| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children, adolescents and young adults with refractory or recurrent low-grade gliomas |
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| E.1.1.1 | Medical condition in easily understood language |
| Children, adolescents and young adults with refractory or recurrent low-grade gliomas |
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| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065443 |
| E.1.2 | Term | Malignant glioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038111 |
| E.1.2 | Term | Recurrent cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070308 |
| E.1.2 | Term | Refractory cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
• Phase I part: to define the recommended dose (RD) of nilotinib and vinblastine when used in combination
• Phase II part: to evaluate the efficacy of vinblastine in combination with nilotinib (VINILO) at the RD, as compared to vinblastine alone, in terms of progression-free survival, in children, adolescents, and young adults with refractory or recurrent low grade glioma.
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| E.2.2 | Secondary objectives of the trial |
1.To measure the impact of the VINILO combination compared to vinblastine alone, in terms of response rate (RR), progression-free survival time ratio (PFS2/PFS1-ratio), time-to-treatment failure, overall survival (OS), long-term effects and patient-related outcome
2.To describe and compare, on the whole duration of treatment, the toxicity related to the VINILO combination with that of vinblastine alone
3.To describe the feasibility of the treatment and the compliance
4. To provide pharmacokinetics data on both drugs when given in combination
5. To identify the predictive value of early functional MRI changes
6. To assess the inter-observers agreement of radiologic response assessment
Exploratory:
1.To monitor immunological changes in relationship with treatment
2.To identify biological markers predictive of the response to therapy (tumor, serum and pharmacogenetic biomarkers)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent signed by the patient, or parents or legal representative and assent of the minor child.
2. Age: 6 months to < 21 years of age at time of study entry
3. Histologically confirmed low-grade glioma in non-NF1 patients (no further biopsy is needed at study entry). For patients with NF1, no biopsy is required to confirm the radiological diagnosis of the low grade glioma.
4. Relapse or refractory tumor after at least one first-line therapy, not taking into account surgery only.
5. Evaluable Disease on morphologic MRI
6. Karnofsky performance status score ≥70% for patients >12 years of age, or Lansky score ≥70% for patients ≤12 years of age, including patients with motor paresis due to disease.
7. Life expectancy ≥ 3 months.
8. Adequate organ function:
• Adequate hematopoietic function: neutrophils 1.0 x 109/L, platelets 100 x 109/L; hemoglobin 8 g/dL
• Adequate renal function: serum creatinine < 1.5 x ULN for age
0 – 1 year: ≤ 40 μmol/L
1 – 15 years: ≤ 65 μmol/L
15 – 20 years: ≤ 110 μmol/L
In case serum creatinine >1.5 ULN according to age, creatinine clearance has to be >70 mL/min/1.73 m2 or glomerular filtration rate measurement >70% of the expected value
• Adequate electrolytes levels: potassium, magnesium, phosphor, total calcium ≥ Lower Limit of Normal (LLN)
• Adequate hepatic function: total bilirubin ≤1.5 x ULN; AST and ALT ≤2.5 x ULN.
• Absence of peripheral neuropathy ≥ grade 2 (Common Toxicity Criteria Adverse Event, NCI CTCAE v4.0)
• Adequate cardiac function:
Shortening Fraction (SF) ≥ 28% (35% for children <3 years) and Left Ventricular Ejection Fraction (LVEF) ≥ 50% at baseline, as determined by echocardiography
Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the QTcF formula) or other clinically significant ventricular or atrial arrhythmia
9. Wash-out period of at least
• 3 weeks in case of preliminary chemotherapy,
• 6 weeks in case of nitrosourea-containing chemotherapy,
• 2 weeks in the case of treatment with vincristine only
• 6 weeks in case of radiation therapy
10. Possibility of receiving the therapeutic schedule as indicated in the protocol
11. Patients with reproductive potential must use effective contraception during their treatment and for up to 90 days after the last dose. Females with reproductive potential must have a negative pregnancy test <= 7 days before starting Nilotinib and/or Vinbastine.
12. Patients already treated with one of the two drugs can be enrolled in the trial provided that rechallenging them with the same drug could be considered acceptable
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| E.4 | Principal exclusion criteria |
1. Concomitant anti-tumor treatment
2. Not recovered to <Grade 2 from the acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy
3. Known intolerance or hypersensitivity to Vinblastine
4. Existence of another severe systemic disease
5. Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines,
6. Any concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the patient
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib.
