CA209-025

Bristol-Myers Squibb

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, clinical.trials@bms.com

Bristol-Myers Squibb, Bristol-Myers Squibb Study Director, Clinical.Trials@bms.com

No

No

No

Final

19 Jul 2021

No

Yes

19 Jul 2021

No

Overall Survival (OS) is defined as the time from randomization to the date of death. A subject who has not died will be censored at last known alive date.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

09 Oct 2012

No

Yes

Argentina: 35

Australia: 27

Austria: 13

Belgium: 12

Brazil: 12

Canada: 26

Czechia: 13

Denmark: 22

Finland: 11

France: 69

Germany: 23

Greece: 6

Ireland: 11

Israel: 13

Italy: 38

Japan: 63

Norway: 5

Poland: 17

Romania: 5

Russian Federation: 9

Spain: 34

Sweden: 11

United Kingdom: 26

United States: 320

821

290

0

0

0

0

0

0

497

318

6

Randomized (Pre-treatment)

Randomised - controlled

Yes

BMS-936558

Solution for injection

Intravascular use

3mg/kg IV Q2 weeks or 480mg IV Q4 weeks

everolimus

Buccal tablet

Oral use

5mg PO QD

everolimus

Buccal tablet

Oral use

10mg PO QD

Treatment Period

Randomised - controlled

Yes

BMS 936-558

Solution for injection

Intravascular use

3mg/kg IV Q2 weeks or 480mg IV Q4 weeks

everolimus

Buccal tablet

Oral use

5mg PO QD

everolimus

Buccal tablet

Oral use

10mg PO QD

Nivolumab

Everolimus

Nivolumab

Everolimus

Nivolumab

Everolimus

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p < 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria. 99999 represent NA

Primary

Randomization until 398 deaths, up to May 2015 (approximately 30 months)

Nivolumab v Everolimus

821

Pre-specified

0.73

2-sided

ORR is defined as Percentage of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Tumor assessments began at 8 weeks following randomization and continued every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or death. CIs used Clopper and Pearson.

Secondary

from randomization up to disease progression or death (approximately up to 105 Months)

Duration of objective response is defined as the time from study start date to response, CR or partial response, PR) to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. For participants who neither progress nor die, the duration of objective response were censored at the same time they were censored for the primary definition. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Based on Kaplan-Meier Estimates.

Secondary

From randomization to date of disease progression or death or censoring if no progression or death occurred (approximately 105 months)

Time to objective response is defined as the time from randomization to first response (complete response, CR or partial response, PR). CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference.

Secondary

Randomization to date of first response (approximately 105 months)

PFS=time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. Participants who die without a reported prior progression and without subsequent anti-cancer therapy were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the date they were randomized. Participants who received any subsequent anti-cancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to or on initiation date of the subsequent anti-cancer therapy. Progressive disease: >=20% increase in sum of target lesion diameters and sum must show absolute increase of >=5mm; smallest sum on study as reference. Based on Kaplan-Meier Estimates.

Secondary

from randomization up to disease progression or death (approximately up to 105 Months)

Nivolumab v Everolimus

821

Pre-specified

0.84

2-sided

Quantifiable PD-L1 expression=percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay. If the PD-L1 staining could not be quantified it was classified as: indeterminate=tumor cell membrane staining hampered for reasons attributed to biology of tumor biopsy specimen and not due to improper sample preparation or handling; not evaluable=tumor biopsy specimen was not optimally collected or prepared. Not evaluable determined from H&E process before the tumor biopsy specimen was sent for evaluation or from H&E process during PD-L1 evaluation; baseline PD-L1 expression=if more than one tumor biopsy specimen was available, the most recently collected specimen with a quantifiable result. If all specimens for a given participant are either indeterminate or not evaluable, then the PD-L1 expression was considered indeterminate as long as at least one specimen is indeterminate. Otherwise, PD-L1 expression was considered not evaluable.

Secondary

Randomization to date of death or date of last contact for patients without documentation of death, up to May 2015 (approximately 30 months)

Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

Secondary

Day of first dose to 30 days post study completion (approximately 106 months)

Disease-related symptom progression rate (DRSPR)=a decrease of two points in the Functional Assessment of Cancer Therapy-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS) questionnaire relative to the participant's baseline FKSI-DRS score with no later increase above this threshold observed during the course of the study. The 9 items of the FKSI-DRS were summarized into a symptom scale ranging in score from 0 to 36, with 0 being the worst possible score and 36 being the best possible score. A single measure reporting a decrease of at least 2 units was considered disease-related symptom progression only if it was the last one available for the participant. In order to consider a questionnaire received as valid, over 50% of the items were to be completed. Calculated by the Clopper-Pearson method for each treatment group.

Secondary

from randomization up to disease progression or death (approximately up to 105 Months)

Aspartate aminotransferase, AST. Alanine aminotransaminase, ALT. Total bilirubin, tBIL. Thyroid stimulating hormone, TSH. Upper limit of normal (ULN). Units per Liter (U/L). Results reported in International System of Units (SI).

Secondary

Day 1 to 30 days post study completion (approximately 106 months)

Common Terminology Criteria (CTC) version 4.0 in International System of Units (SI); Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Hematology parameters=Hemoglobin (Gr 3: < 8.0 g/dL), Platelet Count (Gr 3: 25.0 -< 50.0*10^9 c/L; Gr 4: < 25.0*10^9 c/L), Leukocyte Count (Gr 3: 1.0 -< 2.0*10^3 c/µL; Gr4: < 1.0*10^3 c/µL), Absolute Lymphocyte Count (Gr 3: 0.2 -< 0.5*10^3 c/µL; Gr 4: < 0.2*10^3 c/µL), Absolute Neutrophil Count (Gr 3: 0.5 - < 1.0*10^3 c/µL; Gr 4: < 0.5*10^3 c/µL). Liver Function parameters=Alkaline Phosphatase (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), AST (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), ALT (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), tBIL (Gr 3: > 3.0 - 10.0 mg/dL * ULN; Gr 4: > 10.0 mg/dL * ULN). Renal parameter=Creatinine (Grade: Gr3: > 3.0 - 6.0 mg/dL *ULN; Gr4: > 6.0 mg/dL *ULN). Cells per microliter (c/µL). Cells per Liter (c/L). Grams per deciliter (g/dL). Milligrams per deciliter (mg/dL).

Secondary

Day 1 to 30 days post study completion (approximately 106 months)

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p < 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria. This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date.

Post-hoc

from randomization up to disease progression or death (approximately up to 105 months)

Nivolumab v Everolimus

821

Post-hoc

0.74

2-sided

All-cause mortality was assessed from first dose to study completion (up to 105 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (approximately up to 107 months)

MedDRA24.0

EVEROLIMUS

NIVOLUMAB