Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bevacizumab together with irinotecan works in treating young patients with recurrent, progressive, or refractory glioma, medulloblastoma, ependymoma, or low grade glioma. Monoclonal antibodies, such as bevacizumab, 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. Bevacizumab may also stop the growth of glioma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A [closed to accrual as of 4/21/2009]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B [closed to accrual as of 4/21/2009]). II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C [closed to accrual as of 10/27/2009]) or recurrent or progressive ependymoma (Stratum D [closed to accrual as of 7/29/2010]). III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E [closed to accrual as of 7/29/2010]). SECONDARY OBJECTIVES: I. Estimate the rate of treatment-related toxicity of this regimen in these patients. II. Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients. III. Estimate the distributions of survival and event-free survival of these patients. IV. Correlate functional changes in tumor with progression-free survival and response using MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography. OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade glioma [closed to accrual as of 4/21/2009] vs intrinsic brain stem tumor [closed to accrual as of 4/21/2009] vs medulloblastoma [closed to accrual as of 10/27/2010] vs ependymoma [closed to accrual as of 7/29/2010] vs low grade glioma [closed to accrual as of 7/29/2010]). Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment. After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.

Official Title
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Phase II Study of Bevacizumab Plus Irinotecan (Camptosar™) in Children With Recurrent, Progressive, or Refractory Malignant Gliomas, Diffuse/Intrinsic Brain Stem Gliomas, Medulloblastomas, Ependymomas and Low Grade Gliomas

Conditions
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Childhood Cerebral Anaplastic Astrocytoma, Childhood Oligodendroglioma, Childhood Spinal Cord Neoplasm, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Ependymoma, Recurrent Childhood Medulloblastoma

Intervention / Treatment
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* Biological: Bevacizumab
* Radiation: Fludeoxyglucose F-18
* Drug: Irinotecan Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed high-grade glioma (WHO grade III or IV) at any site within the brain, including the following: Anaplastic astrocytoma Glioblastoma multiforme (including giant cell and gliosarcoma subtypes) Anaplastic oligodendroglioma Anaplastic ganglioglioma Anaplastic oligoastrocytoma Diffuse brain stem glioma Histologic confirmation not required Histologically confirmed medulloblastoma Histologically confirmed ependymoma Primary spinal cord malignant glioma with measurable metastatic disease within the brain Histologic confirmation required Neuraxis dissemination allowed provided there is bidimensionally measurable disease within the brain and spinal cord Low grade glioma at any site within the brain with or without spinal cord disease Recurrent, progressive, or refractory disease (must have received prior chemoradiotherapy) No more than 2 prior chemotherapy regimens following relapse Bidimensionally measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 2 planes If there is spinal cord disease as well, response assessment will be based only upon the measurable tumor in the brain No diffuse gliomatosis cerebri with < 1 discrete, measurable lesion No evidence of new symptomatic CNS hemorrhage (> grade 2) within the past 2 weeks No central non-cerebellar PNET's (e.g., cerebral PNET or pineoblastoma) No spinal cord tumors only Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age) Absolute neutrophil count ≥ 1,500/mm³ (unsupported) Platelet count ≥ 100,000/mm³ (unsupported) Hemoglobin > 8 g/dL (support allowed) Creatinine normal BUN < 25 mg/dL Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and AST ≤ 3 times ULN Neurological deficits must be stable for ≥ 1 week prior to study entry No active renal, cardiac (congestive cardiac failure, myocarditis), or pulmonary disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment No clinically significant unrelated systemic illness that would preclude study treatment, including any of the following: Serious infections Significant cardiac, pulmonary, hepatic, or other organ dysfunction No uncontrolled systemic hypertension, defined as systolic blood pressure (BP) and/or diastolic BP > 95th percentile for age No stroke, myocardial infarction, or unstable angina within the past 6 months No clinically significant peripheral vascular disease No significant traumatic injury within the past 6 weeks No evidence of bleeding diathesis, coagulopathy, or PT INR > 1.5 Urine protein/creatinine ratio ≤ 1.0 No abdominal fistula or gastrointestinal perforation within the past 6 months No serious nonhealing wound, ulcer, or bone fracture At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas) At least 7 days since prior investigational or biologic agents (3 weeks if patient experienced ≥ grade 2 myelosuppression or if agent has a prolonged half-life) More than 7 days since prior minor surgery More than 12 weeks since prior craniospinal or focal irradiation to primary tumor or other sites At least 4 weeks since prior major surgery and recovered At least 3 months since prior autologous bone marrow or stem cell transplantation At least 2 weeks since prior colony-forming growth factors (i.e., filgrastim [G-CSF], sargramostim [GM-CSF], epoetin alfa) No prior bevacizumab or irinotecan hydrochloride No anticipated surgery during treatment No concurrent prophylactic G-CSF, GM-CSF, or epoetin alfa Concurrent dexamethasone allowed provided the dose is stable or decreasing over the past week No other concurrent anticancer or investigational drugs No concurrent medications that may interfere with study (e.g., immunosuppressive agents other than corticosteroids) No concurrent therapeutic anticoagulation No concurrent nonsteroidal anti-inflammatory drugs, clopidogrel bisulfate, dipyridamole, or acetylsalicylic acid (aspirin) > 81 mg/day

