E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Phase I part: pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma)
Phase II part: pediatric and adult patients with recurrent or refractory medulloblastoma |
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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 | 10039027 |
E.1.2 | Term | Rhabdomyosarcoma recurrent |
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 | 10031296 |
E.1.2 | Term | Osteosarcoma recurrent |
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 | 10019823 |
E.1.2 | Term | Hepatoblastoma recurrent |
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 | 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 | 10066595 |
E.1.2 | Term | Neuroblastoma recurrent |
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 | 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 |
Phase I part: To determine the MTD or recommended phase II dose of LDE225 in children with advanced solid tumors (recurrent or refractory MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma) when administered on a continuous daily dosing schedule.
Phase II part: To assess preliminary efficacy of LDE225, as determined by ORR in recurrent or refractory MB patients (adult and pediatric combined) regardless of Hh pathway status (activated or non-activated). |
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E.2.2 | Secondary objectives of the trial |
Phase I part:
• To characterize the safety and tolerability of LDE225 in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
• To characterize the PK profile of LDE225 in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
• To assess any preliminary antitumor activity of LDE225 in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
• To assess the Hh gene expression signature in children with advanced solid tumors that are potentially dependent on the Hh signaling pathway.
Phase II part:
• To assess ORR, as a function of Hh status in recurrent or refractory MB patients,
• To assess the DoR as a function of Hh status in recurrent or refractory MB patients,
• To further characterize the safety and tolerability of LDE225 in recurrent or refractory MB patients,
• To further assess the PK of LDE225 in recurrent or refractory MB patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Phase I:
- Patients aged ≥ 12 months and < 18 years
- Histologically confirmed diagnosis of MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma that has progressed despite treatment with standard therapies, or for which no standard treatments are available (patients with brainstem gliomas are excluded from this study)
- Adequate renal function
- Adequate liver function
- Adequate bone marrow function
- Women of child-bearing potential must be using two forms of highly effective methods of contraception throughout the study and for 6 months after the last study treatment.
- Sexually active males must use a condom during intercourse while taking LDE225 and for 6 months after stopping LDE225 treatment
Phase II:
- Patients aged ≥ 12 months
- Histologically confirmed diagnosis of recurrent or refractory MB,
- At least one measureable lesion
- Adequate renal function
- Adequate liver function
- Adequate bone marrow function
- Women of child-bearing potential must be using two forms of highly effective methods of contraception throughout the study and for 6 months after the last study treatment.
- Sexually active males must use a condom during intercourse while taking LDE225 and for 6 months after stopping LDE225 treatment
Other protocol defined inclusion criteria may apply.
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E.4 | Principal exclusion criteria |
- Systemic anticancer treatment within 2 weeks before first dose of study
- Focal radiation therapy within 4 weeks before first dose of study treatment, or full spinal radiotherapy within 3 months of first dose of study treatment.
- Investigational agents within 2 weeks or ≤ 5 x t1/2 (whichever is longer) before start of study therapy.
- Unresolved toxicity greater than CTCAE grade 1 from previous anticancer therapy or radiation therapy, or incomplete recovery from previous surgeryPatients 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
- Major surgery, serious illness, or traumatic injury within 2 weeks of starting study therapy. Patients anticipated to require major surgery within the first 2 cycles of treatment.
- Patients who require a nasogastric tube for drug administration
- 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.
- Patients who have neuromuscular disorders that are associated with elevated CK
- Impaired cardiac function or clinically significant heart disease,
- Pregnant or nursing (lactating) females.
- Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or C
- Impairment of GI function or GI disease
- Patients on concomitant treatment with drugs that are recognized to cause rhabdomyolysis,
- Patients who are planning on embarking on a new strenuous exercise regimen after initiation 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) |
Phase I part:
- Frequency of dose-limiting toxicities (DLTs) associated with daily administration of LDE225
Phase II part:
- ORR defined as the proportion of patients with PR or CR. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I part:
- continuously
Phase II part:
- efficacy assessed every 8 weeks |
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E.5.2 | Secondary end point(s) |
Phase I part:
- Frequency of AEs and SAEs; changes in laboratory values, assessment of physical examinations, vital signs, electrocardiograms, and X-rays of the knee and wrist
- Plasma PK parameters
- Objective response rate (ORR)
- Frequency of Hh pathway gene mutations and expression of Hh target genes in tumor tissue
Phase II part:
- ORR
- DoR
- Frequency of AEs and SAEs; changes in laboratory values, assessment of physical examinations, vital signs, ECGs
- Plasma trough concentrations
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety:
- Continuously
Efficacy
- Every 8 weeks
Others
- As per table 7.1 (Visit evaluation schedule ) of protocol |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
to define the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) |
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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 | Yes |
E.7.1.3.1 | Other trial type description |
To determine the MTD and preliminary efficacy of LDE225 in children and adults with MB |
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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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
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
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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 | 2 |
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 | 2 |
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 |