E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed medulloblastoma characterised by Hedgehog (Hh)-pathway activation |
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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 | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066594 |
E.1.2 | Term | Medulloblastoma recurrent |
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 |
To assess efficacy of LDE225 with respect to the Overall Response Rate (ORR) according to independent central review (ICR) |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy of LDE225 with respect to:
- ORR according to local investigator assessment
- Progression free survival (PFS) according to both ICR and local investigator assessment
- Duration of response (DoR) according to both ICR and local investigator assessment
- Overall survival (OS)
To further characterize the safety and tolerability of LDE225 treatment
To further characterize the pharmacokinetics of LDE225 and any relevant metabolites
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients aged >= 4 months
- Patients with histologically confirmed diagnosis of MB, who have experienced relapse or progression
- Only patients with a test result, using the 5-gene Hh signature assay, indicating Hh-pathway activated MB are eligible for this study.
- At least one measurable lesion
- Adequate renal function
- Adequate liver function
- Adequate bone marrow function
- Serum CK <= 1.5 ULN
Other protocol defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
- Prior treatment with a Smoothened inhibitor
- Systemic anticancer treatment within 2 weeks before first dose of study treatment
- Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months before first dose of study treatment.
- Patients who have neuromuscular disorders that are associated with elevated CK
- Any concurrent severe and/or uncontrolled medical conditions that in the investigator’s opinion could put the patient at greater risk for treatment-related toxicities or confound the interpretation of clinical outcomes.
- Impaired cardiac function
- Clinically significant heart disease
- Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C
- Impairment of GI function or GI disease
- Major surgery, serious illness, or traumatic injury within 2 weeks of first dose of study treatment.
- Unresolved toxicity greater than CTCAE grade 1 from previous anticancer therapy
- Patients anticipated to require major surgery within the first 8 weeks of treatment
- Patients who require a nasogastric tube for drug administration
- Patients on concomitant treatment with drugs that are recognized to cause rhabdomyolysis
- Patients receiving treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5 or are metabolized by CYP2B6 and CYP2C9.
- Patients receiving unstable or increasing doses of corticosteroids
- Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 2 weeks before first dose of study treatment, and for the duration of the study
- Investigational agents within 4 weeks or ≤ 5 x t1/2 (whichever is longer) before first dose of study treatment.
- Pregnant females.
- Patients who are not willing to apply highly effective contraception.
- Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment.
Other protocol defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- PFS (progression free survival)
- DoR (duration of response)
- OS (overall survival)
- Adverse and serious adverse events, clinically significant changes in hematology and chemistry values, assessment of physical and/or neurological examinations, vital signs, electrocardiograms, bone x-rays, dental x-rays, and dental exams (as appropriate for age)
- PK (Cmin)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As defined in table 7-1 of the protocol.
Adverse events: continuously.
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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 | Yes |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 |
Belgium |
Brazil |
Canada |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Russian Federation |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
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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
|
Last patient last visit (LPLV) |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |