Ramucirumab or Anti-PDGFR Alpha Monoclonal Antibody IMC-3G3 in Treating Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as ramucirumab and anti-PDGFR alpha monoclonal antibody IMC-3G3 (Olaratumab), can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. PURPOSE: This phase II trial is studying how well ramucirumab or anti-PDGFR alpha monoclonal antibody IMC-3G3 works in treating patients with recurrent glioblastoma multiforme.

Detailed Description
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OBJECTIVES: Primary To assess the progression-free survival rate at 6 months after treatment with ramucirumab or anti-PDGFR alpha monoclonal antibody IMC-3G3 in patients with recurrent glioblastoma multiforme. Secondary To evaluate the acute and late toxicities associated with these regimens. To assess the objective tumor response rate. To estimate the overall survival of these patients. To describe the pharmacokinetic and pharmacodynamic profiles and immunogenicity of these regimens. OUTLINE: This is a multicenter study. Patients are sequentially assigned to 1 of 2 treatment groups. Group 1: Patients receive ramucirumab IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Group 2: Patients receive anti-PDGFR alpha monoclonal antibody IMC-3G3 IV over 60-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Official Title
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An Open Label, Phase 2 Study Evaluating the Safety and Efficacy of IMC-3G3 or IMC-1121B in Patients With Recurrent Glioblastoma Multiforme

Conditions
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Adult Glioblastoma Multiforme

Intervention / Treatment
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* Biological: olaratumab
* Biological: ramucirumab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed supratentorial glioblastoma multiforme (GBM) Patients with prior low-grade glioma who progressed after radiotherapy ± chemotherapy and are biopsied and found to have GBM are eligible Progressive or recurrent disease after radiotherapy ± chemotherapy Measurable disease by contrast-enhanced MRI or CT scan PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Life expectancy ≥ 3 months Absolute neutrophil count ≥ 1,500/millimeter cubed (mm³) Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 gram/deciliter (g/dL) Creatinine ≤ 1.5 milligram/deciliter (mg/dL) OR creatinine clearance > 60 mL/min Total bilirubin ≤ 1.5 mg/dL Transaminases ≤ 3 times upper limit of normal (ULN) Urine protein ≤ 2+ by dipstick or urinalysis or ≤ 1,000 mg by 24-hour urine collection International Normalized Ratio (INR) ≤ 1.5 Partial Thromboplastin Time (PTT) ≤ 5 seconds above ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 12 weeks after completion of study treatment Mini Mental State Exam score ≥ 15 Able to undergo magnetic resonance imaging (MRI) (i.e., no pacemaker, aneurysm clip, or claustrophobia) No concurrent serious infection or medical illness that would jeopardize the ability of the patient to receive the treatment outlined in this study with reasonable safety including, but not limited to, any of the following: Uncontrolled hypertension Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situation that would limit compliance with study requirements No other malignancy within the past 5 years, except curatively treated carcinoma in situ or basal cell carcinoma of the skin No major bleeding episode within the past 3 months No myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack within the past 6 months No serious or non-healing wound, ulcer, or bone fracture No uncontrolled or poorly controlled hypertension, despite standard medical management No known allergy to any of the treatment components No known HIV positivity or AIDS-related illness No uncontrolled thrombotic or hemorrhagic disorders No grade 3-4 gastrointestinal bleeding within the past 3 months No gross hemoptysis (≥ ½ teaspoon) within the past 2 months PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy At least 3 months since prior radiotherapy At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) At least 2 weeks since prior FDA-approved, non-cytotoxic agents (e.g., celecoxib, thalidomide) At least 3 weeks since prior investigational, non-cytotoxic agents More than 28 days since prior major surgery, including brain biopsy More than 7 days since prior subcutaneous venous access device placement No prior treatment with other agents that directly inhibit Platelet-Derived Growth Factor Receptor (PDGFR)α/β, Platelet-Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF), or Vascular Endothelial Growth Factor Receptor (VEGFR)s No concurrent therapeutic anticoagulation, chronic daily treatment with aspirin (> 325 mg/day), or other known inhibitors of platelet function No concurrent prophylactic hematopoietic growth factors (e.g., erythropoietin, Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte-macrophage Colony Stimulating Factor (GM-CSF), or Interleukin (IL-11) during the first course of treatment No concurrent elective or planned surgery No other concurrent therapy for the tumor (e.g., chemotherapy or investigational agents) Concurrent steroids allowed

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Patients receive ramucirumab IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: ramucirumab<br>* Given IV<br>|
| Experimental: Group 2<br>Patients receive olaratumab IV over 60-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Biological: olaratumab<br>* Given IV<br>* Other names: IMC-3G3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Progression-Free Survival Rate at 6 Months (PFS-6) | PFS was defined as the start of treatment to the earliest date of tumor progression or death from any cause based on the modified Response Assessment in Neuro-Oncology Group through the American Society of Clinical Oncology (RANO) criteria. Progression is defined by any of the following: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. RANO is a standardized response criteria using bi-dimensional measurements of the largest contrast-enhancing area (Macdonald, 1990). | Start of treatment to PD or Death Up To 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events as Assessed by NCI CTCAE v4.0 (National Cancer Institute-Common Terminology Criteria for Adverse Events) | The number of participants who experienced serious adverse events (SAEs) that were considered to be related to ramucirumab or olaratumab. A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section. | Start of Treatment to End of Study (Up to 13 Months) | 
| Percentage of Participants (Pts) With Complete Response (CR), Partial Response (PR) and Minor Response (MR) (Objective Response Rate [ORR]) | The pts achievement of both measurement and confirmation criteria for a status of CR, PR or MR based on the modified RANO criteria.CR requires all of the following:complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks (wks);no new lesions;no corticosteroids;and stable or improved clinically.PR requires all of the following:≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 wks;no new lesions;stable or reduced corticosteroid dose;and stable or improved clinically.MR requires ≥ 25% reduction in sum of products of the perpendicular diameters of all measureable enhancing lesions sustained for at least 4 wks and no new lesions or progression of non-measurable lesions. PD is defined by any of these: ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions;any new lesion;or clinical deterioration. | Start of Treatment to PD Up To 20 Months | 
| Median Overall Survival (OS) | OS is the time from the start of treatment to the date of death. Participants who had not expired by the data analysis cutoff date were censored at their last date known to be alive. | Start of Treatment to Death Up To 27 Months | 
| Pharmacokinetics (PK): Concentration Maximum (Cmax) and Concentration Minimum (Cmin) of Ramucirumab |  | Cycle 7, Day 1: Prior to Infusion,1 hour (hr) Post Infusion | 
| PK: Cmax and Cmin of Olaratumab |  | Cycle 3, Day 1: Prior to Infusion, 1 hr Post Infusion | 
| Pharmacodynamics (PD) Profiles |  | Cycle 7, Day 1: Prior to Infusion, 1 hr Post Infusion | 
| Percentage of Participants With Anti-Olaratumab Antibodies (ADA) | Percentage of Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. | Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months) | 
| Percentage of Participants With Anti-Ramucirumab Antibodies (ADA) | Percentage of Participants with Treatment Emergent (TE) anti-ramucirumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. | Start of Treatment to 30-day Post Infusion Follow Up (Up to 6 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult brain tumor, adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma