A Study of Ramucirumab (LY3009806) in Children With Refractory Solid Tumors

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety of the study drug known as ramucirumab in children with recurrent or refractory solid tumors including central nervous system (CNS) tumors.

Official Title
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A Phase 1 Study Of Ramucirumab, a Human Monoclonal Antibody Against the Vascular Endothelial Growth Factor-2 (VEGFR-2) Receptor in Children With Refractory Solid Tumors, Including CNS Tumors

Conditions
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Pediatric Solid Tumor, Refractory Tumor, Recurrent Tumor, CNS Malignancies

Intervention / Treatment
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* Drug: Ramucirumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A: participants with recurrent or refractory non-CNS solid tumors Part B: participants with recurrent or refractory CNS tumors Measurable or evaluable disease No other therapeutic options Performance Status: Karnofsky ≥50% for participants >16 years and Lansky ≥50 for participants ≤16 years Exclusion Criteria: Active or recent history of serious bleeding events Active or recent history of gastrointestinal perforations, ulcers, fistulas or abscesses Active or recent history of hypertensive crisis or hypertensive encephalopathy Active non-healing wound or bone fracture History of solid organ transplant

Ages Eligible for Study
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Minimum Age: 12 Months
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab<br>(Part A-Non-CNS Solid Tumors) Escalating doses of 8 milligrams per kilogram (mg/kg) or 12 mg/kg Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle. (Part B-CNS Tumors) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: Cyramza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Dose Limiting Toxicities (DLTs): Maximum Tolerated Dose of Ramucirumab | A DLT is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0: 1. Any death not clearly due to the underlying disease or extraneous causes 2. Neutropenic fever 2. Any Grade ≥3 non-hematologic toxicity 3. Grade ≥4 neutropenia or thrombocytopenia >7 days 4. Grade ≥3 thrombocytopenia with bleeding 5. Grade ≥3 nausea/vomiting or diarrhea>72 hours with adequate antiemetic and other supportive care 6. Grade ≥3 fatigue ≥1 week 7. Grade ≥3 electrolyte abnormality that lasts>72 hours, unless the Participant has clinical symptoms, in which case all Grade 3+electrolyte abnormality regardless of duration should count as a DLT. 8. Grade ≥3 prolongation of QT interval corrected using the Fridericia formula on 2 separate electrocardiogram readings approximately 5 min apart. | Baseline to Study Completion (Up to 42 Months) | 
| Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Population Pharmacokinetics (PK): Minimum observed plasma concentration of Ramucirumab. | Predose, Cycle 1 Day 1 (end of infusion (EOI), 1 hour after EOI) and Cycle 1 Day 43 (1 hour after EOI) | 
| Number of Participants With Anti-Ramucirumab Antibodies | Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline. | Predose Cycle 1 Day 1 through Follow-Up (Up to 42 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR) | Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Date of Objective Disease Progression (Up to 42 Months) | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD): Disease Control Rate (DCR) | Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Date of Objective Disease Progression (Up to 42 Months) | 
| Duration of Response (DOR) | DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 42 Months) | 
| Overall Survival | Overall survival is defined as the time from date of randomization to the date of death (due to any cause). For participants whose last known status is alive at the data cutoff date for the analysis, time will be censored as the last contact date prior to the data cutoff date. | Baseline to Date of Death from Any Cause (Up to 42 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed pediatric solid tumors, unspecified childhood solid tumor, brain and central nervous system tumors