| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Glioblastoma Multiforme
For Pediatric - Hign Grade Glioma and DIPG |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent Glioblastoma, a rare and aggressive type of brain tumor. |
|
| 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 | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Overall Survival and Progression Free survival according to RANO criteria and assessed at interim analysis.
Pediatric sub-study - The primary objectives will be the evaluation of safety, tolerability and pharmacokinetics of ABT-414 in a pediatric population < 18 years of age. |
|
| E.2.2 | Secondary objectives of the trial |
Progression Free Survival according to RANO criteria, Objective Response Rate, Overall Survival in the subgroup with EGFRvIII mutation.
Pediatric sub-study - The secondary objective will be to assess the effect of ABT-414 on tumor response per RANO (Response Assessment in
Neuro-Oncology) criteria.
|
|
| 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 |
There is a pharmacogenetic sub-study where the samples will be stored at AbbVie.
There is also an optional translational and genetic sub-study where the samples will be biobanked with EORTC.
There is a paediatric sub-study in patients with high grade gliomas. |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed de novo (primary) GBM with unequivocal tumor progression or recurrence.
2. In case of testing at the time of first progression: either at least 3 months after the end of radiotherapy or have tumor progression that is clearly outside the radiation field or have tumor progression unequivocally proven by surgery/biopsy
3. Age ≥ 18 years
4. Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; such conditions should be assessed with the patient before registration in the trial.
5. Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE] tumor) for central testing of EGFR amplification
6. Presence of EGFR amplification confirmed by central assessment; patients with undetermined EGFR status are excluded
7. WHO Performance status 0 - 2
8. No more than one line of chemotherapy for GBM (concurrent and adjuvant TMZ based chemotherapy including in combination with another investigational agent is considered one line of chemotherapy). Chemotherapy must have been completed at least 4 weeks prior to randomization.
Pediatric sub-study:
• Subject must either have recurrent/progressive tumor or, if newly diagnosed, have completed radiation therapy at least 4 weeks prior to first dose of ABT-414.
• The investigator must confirm that the subject is able to complete the procedures required in order to assess the primary endpoints, including PK blood draws and safety assessments over the first four weeks of therapy including Day 1 of Week 5.
• The investigator believes that the potential benefit of treating the pediatric subject with ABT-414 outweighs the expected risks and that this treatment is in the best interests of the pediatric subject.
• Subjects and/or their legal guardians must be able to understand the risks and potential benefits, and grant assent/consent to participate by signing the applicable pediatric-specific informed assent and/or consent forms.
• Subject has sufficiently recovered from previous therapy.
• (For recurrent disease) No prior RT with a dose over 65Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
• No current or recent (within 4 weeks or 5 half-lives (whichever is shorter) before enrollment) treatment with another investigational drug
• Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula for pediatric patients ≥12 years of age and estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 by modified Schwartz equation for pediatric patients < 12 years of age
• Liver function: Total bilirubin ≤ 1.5 times upper limit of normal (ULN), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) ≤ 3 times ULN. Subjects with Gilbert's syndrome documented in medical history may be enrolled if total bilirubin is < 3 times ULN. Not allowed are subjects with known chronic liver disease and/or cirrhosis documented by the presence of one or more of the following (assessments to be performed per standard of care only if liver disease is suspected):
- Liver biopsy with histologic findings consistent with cirrhosis
- CT or US evidence of liver disease with or without portal hypertension
- Physical examination and clinical and laboratory evidence of chronic liver disease
- Colloid shift on a liver-spleen scan
- A Child-Pugh score of 6 or higher
• Female subjects of childbearing potential must have a negative Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent Units of HCG) within 72 hours prior to enrollment.
• Male subjects that are sexually active with female partner(s) of childbearing potential must agree to use an effective method of contraception from Study Day 1, during the treatment period and for at least 6 months after the last study treatment.
|
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with nitrosoureas
2. Prior treatment with bevacizumab
3. Previous exposure to EGFR targeted agents, including EGFRvIII targeting agents
4. Prior discontinuation of temozolomide chemotherapy for toxicity reasons
5. Prior RT with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven
6. Previous other malignancies, except for any previous malignancy which was treated with curative intent more than 5 years prior to randomization, and except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix
7. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall Survival and Progression Free survival according to RANO criteria and assessed at interim analysis.
Pediatric sub-study - Safety including toxicities according to CTCAE criteria (Percentage of subjects with adverse events from subject's first visit until 49 days after the subject's last dose of study drug) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival at final analysis and Progression Free Survival at interim futility analysis after observation of 45 PFS events. |
|
| E.5.2 | Secondary end point(s) |
• Progression Free Survival
• Overall Response Rate (ORR)
• Overall Survival in the subgroup with Epithelial Growth Factor Receptor (EGFRvIII) mutation.
Pediatric sub-study
- Objective response rate, best response rate, and duration of Response based on RANO criteria
- Overall survival, Time to Progression, and Time to progression-free survival
- Changes in neurological status and functioning (including PedsQL cancer module)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Progression Free Survival as assessed by RANO from date of randomization to date of first objective progression (or death).
• The overall response rate will be evaluated at each assessment of disease according to RANO criteria.
• Subgroup with EGFR vIII mutation will be measured up to 28 months (study length), until death, or lost to follow up.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
|
| 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| 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
|
| Subjects will be followed until death or lost to follow up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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