A Study of Abemaciclib (LY2835219) in Combination With Other Anti-Cancer Treatments in Children and Young Adult Participants With Solid Tumors, Including Neuroblastoma

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Relapsed Solid Tumor, Refractory Solid Tumor

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: Irinotecan
* Drug: Temozolomide
* Drug: Dinutuximab
* Drug: GM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Abemaciclib + Irinotecan + Temozolomide<br>Abemaciclib given orally, irinotecan given intravenously (IV) and temozolomide given orally. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Irinotecan<br>* Administered IV<br>Drug: Temozolomide<br>* Administered orally or IV<br>|
| Experimental: Dose Expansion: Abemaciclib + Irinotecan + Temozolomide<br>Abemaciclib given orally, irinotecan given IV and temozolomide given orally. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Irinotecan<br>* Administered IV<br>Drug: Temozolomide<br>* Administered orally or IV<br>|
| Experimental: Dose Escalation: Abemaciclib + Temozolomide<br>Abemaciclib and temozolomide given orally. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Temozolomide<br>* Administered orally or IV<br>|
| Experimental: Dose Expansion: Abemaciclib + Temozolomide<br>Abemaciclib and temozolomide given orally. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Temozolomide<br>* Administered orally or IV<br>|
| Experimental: Part C Stage 1: Abemaciclib in Combination with Dinutuximab, GM-CSF, Irinotecan, and Temozolomide<br>Abemaciclib given orally, dinutuximab given IV, granulocyte macrophage colony-stimulating factor (GM-CSF) given subcutaneously (subQ), irinotecan given IV and temozolomide given orally or IV. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Irinotecan<br>* Administered IV<br>Drug: Temozolomide<br>* Administered orally or IV<br>Drug: Dinutuximab<br>* Administered IV<br>Drug: GM-CSF<br>* Administered subQ<br>|
| Experimental: Part C Stage 2: Abemaciclib in Combination with Dinutuximab, GM-CSF, Irinotecan, and Temozolomide<br>Abemaciclib given orally, dinutuximab given IV, GM-CSF given subQ, irinotecan given IV and temozolomide given orally or IV. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Irinotecan<br>* Administered IV<br>Drug: Temozolomide<br>* Administered orally or IV<br>Drug: Dinutuximab<br>* Administered IV<br>Drug: GM-CSF<br>* Administered subQ<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number or Participants with Dose Limiting Toxicities (DLTs) | Number of Participants with DLTs | Cycle 1 (21 Day Cycle) | 
| Pharmacokinetics (PK): Mean Steady State Concentrations of Abemaciclib | PK: Mean Steady State Concentrations of Abemaciclib | Cycle 1 through Cycle 3 (21 Day Cycle) | 
| PK: Mean Steady State Concentrations of Irinotecan | PK: Mean Steady State Concentrations of Irinotecan | Cycle 1 through Cycle 3 (21 Day Cycle) | 
| PK: Mean Steady State Concentrations of Temozolomide | PK: Mean Steady State Concentrations of Temozolomide | Cycle 1 through Cycle 3 (21 Day Cycle) | 
| Objective Response Rate (ORR): Percentage of Participants with Best Response of Complete Response (CR), Partial Response (PR), or Minimal Response (MR): Part C, only | ORR: Percentage of Participants with Best Response of CR, PR or MR per International Neuroblastoma Response Criteria (INRC) | Baseline through Disease Progression or Death (Estimated up to 24 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR): Percentage of Participants with Best Response of Complete Response (CR) or Partial Response (PR): Parts A and B, only | ORR: Percentage of Participants with Best Response of CR or PR per Response Evaluation Criteria in Solid Tumors (RECIST) or Response Assessment in Neuro-Oncology (RANO) | Baseline through Disease Progression or Death (Estimated up to 24 Months) | 
| Duration of Response (DoR) | DoR | Date of First Evidence of a CR, PR, or MR (Part C, only) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 24 Months) | 
| Clinical Benefit Rate (CBR): Percentage of Participants with Best Overall Response of CR, PR, MR (Part C, only) or SD With a Duration of At Least 6 Months | CBR: Percentage of Participants with Best Overall Response of CR, PR, MR (Part C, only) or SD With a Duration of at Least 6 Months | Baseline through Disease Progression or Death Due to Any Cause (Estimated up to 24 Months) | 
| Disease Control Rate (DCR): Percentage of Participants with a Best Overall Response of CR, PR, MR (Part C, only), and Stable Disease (SD) | DCR: Percentage of Participants with a Best Overall Response of CR, PR, MR (Part C, only), and SD | Baseline through Measured Progressive Disease (Estimated up to 24 Months) | 
| Progression-Free Survival (PFS): Part C, Only | PFS | Baseline through Progressive Disease or Death (Estimated up to 24 Months) | 
| Acceptability Questionnaire | Participants were evaluated for abemaciclib acceptability (palatability and ease of administration) using a 5-category questionnaire. Participants were asked to answer one of the following to describe the acceptability of abemaciclib: Very difficult, difficult, neither easy nor difficult, easy, or very easy | Cycle 2 Day 1 (21 Day Cycles) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDK4, CDK6, Ewing's sarcoma, Neuroblastoma, Recurrent neuroblastoma, Malignant rhabdoid tumor, Rhabdomyosarcoma, Osteosarcoma, Brain tumor, Glioblastoma, Malignant glioma, Diffuse intrinsic pontine glioma, Medulloblastoma, Ependymoma, Solid tumor, High-grade glioma