Clinical trial NCT01984242: A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PD-L1] Antibody) as Monotherapy or in Combination With Bevacizumab (Avastin®) Compared to Sunitinib (Sutent®) in Participants With Untreated Advanced Renal Cell Carcinoma
Official title: A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Administered as Monotherapy or in Combination With Bevacizumab Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-11-14
Enrollment: 305
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, randomized, open-label study will evaluate the efficacy, safety and tolerability of atezolizumab as monotherapy or in combination with bevacizumab versus sunitinib in participants with histologically confirmed, inoperable, locally advanced or metastatic renal cell carcinoma who have not received prior systemic therapy either in the adjuvant or metastatic setting.


Eligibility criteria: Inclusion Criteria:

* Unresectable advanced or metastatic renal cell carcinoma with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic agents, including treatment in the adjuvant setting
* Measurable disease, as defined by RECIST v1.1
* Karnofsky performance score greater than or equal to (\>/=) 70
* Adequate hematologic and end-organ function as defined by protocol
* Women of childbearing potential and male participants with partners of childbearing potential must agree to use highly effective methods of contraception as defined by protocol

Exclusion Criteria:

Disease-Specific Exclusions:

* Radiotherapy for renal cell carcinoma within 14 days prior to Cycle 1, Day 1 with the exception of single-fraction radiotherapy given for the indication of pain control
* Known active malignancies or metastasis of the brain or spinal cord or leptomeningeal disease, as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Uncontrolled hypercalcemia or symptomatic hypercalcemia
* Malignancies other than renal cell carcinoma within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death, treated with expected curative outcome

General Medical Exclusions:

* Life expectancy of less than (\<) 12 weeks
* Pregnant and lactating women
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* History of autoimmune disease
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Participants with active or chronic hepatitis B, active hepatitis C, Human Immunodeficiency Virus (HIV) positive test, significant cardiovascular disease
* Prior allogeneic stem cell or solid organ transplant

Exclusion Criteria Related to Medications:

* Prior treatment with Cluster of Differentiation 137 (CD137) agonists, anti-Cytotoxic T-Lymphocyte Antigen-4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
* Treatment with systemic immunostimulatory agents for any reason within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
* Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1

Bevacizumab- and Sunitinib-Specific Exclusions:

* Inadequately controlled hypertension
* Prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association Class II or greater congestive heart failure
* History of myocardial infarction or unstable angina, stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1

