RAD001

Comparison of response rates in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. Response means at least a 50% reduction from baseline in partial-onset seizure frequency during the maintenance period of the core phase.

Comparison of median percent change from baseline in weekly seizure frequency in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase. Percentage change from baseline in average weekly seizure frequency during the maintenance period of the Core phase (SFcfb) = 100 × (SFB - SFM) ÷ SFB where: SFB is the average weekly seizure frequency in the Baseline phase SFM is the average weekly seizure frequency in the maintenance period of the Core phase A positive percentage change from baseline (SFcfb) means a reduction in seizure frequency whereas a negative percentage change from baseline (SFcfb) means an increase in seizure frequency.

To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.

To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).

Progression Free survival is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary statistical analysis of PFS was based on central radiological assessments using a one-sided stratified log-rank test. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study. Kaplan-Meier methodology was used to estimate the median PFS for each treatment group.

Evaluation of the safety of RAD001 compared with placebo in patients with TSC focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.

Baseline and 6 month Timepoint scores are reported for the following primary outcome measures: 1. Peabody Picture Vocabulary Test 4 (PPVT-4; Receptive Language Measure). Scores reported as (mean, SD). Range=40-160, higher scores are better. 2. Expressive Vocabulary Test 2 (EVT-2; Expressive Language Measure). Scores reported as (mean, SD). Range=40-160, higher scores are better. 3. Wide Range Assessment of Memory and Learning 2 (WRAML2; Measure of Verbal Memory and Attention ). Scores reported as (mean, SD). Range=1-19, higher scores are better. 4. Vineland Adaptive Behavior Scales-II (VABS-II; Measure of Adaptive Behavior). Scores reported as (mean, SD). Range = 40-160, higher scores are better. 5. Purdue Pegboard Test (Measure of Fine Motor Speed and Coordination). Scores reported as (mean, SD). Range = 40-160, higher scores are better.

Scores are reported for baseline and 6 month timepoints on the Cambridge Neuropsychological Test Automated Battery (CANTAB) subscales below. For all subscales, scores are reported as the mean difference between the study subjects and a normative population matched for age, gender and IQ (e.g., subject subscale score - mean of matched normative group = reported score). Higher scores represent a better outcome. 1. Spatial Span (SSP) (spatial memory span) Range: -3 to 3 2. Spatial Working Memory (working memory) Range: -3 to 3 3. Pattern Recognition Memory (PRM) (visual pattern recognition memory) Range: -3 to 3 4. Spatial Recognition Memory (SRM) (spatial recognition memory) Range: -4 to 4 5. Rapid Visual Information Processing (RVIP) (sustained attention) Range: -4 to 4 6. Stockings of Cambridge (SOC) (spatial planning) Range: -4 to 4 7. Intra-Extra Dimensional Set Shift (IDED) (cognitive flexibility) Range: -5 to 5 8. Reaction Time (processing speed) Range: -5 to 5

Clinical benefit rate is defined as the number of patients with complete response (CR), partial response (PR), or stable disease (SD) that lasts at least 6 months. Response was assessed every 2 cycles of treatment (6 weeks) by computed tomography (CT), CT/positron emission tomography (PET), or magnetic resonance imaging (MRI). Overall response evaluation is based on Response Evaluation Criteria In Solid Tumors 1.0 (RECIST 1.0). Per RECIST 1.0 for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Reported as percentage of patients who experienced grade 3 and higher hematological adverse events (AEs) related to the study drugs.

Reported as percentage of patients who experienced grade 3 and higher non-hematological AEs related to the study drugs.

Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free.

PFS during second-line treatment was defined as the time from the date of enrollment to the date of the first documented disease progression or death due to any cause. The primary analysis of PFS was based on a local radiology review of CT scans and MRI collected until the participant experienced disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.

