CRAD001O2301

Novartis Pharma AG

CH-4002, Basel, Switzerland,

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, trialandresults.registries@novartis.com

Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, trialandresults.registries@novartis.com

No

No

No

Final

15 Oct 2013

No

Yes

15 Oct 2013

No

The primary objective was to compare overall survival between the combination treatment of everolimus plus best supportive care (BSC) to placebo plus BSC in patients with advanced hepatocellular carcinoma (HCC) whose disease had progressed while on or after sorafenib treatment or who were intolerant to sorafenib.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

28 Apr 2010

No

Yes

Australia: 16

Austria: 13

Belgium: 19

Canada: 12

China: 13

France: 113

Germany: 57

Greece: 7

Hong Kong: 9

Hungary: 7

Israel: 2

Italy: 56

Japan: 82

Korea, Republic of: 32

Spain: 13

Taiwan: 26

Thailand: 11

United States: 58

546

285

0

0

0

0

0

0

248

298

0

Overall Study (overall period)

Randomised - controlled

Yes

Everolimus

RAD001

Tablet

Oral use

Everolimus (daily oral dose of 7.5 mg) was formulated as tablets of 2.5 mg strength and blister-packed in units of 10 tablets

Matching Placebo

Tablet

Oral use

Matching placebo (daily oral dose of 7.5 mg) to the everolimus 2.5 mg tablet strength was blister-packed in units of 10 tablets

Everolimus + Best Supportive Care (BSC)

Placebo + Best Supportive Care

Everolimus + Best Supportive Care (BSC)

Placebo + Best Supportive Care

Everolimus 5mg + Best Supportive Care (BSC)

Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed.

Everolimus 7.5mg + Best Supportive Care (BSC)

Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.

Everolimus 5mg + Best Supportive Care (BSC)

Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed.

Everolimus 7.5mg + Best Supportive Care (BSC)

Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.

OS was defined as the time from the date of randomization to the date of death from any cause. The comparison of OS between the 2 arms was done using a stratified log-rank test at one-sided 2.5% level of significance.

Primary

When 454 OS events were observed

using Kaplan-Meier method and Cox PH model

Placebo + Best Supportive Care v Everolimus + Best Supportive Care (BSC)

546

Pre-specified

TTP was defined as the time from the date of randomization to the date of the first documented radiologic confirmation of disease progression. Since the study did not meet the primary objective, TTP was not formally tested.

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

DCR is defined as the proportion of participants with a best objective response (BOR) of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST. The BOR was the best response recorded from the start of the treatment until disease progression. CR is disappearance of all target lesions; PR is at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD is at least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient

Change in Eastern Cooperative Oncology Group (ECOG) were assessed by time to definitive performance status deterioration by at least one category on the ECOG scale. Deterioration was considered definitive if no improvement in the ECOG PS was observed at a subsequent measurement. ECOG PS: 0=Fully active, able to carry on all pre-disease performance without restriction, 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2=Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5=Dead

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

The primary quality of life endpoint was the time to definitive 5% deterioration from baseline in the global health status/quality of life scale of the EORTC QLQ-C30 questionnaire. Definitive deterioration by at least 5% is defined as a decrease in score by at least 5% compared to baseline, with no later observed increase above this threshold. The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the healthrelated quality of life (QoL) of cancer patients participating in international clinical trials. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

Cmin is the pre-dose blood concentration at steady-state (ng/mL). Pre-dose (Cmin) blood samples were collected from all patients in both arms at Visit 3. Steady-state for the Cmin sample was defined as continuous administration of the same dose in the last 4 days prior to the collection of the Cmin sample. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid pre-dose (Cmin) everolimus samples were included in the analysis.

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.

Cmax is the maximum (peak) blood drug concentration after dose administration (ng/mL) calculated as the maximum of C1h and C2h. C1h was 1 hour post-dose blood concentration (ng/mL) and C2h was 2 hour post-dose blood concentration (ng/mL). C1h and C2h post-dose samples were collected from all patients in both arms at Visit 3. Steady-state for the C1h and C2h samples was defined as continuous administration of the same dose in the previous 4 days and the day on which the C1h and C2h samples were collected. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid C1h and C2h everolimus samples were included in the analysis.

Secondary

Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

16.1

Everolimus 7.5mg/d

Placebo