Cycle)
DLT was 1 of the following adverse events likely related to abemaciclib/combination and fulfils any 1 of the following criteria graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0: * Any non-hematologic Grade (G) ≥3 toxicity, except: * G3 diarrhea lasting \<72 hour (h) * Acute irinotecan-associated diarrhea lasting \<7 days * G≥3 nausea, vomiting, constipation that lasts \<72 h * G3 mucositis/stomatitis lasting \<72 h * G3 fever/infection * G≥3 electrolyte abnormality that lasts \<72 h, is not complicated, and resolves spontaneously or responds to conventional medication; * G≥3 amylase/lipase that is not associated with symptoms/clinical manifestations of pancreatitis; or * AST/ALT elevation resolving to eligibility criteria within 7 days; * Hematologic toxicities considered a DLT: * A \>14-day Cycle 2 delay due to neutropenia/thrombocytopenia * G≥3 thrombocytopenia with significant bleeding; or * G≥ 4 neutropenic fever
Maximum Tolerated Dose (MTD) of Abemaciclib in Part A
时间窗: Cycle 1 (21 Days)
The MTD was defined as the highest dose level at which less than 33% of participants experienced a DLT.
Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Tlast (AUC0-tlast) of Abemaciclib in Part A
时间窗: Pre-dose, 1, 2.5, 4, and 6 hours post Day 1 dose of Cycle 1 and Cycle 2 (21 Day Cycle)
PK: (AUC0-tlast) was reported.
PK: (AUC0-tlast) of Irinotecan in Part A
时间窗: 2.5, 4, and 6 hours post Day 1 dose of Cycle 1 and Cycle 2 (21 Day Cycle)
PK: AUC0-tlast) was reported.
PK: (AUC0-tlast) of Temozolomide in Part A
时间窗: 1, 2.5, 4, and 6 hours post Day 1 dose of Cycle 1 and Cycle 2 (21 Day Cycle)
PK: AUC0-tlast was reported.
RP2D of Abemaciclib in Combination With Temozolomide (Part B)
时间窗: Cycles 1 and 2 (21 Day Cycles)
The RP2D of abemaciclib was determined based on the totality of safety, tolerability, and pharmacokinetic results. RP2D of abemaciclib in combination with 150 mg/m²/day temozolomide on days 1-5 of 21-day cycles was reported.
Number or Participants With DLTs in Part B
时间窗: Cycle 1 (21 Day Cycle)
A DLT was 1 of the following adverse events likely related to abemaciclib/combination and fulfils any 1 of the following criteria graded as per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0: * Any non-hematologic Grade (G) ≥3 toxicity, except: * G3 diarrhea lasting \<72 hr * Acute irinotecan-associated diarrhea lasting \<7 days * G≥3 nausea, vomiting, constipation that lasts \<72 hr * G3 mucositis/stomatitis lasting \<72 hr * G3 fever/infection * G≥3 electrolyte abnormality that lasts \<72 hr, is not complicated, and resolves spontaneously or responds to conventional medication; * G≥3 amylase/lipase that is not associated with symptoms/clinical manifestations of pancreatitis; or * AST/ALT elevation resolving to eligibility criteria within 7 days; * Hematologic toxicities considered a DLT: * A \>14-day Cycle 2 delay due to neutropenia/thrombocytopenia * G≥3 thrombocytopenia with significant bleeding; or * G≥ 4 neutropenic fever
MTD of Abemaciclib in Part B
时间窗: Cycle 1 (21 Days)
The MTD was defined as the highest dose level at which less than 33% of participants experienced a DLT.
PK: AUC0-tlast of Abemaciclib in Part B
时间窗: Pre-dose, 1, 2.5, 4, and 6 hours post Day 1 dose of Cycle 1 and Cycle 2 (21 Day Cycle)
PK: AUC0-tlast was reported.
PK: AUC0-tlast of Temozolomide in Part B
时间窗: 1, 2.5, 4, and 6 hours post Day 1 dose of Cycle 1 and Cycle 2 (21 Day Cycle)
PK: AUC0-tlast was reported.
Number of Participants With Overall Response Rate (ORR) in Part C.
时间窗: Date of first dose to disease progression or death (Up to 25 Months)
ORR: Number of participants with best response of Complete Response (CR), Partial Response (PR), or Minor Response (MR) per International Neuroblastoma Response Criteria (INRC). * CR is defined as complete response in all response components: * Primary Tumor: \<10 mm residual soft tissue primary site and complete resolution of MIBG-avid tumors * Soft tissue and bone metastatic response: nonprimary target and nontarget lesions \<10 mm and nodes identified as targets decreased to short axis \<10mm and MIBG-avid update of nonprimary lesions completely resolved * Bone marrow response: no tumor infiltration on reassessment; disappearance of all target lesions; * PR is defined as PR in \>1component and all other components are either CR, minimal disease (MD) (bone marrow only), PR (soft tissue or bone), or not involved (NI) and no components with progressive disease (PD). * MR is defined PR or CR in \>1 component and SD in \>1 component and no component with PD
次要结局
- Percentage of Participants With Overall Response Rate (ORR): Part A(Date of first dose to disease progression or death (Up to 25 Months))
- Percentage of Participants With ORR: Part B(Date of first dose to disease progression or death (Up to 25 Months))
- Duration of Response (DoR): Parts A and B.(Date of first evidence of a CR or PR to date of objective disease progression or death due to any cause (Up to 25 Months))
- Duration of Response (DoR): Part C(Date of first evidence of a CR, PR, or MR to date of objective disease progression or death due to any cause (Up to 25 Months))
- Percentage of Participants With Clinical Benefit Rate (CBR): Part A(Date of first dose to disease progression or death due to any cause (Up to 25 Months))
- Percentage of Participants With CBR: Part B(Date of first dose to disease progression or death due to any cause (Up to 25 Months))
- Percentage of Participants With Disease Control Rate (DCR): Part A(Date of first dose to measured progressive disease (Up to 25 Months))
- Percentage of Participants With DCR: Part B(Date of first dose to measured progressive disease (Up to 25 Months))
- Progression-Free Survival (PFS): Part C(Date of first dose to progressive disease or death (Up to 25 Months))
- Abemaciclib Tablet Acceptability(Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1 (21 Day Cycles))