| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable or progressive low grade glioma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Brain tumor that cannot be surgically removed or is progressing in growth |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018338 |
| E.1.2 | Term | Glioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Efficacy Objectives: To evaluate the efficacy of the addition of Bevacizumab to Vinblastine compared with Vinblastine alone in chemotherapy–naïve pediatric patients with unresectable or progressive low grade gliomas (LGG) as measured by Response Rate (RR) at 6 months from randomization.
Safety Objectives, to evaluate:
1. safety of combination of Vinblastine and Bevacizumab compared with Vinblastine alone in pediatric patients with LGG, focusing on serious adverse events, Grade ≥ 3 adverse events/laboratory toxicities.
2. define and describe toxicities of the agents in combination and of single agent Vinblastine in this treatment naïve population.
3. effect of Bevacizumab on growth and puberty. To analyze children’s growth following treatment until completion of puberty.
|
|
| E.2.2 | Secondary objectives of the trial |
1. Overall survival at the end of the study.
2. To determine 6 month, 12 month and 2 year progression free survival between vinblastine alone versus in combination with Bevacizumab.
3. To evaluate the difference in visual outcome measures in children with optic pathway gliomas treated with vinblastine alone or in combination with Bevacizumab.
4. To determine if the prevalence of cognitive deficits measured by the NIH Toolbox Cognitive Battery, in children and adolescents (aged 3 -17) treated for LGG at 1 year off therapy, is significantly higher than the normative population (> 14%) in specific domains.
5. To determine the effects of Bevacizumab on cognitive function in the pediatric population.
6. To determine if the prevalence of QOL difficulties measured by the PROMIS self- and parent-proxy reports, in children and adolescents (aged 5 -17) treated for LGG at 1 year off therapy, is significantly higher than the normative population (> 14%) in specific domains. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
All sub-studies and corresponding objectives are embedded within the larger therapeutic study. There is no separate protocol for the sub-studies.
Objectives sub-study 1 "Quality of Life Study":
* To determine if the prevalence of cognitive deficits measured by the NIH Toolbox Cognitive Battery, in children and adolescents (aged 3 -17) treated for LGG at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: working memory, executive function, processing speed, episodic memory, and attention.
* To determine the effects of Bevacizumab on cognitive function in the pediatric population.
* To determine if the prevalence of QOL difficulties measured by the PROMIS self- and parent-proxy reports, in children and adolescents (aged 5 -17) treated for LGG at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: fatigue, physical activity, anxiety, depression, and peer relationships.
* To determine demographic (e.g., SES, gender), disease (e.g., risk status), treatment, and behavioral predictors of neurocognitive and QOL deficits as measured by the NIH Toolbox Cognitive and PROMIS batteries in children and adolescents with LGG.
* To determine the prevalence of cognitive deficits in PLGG population.
Objectives sub-study 2 "Visual Companion Study (for children with low grade glioma involving the optic pathway)":
* To evaluate the difference in visual outcome measures in children with optic pathway gliomas treated with vinblastine alone or in combination with Bevacizumab.
Objectives sub-study 3 "Additional Blood Sample Collection Study":
* Cell-line establishment and constitutional DNA analysis for future research purposes
* Exploratory biomarker analyses
Other exploratory objectives:
1. To prospectively determine the role of BRAF mutation/fusion in PLGG and correlate this with outcome and response to therapy.
2. To determine the presence and prognostic significance of other mutations, including RAF1, FGFR1, MYB, MYBL1, PTPN11, NTRK2, H3F3A, ATRX and CDNK2A deletions among others.
3. To stratify PLGG based on methylation profile, using methylation arrays.
4. To determine demographic (e.g., SES, gender), disease (e.g., risk status), treatment, and behavioral predictors of neurocognitive and QOL deficits as measured by the NIH Toolbox Cognitive and PROMIS batteries in children and adolescents with LGG.
To determine the prevalence of cognitive deficits in PLGG population.
6. To examine the role of vascularity (including MVD) in PLGG and investigate potential biomarkers to assist in determining the population of best responders to anti-angiogenic therapy in PLGG.
7. To assess the use of novel MR biomarkers to assess disease response in these patients and to correlate these with traditional imaging tools. |
|
| E.3 | Principal inclusion criteria |
1. Children and adolescents aged 6 months to < 18 years old with Low Grade Glioma.
2. All patients must submit tumor tissue (fresh tumor tissue is recommended) and have pathological confirmation of LGG and determination of BRAF characteristics from the Hospital for Sick Children. Exceptions will be made for patients with neurofibromatosis type 1 who have not previously had a biopsy. NF1 patients are eligible without tissue confirmation if not available but must have definitive clinical or radiographic evidence of tumor progression or risk for significant neurologic deterioration requiring immediate therapy. If a tissue sample for NF1 patients is available from a previous biopsy, it is required to be submitted for Central Review at the Hospital for Sick Children.