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Radiation: Fludeoxyglucose F-18<br>* Undergo fludeoxyglucose F18 PET<br>* Other names: Fluorodeoxyglucose F18;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate Sustained for ≥ 8 Weeks | Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is >= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol. | From day 1 of treatment up to 24 weeks | 
| Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E) | Disease stabilization is defined as a complete response(CR) or partial response(PR) observed during the first four courses and sustained for 8 weeks; or stable disease (SD) sustained for 6 courses characterized by SD at the end of course 2, at the end of course 4 and at the end of course 6. CR is complete disappearance of all enhancing tumor. PR is >= 50% reduction in tumor size. SD is at least stable and maintenance corticosteroid dose not increased in neurologic examination. | From day 1 of treatment up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity | Adverse events are monitored and graded according to the Common Terminology Criteria for Adverse Events. The grade 1 = mild, grade 2=moderate, grade 3 =severe, grade 4=life threatening/disabling, grade 5=death. | From day 1 of treatment until off study | 
| Cumulative Incidence of Sustained Objective Responses | Cumulative incidence of sustained objective response provides a percentage of participants experiencing the event of interest at a given follow-up time point (for example, 6-months, 1-year, etc.) in the presence of competing events such as progressive disease or death, and it is estimated using the event data for both the event of interest and the competing events experienced by the study participants. In this sense, it is different than the incidence rates estimated in epidemiological studies in terms of 'incidences per 1000 person years. 6-month Cumulative incidence of sustained objective responses will be reported separately for each stratum. | From the first imaging after treatment up to 2 years | 
| Progression-free Survival | Progression-Free survival is the interval of time between of protocol treatment and minimum date of documentation of progressive Disease,second malignancy,death due to any cause, or date of last follow-up. Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression,OR the appearance of new tumor OR a > 25% increase in the sum of the products of two longest perpendicular diameters of all measurable tumors. K-M method was used to estimate progression-free survival. | From start of treatment up to 2 years | 
| Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging | Perfusion ratio obtained from magnetic resonance(MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the perfusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from perfusion ratio at Baseline to perfusion ratio at Day 15(values of perfusion ratio at Day 15 - values of perfusion ratio at baseline). The higher of perfusion ratio is worse. MR perfusion ratio is perfusion solid part of tumor from CBV divided by perfusion frontal while matter. There is no a unit available. | Baseline and day 15 | 
| Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image | Diffusion ratio obtained from magnetic resonance (MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the diffusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from diffusion ratio at Baseline to diffusion ratio at Day 15 (values of diffusion ratio at Day 15 -values of diffusion ration at baseline). The higher of diffusion ratio is better. MR diffusion ratio is the diffusion solid part of tumor divided by the diffusion frontal white matter. There is no a unit available. | Baseline and day 15 | 
| Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates | Using Cox proportional hazards models, the association of tumor volume based on FLAIR images with PFS will be investigated for those strata that have a sufficient number of participants with volume FLAIR measurements. Volumetric magnetic resonance imaging is performed to investigate surrogate markers of tumor growth. Volume FLAIR measurements were longitudinal. As we are not comparing the strata, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on FLAIR. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years | 
| Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates | Using Cox Proportional hazards Models, the association of Log-transformed tumor enhancing volume with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Tumor enhancing volumes were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor enhancing volume. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | 
| Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates | Using Cox Proportional Hazards Models, the association of cystic necrosis with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Volumes of cystic necrosis were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on cystic necrosis. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | 
| Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | Using Cox Proportional Hazards Models, the association of tumor diffusion ratios with progression-free survival will be investigated. Magnetic resonance (MR) diffusion imaging is performed to investigate surrogate markers of tumor growth. Tumor diffusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. And we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor diffusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | 
| Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates | Using Cox Proportional Hazards Models, the association of tumor perfusion ratio with progression-free survival will be investigated. Magnetic resonance (MR) perfusion imaging is performed to investigate surrogate markers of tumor growth. Tumor perfusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume perfusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years | 
| Volume of Distribution | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the volume of distribution. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology ,2016 volume 81(1):148-160. The estimates of the volume of distribution were calculated by the model described in the paper. | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | 
| Systemic Clearance | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the systemic clearance. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology, 2016 volume 81(1):148-160. The estimates of the systemic clearance were calculated by the model described in the paper. | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | 
| Terminal Half-life | Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the PK parameters. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation published by British Journal of Clinical Pharmacology,2016 volume 81(1):148-160. The estimates of the terminal half-life were calculated by the method described in the paper. | Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1 | 
| Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15 | The change in VEGF-R2 was calculated from baseline to the time of the 2nd dose (values of 24-48 hours after the 2nd dose at Day 15 - values of pre-dose 1 Day1, i.e., baseline). VEGF-R2 is measured in the relative phosphorylation score which is generated as a ratio of normalized phosphorylated VEGF-R2 versus normalized total VEGF-R2 protein. | Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1 | 
| Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging | The changes in VEGF-R2 are calculated by values at Day 15 minus values at baseline for the patients who had the changes in perfusion from magnetic resonance perfusion imaging. The purpose of reporting descriptive statistics of changes of VEGF-R2 is to provide the information for the correlation coefficients in Section 19. | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | 
| Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) | The change of perfusion in magnetic resonance imaging is calculated by taking the difference between the Day-15 measurements and the Baseline measurements for patients who had the changes of VEGF-R2. The purpose of reporting the descriptive statistics is to provide the information for the correlation coefficients reported in the next section, Section 19. MR perfusion ratio is the ratio of the perfusion measurements in the tumor and the perfusion measurerement in comparative frontal while matter, which is the comparative healthy part of the brain. | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | 
| Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging | Spearman correlation coefficient is used to measure the correlation of the changes in VEGF-R2 with the changes in perfusion ratios. The changes are calculated by values at Day 15 minus values at baseline for VEGF-2 in Section 17 above and perfusion in Section 18 above, respectively. The correlation coefficients are reported in each stratum separately. | Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1 | 
| Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. | Baseline | 
| Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. | Baseline | 
| Number of Patients With High VEGF-A Expression at Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. | Baseline | 
| Number of Patients With High VEGF-R2 Expression at Baseline | The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum. | Baseline | 
| Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression | The association of hypoxia inducible factor-2alpha expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with hypoxia inducible factor-2alpha measurements. The hazard ratio was reported for patients who had hypoxia inducible factor-2alpha expression. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | 
| Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression | The association of CA9 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with CA9 measurements. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | 
| Progression-free Survival Hazard Ratio by VEGF-A Expression | The association of VEGF-A expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-A measurements. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study | 
| Progression-free Survival Hazard Ratio by VEGF-R2 Expression | The association of VEGF-R2 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-R2 measurements. | From start of treatment until the earliest of progressive disease, death, second malignancy or off study |