| 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 | 21.1 |
| 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 | 20.0 |
| 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 | 21.1 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 and in NF1 patients with low grade glioma at diagnosis.
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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 tumor response, functionnal status (visual acuity…), progression-free survival time ratio (PFS2/PFS1-ratio), and overall survival (OS)
2. To describe and compare, on the whole duration of treatment, the acute toxicity related to the VINILO combination with that of vinblastine alone; and to compare the long-term effects of both regimens
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
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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 where appropriate
2. Age: 6 months to < 21 years of age at time of study entry
3. Diagnosis: one of the three conditions listed below
-Refractory or recurrent low-grade glioma after at least one first-line therapy with pathological documentation in non NF1 patients (no further biopsy is needed at study entry)
-Refractory or recurrent low-grade glioma after at least one first-line therapy in NF1 patients, with or without pathological documentation. For patients with NF1 and optic pathway glioma, no biopsy is required to confirm the radiological diagnosis of the low grade glioma.
-Low grade glioma at diagnosis in NF1 patients when the use of chemotherapy is considered for the treatment in case of threat to vision or unequivocal radiological tumor progression. Pathological documentation is advised but not mandatory.
4. Evaluable Disease on morphologic MRI
5. 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.
6. Life expectancy ≥ 3 months.
7. Administration of stable dose of steroids for at least one week
8.Adequate organ function
9. Adequate cardiac function:
10. 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
11. Possibility of receiving the therapeutic schedule as indicated in the protocol
12. Patients with reproductive potential must use effective /acceptable birth method control (as defined per CTFG guidelines) during their treatment and for up to 90 days after the last dose. F
13. 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)
11. Positive rest for Hepatitis B virus surface antigen
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 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
2) Efficacy criteria
Tumor response will be based on two-dimension measurement and to RANO Criteria. All tumor reduction >25% (CR or PR or MR) will be considered as success.
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.
Modification of functionnal status. In particular, for optic pathway glioma, quantitative assessment of visual acuity and qualitative changes in visual field will be assessed.
Overall survival computed from the date of study entry to the date of death, from any cause.
3) Dose intensity of each drug computed on the whole treatment duration and per month. Duration of treatment and reasons for the end of treatment.
4) Pharmacokinetics dosage of both drugs (for 30 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 of treatment
6) Tumor biomarkers will be studied on paraffin tumor samples
7) Pharmacogenetic biomarker (enzyme polymorphism)
8) Long-term follow-up: height, weight, pubertal growth, phospho-calcic evaluation and cardiac function |
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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 | Yes |
| 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 | No |
| 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 | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | 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
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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