CRAD001LDE36T

iOMEDICO AG

Hanferstr. 28, Freiburg, Germany, 79108

iOMEDICO AG, iOMEDICO AG, 0049 076115242-0, info@iomedico.com

iOMEDICO AG, iOMEDICO AG, 0049 076115242-0, info@iomedico.com

No

No

No

Final

12 Mar 2018

Yes

26 Sep 2017

Yes

26 Sep 2017

Yes

The primary objective of the study is to assess the rate of patients who are free of disease progression after 6 months of treatment with everolimus.

The informed consent form (ICF) of patient was obtained in accordance with a) §40 I 3 No. Lit. b) II 1 AMG and §40 I 3 No. 3 Lit. c) IIa 1&2 AMG by the investigator prior to inclusion of each patient into the study. The nature, objective and consequences of the study, the possible benefits and disadvantages or risks, and the study procedures were explained to each patient orally and in writing. The patients were informed that their participation was voluntary, that they were free to withdraw from the study at any time, and that choosing not to participate would not impact the patient’s care or future treatment. The patients were also informed that, by signing the ICF, they explicitly permitted authorized representatives of the sponsor and the regulatory authorities to access study-related personal data to the extent permitted by the applicable law(s) and/or regulations without violating the confidentiality of the patient to the extent permitted by the applicable law(s) and/or regulations. The patients were also informed that their consent to access their data might not be revoked. Each patient was given sufficient time to read and discuss the ICF with the investigator prior to giving his/her written consent. Before entry to the study and prior to the conduct of any study-related procedure consent was recorded by means of the patient’s dated signature. The patient was then given a copy of the information sheet and his/her signed consent form. Only eligbile patients were included into this study. Safety assessments consisted of monitoring and recording of (serious) adverse events until 30 days after the end of treatment and regular monitoring of hematology, blood chemistry, vital signs and physical condition during treatment phase. Dose adjustments were permitted for patients who did not tolerate dosing as per protocol.

21 Mar 2011

Yes

Yes

Germany: 63

63

63

0

0

0

0

0

0

31

32

0

Overall trial (overall period)

Not applicable

not applicable

Everolimus

RAD-001

Afinitor (R)

Tablet

Oral use

Everolimus, the study drug, was used as commercially available, formulated tablets of 10 mg strength, and 2.5 mg and 5 mg strength for dose modifications, respectively. The study drug was available on prescription by the treating physician.

Overall trial (overall period)

Per-Protocol Population (PP)

The Per Protocol (PP) population consists of all patients of the FAS • without any major protocol deviations (failure of any inclusion / exclusion criteria, no tumor assessment until day 182) • who have completed the minimum exposure requirement of having a relative dose intensity over the first 2 cycles of treatment of at least 50%. However, if a patient progressed, discontinued for adverse event or died before the minimum exposure requirement could be met, or before he/she could become evaluable for efficacy, that patient will still be included in the PP Set. If the numbers of patients in the PP population is more than 10% smaller than the number of patients in the FAS, the demographic and other baseline data will also be summarized descriptively for the PP population. Also a supportive analysis of the primary and secondary objectives will be performed on the basis of the PP population.

Full Analysis (FAS)

The FAS comprised all enrolled patients having received at least one dose of everolimus. The FAS was the relevant analysis population used in all efficacy evaluations including demographic and other baseline characteristics as well as study treatment evaluations.

Everolimus Treatment (FAS)

Per-Protocol Population (PP)

The Per Protocol (PP) population consists of all patients of the FAS • without any major protocol deviations (failure of any inclusion / exclusion criteria, no tumor assessment until day 182) • who have completed the minimum exposure requirement of having a relative dose intensity over the first 2 cycles of treatment of at least 50%. However, if a patient progressed, discontinued for adverse event or died before the minimum exposure requirement could be met, or before he/she could become evaluable for efficacy, that patient will still be included in the PP Set. If the numbers of patients in the PP population is more than 10% smaller than the number of patients in the FAS, the demographic and other baseline data will also be summarized descriptively for the PP population. Also a supportive analysis of the primary and secondary objectives will be performed on the basis of the PP population.

Full Analysis (FAS)

The FAS comprised all enrolled patients having received at least one dose of everolimus. The FAS was the relevant analysis population used in all efficacy evaluations including demographic and other baseline characteristics as well as study treatment evaluations.