3. Patients must have progressive disease following surgical excision based on clear radiological or clinical evidence of progression, or an incomplete excision (< 95% or > 1.0 cm2 residual tumor) with necessity to begin treatment because of a risk of neurological impairment with progression.
4. All patients on study must have measurable tumor (> 1.0 cm2 of residual tissue if resection has been performed) within 28 days of enrollment.
5. Patients must have received no prior therapy including chemotherapy, biological modifiers and/or radiation treatment for the tumor with the exception of surgery.
6. Patient is able to start treatment within 14 working days after randomization.
7. Post pubertal teenagers who are sexually active agree to use two methods of contraception during the treatment period and for at least 6 months after the last dose of study drug.
8. Lansky performance status > 50% for patients < 16 years of age. Karnofsky performance status > 50% for patients ≥ 16 years of age.
9. Patients with neurologic deficits must have deficits that are stable for a minimum of 1 week prior to enrollment.
10. Patients receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to enrollment.
11. Life expectancy > 2 months at the time of enrollment.
12. Parents/guardians must provide written informed consent and to agree that they (and the patient) will comply with the study protocol.
13. Written assent by patient according to institutional guidelines.
14. Patients must have adequate bone marrow function within 2 weeks prior to enrollment:
• Hemoglobin ≥ 10 g/dL (may be supported)
• Neutrophil count ≥ 1.0 × 109/L
• Platelet count ≥ 100 × 109/L (transfusion independent)
15. Patients not on a therapeutic dose of an anti-coagulant must have an INR ≤ 1.5 and an aPTT ≤ 1.5x institutional ULN for age within 2 weeks prior to enrollment. Anti-coagulation is permitted prior to enrollment on the condition that the patient is, according to the local clinical practice guidelines or approved product labeling, adequately anti-coagulated prior to enrollment.
16. Patients must have satisfactory liver function within 2 weeks prior to enrollment:
• AST ≤ 3x institutional ULN for age
• ALT ≤ 3x institutional ULN for age
• Total Bilirubin ≤ 1.5x institutional ULN for age
17. Patients must have satisfactory renal parameters and meet the following criteria function within 2 weeks prior to enrollment:
• Serum creatinine must be ≤ 1.5 x ULN for age. If the serum creatinine is ≥ 1.5× ULN, the glomerular filtration rate (either estimated or formal) must be >90 mL/min/1.73 m2, for patient to be enrolled.
• Absence of clinically significant proteinuria, as defined by screening of the early morning urine (urine protein < 1g/L and/or albumin/creatinine ratio < 1.0 (mg/mmol)). If urine protein ≥ 1g/L, then Urine Protein Creatinine (UPC) ratio should be calculated. If UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg/24 hours for patient enrollment.
Quality of Life Correlative Study Inclusion Criteria (Optional/Sub-study)
1. Age ≥ 3 and < 18 years.
2. English- or Spanish-speaking.
3. No known history of a significant neurodevelopmental disorder prior to diagnosis of LGG (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation). Patients with NF1 are not excluded.
4. No significant motor or sensory impairment that would prevent computer use and perception of the visual and auditory test stimuli. |
|
| E.4 | Principal exclusion criteria |
1. Children under 6 months of age.
2. Pregnant or lactating females.
3. Use of any investigational agent, systemic, targeted or immunotherapy prior to the first dose of study treatment.
4. Any bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation).
5. Patients with evidence of new symptomatic CNS hemorrhage (> grade I) on baseline MRI.
6. Any significant cardiovascular disease, e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis, CVAs, transient ischemic attacks (TIAs), and systemic hypertension (i.e., a systolic and diastolic BP ≥ 95th percentile for age, sex), prior history of hypertensive crisis or hypertensive encephalopathy or stroke, uncontrolled cardiac arrhythmia within 6 months prior to enrollment.
7. Any previous venous thromboembolism Grade 3 or higher (NCI CTCAE v. 4.03).
8. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
9. Unresolved infection.
10. An active peptic or duodenal ulcer.
11. Major surgical procedure, brain surgery, open biopsy or significant traumatic injury within 28 days prior to enrollment or the anticipation of the need for major (elective) surgery during the course of the study treatment.
12. Intermediate surgical procedure within 2 weeks of enrollment.
13. Minor surgical procedures within 3 days prior to the start of treatment (including the placement of a central line, including PICC line). Insertion of a port-a-cath will require a 7 days interval prior to the start of treatment.
14. Non-healing surgical wound.
15. A bone fracture that has not satisfactorily healed.
16. Concomitant use of the following:
Aspirin (> 325mg/day) within 10 days of enrollment
• Clopidogrel (> 75mg/day) within 10 days of enrollment
• Use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes with INR and aPTT outside therapeutic standards according to institutional guidelines within 10 days of first dose of Bevacizumab. Note: The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of the Baseline Visit. Prophylactic use of anticoagulants is allowed.
17. Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Outcome Measures:
Objective response rate (minor response plus partial response plus complete response) occurring within 6 months after randomization, as determined by the central imaging review using MRI (T1/T2/FLAIR sequences).
Response rate is composed of the combination of minor response (MR), partial response (PR) and complete response (CR). The response to be measured by calculation of the product of the greatest tumor diameter and the perpendicular diameter on MRI using T1/T2/FLAIR sequences. MR = 25-50% response, PR = >50% response, CR = no residual tumor. Stable disease (SD) = <25% decrease. Solid and cystic areas are to be measured separately and only solid tumor enlargement is considered progression. Changes in cyst size are common in low grade glioma and – even if cyst enlargement requires specific management such as drainage of placement of a reservoir – this will not be considered as progressive disease in the absence of progression of the solid tumor component. Please note also that minor and transient increase in size of the tumor is not considered as progression. Progression ((PD) = >25% increase in 2D measured by MRI) must be confirmed on 2 consecutive MRI scans with the second scan being performed at least 4 weeks after the first. In case of less than 25% increase in 2D measured by MRI in the presence of clinical (including visual) deterioration, physicians should contact the primary investigator to determine progressive disease.
Visual Companion Study Outcome Measures (for children with low grade glioma involving the optic pathway). Primary outcome measures:
1. Teller Grating Acuity.
2. Recognition visual acuity testing using the ATS protocol for “H.O.T.V.” optotypes. Only performed in those old enough to complete.
Safety outcome measures:
1. Monitoring and recording of the incidence, nature, and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
2. Safety analysis will include all randomized patients who received at least one dose of study drug (Vinblastine or Vinblastine + Bevacizumab), with patients grouped according to the treatment actually received. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim-analysis is planned to be performed on the primary endpoint when 50% of patients have been randomized and have completed the 6 months follow-up. The O’Brien-Fleming approach will be used and given only one interim analysis is planned, should the p-value for the interim analysis be greater than 0.0054 continuation of the trial would be considered futile.
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. Hereafter all endpoints will be evaluated. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Outcome Measures:
Overall survival (OS), defined as the time from the date of randomization to the date of death regardless of the cause of death. Patients who were alive at the time of the analysis will be censored at the date of the last follow up assessment. Patients without follow up assessment will be censored at the day of last dose and patients with no post baseline information will be censored at the time of randomization.
Progression-free survival (PFS), defined as the time from the date of randomization to the date of disease progression, as determined by the central imaging review panel using MRI (T1/T2/FLAIR sequences), or death from any cause during the study (defined as within 42 days after the last dose of study drug).
All MRI scans will be reviewed centrally by an independent neuroradiologist blinded from clinical information.
Histology will be verified by central review where tissue is available.
Visual Companion Study Outcome Measures (for children with low grade glioma involving the optic pathway). Secondary outcome measures:
1. Visual field testing done using the age appropriate method (i.e. confrontation, Goldman or Humphrey) and scored as the number of abnormal quadrants per eye.
2. Optic nerve pallor: presence/absence each visit.
3. Optic coherence tomography (OCT) of the circumpapillary retinal nerve fiber layer and macular ganglion cell layer (only for institutions equipped with OCT). For younger children unable to cooperate with traditional desktop OCT during the ophthalmology examination, OCT can be performed during sedation for their MRI using hand-held OCT [100-103]. OCT will be reviewed centrally.
Quality of Life Outcome Measures:
1. PROMIS pediatric self- and proxy-reported health measures, including modules in the domains relevant to QOL issues in children and adolescents receiving treatment for LGG (i.e. Fatigue, Physical Activity, Depressive symptoms, Anxiety, Cognitive functioning, and Peer Relations). Parent-proxy measures only will be obtained for children aged 5-7; both Parent-proxy and self-report will be obtained from children aged 8+.
2. NIH Toolbox Early Childhood Cognition Battery (for children aged 3-6) and NIH Toolbox Cognition Battery (for children aged 7+). Cognitive tests in the battery are computerized, and can be administered in approximately 15 minutes (for children aged 3-6) and 35 minutes (children aged 7+). Tasks will evaluate domains of cognitive functioning including executive functioning, attention, working memory, processing speed, language, and episodic memory.
QOL measures will be reviewed centrally.
Exploratory Outcome Measures:
1. Identification of BRAF mutation/fusion rate and role in PLGG, including correlation with treatment response and outcome.
2. Identification of prognostically significant genetic alterations in other genes in PLGG.
3. Creation of PLGG classification based on methylation profile.
4. Identification of demographic (e.g., SES, gender), disease (e.g., risk status), treatment, and behavioral predictors of neurocognitive and QOL deficits in children and adolescents with LGG.
5. Identification of the role of vascularity and role of anti-angiogenic targeted therapy in PLGG.
6. Identification of novel MR biomarkers useful in predicting tumor response to therapy and validation it in PLGG population in correlation with traditional imaging tools (MRI/CT). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The end of the study is defined as the date when the last patient, last visit (LPLV) occurs. Hereafter all endpoints will be evaluated. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| (Neuro)cognitive and QOL deficits.Biomarkers.Tumour vascularity. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| New Zealand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
Print