Primary outcomes:
measure: Percentage of Participants With Disease Progression Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Via Independent Review Committee (IRC) Assessment or Death in Intent-to-Treat (ITT) Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Progression-Free Survival (PFS) Per RECIST v1.1 Via IRC Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via IRC Assessment or Death in Immune Cell 1/2/3 (IC1/2/3) Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via IRC Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
Secondary outcomes:
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via IRC Assessment or Death in Participants Who Have Tumors With Higher Than Median Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via IRC Assessment in Participants Who Have Tumors With Higher Than Median Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via Investigator Assessment or Death in Participants Who Have Tumors With Higher Than Median Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via Investigator Assessment in Participants Who Have Tumors With Higher Than Median Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via IRC Assessment or Death in Participants Who Have Tumors With Higher Than the 33rd Percentile Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via IRC Assessment in Participants Who Have Tumors With Higher Than the 33rd Percentile Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via Investigator Assessment or Death in Participants Who Have Tumors With Higher Than the 33rd Percentile Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via Investigator Assessment in Participants Who Have Tumors With Higher Than the 33rd Percentile Expression of an Immune Gene Signature
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via Investigator Assessment or Death in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via Investigator Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via Investigator Assessment or Death in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v1.1 Via Investigator Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response (Complete Response [CR] or Partial Response [PR]) Per RECIST v1.1 Via IRC Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per RECIST v1.1 Via IRC Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per RECIST v1.1 Via Investigator Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per RECIST v1.1 Via Investigator Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per Modified RECIST Via Investigator Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per Modified RECIST Via Investigator Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per Modified RECIST Via Investigator Assessment or Death in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per Modified RECIST Via Investigator Assessment in ITT Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per Modified RECIST Via Investigator Assessment or Death in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per Modified RECIST Via Investigator Assessment in IC1/2/3 Population
timeFrame: From randomization until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Duration of Response (DOR) Per RECIST v1.1 Via IRC Assessment in ITT Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per RECIST v1.1 Via Investigator Assessment in ITT Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per RECIST v1.1 Via IRC Assessment in IC1/2/3 Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per RECIST v1.1 Via Investigator Assessment in IC1/2/3 Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per Modified RECIST Via Investigator Assessment in ITT Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per Modified RECIST Via Investigator Assessment in IC1/2/3 Population
timeFrame: From CR or PR until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants Who Died in ITT Population
timeFrame: Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Overall Survival (OS) in ITT Population
timeFrame: Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants Who Died in IC1/2/3 Population
timeFrame: Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: OS in IC1/2/3 Population
timeFrame: Randomization until death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Objective Response Per RECIST v1.1 Via Investigator Assessment in Crossover Population
timeFrame: From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: DOR Per RECIST v1.1 Via Investigator Assessment in Crossover Population
timeFrame: From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Disease Progression Per RECIST v1.1 Via Investigator Assessment or Death in Crossover Population
timeFrame: From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: PFS Per RECIST v.1.1 Via Investigator Assessment in Crossover Population
timeFrame: From start of crossover treatment until disease progression or death due to any cause (until data cut-off date 17 October 2016, up to approximately 2.75 years)
measure: Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to Atezolizumab
timeFrame: Cycle 1 Day 1 until treatment discontinuation (until data cut-off date 17 October 2016, up to approximately 2.75 years) (1 cycle=6 weeks)
measure: Maximum Serum Concentration (Cmax) of Atezolizumab
timeFrame: 30 minutes after end of infusion on Cycle 1 Day 1 (1 cycle=6 weeks) (infusion length for first dose=60 minutes)
measure: Minimum Serum Concentration (Cmin) of Atezolizumab
timeFrame: Pre-infusion (0 hour) on Day 1 of Cycles 2 and 4; Day 22 of Cycles 1, 2, and 4 (1 cycle=6 weeks) (infusion length=30-60 minutes)
measure: Cmax of Bevacizumab
timeFrame: 30 minutes after end of infusion on Day 1 of Cycles 1 and 2 (1 cycle=6 weeks) (infusion length=30-90 minutes)
measure: Cmin of Bevacizumab
timeFrame: For Atezolizumab and Bevacizumab Arm: at First-line treatment discontinuation (up to approximately 2.75 years); For Crossover Arms: pre-infusion (0 hour) on Day 1 of Cycle 2 (1 cycle=6 weeks) (infusion length=30-90 minutes)
measure: M.D. Anderson Symptom Inventory (MDASI) Interference Score
timeFrame: Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)
measure: Brief Fatigue Inventory (BFI) Fatigue Level Score
timeFrame: Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)
Other outcomes:
measure: EuroQoL 5 Dimension (EQ-5D) Questionnaire Score
timeFrame: Days 1 and 22 of Cycles 1 to 24; Day 1 of Cycle 25; treatment discontinuation (up to approximately 2.75 years) (1 cycle=6 weeks)
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Research Institute - Bisgrove
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Aurora
country: United States
facility: Univ Colorado Health Sci Ctr
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Ctr - Denver (Williams)
state: Colorado
city: New Haven
country: United States
facility: Yale Uni School of Medicine; Section of Medical Oncology
state: Connecticut
city: Washington
country: United States
facility: Georgetown U; Lombardi Comp Can
state: District of Columbia
city: Fort Myers
country: United States
facility: SCRI Florida Cancer Specialists South
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic-Jacksonville
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialist, North Region
state: Florida
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Inst.
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute.
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: New York
country: United States
facility: Memorial Sloan-Kettering
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation; Taussig Cancer Center
state: Ohio
city: Eugene
country: United States
facility: Oncology Associates of Oregon, P.C
state: Oregon
city: Tigard
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Oregon
city: Nashville
country: United States
facility: Tennessee Oncology PLLC - Nashville (20th Ave)
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology-Baylor Sammons Cancer Center
state: Texas
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou; Service D'Oncologie Medicale
city: Pessac
country: France
facility: CHU Bordeaux
city: Villejuif
country: France
facility: Institut Gustave Roussy; Departement Oncologie Medicale
city: Hannover
country: Germany
facility: Medizinische Hochschule; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
city: Muenchen
country: Germany
facility: Klinikum rechts der Isar der TU München; Klinikapotheke
city: München
country: Germany
facility: Klinikum d.Universität München Campus Großhadern
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2
state: Lombardia
city: Arezzo
country: Italy
facility: Medical Oncology, Arezzo
state: Toscana
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica
state: Toscana
city: Warszawa
country: Poland
facility: Centrum Med. Ostrobramska NZOZ Magodent
city: Cluj Napoca
country: Romania
facility: Prof. Dr. I. Chiricuta Institute of Oncology
city: Cluj-Napoca
country: Romania
facility: Medisprof SRL
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona. Unidad de Nuevas Terapias;Oncology Department
city: Madrid
country: Spain
facility: Hosp de Madrid Norte Sanchinarro; Centro Integral; Onco Clara Campal
city: London
country: United Kingdom
facility: Barts and the London NHS Trust.
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
city: Manchester
country: United Kingdom
facility: Christie Hospital Nhs Trust; Medical Oncology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Pal SK, McDermott DF, Atkins MB, Escudier B, Rini BI, Motzer RJ, Fong L, Joseph RW, Oudard S, Ravaud A, Bracarda S, Suarez C, Lam ET, Choueiri TK, Ding B, Quach C, Hashimoto K, Schiff C, Piault-Louis E, Powles T. Patient-reported outcomes in a phase 2 study comparing atezolizumab alone or with bevacizumab vs sunitinib in previously untreated metastatic renal cell carcinoma. BJU Int. 2020 Jul;126(1):73-82. doi: 10.1111/bju.15058. Epub 2020 Apr 24.