E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study will evaluate the antitumor activity of RAD001 versus placebo in patients with subependymal giant cell astrocytomas (SEGA) associated with Tuberous Sclerosis Complex (TSC). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060971 |
E.1.2 | Term | Astrocytoma malignant |
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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 |
To compare the SEGA response rate in patients with TSC-associated SEGA on RAD001 versus placebo. |
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E.2.2 | Secondary objectives of the trial |
To compare RAD001 versus placebo with respect to: 1. Change from baseline in frequency of epileptiform events. 2. Time to SEGA progression. 3. Skin lesion response rate. 4. Change from baseline in plasma angiogenic molecules, e.g. VEGF, basic FGF, PLGF, soluble VEGF receptor1, and soluble VEGF receptor2. 5. Renal function assessed using calculated creatinine clearance. 6. Safety as assessed by the NCI Common Toxicity Criteria, version 3.0. In RAD001 treatment arm to : 7. Characterize the pharmacokinetics of RAD001 in this patient population, specifically in terms of exposure. 8. Describe the duration of SEGA response, the time to SEGA response and the duration of skin lesion response. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female of any age. 2. Clinically definite diagnosis of tuberous sclerosis according to the modified Gomez criteria (Roach et al, 1998; Hyman and Whittemore, 2000, Table 5-1). Clinically definite diagnosis is defined as either of the following: a. Two Major Features from Table 5-1. b. One Major Feature plus two Minor Features from Table 5-1. 3. Presence of at least one SEGA lesion ≥ 1.0 cm in its longest diameter using MRI. Note: SEGA lesions are only diagnosed in patients with TSC. They arise in the subependymal layer of the lateral ventricle and are always located near the foramen of Monro and enhance homogeneously with contrast on MRI with no evidence of surrounding edema. 4. A recent MRI of the brain completed within 3 weeks (21 days) prior to the patients randomization must be compared with an MRI of the brain performed at an earlier stage of patient care (pre-baseline) and should demonstrate at least one of the following: a. Serial growth, defined as at least a 25% increase in SEGA volume, or b. Presence of a new SEGA lesion ≥ 1 cm in its longest diameter, or c. New or worsening hydrocephalus defined by assessment of ventricular configuration changes, ventricular cap signs (periventricular edema) and qualitative assessment of CSF flow dynamics. Notes: If a previous MRI is not available, a comparative review of two previous CT scans is also acceptable to establish any of the above mentioned three conditions. In this case, baseline/screening MRI should still be performed. If only one prior CT scan was available, a second CT scan should be obtained to allow like to like comparison of cranial images. Again, the baseline MRI should still be performed. CT scans should be digitized and sent to the central reviewer for confirmation of eligibility. If the pre-baseline MRI or CT was only available on film (non-digital format) or software for volumetric assessment was not available at the local site, the local radiologist should make a qualitative assessment of the above-mentioned three criteria. The non-digital MRI or CT must also be sent to Central Radiology for review. 5. If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study. 6. Written informed consent. Parents or legal guardians must sign the informed consent for patients under 18 years old and for patients with developmental delays. In addition, all minors aged 7 through 14 must sign an assent form, while minors aged 15 up to 17 must sign an assent line on the Informed Consent Form that will be signed by the parents or the legal guardians. |
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E.4 | Principal exclusion criteria |
1. Patients for whom SEGA related surgery is likely to be required, in the opinion of the investigator. 2. Prior brain surgery. 3. History of myocardial infarction, angina or stroke related to atherosclerosis 4. Impaired lung function, defined as any of the following: a. FEV1 &#8804; 70% of predicted, or b. DLCO &#8804; 70% of predicted, or c. &#8804; 88% O2 saturation at rest in room air, or d. for patients unable to perform pulmonary function testing: i. clinical evidence of significantly impaired lung function, or ii. radiological evidence of significant lung disease other than LAM Note: Patients unable to perform a pulmonary function test (e.g. younger children, patients with developmental delay) will have a baseline chest CT scan performed 5. Significant hematological or hepatic abnormality (i.e. transaminase levels > 2.5 x ULN or serum bilirubin > 1.5 x ULN, hemoglobin < 9 g/dL, platelets < 80,000/ mm3, absolute neutrophil count < 1,000/mm3). 6. Pregnancy or breast feeding. 7. Intercurrent infection at date of randomization. 8. Prior history of organ transplant. 9. Recent surgery (involving entry into a body cavity or requiring sutures) within the 2 months prior to randomization. 10. Prior therapy with mTOR inhibitors (e.g.sirolimus, temsirolimus, everolimus). 11. Use of an investigational drug within the 30 days prior to randomization. 12. Uncontrolled hyperlipidemia: Fasting serum cholesterol > 300 mg/dL OR > 7.75 mmol/L AND Fasting triglycerides > 2.5 x ULN. 13. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN. 14. Patients with bleeding diathesis or on oral anti-vitamin K medication (except low dose warfarin). 15. Patients with known history of HIV seropositivity. 16. Inability to attend scheduled clinic visits. 17. For the purpose of MRI assessments: a. Ferromagnetic metal implants (e.g., braces, some types of aneurysm clips, shrapnel) unless approved as safe for use in MR scanner b. Patients suffering from uncontrollable claustrophobia or physically unable to fit into the machine (e.g., obesity, etc). 18. Serum creatinine > 1.5 x ULN. 19. History of malignancy in the past two years, other than squamous or basal cell skin cancer. 20. Use of estrogen containing medications. |
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E.5 End points |
E.5.1 | Primary end point(s) |
SEGA response rate is determined from the Independent Central Radiological Review of MRIs. SEGA response rate is defined as the proportion of patients with a reduction in SEGA volume of at least 50% relative to baseline, where SEGA volume is the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan at least 4 weeks later. In addition, response requires that: the non-target SEGA lesions have not unequivocally worsened no new SEGA lesions (of &#8805;1cm) are identified there is no new or worsening hydrocephalus, defined by central radiological assessment of ventricular configuration changes, ventricular cap signs (periventricular edema) and quantitative assessment of CSF flow dynamics. SEGA response rate will be determined in the Full Analysis Set (FAS), defined as all randomized patients analyzed according to the treatment they were assigned to at randomization. |
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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 | 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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 6 |
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 | Information not present in EudraCT |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
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 |