8. Simultaneous treatment with strong cytochromes P450 CYP3A4 inhibitors (e.g. antiepileptic drugs, see complete list in the Appendix 5).
9. Simultaneous treatment with antiarrythmic drugs and other drugs known to prolong QT interval (cloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, cisapride and pimozide). A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (Appendix 6)
10. Impaired cardiac function including any one of the following:
• Clinically significant resting brachycardia (<50 beats per minute).
• QTc > 450 msec on baseline ECG. If QTc >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
• Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension).
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias (including congenital long QT syndrome or a known family history of congenital long QT syndrome)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I part – Safety assessment
Dose-Limiting Toxicity (DLT), assessed over the first 28-day cycle, defined as
• Grade > 3 neutropenia (<1 x 109/L) for more than 7 days;
• Grade > 2 thrombopenia (<75 x 109/L) during a time period of more than 7 days.
• Grade 3 or grade 4 non-hematological toxicity, excluding grade 3 nausea, vomiting, fever, and hepatic toxicity that is rapidly reversible (i.e. returns to < 2.5 x ULN within 2 weeks after study drug discontinuation), and symptoms that are related to tumor progression.
Phase II part – Efficacy assessment
PFS computed as the time interval between the date of study entry and the date of tumor progression or death (whatever the cause of death). The progression will be defined either radiologically (>25% increase in two-dimension measurements or appearance of new lesions compared to the baseline or to the best response after initiation of therapy) or clinically by new symptoms related to tumor progression (significant decrease of visual acuity, new or worsening neurological deficit). Hydrocephaly is not considered as progression per se.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For phase I: assessed over the first 28-day cycle
For phase II: PFS computed as the time interval between the date of study entry and the date of tumor progression or death (whatever the cause of death). |
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| E.5.2 | Secondary end point(s) |
1) Safety monitoring during the treatment
Clinical and laboratory toxicities / symptoms will be graded according to NCI-CTCAE v4.0 over the whole treatment duration. The adverse events which are not reported in the NCI-CTC will be graded as mild, moderate, severe, and life-threatening. In particular, cardiac function will be monitored with echocardiography and ECG.
2) Efficacy criteria
Tumor response will be based on two-dimension measurement and to RANO Criteria (van den Bent, Lancet Oncol 2011). The radiological imaging will be reanalyzed after the study by a radiologist panel, according to the RANO criteria and to the newly defined RAPNO Criteria, once they will be available.
All tumor reduction >25% (CR or PR or MR) will be considered as success. Morphologic MRI will be performed every 3 months prior to the new cycle, apart from the week 4 early evaluations in case functional MRI is performed. Primary objective of the study is PFS and thus objective response does not need to be confirmed at 4 to 6 weeks. Baseline MRI and that related to the best response will be centrally reviewed by an independent international radiology panel.
Growth modulation index or progression-free survival time ratio (PFS2/PFS1-ratio), defined as the ratio of a patient’s progression-free survival time from start of study treatment (VINILO or Vinblastine alone), PFS2, relative to the progression-free survival time observed from the patient’s most recent prior anticancer treatment, PFS1, which serves as the patient-specific historical control value.
Time-to-treatment failure, defined as the time from date of study entry to the first date among death from any cause, PD, or study treatment discontinuation due to any reason other than “protocol complete”. For patients who discontinue due to protocol complete, or for patient not known to have discontinued as of the data cut-off date, TtTF will be censored at the last contact date.
Overall survival
3) Dose intensity of each drug administered computed on the whole treatment duration and per month.
4) Pharmacokinetics dosage of both drugs (for all patients recruited in the phase I and in 20 patients of each arm of the phase II part)
5) Functional MRI (perfusion sequence). This dynamic imaging technique will be performed with contrast after 1 month and 3 months of treatment and compared to that performed at study entry. This evaluation will be performed in selected centers .
6) Tumor biomarkers will be studied on paraffin tumor samples (histological subtype, vascular density with monoclonal antibody anti-CD105/endoglin, proliferation index MIB1, immunohistochemical expression of c-kit, PDGFR alpha and beta, and basic protein of myelin or MBP, telomeres length using Q-FISH technique, BRAF status).
7) Pharmacogenetic biomarker (enzyme polymorphism)
8) Immunological monitoring (according to section 1.10)
9) Long-term follow-up: height, weight, pubertal growth, cardiac function, health status, and reporting health-related quality of life measured by HUI Mark 3. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| over the whole study duration |
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| 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 | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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