The primary objective was the assessment of rate of patients who were free of disease progression after 6 months of treatment with everolimus (Kaplan-Meier method for estimating PFS). PFS: time interval between start of everolimus treatment and event / documented event / caesura because of disease progression or death. For 3 patients in FAS (1 in PP) symptomatic deterioration led to treatment discontinuation. These deteriorations were considered as event for PFS analysis. Final result: 6 months PFS rate [n%, [95%-CI])]: 39.3% (27.0% - 51.3%) (FAS) bzw. 44.6% (30.0% - 58.2%) (PP) Results of predefined subgroup analysis (FAS): - Patient aged ≥65 year: 54.4% (35.2% - 70.1%), Patient aged < 65 year: 23.7% (10.5% - 39.9%) - Male Pat. : 42.2% (27.9% - 55.9%) female Pat.: 45.8% (29.6% - 60.6%) - Patients with BMI >25kg/m² 51.4% (34.7% - 65.7%), Pat. With BMI ≤25kg/m² 18.2% (5.7% - 36.3%) - Patients with ECOG 0: 41.6% (25.0% - 57.5%) Patients with ECOG ≥1: 37.0% (19.6% - 54.6%)

Primary

Time from first day of intake of everolimus until disease progression or death of any cause.

The Kaplan-Meier product-limit method was used to describe PFS (median, 95% confidence intervals, and plots). PFS was analyzed at the final analysis cut-off date and was also be calculated for each stratum defined by the result of prior TKI-treatment. Final result: The median PFS (median, months) [95% CI] was: 3.8 ( 3.2 - 6.2) (FAS) resp. 5.3 ( 3.2 - 8.1) (PP) Results of predefined subgroup analysis (FAS) were: Patient aged ≥65 year: 6.9 ( 3.7 - 9.4), Patient aged < 65 year: 3.2 ( 1.7 - 3.8) Male Pat: 4.0 ( 3.2 - 8.1), female Pat: 3.6 ( 1.1 - 6.2) Patients with BMI >25kg/m²: 6.2 ( 3.6 - 8.4), Pat. with BMI ≤25kg/m²: 2.2 ( 1.6 - 4.7) Patients with ECOG 0: 3.8 ( 2.0 - 9.3), Patients with ECOG ≥1: 7.8 ( 5.6 - 22.1)

Secondary

PFS is defined as the time interval between start of everolimus treatment and event / documented event / Caesura because ofdisease progression or death due to any cause. The PFS was estimated by Kaplan-Meier analysis.

Tumor evaluation was assessed acc. to RECIST 1.1. Best response and objective response rate (ORR=CR [Complete Remission] + PR [Partial Remission]) were calculculated and summarized in terms Patient numbers and of percentage rates. Final result: The overall Response rate (number of patients (%)) was: 5 (7.9%) (FAS) resp. 4 ( 8.2%) (PP) Results of predefined subgroup analysis (FAS) were: Patient aged ≥65 year: 3 (9.4%), Patient aged < 65 year: 2 (6.5%) Male Pat: 4 (8.3%), female Pat: 1 (6.7%) Patients with BMI >25kg/m²: 4 (9.8%), Pat. With BMI ≤25kg/m²: 1 (4.5%) Patients with ECOG 0: 5 (13.9%), Patients with ECOG ≥1: 0 Missing / not done: response never evaluated. For 1 patient in PP response was never evaluated (Patient ID 10003). Nevertheless, this patient is not excluded from PP since he died about 4 months after date of informed consent. CR = complete remission; PR = partial remission; SD = stable disease; PD = progressive disease; NE = not evaluable;

Secondary

Time from baseline (up to 30 days prior to the first intake of study medication) until progressive disease. Patients alive at the end of observation time were right-censored at the date of last contact.

OS was determined using the method of Kaplan-Meier. During the course of the study, death was documented in 45 (71.4%) and 32 (65.3%) patients in the FAS and PP population, respectively. Final result: The median OS (months) [95% CI] was: 16.8 (14.3 - 24.3) (FAS) resp. 22.9 (15.8 - 36.1) (PP) Results of predefined subgroup analysis (FAS) were: Patient aged ≥65 year: 24.3 (14.0 - 47.9), Patient aged < 65 year: 16.3 ( 8.9 - 21.8) Male Pat: 4.0 20.4 (14.3 - 36.1), female Pat: 16.3 ( 5.1 - 21.8) Patients with BMI >25kg/m²: 24.3 (16.8 - 47.9), Pat. With BMI ≤25kg/m²: 12.0 ( 4.0 - 15.8) Patients with ECOG 0: 24.1 (15.8 - 59.7), Patients with ECOG ≥1: 10.8 ( 6.8 - 22.9)

Secondary

Overall survival is defined as time from first administration of everolimus to death due to any cause. Data of patients alive at the end of observation time were right-censored at the date of last contact.

AEs, SAEs and fatal SAEs (regardless of causality) were collected from the intake of the first dose of everolimus until 30 days after the last intake, even if the event is not considered to be related to everolimus.

Treatment-emergent AEs (TEAEs) overall and as characterized by CTCAE severity grade, MedDRA (Medical Dictionary for Regulatory Activities) classified SOC (System Organ Class) and PT (Preferred Term). An AE was classified as drug-related if the relationship was classified as “related to everolimus” by the investigator.

20.1

Everolimus treatment