PFSR at 6 months based on central review

Tumor response and disease progression were assessed using response evaluation criteria in solid tumors (RECIST), version 1.0. All target and non-target lesions identified at baseline were assessed using the same method, CT scan with contrast or MRI with contrast, throughout the trial. All scans were reviewed by independent, central radiology. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.

This phase 1 clinical trial used a standard 3 + 3 design. Four dose levels of everolimus were planned to be evaluated, and the standard 3 + 3 design with dose de-escalation was used in the trial. Namely, 3 patients were assigned to starting dose level 1. If no dose-limiting toxicity (DLT) was observed, the trial proceeded to the next dose level, and another cohort of 3 patients was enrolled. If at least 2 of the 3 patients experienced at least 1 DLT, then the dose level decreased; otherwise, if only 1 patient experienced DLT, then 3 more patients were enrolled at the same dose level. If none of the 3 additional patients experienced DLT, the dose was escalated; otherwise, the dose level decreased. Dose reduction continued until a dose level was reached at which 6 patients had been treated and at most 1 DLT was observed.

A dose limiting toxicity was defined as an adverse event or laboratory abnormality that occurs to patients on the Phase I portion of the trial, during the first 21 days following the first dose of RAD001/docetaxel during cycle 1, judged to be related to RAD001/docetaxel and meeting any of the following criteria: Hematologic Toxicity: CTCAE grade 4 neutropenia \> 7 days or any Grade 3 or 4 neutropenia with fever Or CTCAE grade 3 or 4 thrombocytopenia \> 7 days Non-hematologic toxicity: The occurrence of non-hematologic CTCAE grade 3 or 4 adverse events will be considered dose limiting, except for the following: 1. CTCAE grade 3 nausea or grade 3 or 4 vomiting CTCAE grade 3 or 4 vomiting will only be considered dose limiting if it occurs despite the use of standard anti-emetics. 2. CTCAE grade 3 or 4 fever identified with a source (i.e. infection, tumor) 3. CTCAE grade 3 or 4 alkaline phosphatase.

Assessed safety and tolerability of the combination administration of RAD001 and imatinib when given to patients with imatinib-refractory gastro-intestinal stromal tumors (GIST) by number of participants with adverse events.

Assessed clinical efficacy of the combination regimen in this patient population per BOR by Overall response (CR + PR). Complete response: Disappearance of all target lesions; Partial response: ≥ 30% decrease in the sum of the longest diameter of target lesions compared to baseline (and not ≥20% increase compared to smallest sum).

Assessed the pharmacokinetics (PK) of the combination administration of RAD001 and imatinib in this patient population.

Assessed clinical efficacy of the combination regimen in this patient population per Overall Survival (OS). Overall survival was defined as the time from date of start of treatment to date of death due to any cause. For patients still receiving study medication at the time of the analysis, survival was censored at the date of last examination. If a patient was not known to have died but was no longer continuing with study medication, survival was censored at the date of last contact.

Assessed clinical efficacy of the combination regimen in this patient population per Progression-free survival (PFS). Progression-free survival (PFS) was the time from date of start of treatment to the date of first documented progression or death due to any cause. Per protocol (PP) population includes patients with no known overall lesion response during 4 months +/- 2 weeks, or who later had response of CR/PR/stable disease (SD). PP population excludes patients with no known response during 4 months + / -2 weeks and no subsequent CR/PR/SD.

Assessed clinical efficacy of the combination regimen in this patient population per Progression-free survival (PFS). Progression-free survival (PFS) was the time from date of start of treatment to the date of first documented progression or death due to any cause. If a patient had not progressed or died, progression-free survival was censored at the time of last adequate tumor assessment. According to the study protocol no tumor assessments were performed after discontinuation of treatment with study drug. Therefore, for all patients who discontinued treatment without a documented progression but died thereafter, death was considered as PFS event only if it occurred within the regular safety follow-up of 28 days after discontinuation. Otherwise, the PFS time was censored at the last adequate tumor assessment.